Liraglutide

1 INDICATIONS AND USAGE Liraglutide Injection is indicated: as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Limitations of Use : Liraglutide Injection contains liraglutide. Coadministration with other liraglutide-containing products is not recommended. Liraglutide Injection is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated: as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus ( 1 ). Limitations of Use : Coadministration with other liraglutide-containing products is not recommended.

2 DOSAGE AND ADMINISTRATION Adult Patients : Initiate at 0.6 mg injected subcutaneously once daily for one week then increase to 1.2 mg daily. If additional glycemic control is required, increase the dose to 1.8 mg daily after one week of treatment with the 1.2 mg daily dose. ( 2.1 ) Pediatric Patients : Initiate at 0.6 mg injected subcutaneously once daily for at least one week. If additional glycemic control is required increase the dose to 1.2 mg daily and if additional glycemic control is still required, increase the dose to 1.8 mg daily after at least one week of treatment with the 1.2 mg daily dose. ( 2.1 ) Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no particles. ( 2.3 ) Inject liraglutide injection subcutaneously once-daily at any time of day, independently of meals, in the abdomen, thigh or upper arm. ( 2.3 ) When using liraglutide injection with insulin, administer as separate injections. Never mix. ( 2.3 ) 2.1 Recommended Dosage Adult Patients The recommended starting dosage of liraglutide injection is 0.6 mg injected subcutaneously once daily for one week. The 0.6 mg once daily dosage is intended to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions ( 5.6 ), Adverse Reactions ( 6.1 )] during initial titration and is not effective for glycemic control in adults. After one week at the 0.6 mg once daily dosage, increase the dosage to 1.2 mg injected subcutaneously once daily. If additional glycemic control is required, increase the dosage to the maximum recommended dosage of 1.8 mg injected subcutaneously once daily after at least one week of treatment with the 1.2 mg once daily dosage. Pediatric Patients Aged 10 Years and Older The recommended starting dosage of liraglutide injection is 0.6 mg injected subcutaneously once daily. If additional glycemic control is required, increase the dosage in 0.6 mg increments after at least one week on the current dosage, to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions ( 5.6 ), Adverse Reactions ( 6.1 )] . The maximum recommended dosage is 1.8 mg injected subcutaneously once daily. 2.2 Recommendations Regarding Missed Dose Instruct patients who miss a dose of liraglutide injection to resume the once daily dosage regimen as prescribed with the next scheduled dose. Do not administer an extra dose or increase the dose to make up for the missed dose. If more than 3 days have elapsed since the last liraglutide injection dose, reinitiate liraglutide injection at 0.6 mg once daily to reduce the risk of gastrointestinal adverse reactions associated with reinitiation of treatment. Upon reinitiation, liraglutide injection should be titrated at the discretion of the healthcare provider. 2.3 Important Administration Instructions Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no particles. Inject liraglutide injection subcutaneously once daily at any time of day, independently of meals. Inject liraglutide injection subcutaneously in the abdomen, thigh or upper arm. No dosage adjustment is needed if changing the injection site and/or timing. Rotate injection sites within the same region in order to reduce the risk of cutaneous amyloidosis [see Adverse Reactions ( 6.2 )] . When using liraglutide injection with insulin, administer as separate injections. Never mix. It is acceptable to inject liraglutide injection and insulin in the same body region but the injections should not be adjacent to each other.

5 WARNINGS AND PRECAUTIONS Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including liraglutide. Discontinue if pancreatitis is suspected. ( 5.2 ) Never Share a Liraglutide Injection Pen Between Patients , even if the needle is changed. (5.3) Hypoglycemia : Adult patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with liraglutide regardless of insulin and/or metformin use. Reduction in the dose of insulin secretagogues or insulin may be necessary. (5.4) Acute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.5 ) Severe Gastrointestinal Adverse Reactions : Use has been associated with gastrointestinal adverse reactions, sometimes severe. Liraglutide injection is not recommended in patients with severe gastroparesis. ( 5.6 ) Hypersensitivity Reactions : Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue liraglutide injection and promptly seek medical advice. ( 5.7 ) Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.8 ) Pulmonary Aspiration During General Anesthesia or Deep Sedation : Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.9 ) 5.1 Risk of Thyroid C-cell Tumors Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical Toxicology ( 13.1 )] . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether liraglutide will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. Liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of liraglutide and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with liraglutide. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including liraglutide [see Adverse Reactions ( 6 )] . After initiation of liraglutide injection, observe patients carefully for signs and symptoms of acute pancreatitis which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue liraglutide injection and initiate appropriate management. 5.3 Never Share a Liraglutide Injection Pen Between Patients Liraglutide injection pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens. 5.4 Hypoglycemia Adult patients receiving liraglutide in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with liraglutide regardless of insulin and/or metformin use. [see Adverse Reactions (6.1) , Drug Interactions (7.2) ] . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications and pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.5 Acute Kidney Injury Due to Volume Depletion There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with liraglutide [see Adverse Reactions ( 6.2 )] . The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea [see Adverse Reactions ( 6.1 )] . Monitor renal function in patients reporting adverse reactions to liraglutide that could lead to volume depletion, especially during dosage initiation and escalation of liraglutide injection [see Use in Specific Populations ( 8.6 )] . 5.6 Severe Gastrointestinal Adverse Reactions Use of GLP-1 receptor agonists, including liraglutide, has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions ( 6 )] . In liraglutide injection clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving liraglutide (1.2 mg 4.4 %, 1.8 mg 4.2 %) than placebo (1.1 %). Severe gastrointestinal adverse reactions have also been reported postmarketing with GLP-1 receptor agonists. Liraglutide injection is not recommended in patients with severe gastroparesis. 5.7 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with liraglutide [see Adverse Reactions ( 6.2 )] . If a hypersensitivity reaction occurs, discontinue liraglutide injection; treat promptly per standard of care, and monitor until signs and symptoms resolve. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-receptor agonist because it is unknown whether such patients will be predisposed to these reactions with liraglutide. Liraglutide is contraindicated in patients who have had a serious hypersensitivity reaction to liraglutide or any of the excipients in liraglutide injection [see Contraindications ( 4 )] . 5.8 Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated. 5.9 Pulmonary Aspiration During General Anesthesia or Deep Sedation Liraglutide delays gastric emptying [see Clinical Pharmacology ( 12.2 )] . There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking liraglutide injection, including whether modifying preoperative fasting recommendations or temporarily discontinuing liraglutide injection could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking liraglutide injection.

7 DRUG INTERACTIONS Effects of delayed gastric emptying on oral medications : Liraglutide delays gastric emptying and may impact absorption of concomitantly administered oral medications. ( 7 ) 7.1 Effects of Delayed Gastric Emptying on Oral Medications Liraglutide causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide injection did not affect the absorption of the tested orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide injection. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin Liraglutide stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving liraglutide in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating liraglutide injection, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.1 )].

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] Hypoglycemia [see Warnings and Precautions ( 5.4 )] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.5 )] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.6 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence ≥5%) in clinical trials are nausea, diarrhea, vomiting, decreased appetite, dyspepsia, constipation. ( 6.1 ) Immunogenicity-related events, including urticaria, were more common among liraglutide-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. ( 12.6 ) To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common Adverse Reactions The safety of liraglutide injection in patients with type 2 diabetes mellitus was evaluated in 5 glycemic control, placebo-controlled trials in adults and one trial of 52 weeks duration in pediatric patients 10 years of age and older [see Clinical Studies ( 14.1 )] . The data in Table 1 reflect exposure of 1,673 adult patients to liraglutide and a mean duration of exposure to liraglutide of 37.3 weeks. The mean age of adult patients was 58 years, 4% were 75 years or older and 54% were male. The population was 79% White, 6% Black or African American, 13% Asian; 4% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 9 years and a mean HbA 1c of 8.4%. Baseline estimated renal function was normal or mildly impaired in 88% and moderately impaired in 12% of the pooled population. Table 1 shows common adverse reactions in adults, excluding hypoglycemia, associated with the use of liraglutide injection for the treatment of type 2 diabetes mellitus. These adverse reactions occurred more commonly on liraglutide than on placebo and occurred in at least 5% of patients treated with liraglutide. Overall, the type, and severity of adverse reactions in pediatric patients 10 years of age and older and above were comparable to that observed in the adult population. Table 1. Adverse Reactions Reported in ≥ 5% of Adult Patients Treated with Liraglutide Injection for Type 2 Diabetes Mellitus Placebo N=661 Liraglutide 1.2 mg N= 645 Liraglutide 1.8 mg N= 1,024 Adverse Reaction (%) (%) (%) Nausea 5 18 20 Diarrhea 4 10 12 Headache 7 11 10 Nasopharyngitis 8 9 10 Vomiting 2 6 9 Decreased appetite 1 10 9 Dyspepsia 1 4 7 Upper Respiratory Tract Infection 6 7 6 Constipation 1 5 5 Back Pain 3 4 5 Cumulative proportions were calculated combining studies using Cochran-Mantel-Haenszel weights. In an analysis of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1 . Other Adverse Reactions Gastrointestinal Adverse Reactions In the pool of 5 glycemic control, placebo-controlled adult clinical trials, withdrawals due to gastrointestinal adverse reactions, occurred in 4.3% of liraglutide-treated patients and 0.5% of placebo-treated patients. Severe gastrointestinal adverse reactions were reported more frequently among patients receiving liraglutide (1.2 mg 4.4 %, 1.8 mg 4.2 %) than placebo (1.1 %). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2 to 3 months of the trials. Injection site reactions Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of liraglutide-treated adult patients in the five double-blind, glycemic control trials of at least 26 weeks duration. Less than 0.2% of liraglutide-treated patients discontinued due to injection site reactions. Hypoglycemia In 5 adult glycemic control, placebo-controlled clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 8 liraglutide-treated patients (7.5 events per 1,000 patient-years). Of these 8 liraglutide-treated patients, 7 patients were concomitantly using a sulfonylurea. Table 2. Adult Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in 26-week Combination Therapy Placebo-controlled Trials Placebo Comparator Liraglutide Treatment Add-on to Metformin Placebo + Metformin (N = 121) Liraglutide + Metformin (N = 724) Patient not able to self-treat 0 0.1 (0.001) Patient able to self-treat 2.5 (0.06) 3.6 (0.05) Add-on to Glimepiride Placebo + Glimepiride (N = 114) Liraglutide + Glimepiride (N = 695) Patient not able to self-treat 0 0.1 (0.003) Patient able to self-treat 2.6 (0.17) 7.5 (0.38) Not classified 0 0.9 (0.05) Add-on to Metformin + Rosiglitazone Placebo + Metformin + Rosiglitazone (N = 175) Liraglutide + Metformin + Rosiglitazone (N = 355) Patient not able to self-treat 0 0 Patient able to self-treat 4.6 (0.15) 7.9 (0.49) Not classified 1.1 (0.03) 0.6 (0.01) Add-on to Metformin + Glimepiride Placebo + Metformin + Glimepiride (N = 114) Liraglutide + Metformin + Glimepiride (N = 230) Patient not able to self-treat 0 2.2 (0.06) Patient able to self-treat 16.7 (0.95) 27.4 (1.16) Not classified 0 0 “Patient not able to self-treat” is defined as an event requiring the assistance of another person for treatment. In a 26-week placebo-controlled clinical trial in pediatric patients 10 years of age and older with a 26-week open-label extension, 21.2% of liraglutide-treated patients (mean age 14.6 years) with type 2 diabetes mellitus, had hypoglycemia with a blood glucose <54 mg/dL with or without symptoms (335 events per 1,000 patient years). No severe hypoglycemic episodes occurred in the liraglutide treatment group (severe hypoglycemia was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions). Papillary thyroid carcinoma In adult glycemic control trials of liraglutide injection, there were 7 reported cases of papillary thyroid carcinoma in patients treated with liraglutide and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1,000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Pancreatitis In glycemic control trials of liraglutide injection, there have been 13 cases of pancreatitis among liraglutide-treated patients and 1 case in a comparator (glimepiride) treated patient (2.7 vs. 0.5 cases per 1,000 patient-years). Nine of the 13 cases with liraglutide were reported as acute pancreatitis and four were reported as chronic pancreatitis. In one case in a liraglutide-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. Cholelithiasis and cholecystitis In adult glycemic control trials of liraglutide injection, the incidence of cholelithiasis was 0.3% in both liraglutide-treated and placebo-treated patients. The incidence of cholecystitis was 0.2% in both liraglutide-treated and placebo-treated patients. Laboratory Tests Bilirubin In the five adult glycemic control trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4% of liraglutide-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. Calcitonin Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. At the end of the adult glycemic control trials, adjusted mean serum calcitonin concentrations were higher in liraglutide-treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. Between group differences in adjusted mean serum calcitonin values were approximately 0.1 ng/L or less. Among adult patients with pretreatment calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of liraglutide-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients. The clinical significance of these findings is unknown. Lipase and Amylase In one adult glycemic control trial in renal impairment patients, a mean increase of 33% for lipase and 15% for amylase from baseline was observed for liraglutide-treated patients while placebo-treated patients had a mean decrease in lipase of 3% and a mean increase in amylase of 1%. The clinical significance of elevations in lipase or amylase with liraglutide is unknown in the absence of other signs and symptoms of pancreatitis [see Warnings and Precautions ( 5.2 )]. Vital signs Liraglutide injection did not have adverse effects on blood pressure. Mean increases from baseline in heart rate of 2 to 3 beats per minute have been observed in adult patients treated with liraglutide compared to placebo. 6.2 Postmarketing Experience The following additional adverse reactions have been reported during post-approval use of liraglutide injection. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: Acute pancreatitis; hemorrhagic and necrotizing pancreatitis sometimes resulting in death; ileus, intestinal obstruction, severe constipation including fecal impaction, nausea, vomiting and diarrhea leading to dehydration Hepatobiliary: Elevations of liver enzymes, hyperbilirubinemia, cholestasis, cholecystitis, cholelithiasis requiring cholecystectomy, hepatitis Hypersensitivity: Angioedema, anaphylactic reactions, pruritus Neoplasms: Medullary thyroid carcinoma Neurologic: Dysgeusia, dizziness, dysesthesia Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation. Renal: Acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis; and increased serum creatinine Skin and subcutaneous tissue: Cutaneous amyloidosis, alopecia

14 CLINICAL STUDIES 14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus In glycemic control trials in adults, liraglutide injection has been studied as monotherapy and in combination with one or two oral anti-diabetic medications or basal insulin. In each of the placebo controlled trials, treatment with liraglutide produced clinically and statistically significant improvements in hemoglobin A 1c and fasting plasma glucose (FPG) compared to placebo. All liraglutide-treated patients started at 0.6 mg/day. The dose was increased in weekly intervals by 0.6 mg to reach 1.2 mg or 1.8 mg for patients randomized to these higher doses. Liraglutide 0.6 mg is not effective for glycemic control and is intended only as a starting dose to reduce gastrointestinal intolerance [see Dosage and Administration (2 )] . Monotherapy In this 52-week trial, 746 adult patients with type 2 diabetes mellitus were randomized to liraglutide 1.2 mg, liraglutide 1.8 mg, or glimepiride 8 mg. Patients who were randomized to glimepiride were initially treated with 2 mg daily for two weeks, increasing to 4 mg daily for another two weeks, and finally increasing to 8 mg daily. Treatment with liraglutide 1.8 mg and 1.2 mg resulted in a statistically significant reduction in HbA 1c compared to glimepiride ( Table 3 ). The percentage of patients who discontinued due to ineffective therapy was 3.6% in the liraglutide 1.8 mg treatment group, 6% in the liraglutide 1.2 mg treatment group, and 10.1% in the glimepiride-treatment group. The mean age of participants was 53 years, and the mean duration of diabetes was 5 years. Participants were 49.7% male, 77.5% White, 12.6% Black or African American and 35% of Hispanic or Latino ethnicity. The mean BMI was 33.1 kg/m 2 . Table 3. Results of a 52-week Monotherapy Trial in Adults with Type 2 Diabetes Mellitus a Liraglutide 1 .8 mg Liraglutide 1.2 mg Glimepiride 8 mg Intent-to-Treat Population (N) 246 251 248 HbA 1c (%) (Mean) Baseline 8.2 8.2 8.2 Change from baseline (adjusted mean) b -1.1 -0.8 -0.5 Difference from glimepiride arm (adjusted mean) b -0.6** -0.3* 95% Confidence Interval (-0.8, -0.4) (-0.5, -0.1) Percentage of patients achieving HbA 1c <7% 51 43 28 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 172 168 172 Change from baseline (adjusted mean) b -26 -15 -5 Difference from glimepiride arm (adjusted mean) b -20** -10* 95% Confidence Interval (-29, -12) (-19, -1) Body Weight (kg) (Mean) Baseline 92.6 92.1 93.3 Change from baseline (adjusted mean) b -2.5 -2.1 +1.1 Difference from glimepiride arm (adjusted mean) b -3.6** -3.2** 95% Confidence Interval (-4.3, -2.9) (-3.9, -2.5) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value * p-value <0.05 ** p-value <0.0001 Figure 3. Mean HbA 1c for Adult Patients with Type 2 Diabetes Mellitus who Completed the 52-week Trial and for the Last Observation Carried Forward (LOCF, intent-to-treat) Data at Week 52 (Monotherapy) Combination Therapy Add-on to Metformin In this 26-week trial, 1,091 adult patients with type 2 diabetes mellitus were randomized to liraglutide 0.6 mg, liraglutide 1.2 mg, liraglutide 1.8 mg, placebo, or glimepiride 4 mg (one-half of the maximal approved dose in the United States), all as add-on to metformin. Randomization occurred after a 6-week run-in period consisting of a 3-week initial forced metformin titration period followed by a maintenance period of another 3 weeks. During the titration period, doses of metformin were increased up to 2,000 mg/day. Treatment with liraglutide 1.2 mg and 1.8 mg as add-on to metformin resulted in a significant mean HbA 1c reduction relative to placebo add-on to metformin and resulted in a similar mean HbA 1c reduction relative to glimepiride 4 mg add-on to metformin ( Table 4 ). The percentage of patients who discontinued due to ineffective therapy was 5.4% in the liraglutide 1.8 mg + metformin treatment group, 3.3% in the liraglutide 1.2 mg + metformin treatment group, 23.8% in the placebo + metformin treatment group, and 3.7% in the glimepiride + metformin treated group. The mean age of participants was 57 years, and the mean duration of diabetes was 7 years. Participants were 58.2% male, 87.1% White and 2.4% Black or African American. The mean BMI was 31.0 kg/m 2 . Table 4. Results of a 26-week Trial of Liraglutide as Add-on to Metformin in Adults with Type 2 Diabetes Mellitus a Liraglutide 1.8 mg + Metformin Liraglutide 1.2 mg + Metformin Placebo + Metformin Glimepiride 4 mg † + Metformin Intent-to-Treat Population (N) 242 240 121 242 HbA 1c (%) (Mean) Baseline 8.4 8.3 8.4 8.4 Change from baseline (adjusted mean) b -1 -1 +0.1 -1 Difference from placebo + metformin arm (adjusted mean) b -1.1** -1.1** 95% Confidence Interval (-1.3, -0.9) (-1.3, -0.9) Difference from glimepiride + metformin arm (adjusted mean) b 0 0 95% Confidence Interval (-0.2, 0.2) (-0.2, 0.2) Percentage of patients achieving HbA 1c <7% 42 35 11 36 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 181 179 182 180 Change from baseline (adjusted mean) b -30 -30 +7 -24 Difference from placebo + metformin arm (adjusted mean) b -38** -37** 95% Confidence Interval (-48, -27) (-47, -26) Difference from glimepiride + metformin arm (adjusted mean) b -7 -6 95% Confidence Interval (-16, 2) (-15, 3) Body Weight (kg) (Mean) Baseline 88 88.5 91 89 Change from baseline (adjusted mean) b -2.8 -2.6 -1.5 +1 Difference from placebo + metformin arm (adjusted mean) b 95% Confidence Interval -1.3* (-2.2, -0.4) -1.1* (-2, -0.2) Difference from glimepiride + metformin arm (adjusted mean) b -3.8** -3.5** 95% Confidence Interval (-4.5, -3) (-4.3, -2.8) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value † For glimepiride, one-half of the maximal approved United States dose. * p-value <0.05 ** p-value <0.0001 Liraglutide Compared to Sitagliptin, Both as Add-on to Metformin In this 26–week, open-label trial, 665 adult patients with type 2 diabetes mellitus on a background of metformin ≥1,500 mg per day were randomized to liraglutide 1.2 mg once daily, liraglutide 1.8 mg once daily or sitagliptin 100 mg once-daily, all dosed according to approved labeling. Patients were to continue their current treatment on metformin at a stable, pre-trial dose level and dosing frequency. The mean age of participants was 56 years, and the mean duration of diabetes was 6 years. Participants were 52.9% male, 86.6% White, 7.2% Black or African American and 16.2% of Hispanic or Latino ethnicity. The mean BMI was 32.8 kg/m 2 . The primary endpoint was the change in HbA 1c from baseline to Week 26. Treatment with liraglutide 1.2 mg and liraglutide 1.8 mg resulted in statistically significant reductions in HbA 1c relative to sitagliptin 100 mg ( Table 5 ). The percentage of patients who discontinued due to ineffective therapy was 3.1% in the liraglutide 1.2 mg group, 0.5% in the liraglutide 1.8 mg treatment group, and 4.1% in the sitagliptin 100 mg treatment group. From a mean baseline body weight of 94 kg, there was a mean reduction of 2.7 kg for liraglutide 1.2 mg, 3.3 kg for liraglutide 1.8 mg, and 0.8 kg for sitagliptin 100 mg. Table 5. Results of a 26-week Open-label Trial of Liraglutide Compared to Sitagliptin (both in combination with metformin) in Adults with Type 2 Diabetes Mellitus a Liraglutide 1.8 mg + Metformin Liraglutide 1.2 mg + Metformin Sitagliptin 100 mg + Metformin Intent-to-Treat Population (N) 218 221 219 HbA 1c (%) (Mean) Baseline 8.4 8.4 8.5 Change from baseline (adjusted mean) -1.5 -1.2 -0.9 Difference from sitagliptin arm (adjusted mean) b 95% Confidence Interval -0.6** (-0.8, -0.4) -0.3** (-0.5, -0.2) Percentage of patients achieving HbA 1c <7% 56 44 22 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 179 182 180 Change from baseline (adjusted mean) -39 -34 -15 Difference from sitagliptin arm (adjusted mean) b 95% Confidence Interval -24** (-31, -16) -19** (-26, -12) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value ** p-value <0.0001 Figure 4. Mean HbA 1c for Adult Patients with Type 2 Diabetes Mellitus who Completed the 26-week Trial and for the Last Observation Carried Forward (LOCF, intent-to-treat) Data at Week 26 Combination Therapy with Metformin and Insulin This 26-week open-label trial enrolled 988 adult patients with type 2 diabetes mellitus with inadequate glycemic control (HbA 1c 7 to 10%) on metformin (≥1,500 mg/day) alone or inadequate glycemic control (HbA 1c 7 to 8.5%) on metformin (≥1,500 mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued the sulfonylurea then all patients entered a 12-week run-in period during which they received add-on therapy with liraglutide titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%) achieved HbA 1c <7% with liraglutide 1.8 mg and metformin and continued treatment in a non-randomized, observational arm. Another 167 patients (17%) withdrew from the trial during the run-in period with approximately one-half of these patients doing so because of gastrointestinal adverse reactions [ see Adverse Reactions (6.1) ] . The remaining 323 patients with HbA 1c ≥7% (33% of those who entered the run-in period) were randomized to 26 weeks of once-daily insulin detemir administered in the evening as add-on therapy (N=162) or to continued, unchanged treatment with liraglutide 1.8 mg and metformin (N=161). The starting dose of insulin detemir was 10 units/day and the mean dose at the end of the 26-week randomized period was 39 units/day. During the 26 week randomized treatment period, the percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized to continued treatment with liraglutide 1.8 mg and metformin and 1.2% in the group randomized to add-on therapy with insulin detemir. The mean age of participants was 57 years, and the mean duration of diabetes was 8 years. Participants were 55.7% male, 91.3% White, 5.6% Black or African American and 12.5% of Hispanic or Latino ethnicity. The mean BMI was 34 kg/m 2 . Treatment with insulin detemir as add-on to liraglutide 1.8 mg + metformin resulted in statistically significant reductions in HbA 1c and FPG compared to continued, unchanged treatment with liraglutide 1.8 mg + metformin alone ( Table 6 ). From a mean baseline body weight of 96 kg after randomization, there was a mean reduction of 0.3 kg in the patients who received insulin detemir add-on therapy compared to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with liraglutide 1.8 mg + metformin alone. Table 6. Results of a 26-week Open-label Trial of Insulin Detemir as Add-on to Liraglutide + Metformin Compared to Continued Treatment with Liraglutide + Metformin Alone in Adult Patients with Type 2 Diabetes Mellitus not Achieving HbA 1c < 7% after 12 Weeks of Metformin and Liraglutide a Insulin detemir + Liraglutide + Metformin Liraglutide + Metformin Intent-to-Treat Population (N) 162 157 HbA 1c (%) (Mean) Baseline (week 0) 7.6 7.6 Change from baseline (adjusted mean) -0.5 0 Difference from Liraglutide + metformin arm (LS mean) b -0.5** 95% Confidence Interval (-0.7, -0.4) Percentage of patients achieving HbA 1c <7% 43 17 Fasting Plasma Glucose (mg/dL) (Mean) Baseline (week 0) 166 159 Change from baseline (adjusted mean) -39 -7 Difference from Liraglutide + metformin arm (LS mean) b -31** 95% Confidence Interval (-39, -23) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value ** p-value <0.0001 Add-on to Sulfonylurea In this 26-week trial, 1,041 adult patients with type 2 diabetes mellitus were randomized to liraglutide 0.6 mg, liraglutide 1.2 mg, liraglutide 1.8 mg, placebo, or rosiglitazone 4 mg (one-half of the maximal approved dose in the United States), all as add-on to glimepiride. Randomization occurred after a 4-week run-in period consisting of an initial, 2-week, forced-glimepiride titration period followed by a maintenance period of another 2 weeks. During the titration period, doses of glimepiride were increased to 4 mg/day. The doses of glimepiride could be reduced (at the discretion of the investigator) from 4 mg/day to 3 mg/day or 2 mg/day (minimum) after randomization, in the event of unacceptable hypoglycemia or other adverse events. The mean age of participants was 56 years, and the mean duration of diabetes was 8 years. Participants were 49.4% male, 64.4% White and 2.8% Black or African American. The mean BMI was 29.9 kg/m 2 . Treatment with liraglutide 1.2 mg and 1.8 mg as add-on to glimepiride resulted in a statistically significant reduction in mean HbA 1c compared to placebo add-on to glimepiride ( Table 7 ). The percentage of patients who discontinued due to ineffective therapy was 3% in the liraglutide 1.8 mg + glimepiride treatment group, 3.5% in the liraglutide 1.2 mg + glimepiride treatment group, 17.5% in the placebo + glimepiride treatment group, and 6.9% in the rosiglitazone + glimepiride treatment group. Table 7. Results of a 26-week Trial of Liraglutide as Add-on to Sulfonylurea in Adult Patients with Type 2 Diabetes Mellitus a Liraglutide 1.8 mg + Glimepiride Liraglutide 1.2 mg + Glimepiride Placebo + Glimepiride Rosiglitazone 4 mg † + Glimepiride Intent-to-Treat Population (N) 234 228 114 231 HbA 1c (%) (Mean) Baseline 8.5 8.5 8.4 8.4 Change from baseline (adjusted mean) b -1.1 -1.1 +0.2 -0.4 Difference from placebo + glimepiride arm (adjusted mean) b -1.4** -1.3** 95% Confidence Interval (-1.6, -1.1) (-1.5, -1.1) Percentage of patients achieving HbA 1c <7% 42 35 7 22 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 174 177 171 179 Change from baseline (adjusted mean) b -29 -28 +18 -16 Difference from placebo + glimepiride arm (adjusted mean) b -47** -46** 95% Confidence Interval (-58, -35) (-58, -35) Body Weight (kg) (Mean) Baseline 83 80 81.9 80.6 Change from baseline (adjusted mean) b -0.2 +0.3 -0.1 +2.1 Difference from placebo + glimepiride arm (adjusted mean) b -0.1 0.4 95% Confidence Interval (-0.9, 0.6) (-0.4, 1.2) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value † For rosiglitazone, one-half of the maximal approved United States dose. ** p-value <0.0001 Add-on to Metformin and Sulfonylurea In this 26-week trial, 581 adult patients with type 2 diabetes mellitus were randomized to liraglutide 1.8 mg, placebo, or insulin glargine, all as add-on to metformin and glimepiride. Randomization took place after a 6-week run-in period consisting of a 3-week forced metformin and glimepiride titration period followed by a maintenance period of another 3 weeks. During the titration period, doses of metformin and glimepiride were to be increased up to 2,000 mg/day and 4 mg/day, respectively. After randomization, patients randomized to liraglutide 1.8 mg underwent a 2 week period of titration with liraglutide. During the trial, the liraglutide and metformin doses were fixed, although glimepiride and insulin glargine doses could be adjusted. Patients titrated glargine twice-weekly during the first 8 weeks of treatment based on self-measured fasting plasma glucose on the day of titration. After Week 8, the frequency of insulin glargine titration was left to the discretion of the investigator, but, at a minimum, the glargine dose was to be revised, if necessary, at Weeks 12 and 18. Only 20% of glargine-treated patients achieved the pre-specified target fasting plasma glucose of ≤100 mg/dL. Therefore, optimal titration of the insulin glargine dose was not achieved in most patients. The mean age of participants was 58 years, and the mean duration of diabetes was 9 years. Participants were 56.5% male, 75.0% White and 3.6% Black or African American. The mean BMI was 30.5 kg/m 2 . Treatment with liraglutide as add-on to glimepiride and metformin resulted in a statistically significant mean reduction in HbA 1c compared to placebo add-on to glimepiride and metformin ( Table 8 ). The percentage of patients who discontinued due to ineffective therapy was 0.9% in the liraglutide 1.8 mg + metformin + glimepiride treatment group, 0.4% in the insulin glargine + metformin + glimepiride treatment group, and 11.3% in the placebo + metformin + glimepiride treatment group. Table 8. Results of a 26-week Trial of Liraglutide as Add-on to Metformin and Sulfonylurea in Adult Patients with Type 2 Diabetes Mellitus a Liraglutide 1.8 mg + Metformin + Glimepiride Placebo + Metformin + Glimepiride Insulin glargine † + Metformin + Glimepiride Intent-to-Treat Population (N) 230 114 232 HbA 1c (%) (Mean) Baseline 8.3 8.3 8.1 Change from baseline (adjusted mean) b -1.3 -0.2 -1.1 Difference from placebo + metformin + glimepiride arm (adjusted mean) b -1.1** 95% Confidence Interval (-1.3, -0.9) Percentage of patients achieving HbA 1c <7% 53 15 46 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 165 170 164 Change from baseline (adjusted mean) b -28 +10 -32 Difference from placebo + metformin + glimepiride arm (adjusted mean) b -38** 95% Confidence Interval (-46, -30) Body Weight (kg) (Mean) Baseline 85.8 85.4 85.2 Change from baseline (adjusted mean) b -1.8 -0.4 1.6 Difference from placebo + metformin + glimepiride arm (adjusted mean) b -1.4* 95% Confidence Interval (-2.1, -0.7) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value † For insulin glargine, optimal titration regimen was not achieved for 80% of patients. * p-value <0.05 ** p-value <0.0001 Liraglutide Compared to Exenatide, Both as Add-on to Metformin and/or Sulfonylurea Therapy In this 26–week, open-label trial, 464 adult patients with type 2 diabetes mellitus on a background of metformin monotherapy, sulfonylurea monotherapy or a combination of metformin and sulfonylurea were randomized to once daily liraglutide 1.8 mg or exenatide 10 mcg twice daily. Maximally tolerated doses of background therapy were to remain unchanged for the duration of the trial. Patients randomized to exenatide started on a dose of 5 mcg twice-daily for 4 weeks and then were escalated to 10 mcg twice-daily. The mean age of participants was 57 years, and the mean duration of diabetes was 8 years. Participants were 51.9% male, 91.8% White, 5.4% Black or African American and 12.3% of Hispanic or Latino ethnicity. The mean BMI was 32.9 kg/m 2 . Treatment with liraglutide 1.8 mg resulted in statistically significant reductions in HbA 1c and FPG relative to exenatide ( Table 9 ). The percentage of patients who discontinued for ineffective therapy was 0.4% in the liraglutide treatment group and 0% in the exenatide treatment group. Both treatment groups had a mean decrease from baseline in body weight of approximately 3 kg. Table 9. Results of a 26-week Open-label Trial of Liraglutide versus Exenatide (both in combination with metformin and/or sulfonylurea) in Adult Patients with Type 2 Diabetes Mellitus a Liraglutide 1.8 mg once daily + metformin and/or sulfonylurea Exenatide 10 mcg twice daily + metformin and/or sulfonylurea Intent-to-Treat Population (N) 233 231 HbA 1c (%) (Mean) Baseline 8.2 8.1 Change from baseline (adjusted mean) b -1.1 -0.8 Difference from exenatide arm (adjusted mean) b 95% Confidence Interval -0.3** (-0.5, -0.2) Percentage of patients achieving HbA 1c <7% 54 43 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 176 171 Change from baseline (adjusted mean) b -29 -11 Difference from exenatide arm (adjusted mean) b 95% Confidence Interval -18** (-25, -12) a Intent-to-treat population using last observation carried forward b Least squares mean adjusted for baseline value ** p-value <0.0001 Add-on to Metformin and Thiazolidinedione In this 26-week trial, 533 adult patients with type 2 diabetes mellitus were randomized to liraglutide 1.2 mg, liraglutide 1.8 mg or placebo, all as add-on to rosiglitazone (8 mg) plus metformin (2,000 mg). Patients underwent a 9 week run-in period (3-week forced dose escalation followed by a 6-week dose maintenance phase) with rosiglitazone (starting at 4 mg and increasing to 8 mg/day within 2 weeks) and metformin (starting at 500 mg with increasing weekly increments of 500 mg to a final dose of 2,000 mg/day). Only patients who tolerated the final dose of rosiglitazone (8 mg/day) and metformin (2,000 mg/day) and completed the 6-week dose maintenance phase were eligible for randomization into the trial. The mean age of participants was 55 years, and the mean duration of diabetes was 9 years. Participants were 61.6% male, 84.2% White, 10.2% Black or African American and 16.4% of Hispanic or Latino ethnicity. The mean BMI was 33.9 kg/m 2 . Treatment with liraglutide as add-on to metformin and rosiglitazone produced a statistically significant reduction in mean HbA 1c compared to placebo add-on to metformin and rosiglitazone ( Table 10 ). The percentage of patients who discontinued due to ineffective therapy was 1.7% in the liraglutide 1.8 mg + metformin + rosiglitazone treatment group, 1.7% in the liraglutide 1.2 mg + metformin + rosiglitazone treatment group, and 16.4% in the placebo + metformin + rosiglitazone treatment group. Table 10. Results of a 26-week Trial of Liraglutide as Add-on to Metformin and Thiazolidinedione in Adult Patients with Type 2 Diabetes Mellitus a Liraglutide 1.8 mg + Metformin + Rosiglitazone Liraglutide 1.2 mg + Metformin + Rosiglitazone Placebo + Metformin + Rosiglitazone Intent-to-Treat Population (N) 178 177 175 HbA 1c (%) (Mean) Baseline 8.6 8.5 8.4 Change from baseline (adjusted mean) b -1.5 -1.5 -0.5 Difference from placebo + metformin + rosiglitazone arm (adjusted mean) b -0.9** -0.9** 95% Confidence Interval (-1.1, -0.8) (-1.1, -0.8) Percentage of patients achieving HbA 1c <7% 54 57 28 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 185 181 179 Change from baseline (adjusted mean) b -44 -40 -8 Difference from placebo + metformin + rosiglitazone arm (adjusted mean) b -36** -32** 95% Confidence Interval (-44, -27) (-41, -23) Body Weight (kg) (Mean) Baseline 94.9 95.3 98.5 Change from baseline (adjusted mean) b -2 -1 +0.6 Difference from placebo + metformin + rosiglitazone arm (adjusted mean) b -2.6** -1.6** 95% Confidence Interval (-3.4, -1.8) (-2.4, -1.0) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value ** p-value <0.0001 Liraglutide Compared to Placebo Both With or Without Metformin and/or Sulfonylurea and/or Pioglitazone and/or Basal or Premix Insulin in Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment In this 26-week, double-blind, randomized, placebo-controlled, parallel-group trial in adult patients with type 2 diabetes mellitus, 279 patients with moderate renal impairment, as per MDRD formula (eGFR 30−59 mL/min/1.73 m 2 ), were randomized to liraglutide or placebo once daily. Liraglutide was added to the patient’s stable pre-trial antidiabetic regimen (insulin therapy and/or metformin, pioglitazone, or sulfonylurea). The dose of liraglutide injection was escalated according to approved labeling to achieve a dose of 1.8 mg per day. The insulin dose was reduced by 20% at randomization for patients with baseline HbA 1c ≤ 8% and fixed until liraglutide dose escalation was complete. Dose reduction of insulin and SU was allowed in case of hypoglycemia; up titration of insulin was allowed but not beyond the pre-trial dose. The mean age of participants was 67 years, and the mean duration of diabetes was 15 years. Participants were 50.5% male, 92.3% White, 6.6% Black or African American, and 7.2% of Hispanic or Latino ethnicity. The mean BMI was 33.9 kg/m 2 . Approximately half of patients had an eGFR between 30 and <45 mL/min/1.73 m 2 . Treatment with liraglutide resulted in a statistically significant reduction in HbA 1c from baseline at Week 26 compared to placebo (see Table 11 ). 123 patients reached the 1.8 mg dose of liraglutide. Table 11. Results of a 26-week Trial of Liraglutide Compared to Placebo in Adult Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment a Liraglutide 1.8 mg + insulin and/or OAD Placebo + insulin and/or OAD Intent to Treat Population (N) 140 137 HbA 1c (%) Baseline (mean) 8.1 8.0 Change from baseline (estimated mean) b, c -0.9 -0.4 Difference from placebo b, c 95% Confidence Interval -0.6* (-0.8, -0.3) Proportion achieving HbA 1c < 7% d 39.3 19.7 FPG (mg/dL) Baseline (mean) 171 167 Change from baseline (estimated mean) e -22 -10 Difference from placebo e 95% Confidence Interval -12** (-23, -0.8) a Intent-to-treat population b Estimated using a mixed model for repeated measurement with treatment, country, stratification groups as factors and baseline as a covariate, all nested within visit. Multiple imputation method modeled “wash out” of the treatment effect for patients having missing data who discontinued treatment. c Early treatment discontinuation, before week 26, occurred in 25% and 22% of liraglutide and placebo patients, respectively. d Based on the known number of subjects achieving HbA 1c < 7%. When applying the multiple imputation method described in b) above, the estimated percents achieving HbA 1c < 7% are 47.6% and 24.9% for liraglutide and placebo, respectively. e Estimated using a mixed model for repeated measurement with treatment, country, stratification groups as factors and baseline as a covariate, all nested within visit. *p-value <0.0001 **p-value <0.05 Figure 3 Figure 4 14.2 Glycemic Control Trial in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus Liraglutide injection was evaluated in a 26-week, double-blind, randomized, parallel group, placebo controlled multi-center trial ( NCT01541215 ), in 134 pediatric patients with type 2 diabetes mellitus aged 10 years and older. Patients were randomized to liraglutide once-daily or placebo once-daily in combination with metformin with or without basal insulin treatment. All patients were on a metformin dose of 1,000 to 2,000 mg prior to randomization. The basal insulin dose was decreased by 20% at randomization and liraglutide was titrated weekly by 0.6 mg for 2 to 3 weeks based on tolerability and an average fasting plasma glucose goal of ≤110 mg/dL. The mean age was 14.6 years: 29.9% were ages 10-14 years, and 70.1% were greater than 14 years of age. 38.1% were male, 64.9% were White, 13.4% were Asian, 11.9% were Black or African American; 29.1% were of Hispanic or Latino ethnicity. The mean BMI was 33.9 kg/m 2 and the mean BMI SDS was 2.9. 18.7% of patients were using basal insulin at baseline. The mean duration of diabetes was 1.9 years and the mean HbA 1c was 7.8%. At week 26, treatment with liraglutide was superior in reducing HbA 1c from baseline versus placebo. The estimated treatment difference in HbA 1c reduction from baseline between liraglutide and placebo was -1.06% with a 95% confidence interval of [-1.65%; -0.46%] (see Table 12 ). Table 12. Results at Week 26 in a Trial Comparing Liraglutide in Combination with Metformin With or Without Basal Insulin versus Placebo in Combination with Metformin With or Without Basal Insulin in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus Liraglutide+metformin±basal insulin Placebo+metformin±basal insulin N 66 68 HbA 1c (%) Baseline 7.9 7.7 End of 26 weeks 7.1 8.2 Adjusted mean change from baseline after 26 weeks a -0.64 0.42 Treatment difference [95% CI] Liraglutide vs Placebo -1.06 [-1.65; -0.46]* Percentage of patients achieving HbA 1c <7% b 63.7 36.5 FPG (mg/dL) Baseline 157 147 End of 26 weeks 132 166 Adjusted mean change from baseline after 26 weeks a -19.4 14.4 Treatment difference [95% CI] Liraglutide vs Placebo -33.83 [-55.74 ; -11.92] a The change from baseline to end of treatment visit in HbA 1c and FPG was analyzed using a pattern mixture model with multiple imputation. Missing observations (10.6% in the liraglutide, 14.5% in the placebo) were imputed from the placebo arm based on multiple (x10,000) imputations. The data for week 26 was then analyzed with an ANCOVA model containing treatment, sex and age group as fixed effects and baseline value as covariate. b Categories are derived from continuous measurements of HbA 1c using a pattern mixture model with multiple imputation for missing observations. * p-value <0.001

1 INDICATIONS AND USAGE SAXENDA is indicated in combination with a reduced calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in: • Adults and pediatric patients aged 12 years and older with body weight greater than 60 kg and obesity. • Adults with overweight in the presence of at least one weight-related comorbid condition. Limitations of Use • SAXENDA contains liraglutide. Coadministration with other liraglutide-containing products or with any other glucagon-like peptide-1 (GLP-1) receptor agonist is not recommended. • The safety and effectiveness of SAXENDA in pediatric patients with type 2 diabetes have not been established. SAXENDA is a glucagon like peptide 1 (GLP-1) receptor agonist indicated in combination with a reduced calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in: • Adults and pediatric patients aged 12 years and older with body weight greater than 60 kg and obesity. ( 1 ) • Adults with overweight in the presence of at least one weight-related comorbid condition. ( 1 ) Limitations of Use: • Coadministration with other liraglutide-containing products or with any other GLP-1 receptor agonist is not recommended. ( 1 ) • The safety and effectiveness of SAXENDA in pediatric patients with type 2 diabetes have not been established. ( 1 )

2 DOSAGE AND ADMINISTRATION • Inject SAXENDA subcutaneously in the abdomen, thigh, or upper arm once daily at any time of day, without regard to the timing of meals. ( 2.1 ) • The recommended dose of SAXENDA is 3 mg daily. ( 2.2 ) • Initiate at 0.6 mg per day for one week. In weekly intervals, increase the dose until a dose of 3 mg is reached. ( 2.2 ) • If pediatric patients do not tolerate an increased dose during dose escalation, the dose may also be lowered to the previous level. Dose escalation for pediatric patients may take up to 8 weeks. ( 2.2 ) • Pediatric patients who do not tolerate 3 mg daily may have their dose reduced to 2.4 mg daily. ( 2.2 ) • Adult patients with type 2 diabetes should monitor blood glucose prior to starting SAXENDA and during SAXENDA treatment. ( 2.2 ) 2.1 Important Administration Instructions • Prior to initiation of SAXENDA, train patients on proper injection technique. Refer to the accompanying Instructions for Use for complete administration instructions with illustrations. • Inspect SAXENDA visually prior to each injection. Only use if solution is clear, colorless, and contains no particles. • Administer SAXENDA in combination with a reduced-calorie diet and increased physical activity. • Inject SAXENDA subcutaneously once daily at any time of day, without regard to the timing of meals. • Inject SAXENDA subcutaneously in the abdomen, thigh, or upper arm. No dosage adjustment is needed if changing the injection site and/or timing. • Rotate injection sites within the same region in order to reduce the risk of cutaneous amyloidosis [see Adverse Reactions ( 6.2) ] . • If a dose is missed, resume the once-daily regimen as prescribed with the next scheduled dose. Do not administer an extra dose or increase the dose to make up for the missed dose. • If more than 3 days have elapsed since the last SAXENDA dosage, reinitiate SAXENDA at 0.6 mg daily and follow the dosage escalation schedule in Table 1 , to reduce the risk of gastrointestinal adverse reactions associated with reinitiation of treatment. 2.2 Dosage in Adults and Pediatric Patients Aged 12 Years and Older • Initiate SAXENDA with a dose of 0.6 mg daily for one week. Then follow the dosage escalation schedule in Table 1 to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions ( 5.7 ), Adverse Reactions ( 6.1 )]. Table 1. Dosage Escalation Schedule Week Daily Dose 1 0.6 mg 2 1.2 mg 3 1.8 mg 4 2.4 mg 5 and onward 3 mg Adult Patients • For adults, the recommended dosage of SAXENDA is 3 mg daily, lower dosages are for titration only. • Discontinue SAXENDA if the patient cannot tolerate the 3 mg dosage. • If patients do not tolerate an increased dose during dosage escalation, consider delaying dosage escalation for approximately one additional week. • Evaluate the change in body weight 16 weeks after initiating SAXENDA and discontinue SAXENDA if the patient has not lost at least 4% of baseline body weight, since it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. • In adult patients with type 2 diabetes, monitor blood glucose prior to starting SAXENDA and during SAXENDA treatment. Pediatric Patients • For pediatric patients, the recommended maintenance dosage of SAXENDA is 3 mg daily. Pediatric patients who do not tolerate 3 mg daily may have their maintenance dose reduced to 2.4 mg daily. Discontinue SAXENDA if the patient cannot tolerate the 2.4 mg dose. • If pediatric patients do not tolerate an increased dose during dosage escalation, the dose may also be lowered to the previous level. Dosage escalation for pediatric patients may take up to 8 weeks. • Evaluate the change in BMI after 12 weeks on the maintenance dose and discontinue SAXENDA if the patient has not had a reduction in BMI of at least 1% from baseline, since it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.

5 WARNINGS AND PRECAUTIONS • Acute Pancreatitis: Has been observed in patients treated with GLP-1 receptor agonists, including SAXENDA. Discontinue if pancreatitis is suspected. ( 5.2 ) • Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.3 ) • Hypoglycemia: Can occur in adults when SAXENDA is used with an insulin secretagogue (e.g. a sulfonylurea) or insulin. The risk may be lowered by a reduction in the dose of concomitantly administered insulin secretagogues or insulin. In the pediatric clinical trial, patients did not have type 2 diabetes. Hypoglycemia occurred in SAXENDA-treated pediatric patients. Inform all patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. ( 5.4 ) • Heart Rate Increase: Monitor heart rate at regular intervals. ( 5.5 ) • Acute Kidney Injury Due to Volume Depletion: Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.6 ) • Severe Gastrointestinal Adverse Reactions: Use has been associated with gastrointestinal adverse reactions, sometimes severe. SAXENDA is not recommended in patients with severe gastroparesis. ( 5.7 ) • Hypersensitivity Reactions: Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue SAXENDA and other suspect medications and promptly seek medical advice. ( 5.8 ) • Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.9 ) 5.1 Risk of Thyroid C-cell Tumors Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical Toxicology ( 13.1 )] . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether SAXENDA will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. SAXENDA is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of SAXENDA and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with SAXENDA. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC, and patients with MTC usually have calcitonin values greater than 50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including liraglutide [see Adverse Reactions ( 6 )] . After initiation of SAXENDA, observe patients carefully for signs and symptoms of acute pancreatitis which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue SAXENDA and initiate appropriate management. 5.3 Acute Gallbladder Disease In SAXENDA clinical trials in adults, 2.2% of SAXENDA-treated patients reported adverse events of cholelithiasis versus 0.8% of placebo-treated patients. The incidence of cholecystitis was 0.8% in SAXENDA-treated patients versus 0.4% in placebo-treated patients. The majority of SAXENDA-treated patients with adverse events of cholelithiasis and cholecystitis required cholecystectomy. Substantial or rapid weight loss can increase the risk of cholelithiasis; however, the incidence of acute gallbladder disease was greater in SAXENDA-treated patients than in placebo-treated patients even after accounting for the degree of weight loss. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated. 5.4 Hypoglycemia Adult patients with type 2 diabetes mellitus on an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia with use of SAXENDA, including severe hypoglycemia. In patients with type 2 diabetes, monitor blood glucose prior to starting SAXENDA and during SAXENDA treatment [see Dosage and Administration ( 2 ), Adverse Reactions ( 6.1 )] . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. In the pediatric clinical trial, patients did not have type 2 diabetes but were provided with blood glucose meters. Clinically significant hypoglycemia, defined as blood glucose <54 mg/dL, occurred in 1.6% of the SAXENDA- treated patients compared to 0.8% of placebo-treated patients [see Adverse Reactions ( 6.1 )] . Inform all pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.5 Heart Rate Increase Mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed with routine clinical monitoring in SAXENDA-treated adult patients compared to placebo in clinical trials. More patients treated with SAXENDA, compared with placebo, had changes from baseline at two consecutive visits of more than 10 bpm (34% versus 19%, respectively) and 20 bpm (5% versus 2%, respectively). At least one resting heart rate exceeding 100 bpm was recorded for 6% of SAXENDA-treated patients compared with 4% of placebo-treated patients, with this occurring at two consecutive study visits for 0.9% and 0.3%, respectively. Tachycardia was reported as an adverse reaction in 0.6% of SAXENDA-treated patients and in 0.1% of placebo-treated patients. In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, SAXENDA treatment was associated with a heart rate that was 4 to 9 bpm higher than that observed with placebo. In a pediatric clinical trial, mean increases from baseline in resting heart rate of 3 to 7 bpm were observed with SAXENDA treatment. Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients should inform health care providers of palpitations or feelings of a racing heartbeat while at rest during SAXENDA treatment. For patients who experience a sustained increase in resting heart rate while taking SAXENDA, SAXENDA should be discontinued. 5.6 Acute Kidney Injury Due to Volume Depletion There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with liraglutide [see Adverse Reactions ( 6.2 )] . The majority of the reported events occurred in patients who had experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea [see Adverse Reactions ( 6.1 )] . Monitor renal function in patients reporting adverse reactions to SAXENDA that could lead to volume depletion, especially during dosage initiation and escalation [see Use in Specific Populations ( 8.6 )] . 5.7 Severe Gastrointestinal Adverse Reactions Use of GLP-1 receptor agonists, including liraglutide, has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6)] . In SAXENDA clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving SAXENDA (4.8%) than placebo (1.4%). Severe gastrointestinal adverse reactions have also been reported postmarketing with GLP-1 receptor agonists. SAXENDA is not recommended in patients with severe gastroparesis. 5.8 Hypersensitivity Reactions There have been reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with SAXENDA [see Contraindications ( 4 ), Adverse Reactions ( 6.1 , 6.2 )] . If a hypersensitivity reaction occurs, the patient should discontinue SAXENDA and other suspect medications and promptly seek medical advice. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with SAXENDA. 5.9 Pulmonary Aspiration During General Anesthesia or Deep Sedation SAXENDA delays gastric emptying [see Clinical Pharmacology ( 12.2 )] . There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking SAXENDA, including whether modifying preoperative fasting recommendations or temporarily discontinuing SAXENDA could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking SAXENDA.

7 DRUG INTERACTIONS SAXENDA delays gastric emptying. May impact absorption of concomitantly administered oral medications. Use with caution. ( 7 ) 7.1 Oral Medications SAXENDA causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide did not affect the absorption of the tested orally administered medications to any clinically relevant degree. Nonetheless, monitor for potential consequences of delayed absorption of oral medications concomitantly administered with SAXENDA.

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-Cell Tumors [see Warnings and Precautions ( 5.1 )] • Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] • Acute Gallbladder Disease [see Warnings and Precautions ( 5.3 )] • Risk for Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy [see Warnings and Precautions ( 5.4 )] • Heart Rate Increase [see Warnings and Precautions ( 5.5 )] • Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.6 )] • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.7 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.8 )] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.9 )] Most common adverse reactions, reported in greater than or equal to 5% are: nausea, diarrhea, constipation, vomiting, injection site reactions, headache, hypoglycemia, dyspepsia, fatigue, dizziness, abdominal pain, increased lipase, upper abdominal pain, pyrexia, and gastroenteritis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-844-363-4448 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. SAXENDA was evaluated for safety in 5 double-blind, placebo controlled trials that included 3,384 overweight or obese adult patients treated with SAXENDA for a treatment period up to 56 weeks (3 trials), 52 weeks (1 trial), and 32 weeks (1 trial) and one trial of 56 weeks in 125 pediatric patients with obesity aged 12 years and older [see Clinical Studies ( 14.1 , 14.2 )]. All patients received study drug in addition to a reduced-calorie diet and increased physical activity counseling. In the adult trials, patients received SAXENDA for a mean treatment duration of 46 weeks (median, 56 weeks). Baseline characteristics included a mean age of 47 years, 71% female, 85% white, 39% with hypertension, 15% with type 2 diabetes, 34% with dyslipidemia, 29% with a BMI greater than 40 kg/m 2 , and 9% with cardiovascular disease. In one of the 56-week trials, a subset of patients (with abnormal glucose measurements at randomization) [see Clinical Studies ( 14.1 )] were enrolled for a placebo-controlled 160-week period instead, followed by a 12-week off-treatment follow-up. For those participating in this 160-week period, patients received SAXENDA for a mean treatment duration of 110 weeks (median, 159 weeks). For all trials, dosing was initiated and increased weekly to reach the 3 mg dose. In adult clinical trials, 9.8% of patients treated with SAXENDA and 4.3% of patients treated with placebo prematurely discontinued treatment as a result of adverse reactions. The most common adverse reactions leading to discontinuation were nausea (2.9% versus 0.2% for SAXENDA and placebo, respectively), vomiting (1.7% versus less than 0.1%), and diarrhea (1.4% versus 0%). Adverse reactions reported in greater than or equal to 2% of SAXENDA-treated adult patients and more frequently than in placebo-treated patients are shown in Table 2 . Adverse reactions reported in greater than or equal to 3% of SAXENDA-treated pediatric patients and more frequently than in placebo-treated patients are shown in Table 3 . Table 2. Adverse Reactions Occurring in ≥2% of SAXENDA-treated Adult Patients and More Frequently than Placebo Placebo N=1941 % SAXENDA N=3384 % Nausea 13.8 39.3 Diarrhea 9.9 20.9 Constipation 8.5 19.4 Vomiting 3.9 15.7 Injection Site Reaction 1 10.5 13.9 Headache 12.6 13.6 Hypoglycemia in T2DM 2 6.6 12.6 Dyspepsia 2.7 9.6 Fatigue 4.6 7.5 Dizziness 5 6.9 Abdominal Pain 3.1 5.4 Increased Lipase 2.2 5.3 Upper Abdominal Pain 2.7 5.1 Gastroenteritis 3.2 4.7 Gastroesophageal Reflux Disease 1.7 4.7 Abdominal Distension 3 4.5 Eructation 0.2 4.5 Urinary Tract Infection 3.1 4.3 Flatulence 2.5 4 Viral Gastroenteritis 1.6 2.8 Insomnia 1.7 2.4 Dry Mouth 1 2.3 Asthenia 0.8 2.1 Anxiety 1.6 2 1 The most common reactions, each reported by 1% to 2.5% of SAXENDA-treated patients and more commonly than by placebo-treated patients, included erythema, pruritus, and rash at the injection site. 2 Defined as blood glucose <54 mg/dL with or without symptoms of hypoglycemia in patients with type 2 diabetes not on concomitant insulin (Study 2, SAXENDA N=423, Placebo N=212). See text below for further information regarding hypoglycemia in patients with and without type 2 diabetes. T2DM = type 2 diabetes mellitus. Table 3. Adverse Reactions Occurring in ≥3% of SAXENDA-treated Pediatric Patients and More Frequently than Placebo in a 56 Week Clinical Trial Placebo N=126 % SAXENDA N=125 % Nausea 14.3 42.4 Vomiting 4 34.4 Diarrhea 14.3 22.4 Hypoglycemia 1 4 15.2 Gastroenteritis 4.8 12.8 Dizziness 3.2 10.4 Pyrexia 7.1 8 Abdominal discomfort 0.8 4.8 Constipation 2.4 4.8 Dyslipidemia 3.2 4.8 Fatigue 3.2 4.8 Cough 3.2 4 Depression 2.4 4 Dyspepsia 2.4 4 Pain in extremity 2.4 4 Injection site pain 3.2 3.2 Flatulence 0 3.2 Increased Blood Creatine Kinase 2.4 3.2 Increased Lipase 0.8 3.2 Rash 0 3.2 1 Defined as blood glucose <70 mg/dL with symptoms of hypoglycemia. Pediatric patients did not have type 2 diabetes mellitus. See text below for more detailed hypoglycemia information. Hypoglycemia Adult Patients with Type 2 Diabetes In a clinical trial in adult patients with type 2 diabetes mellitus and overweight (excess weight) or obesity, severe hypoglycemia (defined as requiring the assistance of another person) occurred in 3 (0.7%) of 422 SAXENDA-treated patients (all taking a sulfonylurea) and in none of the 212 placebo-treated patients. In this trial, among patients taking a sulfonylurea, hypoglycemia defined as a plasma glucose less than 54 mg/dL with or without symptoms occurred in 31 (28.2%) of 110 SAXENDA-treated patients and 7 (12.7%) of 55 placebo-treated patients. The doses of sulfonylureas were reduced by 50% at the beginning of the trial per protocol. Among patients not taking a sulfonylurea, blood glucose less than 54 mg/dL with or without symptoms occurred in 22 (7.1%) of 312 SAXENDA-treated patients and 7 (4.5%) of 157 placebo-treated patients. In a SAXENDA clinical trial in adult patients with overweight (excess weight) or obesity with type 2 diabetes mellitus treated with basal insulin and SAXENDA in combination with a reduced-calorie diet and increased physical activity and up to 2 oral anti-diabetes medications, severe hypoglycemia was reported by 3 (1.5%) of 195 SAXENDA-treated patients and 2 (1%) of 197 placebo-treated patients. No meaningful difference in hypoglycemia, defined as blood glucose less than 54 mg/dL with or without symptoms, was reported between groups. Adult Patients without Type 2 Diabetes In SAXENDA clinical trials in adult patients without type 2 diabetes mellitus, there was no systematic capturing or reporting of hypoglycemia; patients were not provided with blood glucose meters or hypoglycemia diaries. Spontaneously reported symptomatic episodes of unconfirmed hypoglycemia were reported by 46 (1.6%) of 2,962 SAXENDA-treated patients and 19 (1.1%) of 1,729 placebo-treated patients. Fasting plasma glucose values obtained at routine clinic visits less than 54 mg/dL, irrespective of hypoglycemic symptoms, occurred in 2 (0.1%) SAXENDA-treated patients and 1 (0.1%) placebo-treated patients. Pediatric Patients without Type 2 Diabetes In a 56-week placebo-controlled clinical trial of pediatric patients without type 2 diabetes mellitus in which blood glucose meters were provided, 19 (15.2%) of SAXENDA-treated patients had hypoglycemia with a blood glucose less than 70 mg/dL with symptoms as compared to 5 (4%) of placebo-treated patients. Four (4) events of hypoglycemia defined as a plasma glucose less than 54 mg/dL occurred in 2 (1.6%) of 125 SAXENDA-treated patients and 1 event occurred in 1 (0.8%) of 126 placebo-treated patients. No severe hypoglycemic episodes, defined as requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, occurred in the SAXENDA treatment group. Acute Pancreatitis In SAXENDA clinical trials in adults, acute pancreatitis was confirmed by adjudication in 9 (0.3%) of 3,291 SAXENDA-treated patients and 2 (0.1%) of 1843 placebo-treated patients. In addition, there were 2 cases of acute pancreatitis in SAXENDA-treated patients who prematurely withdrew from these clinical trials, occurring 74 and 124 days after the last dose. There were 2 additional cases in SAXENDA-treated patients, 1 during an off-treatment follow-up period within 2 weeks of discontinuing SAXENDA, and 1 that occurred in a patient who completed treatment and was off-treatment for 106 days. In a SAXENDA pediatric clinical trial, pancreatitis was not independently adjudicated. Pancreatitis was reported in 1 (0.8%) SAXENDA-treated patient and resulted in treatment discontinuation. Gastrointestinal Adverse Reactions In the adult clinical trials, approximately 68% of SAXENDA-treated patients and 39% of placebo-treated patients reported gastrointestinal disorders; the most frequently reported was nausea (39% and 14% of patients treated with SAXENDA and placebo, respectively). Severe gastrointestinal adverse reactions were reported more frequently among patients receiving SAXENDA (4.8%) than placebo (1.4 %). There have been reports of gastrointestinal adverse reactions, such as nausea, vomiting, and diarrhea, associated with volume depletion and renal impairment. Most episodes of gastrointestinal events were mild or moderate and did not lead to discontinuation of therapy (6.2% with SAXENDA versus 0.8% with placebo discontinued treatment as a result of gastrointestinal adverse reactions). The percentage of patients reporting nausea declined as treatment continued. Other common adverse reactions that occurred at a higher incidence among SAXENDA-treated patients included diarrhea, constipation, vomiting, dyspepsia, abdominal pain, dry mouth, gastritis, gastroesophageal reflux disease, flatulence, eructation and abdominal distension. There have been reports of gastrointestinal adverse reactions, such as nausea, vomiting, and diarrhea, associated with volume depletion and renal impairment. In a pediatric clinical trial, 8% of patients treated with SAXENDA versus no patients who received placebo discontinued treatment as a result of gastrointestinal adverse reactions. Most adverse reactions leading to discontinuation were due to vomiting and nausea (4.8% and 3.2% of SAXENDA-treated patients, respectively). Cardiovascular Safety Cardiovascular safety was assessed (LEADER, NCT01179048) in 9,340 patients with inadequately controlled type 2 diabetes and cardiovascular disease randomized to liraglutide 1.8 mg or placebo in addition to standard of care treatments for type 2 diabetes for a median duration of 3.5 years. The primary endpoint was the time from randomization to first occurrence of a major adverse cardiovascular event (MACE) defined as: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. No increased risk for MACE was observed with liraglutide 1.8 mg. The total number of primary component MACE endpoints was 1,302 [608 (13.0%) with liraglutide 1.8 mg and 694 (14.9%) with placebo]. Liraglutide 1.8 mg (Victoza) is used in the treatment of type 2 diabetes mellitus in adults. The efficacy of liraglutide at doses below 3 mg daily has not been established for weight reduction. Asthenia, Fatigue, Malaise, Dysgeusia and Dizziness Events of asthenia, fatigue, malaise, dysgeusia and dizziness were mainly reported within the first 12 weeks of treatment with SAXENDA and were often co-reported with gastrointestinal events such as nausea, vomiting, and diarrhea. Immunogenicity The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to SAXENDA cannot be directly compared with the incidence of antibodies of other products. Patients treated with SAXENDA may develop anti-liraglutide antibodies. Anti-liraglutide antibodies were detected in 42 (2.8%) of 1505 SAXENDA-treated adult patients with a post-baseline assessment. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 18 (1.2%) of 1505 SAXENDA-treated patients. Presence of antibodies may be associated with a higher incidence of injection site reactions and reports of low blood glucose. In clinical trials, these events were usually classified as mild and resolved while patients continued on treatment. In a pediatric clinical trial, anti-liraglutide antibodies were detected in 14 (12%) of 117 SAXENDA-treated patients with a post-baseline assessment; 5 (4.3%) had persistent antibodies as defined by more than 2 antibody visits at least 16 weeks apart. Two patients (1.7%) remained positive throughout the follow-up period; 1 (0.9%) had antibodies cross reactive to native GLP-1. No patients had neutralizing antibodies. Allergic Reactions Urticaria was reported in 0.7% of SAXENDA-treated patients and 0.5% of placebo-treated patients. Anaphylactic reactions, asthma, bronchial hyperreactivity, bronchospasm, oropharyngeal swelling, facial swelling, angioedema, pharyngeal edema, type IV hypersensitivity reactions have been reported in patients treated with liraglutide in clinical trials. Cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations, dyspnea, and edema have been reported with marketed use of liraglutide. Anaphylactic reactions may potentially be life-threatening. Breast Cancer In SAXENDA clinical trials in adults, breast cancer confirmed by adjudication was reported in 17 (0.7%) of 2379 SAXENDA-treated women compared with 3 (0.2%) of 1300 placebo-treated women, including invasive cancer (13 SAXENDA- and 2 placebo-treated women) and ductal carcinoma in situ (4 SAXENDA- and 1 placebo-treated woman). The majority of cancers were estrogen- and progesterone-receptor positive. There were too few cases to determine whether these cases were related to SAXENDA. In addition, there are insufficient data to determine whether SAXENDA has an effect on pre-existing breast neoplasia. Papillary Thyroid Cancer In SAXENDA clinical trials in adults, papillary thyroid carcinoma confirmed by adjudication was reported in 8 (0.2%) of 3291 SAXENDA-treated patients compared with no cases among 1,843 placebo-treated patients. Four of these papillary thyroid carcinomas were less than 1 cm in greatest diameter and 4 were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings identified prior to treatment. Colorectal Neoplasms In SAXENDA clinical trials in adults, benign colorectal neoplasms (mostly colon adenomas) confirmed by adjudication were reported in 20 (0.6%) of 3,291 SAXENDA-treated patients compared with 7 (0.4%) of 1,843 placebo-treated patients. Six positively adjudicated cases of malignant colorectal neoplasms were reported in 5 SAXENDA-treated patients (0.2%, mostly adenocarcinomas) and 1 in a placebo-treated patient (0.1%, neuroendocrine tumor of the rectum). Cardiac Conduction Disorders In SAXENDA clinical trials in adults, 11 (0.3%) of 3,384 SAXENDA-treated patients compared with none of the 1,941 placebo-treated patients had a cardiac conduction disorder, reported as first degree atrioventricular block, right bundle branch block, or left bundle branch block. Hypotension Adverse reactions related to hypotension (hypotension, orthostatic hypotension, circulatory collapse, and decreased blood pressure) were reported more frequently with SAXENDA (1.1%) compared with placebo (0.5%) in SAXENDA clinical trials in adults. Systolic blood pressure decreases to less than 80 mmHg were observed in 4 (0.1%) SAXENDA-treated patients compared with no placebo-treated patients. One of the SAXENDA-treated patients had hypotension associated with gastrointestinal adverse reactions and renal failure [see Warnings and Precautions ( 5.6 )] . Laboratory Abnormalities Liver Enzymes Increases in alanine aminotransferase (ALT) greater than or equal to 10 times the upper limit of normal were observed in 5 (0.15%) SAXENDA-treated patients (two of whom had ALT greater than 20 and 40 times the upper limit of normal) compared with 1 (0.05%) placebo-treated patient during the SAXENDA clinical trials. Because clinical evaluation to exclude alternative causes of ALT and aspartate aminotransferase (AST) increases was not done in most cases, the relationship to SAXENDA is uncertain. Some increases in ALT and AST were associated with other confounding factors (such as gallstones). Serum Calcitonin Calcitonin, a biological marker of MTC, was measured throughout the clinical development program [see Warnings and Precautions ( 5.1 )] . More patients treated with SAXENDA in the clinical trials were observed to have high calcitonin values during treatment, compared with placebo. The proportion of patients with calcitonin greater than or equal to 2 times the upper limit of normal at the end of the trial was 1.2% in SAXENDA-treated patients and 0.6% in placebo-treated patients. Calcitonin values greater than 20 ng/L at the end of the trial occurred in 0.5% of SAXENDA-treated patients and 0.2% of placebo-treated patients; among patients with pre-treatment serum calcitonin less than 20 ng/L, none had calcitonin elevations to greater than 50 ng/L at the end of the trial. Serum Lipase and Amylase Serum lipase and amylase were routinely measured in the SAXENDA clinical trials. Among SAXENDA-treated patients, 2.1% had a lipase value at anytime during treatment of greater than or equal to 3 times the upper limit of normal compared with 1.0% of placebo-treated patients. 0.1% of SAXENDA-treated patients had an amylase value at anytime in the trial of greater than or equal to 3 times the upper limit of normal versus 0.1% of placebo-treated patients. The clinical significance of elevations in lipase or amylase with SAXENDA is unknown in the absence of other signs and symptoms of pancreatitis [see Warnings and Precautions ( 5.2 )] . 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of liraglutide, the active ingredient of SAXENDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Acute pancreatitis; hemorrhagic and necrotizing pancreatitis, sometimes resulting in death; ileus, intestinal obstruction, severe constipation including fecal impaction, nausea, vomiting and diarrhea leading to dehydration Hepatobiliary Hyperbilirubinemia, elevations of liver enzymes, cholestasis and hepatitis Hypersensitivity Rash, pruritus, angioedema and anaphylactic reactions Neoplasms Medullary thyroid carcinoma Neurologic Dysesthesia, headache Pulmonary Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation. Renal Acute kidney injury, sometimes requiring hemodialysis; increased serum creatinine General Disorders and Administration Site Conditions Allergic reactions: rash and pruritus Immune System Angioedema and anaphylactic reactions Skin and Subcutaneous Tissue Cutaneous amyloidosis, alopecia

14 CLINICAL STUDIES 14.1 Weight Management Trials in Adults with Overweight or Obesity The safety and efficacy of SAXENDA for chronic weight management in conjunction with reduced caloric intake and increased physical activity were studied in three 56-week, randomized, double-blind, placebo-controlled trials. In all studies, SAXENDA was titrated to 3 mg daily during a 4-week period. All patients received instruction for a reduced-calorie diet (approximately 500 kcal/day deficit) and physical activity counseling (recommended increase in physical activity of minimum 150 mins/week) that began with the first dose of study medication or placebo and continued throughout the trial. Study 1 enrolled 3,731 patients with obesity (BMI greater than or equal to 30 kg/m 2 ) or with overweight (BMI 27-29.9 kg/m 2 ) and at least one weight-related comorbid condition such as treated or untreated dyslipidemia or hypertension; patients with type 2 diabetes mellitus were excluded. Patients were randomized in a 2:1 ratio to either SAXENDA or placebo. Patients were stratified based on the presence or absence of abnormal blood glucose measurements at randomization. All patients were treated for up to 56 weeks. Those patients with abnormal glucose measurements at randomization (2,254 of the 3731 patients) were treated for a total of 160 weeks. At baseline, mean age was 45 years (range 18 to 78), 79% were female, 85% were White, 10% were Black or African American, and 11% were Hispanic/Latino Ethnicity. Mean baseline body weight was 106.3 kg, and mean BMI was 38.3 kg/m 2 . Study 2 was a 56-week trial that enrolled 635 patients with type 2 diabetes and with either overweight or obesity (as defined above). Patients were to have an HbA 1c of 7% to 10% and be treated with metformin, a sulfonylurea, or a glitazone as single agent or in any combination, or with a reduced-calorie diet and physical activity alone. Patients were randomized in a 2:1 ratio to receive either SAXENDA or placebo. The mean age was 55 years (range 18 to 82), 50% were female, 83% were White, 12% were Black or African American, and 10% were Hispanic/Latino Ethnicity. Mean baseline body weight was 105.9 kg and mean BMI was 37.1 kg/m 2 . Study 3 was a 56-week trial that enrolled 422 patients with obesity (BMI greater than or equal to 30 kg/m 2 ) or with overweight (BMI 27-29.9 kg/m 2 ) and at least one weight-related comorbid condition such as treated or untreated dyslipidemia or hypertension; patients with type 2 diabetes mellitus were excluded. All patients were first treated with a low-calorie diet (total energy intake 1,200-1,400 kcal/day) in a run-in period lasting up to 12 weeks. Patients who lost at least 5% of their screening body weight after 4 to 12 weeks during the run-in were then randomized, with equal allocation, to receive either SAXENDA or placebo for 56 weeks. The mean age was 46 years (range 18 to 73), 81% were female, 84% were White, 13% were Black or African American, and 7% were Hispanic/Latino Ethnicity. Mean baseline body weight was 99.6 kg and mean BMI was 35.6 kg/m 2 . The proportions of patients who discontinued study drug in the 56-week trials were 27% for the SAXENDA-treated group and 35% for the placebo-treated group, and in the 160-week trial the proportions of patients who discontinued were 47% and 55%, respectively. In the 56-week trials, approximately 10% of patients treated with SAXENDA and 4% of patients treated with placebo discontinued treatment due to an adverse reaction [see Adverse Reactions ( 6.1 )] . The majority of patients who discontinued SAXENDA due to adverse reactions did so during the first few months of treatment. In the 160-week trial the proportions of patients who discontinued due to an adverse reaction was 13% and 6% for SAXENDA- and placebo-treated patients, respectively. Effect of SAXENDA on Body Weight in 56-week Trials For Study 1 and Study 2, the primary efficacy parameters were mean percent change in body weight and the percentages of patients achieving greater than or equal to 5% and 10% weight loss from baseline to Week 56. For Study 3, the primary efficacy parameters were mean percent change in body weight from randomization to Week 56, the percentage of patients not gaining more than 0.5% body weight from randomization (i.e., after run-in) to Week 56, and the percentage of patients achieving greater than or equal to 5% weight loss from randomization to Week 56. Because losing at least 5% of fasting body weight through lifestyle intervention during the 4- to 12-week run-in was a condition for their continued participation in the randomized treatment period, the results may not reflect those expected in the general population. Table 4 presents the results for the changes in weight observed in Studies 1, 2, and 3. After 56 weeks, treatment with SAXENDA resulted in a statistically significant reduction in weight compared with placebo. Statistically significantly greater proportions of patients treated with SAXENDA achieved 5% and 10% weight loss than those treated with placebo. In Study 3, statistically significantly more patients randomized to SAXENDA than placebo had not gained more than 0.5% of body weight from randomization to Week 56. Table 4. Changes in Weight at Week 56 for Studies 1, 2, and 3 Study 1 (Obesity or overweight with comorbidity) Study 2 (Type 2 diabetes with obesity or overweight) Study 3 (Obesity or overweight with comorbidity following at least 5% weight loss with diet) SAXENDA N=2487 Placebo N=1244 SAXENDA N=423 Placebo N=212 SAXENDA N=212 Placebo N=210 Weight Baseline mean (SD) (kg) 106.2 (21.2) 106.2 (21.7) 105.7 (21.9) 106.5 (21.3) 100.4 (20.8) 98.7 (21.2) Percent change from baseline (LSMean) -7.4 -3 -5.4 -1.7 -4.9 0.3 Difference from placebo (LSMean) (95% CI) -4.5 * (-5.2; -3.8) -3.7 * (-4.7; -2.7) -5.2 * (-6.8; -3.5) % of Patients losing greater than or equal to 5% body weight 62.3% 34.4% 49% 16.4% 44.2% 21.7% Difference from placebo (LSMean) (95% CI) 27.9 * (23.9; 31.9) 32.6 * (25.1; 40.1) 22.6 * (13.9; 31.3) % of Patients losing greater than 10% body weight 33.9% 15.4% 22.4% 5.5% 25.4% 6.9% Difference from placebo (LSMean) (95% CI) 18.5 * (15.2; 21.7) 16.9 * (11.7; 22.1) 18.5 * (11.7; 25.3) SD = Standard Deviation; CI = Confidence Interval * p < 0.0001 compared to placebo. Type 1 error was controlled across the three endpoints. Includes all randomized subjects who had a baseline body weight measurement. All available body weight data during the 56 week treatment period are included in the analysis. In Studies 1 and 2 missing values for Week 56 were handled using multiple imputations analysis. In Study 3 missing values for Week 56 were handled using weighted regression analysis. The cumulative frequency distributions of change in body weight from baseline to Week 56 are shown in Figure 2 for Studies 1 and 2. One way to interpret this figure is to select a change in body weight of interest on the horizontal axis and note the corresponding proportions of patients (vertical axis) in each treatment group who achieved at least that degree of weight loss. For example, note that the vertical line arising from ‑10% in Study 1 intersects the SAXENDA and placebo curves at approximately 34% and 15%, respectively, which correspond to the values shown in Table 4 . Figure 2. Change in body weight (%) from baseline to Week 56 (Study 1 on left and Study 2 on right) The time courses of weight loss with SAXENDA and placebo from baseline through Week 56 are depicted in Figure 3 and Figure 4 . Figure 3. Change from baseline (%) in body weight (Study 1 on left and Study 2 on right) Figure 4. Change from baseline (%) in body weight during Study 3 Effect of SAXENDA on Body Weight in a 160-week Trial (Study 1, Subset of Patients with Abnormal Blood Glucose at Randomization) The numbers and percentages of patients known to have lost greater than or equal to 5% body weight at Week 56 and/or Week 160 in Study 1 (patients with abnormal glucose at randomization only) are summarized in Table 5 for descriptive purposes. Table 5. Changes in Weight at Week 56 and Week 160 for Study 1 (Subset of Patients with Abnormal Blood Glucose at Randomization) SAXENDA N=1505 Placebo N=749 Baseline mean body weight (SD) (kg) 107.5 (21.6) 107.9 (21.8) Number (%) of patients known to lose greater than or equal to 5% body weight at 56 weeks 817 (56%) 182 (25%) Number (%) of patients known to lose greater than or equal to 5% body weight at 160 weeks 424 (28%) 102 (14%) Number (%) of patients known to lose greater than or equal to 5% body weight at both 56 weeks and 160 weeks 391 (26%) 74 (10%) Number (%) of patients with weight assessment at 160 weeks 747 (50%) 322 (43%) SD = Standard Deviation Includes all randomized subjects who had a baseline body weight measurement. All available body weight data at 56 and 160 weeks are included in the analysis. Effect of SAXENDA on Anthropometry and Cardiometabolic Parameters in 56-week Trials Changes in waist circumference and cardiometabolic parameters with SAXENDA are shown in Table 6 for Study 1 (patients without diabetes mellitus) and Table 7 for Study 2 (patients with type 2 diabetes). Results from Study 3, which also enrolled patients without diabetes mellitus, were similar to Study 1. Table 6. Mean Changes in Anthropometry and Cardiometabolic Parameters in Study 1 (Patients without Diabetes) SAXENDA N=2487 Placebo N=1244 Baseline Change from Baseline (LSMean 1 ) Baseline Change from Baseline (LSMean 1 ) SAXENDA minus Placebo (LSMean) Waist Circumference (cm) 115 -8.2 114.5 -4 -4.2 Systolic Blood Pressure (mmHg) 123 -4.3 123.3 -1.5 -2.8 Diastolic Blood Pressure (mmHg) 78.7 -2.7 78.9 -1.8 -0.9 Heart Rate (bpm) 2 71.4 2.6 71.3 0.1 2.5 HbA 1c (%) 5.6 -0.3 5.6 -0.1 -0.2 Baseline % Change from Baseline (LSMean 1 ) Baseline % Change from Baseline (LSMean 1 ) Relative Difference of SAXENDA to Placebo (LSMean) Total Cholesterol (mg/dL) * 193.8 -3.2 194.4 -0.9 -2.3 LDL Cholesterol (mg/dL) * 111.8 -3.1 112.3 -0.7 -2.4 HDL Cholesterol (mg/dL) * 51.4 2.3 50.9 0.5 1.9 Triglycerides (mg/dL) † 125.7 -13 128.3 -4.1 -7.1 Based on last observation carried forward method while on study drug 1 Least squares mean adjusted for treatment, country, sex, pre-diabetes status at screening, baseline BMI stratum and an interaction between pre-diabetes status at screening and BMI stratum as fixed factors, and the baseline value as covariate. 2 See Warnings and Precautions ( 5.5 ) * Baseline value is the geometric mean † Values are baseline median, median % change, and the Hodges-Lehmann estimate of the median treatment difference. Table 7. Mean Changes in Anthropometry and Cardiometabolic Parameters in Study 2 (Patients with Diabetes Mellitus) SAXENDA N=423 Placebo N=212 Baseline Change from Baseline (LSMean 1 ) Baseline Change From Baseline (LSMean 1 ) SAXENDA minus Placebo (LSMean) Waist Circumference (cm) 118.1 -6 117.3 -2.8 -3.2 Systolic Blood Pressure (mmHg) 128.9 -3 129.2 -0.4 -2.6 Diastolic Blood Pressure (mmHg) 79 -1 79.3 -0.6 -0.4 Heart Rate (bpm) 2 74 2 74 -1.5 3.4 HbA 1c (%) 7.9 -1.3 7.9 -0.4 -0.9 Baseline % Change from Baseline (LSMean 1 ) Baseline % Change From Baseline (LSMean 1 ) Relative Difference of SAXENDA to Placebo (LSMean) Total Cholesterol (mg/dL) * 171 -1.4 169.4 2.4 -3.7 LDL Cholesterol (mg/dL) * 86.4 0.9 85.2 3.3 -2.3 HDL Cholesterol (mg/dL) * 45.2 4.8 45.4 1.9 2.9 Triglycerides (mg/dL) † 156.2 -14.5 155.8 -0.7 -13.5 Based on last observation carried forward method while on study drug 1 Least squares mean adjusted for treatment, country, sex, background treatment, baseline HbA 1c stratum and an interaction between background treatment and HbA 1c stratum as fixed factors, and the baseline value as covariate. 2 See Warnings and Precautions ( 5.5 ) * Baseline value is the geometric mean † Values are baseline median, median % change, and the Hodges-Lehmann estimate of the median treatment difference. figure-2 figure-3 figure-4 14.2 Weight Management Trial in Pediatric Patients Ages 12 and Older with Obesity SAXENDA was evaluated in a 56-week, double-blind, randomized, parallel group, placebo controlled multi-center trial in 251 pubertal pediatric patients aged 12 to 17 years, with BMI corresponding to 30 kg/m 2 or greater for adults by international cut-off points 1 and BMI of 95 th percentile or greater for age and sex (NCT02918279). After a 12-week lifestyle run-in period, patients were randomized 1:1 to SAXENDA once-daily or placebo once-daily. The SAXENDA dose was titrated to 3 mg over a 4- to 8-week period based on tolerability as judged by the investigator. Escalation of the trial product was not allowed if the subject had a self-monitored plasma glucose (SMPG) <56 mg/dL or <70 mg/dL in the presence of symptoms of hypoglycemia during the week prior to or during the dose escalation visits. The proportion of patients who reached the 3 mg dose was 82.4%; for 8.8% of patients 2.4 mg was the maximum tolerated dose. The mean age was 14.5 years: 40.6% of patients were male, 87.6% were White, 0.8% were Asian, 8% were Black or African American; 22.3% were of Hispanic or Latino ethnicity. The mean baseline body weight was 100.8 kg, and mean Body Mass Index (BMI) was 35.6 kg/m 2 . The proportions of patients who discontinued study drug were 19.2% for the SAXENDA-treated group and 20.6% for the placebo-treated group; 10.4% of patients treated with SAXENDA and no patients treated with placebo discontinued treatment due to an adverse reaction [see Adverse Reactions ( 6.1 )] . The primary endpoint was change in BMI SDS. At baseline, mean BMI SDS was 3.14 in the SAXENDA group and 3.20 in the placebo group. At Week 56, treatment with SAXENDA resulted in statistically significant reduction in BMI SDS from baseline compared to placebo. The observed mean change in BMI SDS from baseline to Week 56 was -0.23 in the SAXENDA group and -0.00 in the placebo group. The estimated treatment difference in BMI SDS reduction from baseline between SAXENDA and placebo was -0.22 with a 95% confidence interval of -0.37, -0.08; p=0.0022. The time course of change in BMI SDS with SAXENDA and placebo from baseline through Week 56 are depicted in Figure 5 . Figure 5. Change from Baseline in BMI SDS Changes in weight and BMI with SAXENDA are shown in Table 8 . Changes in waist circumference and cardiometabolic parameters with SAXENDA are shown in Table 9 . Table 8. Changes in Weight and BMI at Week 56 for Study 4 (Pediatric Patients Ages 12 to Less than 18) SAXENDA N=125 Placebo N=126 SAXENDA minus Placebo Body Weight Baseline mean Body Weight (kg) 99.3 102.2 Mean Change from Baseline (%) -2.65 2.37 -5.01 BMI Baseline mean BMI (kg/m 2 ) 35.3 35.8 Mean Change from Baseline (%) -4.29 0.35 -4.64 Proportion of patients with greater than or equal to 5% reduction in baseline BMI at Week 56 (%) 43.3% 18.7% 24.6% Proportion of patients with greater than or equal to 10% reduction in baseline BMI at Week 56 (%) 26.1% 8.1% 18% Full Analysis Set. For body weight and BMI, baseline values are means, changes from baseline at Week 56 are estimated means (least-squares) and treatment contrasts at Week 56 are estimated treatment differences. Missing observations were imputed from the placebo arm based on a jump to reference multiple (x100) imputation approach. Table 9. Mean Changes in Anthropometry and Cardiometabolic Parameters in Study 4 (Pediatric Patients Ages 12 to Less than 18) SAXENDA N=125 Placebo N=126 Baseline Change from Baseline Baseline Change from Baseline SAXENDA minus Placebo Waist Circumference (cm) 105 -4.35 107 -1.42 -2.93 Systolic Blood Pressure (mmHg) 116 -1.21 117 0.84 -2.05 Diastolic Blood Pressure (mmHg) 72 0.77 73 -0.46 1.24 Heart Rate (bpm) * 75 1.87 78 -0.14 2.01 HbA 1c (%) 5.3 -0.1 5.3 -0.03 -0.06 Baseline % Change from Baseline Baseline % Change from Baseline Relative Difference of SAXENDA to Placebo Total Cholesterol (mg/dL) ** 154.2 0.84 152.2 -0.03 0.88 LDL Cholesterol (mg/dL) ** 85.5 1.74 82.5 3.01 -1.27 HDL Cholesterol (mg/dL) ** 42.7 5.14 42.7 3.33 1.81 Triglycerides (mg/dL) ** 109.1 -0.12 112.2 -1.35 1.23 * See Warnings and Precautions ( 5.5 ) Full Analysis Set. Baseline values are means, changes from baseline at Week 56 are estimated means (least-squares) and treatment contrasts at Week 56 are estimated treatment differences. Missing observations were imputed from the placebo arm based on a jump to reference multiple (x100) imputation approach. ** Baseline values are geometric means. figure-5

1 INDICATIONS AND USAGE VICTOZA is indicated: • as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus, • to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease. Limitations of Use: VICTOZA contains liraglutide. Coadministration with other liraglutide-containing products is not recommended. VICTOZA is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated: • as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. (1) • to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease. ( 1 ) Limitations of Use : • Coadministration with other liraglutide-containing products is not recommended.

2 DOSAGE AND ADMINISTRATION • Adult Patients : Initiate at 0.6 mg injected subcutaneously once daily for one week then increase to 1.2 mg daily. If additional glycemic control is required, increase the dose to 1.8 mg daily after one week of treatment with the 1.2 mg daily dose. ( 2.1 ) • Pediatric Patients : Initiate at 0.6 mg injected subcutaneously once daily for at least one week. If additional glycemic control is required increase the dose to 1.2 mg daily and if additional glycemic control is still required, increase the dose to 1.8 mg daily after at least one week of treatment with the 1.2 mg daily dose. ( 2.1 ) • Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no particles. ( 2.3 ) • Inject VICTOZA subcutaneously once-daily at any time of day, independently of meals, in the abdomen, thigh or upper arm. ( 2.3 ) • When using VICTOZA with insulin, administer as separate injections. Never mix. ( 2.3 ) 2.1 Recommended Dosage Adult Patients • The recommended starting dosage of VICTOZA is 0.6 mg injected subcutaneously once daily for one week. The 0.6 mg once daily dosage is intended to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions ( 5.6 ), Adverse Reactions ( 6.1 )] during initial titration and is not effective for glycemic control in adults. • After one week at the 0.6 mg once daily dosage, increase the dosage to 1.2 mg injected subcutaneously once daily. • If additional glycemic control is required, increase the dosage to the maximum recommended dosage of 1.8 mg injected subcutaneously once daily after at least one week of treatment with the 1.2 mg once daily dosage. Pediatric Patients Aged 10 Years and Older • The recommended starting dosage of VICTOZA is 0.6 mg injected subcutaneously once daily. • If additional glycemic control is required, increase the dosage in 0.6 mg increments after at least one week on the current dosage, to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions ( 5.6 ), Adverse Reactions ( 6.1 )] . • The maximum recommended dosage is 1.8 mg injected subcutaneously once daily. 2.2 Recommendations Regarding Missed Dose • Instruct patients who miss a dose of VICTOZA to resume the once daily dosage regimen as prescribed with the next scheduled dose. Do not administer an extra dose or increase the dose to make up for the missed dose. • If more than 3 days have elapsed since the last VICTOZA dose, reinitiate VICTOZA at 0.6 mg once daily to reduce the risk of gastrointestinal adverse reactions associated with reinitiation of treatment. Upon reinitiation, VICTOZA should be titrated at the discretion of the healthcare provider. 2.3 Important Administration Instructions • Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no particles. • Inject VICTOZA subcutaneously once daily at any time of day, independently of meals. • Inject VICTOZA subcutaneously in the abdomen, thigh or upper arm. No dosage adjustment is needed if changing the injection site and/or timing. • Rotate injection sites within the same region in order to reduce the risk of cutaneous amyloidosis [see Adverse Reactions ( 6.2 )]. • When using VICTOZA with insulin, administer as separate injections. Never mix. It is acceptable to inject VICTOZA and insulin in the same body region but the injections should not be adjacent to each other.

5 WARNINGS AND PRECAUTIONS • Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including VICTOZA. Discontinue if pancreatitis is suspected. ( 5.2 ) • Never Share a VICTOZA Pen Between Patients , even if the needle is changed. (5.3) • Hypoglycemia : Adult patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with VICTOZA regardless of insulin and/or metformin use. Reduction in the dose of insulin secretagogues or insulin may be necessary. (5.4) • Acute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. (5.5) • Severe Gastrointestinal Adverse Reactions: Use has been associated with gastrointestinal adverse reactions, sometimes severe. VICTOZA is not recommended in patients with severe gastroparesis. ( 5.6 ) • Hypersensitivity Reactions : Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue VICTOZA and promptly seek medical advice. (5.7) • Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. (5.8) • Pulmonary Aspiration During General Anesthesia or Deep Sedation : Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.9 ) 5.1 Risk of Thyroid C-cell Tumors Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical Toxicology ( 13.1 )] . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether VICTOZA will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with VICTOZA have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and VICTOZA use in humans. VICTOZA is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of VICTOZA and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with VICTOZA. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including liraglutide [see Adverse Reactions ( 6 )] . After initiation of VICTOZA, observe patients carefully for signs and symptoms of acute pancreatitis which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue VICTOZA and initiate appropriate management. 5.3 Never Share a VICTOZA Pen Between Patients VICTOZA pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens. 5.4 Hypoglycemia Adult patients receiving VICTOZA in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with VICTOZA regardless of insulin and/or metformin use. [see Adverse Reactions (6.1) , Drug Interactions (7.2) ]. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications and pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.5 Acute Kidney Injury Due to Volume Depletion There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with VICTOZA [see Adverse Reactions (6.2)] . The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea [see Adverse Reactions (6.1)] . Monitor renal function in patients reporting adverse reactions to VICTOZA that could lead to volume depletion, especially during dosage initiation and escalation of VICTOZA. [see Use in Specific Populations (8.6)] . 5.6 Severe Gastrointestinal Adverse Reactions Use of GLP-1 receptor agonists, including liraglutide, has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions ( 6 )] . In VICTOZA clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving VICTOZA (1.2 mg 4.4%, 1.8 mg 4.2%) than placebo (1.1%). Severe gastrointestinal adverse reactions have also been reported postmarketing with GLP-1 receptor agonists. VICTOZA is not recommended in patients with severe gastroparesis. 5.7 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with VICTOZA [see Adverse Reactions ( 6.2 )] . If a hypersensitivity reaction occurs, discontinue VICTOZA; treat promptly per standard of care, and monitor until signs and symptoms resolve. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-receptor agonist because it is unknown whether such patients will be predisposed to these reactions with VICTOZA. VICTOZA is contraindicated in patients who have had a serious hypersensitivity reaction to liraglutide or any of the excipients in VICTOZA [see Contraindications ( 4 )]. 5.8 Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In the LEADER trial [see Clinical Studies ( 14.3 )] , 3.1% of VICTOZA-treated patients versus 1.9% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis [see Adverse Reactions ( 6.1 )] . If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated. 5.9 Pulmonary Aspiration During General Anesthesia or Deep Sedation VICTOZA delays gastric emptying [see Clinical Pharmacology ( 12.2 )] . There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking VICTOZA, including whether modifying preoperative fasting recommendations or temporarily discontinuing VICTOZA could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking VICTOZA.

7 DRUG INTERACTIONS Effects of delayed gastric emptying on oral medications: VICTOZA delays gastric emptying and may impact absorption of concomitantly administered oral medications. ( 7 ) 7.1 Effects of Delayed Gastric Emptying on Oral Medications VICTOZA causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, VICTOZA did not affect the absorption of the tested orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with VICTOZA. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin VICTOZA stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving VICTOZA in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating VICTOZA, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.1 )].

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] • Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] • Hypoglycemia [see Warnings and Precautions ( 5.4 )] • Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.5 )] • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.6 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )] • Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.9 )] • Most common adverse reactions (incidence ≥5%) in clinical trials are nausea, diarrhea, vomiting, decreased appetite, dyspepsia, constipation. (6.1) • Immunogenicity-related events, including urticaria, were more common among VICTOZA-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. (12.6) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-877-484-2869 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common Adverse Reactions The safety of VICTOZA in patients with type 2 diabetes mellitus was evaluated in 5 glycemic control, placebo-controlled trials in adults and one trial of 52 weeks duration in pediatric patients 10 years of age and older [see Clinical Studies ( 14.1 )] . The data in Table 1 reflect exposure of 1,673 adult patients to VICTOZA and a mean duration of exposure to VICTOZA of 37.3 weeks. The mean age of adult patients was 58 years, 4% were 75 years or older and 54% were male. The population was 79% White, 6% Black or African American, 13% Asian; 4% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 9 years and a mean HbA 1c of 8.4%. Baseline estimated renal function was normal or mildly impaired in 88% and moderately impaired in 12% of the pooled population. Table 1 shows common adverse reactions in adults, excluding hypoglycemia, associated with the use of VICTOZA for the treatment of type 2 diabetes mellitus. These adverse reactions occurred more commonly on VICTOZA than on placebo and occurred in at least 5% of patients treated with VICTOZA. Overall, the type, and severity of adverse reactions in pediatric patients 10 years of age and older and above were comparable to that observed in the adult population. Table 1. Adverse reactions reported in ≥5% of Adult Patients Treated with VICTOZA for Type 2 Diabetes Mellitus Placebo N=661 Liraglutide 1.2 mg N= 645 Liraglutide 1.8 mg N= 1024 Adverse Reaction (%) (%) (%) Nausea 5 18 20 Diarrhea 4 10 12 Headache 7 11 10 Nasopharyngitis 8 9 10 Vomiting 2 6 9 Decreased appetite 1 10 9 Dyspepsia 1 4 7 Upper Respiratory Tract Infection 6 7 6 Constipation 1 5 5 Back Pain 3 4 5 Cumulative proportions were calculated combining studies using Cochran-Mantel-Haenszel weights. In an analysis of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1 . Other Adverse Reactions Gastrointestinal Adverse Reactions In the pool of 5 glycemic control, placebo-controlled adult clinical trials, withdrawals due to gastrointestinal adverse reactions, occurred in 4.3% of VICTOZA-treated patients and 0.5% of placebo-treated patients. Severe gastrointestinal adverse reactions were reported more frequently among patients receiving VICTOZA (1.2 mg 4.4%, 1.8 mg 4.2%) than placebo (1.1%). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2 to 3 months of the trials. Injection site reactions Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of VICTOZA-treated adult patients in the five double-blind, glycemic control trials of at least 26 weeks duration. Less than 0.2% of VICTOZA-treated patients discontinued due to injection site reactions. Hypoglycemia In 5 adult glycemic control, placebo-controlled clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 8 VICTOZA-treated patients (7.5 events per 1,000 patient-years). Of these 8 VICTOZA-treated patients, 7 patients were concomitantly using a sulfonylurea. Table 2. Adult Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in 26-Week Combination Therapy Placebo-controlled Trials Placebo Comparator VICTOZA Treatment Add-on to Metformin Placebo + Metformin (N=121) VICTOZA + Metformin (N=724) Patient not able to self-treat 0 0.1 (0.001) Patient able to self-treat 2.5 (0.06) 3.6 (0.05) Add-on to Glimepiride Placebo + Glimepiride (N=114) VICTOZA + Glimepiride (N=695) Patient not able to self-treat 0 0.1 (0.003) Patient able to self-treat 2.6 (0.17) 7.5 (0.38) Not classified 0 0.9 (0.05) Add-on to Metformin + Rosiglitazone Placebo + Metformin + Rosiglitazone (N=175) VICTOZA + Metformin + Rosiglitazone (N=355) Patient not able to self-treat 0 0 Patient able to self-treat 4.6 (0.15) 7.9 (0.49) Not classified 1.1 (0.03) 0.6 (0.01) Add-on to Metformin + Glimepiride Placebo + Metformin + Glimepiride (N=114) VICTOZA + Metformin + Glimepiride (N=230) Patient not able to self-treat 0 2.2 (0.06) Patient able to self-treat 16.7 (0.95) 27.4 (1.16) Not classified 0 0 “Patient not able to self-treat” is defined as an event requiring the assistance of another person for treatment. In a 26-week placebo-controlled clinical trial in pediatric patients 10 years of age and older with a 26-week open-label extension, 21.2% of VICTOZA-treated patients (mean age 14.6 years) with type 2 diabetes mellitus, had hypoglycemia with a blood glucose <54 mg/dL with or without symptoms (335 events per 1,000 patient years). No severe hypoglycemic episodes occurred in the VICTOZA treatment group (severe hypoglycemia was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions). Papillary thyroid carcinoma In adult glycemic control trials of VICTOZA, there were 7 reported cases of papillary thyroid carcinoma in patients treated with VICTOZA and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1,000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Pancreatitis In glycemic control trials of VICTOZA, there have been 13 cases of pancreatitis among VICTOZA-treated patients and 1 case in a comparator (glimepiride) treated patient (2.7 vs. 0.5 cases per 1,000 patient-years). Nine of the 13 cases with VICTOZA were reported as acute pancreatitis and four were reported as chronic pancreatitis. In one case in a VICTOZA-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. Cholelithiasis and cholecystitis In adult glycemic control trials of VICTOZA, the incidence of cholelithiasis was 0.3% in both VICTOZA-treated and placebo-treated patients. The incidence of cholecystitis was 0.2% in both VICTOZA-treated and placebo-treated patients. In the LEADER trial [see Clinical Studies ( 14.3 )] , the incidence of cholelithiasis was 1.5% (3.9 cases per 1,000 patient years of observation) in adult VICTOZA-treated and 1.1% (2.8 cases per 1,000 patient years of observation) in placebo-treated patients, both on a background of standard of care. The incidence of acute cholecystitis was 1.1% (2.9 cases per 1,000 patient years of observation) in adult VICTOZA-treated and 0.7% (1.9 cases per 1,000 patient years of observation) in placebo-treated patients. The majority of events required hospitalization or cholecystectomy. Laboratory Tests Bilirubin In the five adult glycemic control trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4% of VICTOZA-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. Calcitonin Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. At the end of the adult glycemic control trials, adjusted mean serum calcitonin concentrations were higher in VICTOZA-treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. Between group differences in adjusted mean serum calcitonin values were approximately 0.1 ng/L or less. Among adult patients with pretreatment calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of VICTOZA-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients. The clinical significance of these findings is unknown. Lipase and Amylase In one adult glycemic control trial in renal impairment patients, a mean increase of 33% for lipase and 15% for amylase from baseline was observed for VICTOZA-treated patients while placebo-treated patients had a mean decrease in lipase of 3% and a mean increase in amylase of 1%. In the LEADER trial, serum lipase and amylase were routinely measured. Among adult VICTOZA-treated patients, 7.9% had a lipase value at any time during treatment of greater than or equal to 3 times the upper limit of normal compared with 4.5% of placebo-treated patients, and 1% of VICTOZA-treated patients had an amylase value at any time during treatment of greater than or equal to 3 times the upper limit of normal versus 0.7% of placebo-treated patients. The clinical significance of elevations in lipase or amylase with VICTOZA is unknown in the absence of other signs and symptoms of pancreatitis [see Warnings and Precautions ( 5.2 )]. Vital signs VICTOZA did not have adverse effects on blood pressure. Mean increases from baseline in heart rate of 2 to 3 beats per minute have been observed in adult patients treated with VICTOZA compared to placebo. 6.2 Postmarketing Experience The following additional adverse reactions have been reported during post-approval use of VICTOZA. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Gastrointestinal: Acute pancreatitis; hemorrhagic and necrotizing pancreatitis sometimes resulting in death; ileus, intestinal obstruction, severe constipation including fecal impaction, nausea, vomiting and diarrhea leading to dehydration • Hepatobiliary: Elevations of liver enzymes, hyperbilirubinemia, cholestasis, cholecystitis, cholelithiasis requiring cholecystectomy, hepatitis • Hypersensitivity: Angioedema, anaphylactic reactions, pruritus • Neoplasms: Medullary thyroid carcinoma • Neurologic: Dysgeusia, dizziness, dysesthesia • Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation. • Renal: Acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis; and increased serum creatinine • Skin and subcutaneous tissue: Cutaneous amyloidosis, alopecia

14 CLINICAL STUDIES 14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus In glycemic control trials in adults, VICTOZA has been studied as monotherapy and in combination with one or two oral anti-diabetic medications or basal insulin. VICTOZA was also studied in a cardiovascular outcomes trial (LEADER trial). In each of the placebo controlled trials, treatment with VICTOZA produced clinically and statistically significant improvements in hemoglobin A 1c and fasting plasma glucose (FPG) compared to placebo. All VICTOZA-treated patients started at 0.6 mg/day. The dose was increased in weekly intervals by 0.6 mg to reach 1.2 mg or 1.8 mg for patients randomized to these higher doses. VICTOZA 0.6 mg is not effective for glycemic control and is intended only as a starting dose to reduce gastrointestinal intolerance [see Dosage and Administration (2 )] . Monotherapy In this 52-week trial, 746 adult patients with type 2 diabetes mellitus were randomized to VICTOZA 1.2 mg, VICTOZA 1.8 mg, or glimepiride 8 mg. Patients who were randomized to glimepiride were initially treated with 2 mg daily for two weeks, increasing to 4 mg daily for another two weeks, and finally increasing to 8 mg daily. Treatment with VICTOZA 1.8 mg and 1.2 mg resulted in a statistically significant reduction in HbA 1c compared to glimepiride ( Table 3 ). The percentage of patients who discontinued due to ineffective therapy was 3.6% in the VICTOZA 1.8 mg treatment group, 6% in the VICTOZA 1.2 mg treatment group, and 10.1% in the glimepiride-treatment group. The mean age of participants was 53 years, and the mean duration of diabetes was 5 years. Participants were 49.7% male, 77.5% White, 12.6% Black or African American and 35% of Hispanic or Latino ethnicity. The mean BMI was 33.1 kg/m 2 . Table 3. Results of a 52-week Monotherapy Trial in Adults with Type 2 Diabetes Mellitus a VICTOZA 1.8 mg VICTOZA 1.2 mg Glimepiride 8 mg Intent-to-Treat Population (N) 246 251 248 HbA 1c (%) (Mean) Baseline 8.2 8.2 8.2 Change from baseline (adjusted mean) b -1.1 -0.8 -0.5 Difference from glimepiride arm (adjusted mean) b -0.6** -0.3* 95% Confidence Interval (-0.8, -0.4) (-0.5, -0.1) Percentage of patients achieving HbA 1c <7% 51 43 28 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 172 168 172 Change from baseline (adjusted mean) b -26 -15 -5 Difference from glimepiride arm (adjusted mean) b -20** -10* 95% Confidence Interval (-29, -12) (-19, -1) Body Weight (kg) (Mean) Baseline 92.6 92.1 93.3 Change from baseline (adjusted mean) b -2.5 -2.1 +1.1 Difference from glimepiride arm (adjusted mean) b -3.6** -3.2** 95% Confidence Interval (-4.3, -2.9) (-3.9, -2.5) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value * p-value <0.05 ** p-value <0.0001 Figure 3. Mean HbA 1c for Adult Patients with Type 2 Diabetes Mellitus who Completed the 52-week Trial and for the Last Observation Carried Forward (LOCF, intent-to-treat) data at Week 52 (Monotherapy) Combination Therapy Add-on to Metformin In this 26-week trial, 1,091 adult patients with type 2 diabetes mellitus were randomized to VICTOZA 0.6 mg, VICTOZA 1.2 mg, VICTOZA 1.8 mg, placebo, or glimepiride 4 mg (one-half of the maximal approved dose in the United States), all as add-on to metformin. Randomization occurred after a 6-week run-in period consisting of a 3-week initial forced metformin titration period followed by a maintenance period of another 3 weeks. During the titration period, doses of metformin were increased up to 2,000 mg/day. Treatment with VICTOZA 1.2 mg and 1.8 mg as add-on to metformin resulted in a significant mean HbA 1c reduction relative to placebo add-on to metformin and resulted in a similar mean HbA 1c reduction relative to glimepiride 4 mg add-on to metformin ( Table 4 ). The percentage of patients who discontinued due to ineffective therapy was 5.4% in the VICTOZA 1.8 mg + metformin treatment group, 3.3% in the VICTOZA 1.2 mg + metformin treatment group, 23.8% in the placebo + metformin treatment group, and 3.7% in the glimepiride + metformin treated group. The mean age of participants was 57 years, and the mean duration of diabetes was 7 years. Participants were 58.2% male, 87.1% White and 2.4% Black or African American. The mean BMI was 31.0 kg/m 2 . Table 4. Results of a 26-week Trial of VICTOZA as Add-on to Metformin in Adults with Type 2 Diabetes Mellitus a VICTOZA 1.8 mg + Metformin VICTOZA 1.2 mg + Metformin Placebo + Metformin Glimepiride 4 mg † + Metformin Intent-to-Treat Population (N) 242 240 121 242 HbA 1c (%) (Mean) Baseline 8.4 8.3 8.4 8.4 Change from baseline (adjusted mean) b -1 -1 +0.1 -1 Difference from placebo + metformin arm (adjusted mean) b -1.1** -1.1** 95% Confidence Interval (-1.3, -0.9) (-1.3, -0.9) Difference from glimepiride + metformin arm (adjusted mean) b 0 0 95% Confidence Interval (-0.2, 0.2) (-0.2, 0.2) Percentage of patients achieving HbA 1c <7% 42 35 11 36 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 181 179 182 180 Change from baseline (adjusted mean) b -30 -30 +7 -24 Difference from placebo + metformin arm (adjusted mean) b -38** -37** 95% Confidence Interval (-48, -27) (-47, -26) Difference from glimepiride + metformin arm (adjusted mean) b -7 -6 95% Confidence Interval (-16, 2) (-15, 3) Body Weight (kg) (Mean) Baseline 88 88.5 91 89 Change from baseline (adjusted mean) b -2.8 -2.6 -1.5 +1 Difference from placebo + metformin arm (adjusted mean) b 95% Confidence Interval -1.3* (-2.2, -0.4) -1.1* (-2, -0.2) Difference from glimepiride + metformin arm (adjusted mean) b -3.8** -3.5** 95% Confidence Interval (-4.5, -3.0) (-4.3, -2.8) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value † For glimepiride, one-half of the maximal approved United States dose. * p-value <0.05 ** p-value <0.0001 VICTOZA Compared to Sitagliptin, Both as Add-on to Metformin In this 26–week, open-label trial, 665 adult patients with type 2 diabetes mellitus on a background of metformin ≥1,500 mg per day were randomized to VICTOZA 1.2 mg once daily, VICTOZA 1.8 mg once daily or sitagliptin 100 mg once daily, all dosed according to approved labeling. Patients were to continue their current treatment on metformin at a stable, pre-trial dose level and dosing frequency. The mean age of participants was 56 years, and the mean duration of diabetes was 6 years. Participants were 52.9% male, 86.6% White, 7.2% Black or African American and 16.2% of Hispanic or Latino ethnicity. The mean BMI was 32.8 kg/m 2 . The primary endpoint was the change in HbA 1c from baseline to Week 26. Treatment with VICTOZA 1.2 mg and VICTOZA 1.8 mg resulted in statistically significant reductions in HbA 1c relative to sitagliptin 100 mg ( Table 5 ). The percentage of patients who discontinued due to ineffective therapy was 3.1% in the VICTOZA 1.2 mg group, 0.5% in the VICTOZA 1.8 mg treatment group, and 4.1% in the sitagliptin 100 mg treatment group. From a mean baseline body weight of 94 kg, there was a mean reduction of 2.7 kg for VICTOZA 1.2 mg, 3.3 kg for VICTOZA 1.8 mg, and 0.8 kg for sitagliptin 100 mg. Table 5. Results of a 26-week Open-label Trial of VICTOZA Compared to Sitagliptin (both in combination with metformin) in Adults with Type 2 Diabetes Mellitus a VICTOZA 1.8 mg + Metformin VICTOZA 1.2 mg + Metformin Sitagliptin 100 mg + Metformin Intent-to-Treat Population (N) 218 221 219 HbA 1c (%) (Mean) Baseline 8.4 8.4 8.5 Change from baseline (adjusted mean) -1.5 -1.2 -0.9 Difference from sitagliptin arm (adjusted mean) b 95% Confidence Interval -0.6** (-0.8, -0.4) -0.3** (-0.5, -0.2) Percentage of patients achieving HbA 1c <7% 56 44 22 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 179 182 180 Change from baseline (adjusted mean) -39 -34 -15 Difference from sitagliptin arm (adjusted mean) b 95% Confidence Interval -24** (-31, -16) -19** (-26, -12) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value ** p-value <0.0001 Figure 4. Mean HbA 1c for Adult Patients with Type 2 Diabetes Mellitus who Completed the 26-week Trial and for the Last Observation Carried Forward (LOCF, intent-to-treat) data at Week 26 Combination Therapy with Metformin and Insulin This 26-week open-label trial enrolled 988 adult patients with type 2 diabetes mellitus with inadequate glycemic control (HbA 1c 7% to 10%) on metformin (≥1,500 mg/day) alone or inadequate glycemic control (HbA 1c 7% to 8.5%) on metformin (≥1,500 mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued the sulfonylurea then all patients entered a 12-week run-in period during which they received add-on therapy with VICTOZA titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%) achieved HbA 1c <7% with VICTOZA 1.8 mg and metformin and continued treatment in a non-randomized, observational arm. Another 167 patients (17%) withdrew from the trial during the run-in period with approximately one-half of these patients doing so because of gastrointestinal adverse reactions [see Adverse Reactions ( 6.1 )] . The remaining 323 patients with HbA 1c ≥7% (33% of those who entered the run-in period) were randomized to 26 weeks of once-daily insulin detemir administered in the evening as add-on therapy (N=162) or to continued, unchanged treatment with VICTOZA 1.8 mg and metformin (N=161). The starting dose of insulin detemir was 10 units/day and the mean dose at the end of the 26-week randomized period was 39 units/day. During the 26 week randomized treatment period, the percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized to continued treatment with VICTOZA 1.8 mg and metformin and 1.2% in the group randomized to add-on therapy with insulin detemir. The mean age of participants was 57 years, and the mean duration of diabetes was 8 years. Participants were 55.7% male, 91.3% White, 5.6% Black or African American and 12.5% of Hispanic or Latino ethnicity. The mean BMI was 34 kg/m 2 . Treatment with insulin detemir as add-on to VICTOZA 1.8 mg + metformin resulted in statistically significant reductions in HbA 1c and FPG compared to continued, unchanged treatment with VICTOZA 1.8 mg + metformin alone ( Table 6 ). From a mean baseline body weight of 96 kg after randomization, there was a mean reduction of 0.3 kg in the patients who received insulin detemir add-on therapy compared to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with VICTOZA 1.8 mg + metformin alone. Table 6. Results of a 26-week Open-label Trial of Insulin detemir as add on to VICTOZA + Metformin Compared to Continued Treatment with VICTOZA + Metformin alone in Adult Patients with Type 2 Diabetes Mellitus not Achieving HbA 1c <7% after 12 weeks of Metformin and VICTOZA a Insulin detemir + VICTOZA + Metformin VICTOZA + Metformin Intent-to-Treat Population (N) 162 157 HbA 1c (%) (Mean) Baseline (week 0) 7.6 7.6 Change from baseline (adjusted mean) -0.5 0 Difference from VICTOZA + metformin arm (LS mean) b -0.5** 95% Confidence Interval (-0.7, -0.4) Percentage of patients achieving HbA 1c <7% 43 17 Fasting Plasma Glucose (mg/dL) (Mean) Baseline (week 0) 166 159 Change from baseline (adjusted mean) -39 -7 Difference from VICTOZA + metformin arm (LS mean) b -31** 95% Confidence Interval (-39, -23) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value ** p-value <0.0001 Add-on to Sulfonylurea In this 26-week trial, 1,041 adult patients with type 2 diabetes mellitus were randomized to VICTOZA 0.6 mg, VICTOZA 1.2 mg, VICTOZA 1.8 mg, placebo, or rosiglitazone 4 mg (one-half of the maximal approved dose in the United States), all as add-on to glimepiride. Randomization occurred after a 4-week run-in period consisting of an initial, 2-week, forced-glimepiride titration period followed by a maintenance period of another 2 weeks. During the titration period, doses of glimepiride were increased to 4 mg/day. The doses of glimepiride could be reduced (at the discretion of the investigator) from 4 mg/day to 3 mg/day or 2 mg/day (minimum) after randomization, in the event of unacceptable hypoglycemia or other adverse events. The mean age of participants was 56 years, and the mean duration of diabetes was 8 years. Participants were 49.4% male, 64.4% White and 2.8% Black or African American. The mean BMI was 29.9 kg/m 2 . Treatment with VICTOZA 1.2 mg and 1.8 mg as add-on to glimepiride resulted in a statistically significant reduction in mean HbA 1c compared to placebo add-on to glimepiride ( Table 7 ). The percentage of patients who discontinued due to ineffective therapy was 3% in the VICTOZA 1.8 mg + glimepiride treatment group, 3.5% in the VICTOZA 1.2 mg + glimepiride treatment group, 17.5% in the placebo + glimepiride treatment group, and 6.9% in the rosiglitazone + glimepiride treatment group. Table 7. Results of a 26-week Trial of VICTOZA as add-on to Sulfonylurea in Adult Patients with Type 2 Diabetes Mellitus a VICTOZA 1.8 mg + Glimepiride VICTOZA 1.2 mg + Glimepiride Placebo + Glimepiride Rosiglitazone 4 mg † + Glimepiride Intent-to-Treat Population (N) 234 228 114 231 HbA 1c (%) (Mean) Baseline 8.5 8.5 8.4 8.4 Change from baseline (adjusted mean) b -1.1 -1.1 +0.2 -0.4 Difference from placebo + glimepiride arm (adjusted mean) b -1.4** -1.3** 95% Confidence Interval (-1.6, -1.1) (-1.5, -1.1) Percentage of patients achieving HbA 1c <7% 42 35 7 22 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 174 177 171 179 Change from baseline (adjusted mean) b -29 -28 +18 -16 Difference from placebo + glimepiride arm (adjusted mean) b -47** -46** 95% Confidence Interval (-58, -35) (-58, -35) Body Weight (kg) (Mean) Baseline 83 80 81.9 80.6 Change from baseline (adjusted mean) b -0.2 +0.3 -0.1 +2.1 Difference from placebo + glimepiride arm (adjusted mean) b -0.1 0.4 95% Confidence Interval (-0.9, 0.6) (-0.4, 1.2) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value † For rosiglitazone, one-half of the maximal approved United States dose. ** p-value <0.0001 Add-on to Metformin and Sulfonylurea In this 26-week trial, 581 adult patients with type 2 diabetes mellitus were randomized to VICTOZA 1.8 mg, placebo, or insulin glargine, all as add-on to metformin and glimepiride. Randomization took place after a 6-week run-in period consisting of a 3-week forced metformin and glimepiride titration period followed by a maintenance period of another 3 weeks. During the titration period, doses of metformin and glimepiride were to be increased up to 2,000 mg/day and 4 mg/day, respectively. After randomization, patients randomized to VICTOZA 1.8 mg underwent a 2 week period of titration with VICTOZA. During the trial, the VICTOZA and metformin doses were fixed, although glimepiride and insulin glargine doses could be adjusted. Patients titrated glargine twice-weekly during the first 8 weeks of treatment based on self-measured fasting plasma glucose on the day of titration. After Week 8, the frequency of insulin glargine titration was left to the discretion of the investigator, but, at a minimum, the glargine dose was to be revised, if necessary, at Weeks 12 and 18. Only 20% of glargine-treated patients achieved the pre-specified target fasting plasma glucose of ≤100 mg/dL. Therefore, optimal titration of the insulin glargine dose was not achieved in most patients. The mean age of participants was 58 years, and the mean duration of diabetes was 9 years. Participants were 56.5% male, 75.0% White and 3.6% Black or African American. The mean BMI was 30.5 kg/m 2 . Treatment with VICTOZA as add-on to glimepiride and metformin resulted in a statistically significant mean reduction in HbA 1c compared to placebo add-on to glimepiride and metformin ( Table 8 ). The percentage of patients who discontinued due to ineffective therapy was 0.9% in the VICTOZA 1.8 mg + metformin + glimepiride treatment group, 0.4% in the insulin glargine + metformin + glimepiride treatment group, and 11.3% in the placebo + metformin + glimepiride treatment group. Table 8. Results of a 26-week Trial of VICTOZA as Add-on to Metformin and Sulfonylurea in Adult Patients with Type 2 Diabetes Mellitus a VICTOZA 1.8 mg + Metformin + Glimepiride Placebo + Metformin + Glimepiride Insulin glargine † + Metformin + Glimepiride Intent-to-Treat Population (N) 230 114 232 HbA 1c (%) (Mean) Baseline 8.3 8.3 8.1 Change from baseline (adjusted mean) b -1.3 -0.2 -1.1 Difference from placebo + metformin + glimepiride arm (adjusted mean) b -1.1** 95% Confidence Interval (-1.3, -0.9) Percentage of patients achieving HbA 1c <7% 53 15 46 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 165 170 164 Change from baseline (adjusted mean) b -28 +10 -32 Difference from placebo + metformin + glimepiride arm (adjusted mean) b -38** 95% Confidence Interval (-46, -30) Body Weight (kg) (Mean) Baseline 85.8 85.4 85.2 Change from baseline (adjusted mean) b -1.8 -0.4 1.6 Difference from placebo + metformin + glimepiride arm (adjusted mean) b -1.4* 95% Confidence Interval (-2.1, -0.7) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value † For insulin glargine, optimal titration regimen was not achieved for 80% of patients. * p-value <0.05 ** p-value <0.0001 VICTOZA Compared to Exenatide, Both as Add-on to Metformin and/or Sulfonylurea Therapy In this 26-week, open-label trial, 464 adult patients with type 2 diabetes mellitus on a background of metformin monotherapy, sulfonylurea monotherapy or a combination of metformin and sulfonylurea were randomized to once daily VICTOZA 1.8 mg or exenatide 10 mcg twice daily. Maximally tolerated doses of background therapy were to remain unchanged for the duration of the trial. Patients randomized to exenatide started on a dose of 5 mcg twice-daily for 4 weeks and then were escalated to 10 mcg twice-daily. The mean age of participants was 57 years, and the mean duration of diabetes was 8 years. Participants were 51.9% male, 91.8% White, 5.4% Black or African American and 12.3% of Hispanic or Latino ethnicity. The mean BMI was 32.9 kg/m 2 . Treatment with VICTOZA 1.8 mg resulted in statistically significant reductions in HbA 1c and FPG relative to exenatide ( Table 9 ). The percentage of patients who discontinued for ineffective therapy was 0.4% in the VICTOZA treatment group and 0% in the exenatide treatment group. Both treatment groups had a mean decrease from baseline in body weight of approximately 3 kg. Table 9. Results of a 26-week Open-label trial of VICTOZA versus Exenatide (both in combination with metformin and/or sulfonylurea) in Adult Patients with Type 2 Diabetes Mellitus a VICTOZA 1.8 mg once daily + metformin and/or sulfonylurea Exenatide 10 mcg twice daily + metformin and/or sulfonylurea Intent-to-Treat Population (N) 233 231 HbA 1c (%) (Mean) Baseline 8.2 8.1 Change from baseline (adjusted mean) b -1.1 -0.8 Difference from exenatide arm (adjusted mean) b 95% Confidence Interval -0.3** (-0.5, -0.2) Percentage of patients achieving HbA 1c <7% 54 43 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 176 171 Change from baseline (adjusted mean) b -29 -11 Difference from exenatide arm (adjusted mean) b 95% Confidence Interval -18** (-25, -12) a Intent-to-treat population using last observation carried forward b Least squares mean adjusted for baseline value ** p-value <0.0001 Add-on to Metformin and Thiazolidinedione In this 26-week trial, 533 adult patients with type 2 diabetes mellitus were randomized to VICTOZA 1.2 mg, VICTOZA 1.8 mg or placebo, all as add-on to rosiglitazone (8 mg) plus metformin (2,000 mg). Patients underwent a 9 week run-in period (3-week forced dose escalation followed by a 6-week dose maintenance phase) with rosiglitazone (starting at 4 mg and increasing to 8 mg/day within 2 weeks) and metformin (starting at 500 mg with increasing weekly increments of 500 mg to a final dose of 2,000 mg/day). Only patients who tolerated the final dose of rosiglitazone (8 mg/day) and metformin (2000 mg/day) and completed the 6-week dose maintenance phase were eligible for randomization into the trial. The mean age of participants was 55 years, and the mean duration of diabetes was 9 years. Participants were 61.6% male, 84.2% White, 10.2% Black or African American and 16.4% of Hispanic or Latino ethnicity. The mean BMI was 33.9 kg/m 2 . Treatment with VICTOZA as add-on to metformin and rosiglitazone produced a statistically significant reduction in mean HbA 1c compared to placebo add-on to metformin and rosiglitazone ( Table 10 ). The percentage of patients who discontinued due to ineffective therapy was 1.7% in the VICTOZA 1.8 mg + metformin + rosiglitazone treatment group, 1.7% in the VICTOZA 1.2 mg + metformin + rosiglitazone treatment group, and 16.4% in the placebo + metformin + rosiglitazone treatment group. Table 10. Results of a 26-week Trial of VICTOZA as Add-on to Metformin and Thiazolidinedione in Adult Patients with Type 2 Diabetes Mellitus a VICTOZA 1.8 mg + Metformin + Rosiglitazone VICTOZA 1.2 mg + Metformin + Rosiglitazone Placebo + Metformin + Rosiglitazone Intent-to-Treat Population (N) 178 177 175 HbA 1c (%) (Mean) Baseline 8.6 8.5 8.4 Change from baseline (adjusted mean) b -1.5 -1.5 -0.5 Difference from placebo + metformin + rosiglitazone arm (adjusted mean) b -0.9** -0.9** 95% Confidence Interval (-1.1, -0.8) (-1.1, -0.8) Percentage of patients achieving HbA 1c <7% 54 57 28 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 185 181 179 Change from baseline (adjusted mean) b -44 -40 -8 Difference from placebo + metformin + rosiglitazone arm (adjusted mean) b -36** -32** 95% Confidence Interval (-44, -27) (-41, -23) Body Weight (kg) (Mean) Baseline 94.9 95.3 98.5 Change from baseline (adjusted mean) b -2 -1 +0.6 Difference from placebo + metformin + rosiglitazone arm (adjusted mean) b -2.6** -1.6** 95% Confidence Interval (-3.4, -1.8) (-2.4, -1.0) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value ** p-value <0.0001 VICTOZA Compared to Placebo Both With or Without metformin and/or Sulfonylurea and/or Pioglitazone and/or Basal or Premix insulin in Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment In this 26-week, double-blind, randomized, placebo-controlled, parallel-group trial in adult patients with type 2 diabetes mellitus, 279 patients with moderate renal impairment, as per MDRD formula (eGFR 30-59 mL/min/1.73 m 2 ), were randomized to VICTOZA or placebo once daily. VICTOZA was added to the patient’s stable pre-trial antidiabetic regimen (insulin therapy and/or metformin, pioglitazone, or sulfonylurea). The dose of VICTOZA was escalated according to approved labeling to achieve a dose of 1.8 mg per day. The insulin dose was reduced by 20% at randomization for patients with baseline HbA 1c ≤8% and fixed until liraglutide dose escalation was complete. Dose reduction of insulin and SU was allowed in case of hypoglycemia; up titration of insulin was allowed but not beyond the pre-trial dose. The mean age of participants was 67 years, and the mean duration of diabetes was 15 years. Participants were 50.5% male, 92.3% White, 6.6% Black or African American, and 7.2% of Hispanic or Latino ethnicity. The mean BMI was 33.9 kg/m 2 . Approximately half of patients had an eGFR between 30 and <45 mL/min/1.73 m 2 . Treatment with VICTOZA resulted in a statistically significant reduction in HbA 1c from baseline at Week 26 compared to placebo (see Table 11 ). 123 patients reached the 1.8 mg dose of VICTOZA. Table 11. Results of a 26-week Trial of VICTOZA Compared to Placebo in Adult Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment a VICTOZA 1.8 mg + insulin and/or OAD Placebo + insulin and/or OAD Intent to Treat Population (N) 140 137 HbA 1c (%) Baseline (mean) 8.1 8.0 Change from baseline (estimated mean) b, c -0.9 -0.4 Difference from placebo b, c 95% Confidence Interval -0.6* (-0.8, -0.3) Proportion achieving HbA 1c < 7% d 39.3 19.7 FPG (mg/dL) Baseline (mean) 171 167 Change from baseline (estimated mean) e -22 -10 Difference from placebo e 95% Confidence Interval -12** (-23, -0.8) a Intent-to-treat population b Estimated using a mixed model for repeated measurement with treatment, country, stratification groups as factors and baseline as a covariate, all nested within visit. Multiple imputation method modeled “wash out” of the treatment effect for patients having missing data who discontinued treatment. c Early treatment discontinuation, before week 26, occurred in 25% and 22% of VICTOZA and placebo patients, respectively. d Based on the known number of subjects achieving HbA 1c < 7%. When applying the multiple imputation method described in b) above, the estimated percents achieving HbA 1c < 7% are 47.6% and 24.9% for VICTOZA and placebo, respectively. e Estimated using a mixed model for repeated measurement with treatment, country, stratification groups as factors and baseline as a covariate, all nested within visit. * p-value <0.0001 ** p-value <0.05 figure-3 figure-4 14.2 Glycemic Control Trial in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus VICTOZA was evaluated in a 26-week, double-blind, randomized, parallel group, placebo controlled multi-center trial (NCT01541215), in 134 pediatric patients with type 2 diabetes mellitus aged 10 years and older . Patients were randomized to VICTOZA once-daily or placebo once-daily in combination with metformin with or without basal insulin treatment. All patients were on a metformin dose of 1000 to 2000 mg prior to randomization. The basal insulin dose was decreased by 20% at randomization and VICTOZA was titrated weekly by 0.6 mg for 2 to 3 weeks based on tolerability and an average fasting plasma glucose goal of ≤110 mg/dL. The mean age was 14.6 years: 29.9% were ages 10-14 years, and 70.1% were greater than 14 years of age. 38.1% were male, 64.9% were White, 13.4% were Asian, 11.9% were Black or African American; 29.1% were of Hispanic or Latino ethnicity. The mean BMI was 33.9 kg/m 2 and the mean BMI SDS was 2.9. 18.7% of patients were using basal insulin at baseline. The mean duration of diabetes was 1.9 years and the mean HbA 1c was 7.8%. At week 26, treatment with VICTOZA was superior in reducing HbA 1c from baseline versus placebo. The estimated treatment difference in HbA 1c reduction from baseline between VICTOZA and placebo was -1.06% with a 95% confidence interval of [-1.65%; -0.46%] (see Table 12 ). Table 12. Results at week 26 in a trial comparing VICTOZA in combination with metformin with or without basal insulin versus Placebo in combination with metformin with or without basal insulin in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus VICTOZA+metformin±basal insulin Placebo+metformin±basal insulin N 66 68 HbA 1c (%) Baseline 7.9 7.7 End of 26 weeks 7.1 8.2 Adjusted mean change from baseline after 26 weeks a -0.64 0.42 Treatment difference [95% CI] VICTOZA vs Placebo -1.06 [-1.65; -0.46]* Percentage of patients achieving HbA 1c <7% b 63.7 36.5 FPG (mg/dL) Baseline 157 147 End of 26 weeks 132 166 Adjusted mean change from baseline after 26 weeks a -19.4 14.4 Treatment difference [95% CI] VICTOZA vs Placebo -33.83 [-55.74; -11.92] a The change from baseline to end of treatment visit in HbA 1c and FPG was analyzed using a pattern mixture model with multiple imputation. Missing observations (10.6% in the VICTOZA, 14.5% in the placebo) were imputed from the placebo arm based on multiple (x10,000) imputations. The data for week 26 was then analyzed with an ANCOVA model containing treatment, sex and age group as fixed effects and baseline value as covariate. b Categories are derived from continuous measurements of HbA 1c using a pattern mixture model with multiple imputation for missing observations. * p-value <0.001 14.3 Cardiovascular Outcomes Trial in Adult Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease The LEADER trial (NCT01179048) was a multi-national, multi-center, placebo-controlled, double-blind trial. In this study, 9,340 adult patients with inadequately controlled type 2 diabetes mellitus and atherosclerotic cardiovascular disease (CVD) were randomized to VICTOZA 1.8 mg or placebo for a median duration of 3.5 years. The study compared the risk of major adverse cardiovascular events between VICTOZA and placebo when these were added to, and used concomitantly with, background standard of care treatments for type 2 diabetes mellitus. The primary endpoint, major adverse cardiac events (MACE), was the time to first occurrence of a three part composite outcome which included; cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Patients eligible to enter the trial were; 50 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease, chronic kidney disease or New York Heart Association (NYHA) class II and III heart failure (80% of the enrolled population) or were 60 years of age or older and had other specified risk factors for cardiovascular disease (20% of the enrolled population). At baseline, demographic and disease characteristics were balanced. The mean age was 64 years and the population was 64.3% male, 77.5% White, 10.0% Asian, and 8.3% Black or African American. In the study, 12.1% of the population identified as Hispanic or Latino ethnicity. The mean duration of type 2 diabetes mellitus was 12.8 years, the mean HbA 1c was 8.7% and the mean BMI was 32.5 kg/m 2 . A history of previous myocardial infarction was reported in 31% of randomized individuals, a prior revascularization procedure in 39%, a prior ischemic stroke in 11%, documented symptomatic coronary disease in 9%, documented asymptomatic cardiac ischemia in 26%, and a diagnosis of NYHA class II to III heart failure in 14%. The mean eGFR at baseline was 79 mL/min/1.73 m 2 and 41.8% of patients had mild renal impairment (eGFR 60 to 90 mL/min/1.73m 2 ) , 20.7% had moderate renal impairment (eGFR 30 to 60 mL/min/1.73 m 2 ) and 2.4% of patients had severe renal impairment (eGFR <30 mL/min/1.73 m 2 ). At baseline, patients treated their diabetes with; diet and exercise only (3.9%), oral antidiabetic drugs only (51.5%), oral antidiabetic drugs and insulin (36.7%) or insulin only (7.9%). The most common background antidiabetic drugs used at baseline and in the trial were metformin, sulfonylurea and insulin. Use of DPP-4 inhibitors and other GLP-1 receptor agonists was excluded by protocol and sodium-glucose cotransporter-2 (SGLT-2) inhibitors were either not approved or not widely available. At baseline, cardiovascular disease and risk factors were managed with; non-diuretic antihypertensives (92.4%), diuretics (41.8%), statin therapy (72.1%) and platelet aggregation inhibitors (66.8%). During the trial, investigators could modify anti-diabetic and cardiovascular medications to achieve local standard of care treatment targets with respect to blood glucose, lipid, and blood pressure, and manage patients recovering from an acute coronary syndrome or stroke event per local treatment guidelines. For the primary analysis, a Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and to test for superiority on MACE if non-inferiority was demonstrated. Type 1 error was controlled across multiple tests. VICTOZA significantly reduced the occurrence of MACE. The estimated hazard ratio (95% CI) for time to first MACE was 0.87 (0.78, 0.97). Refer to Figure 5 and Table 13 . Vital status was available for 99.7% of subjects in the trial. A total of 828 deaths were recorded during the LEADER trial. A majority of the deaths in the trial were categorized as cardiovascular deaths and non-cardiovascular deaths were balanced between the treatment groups (3.5% in patients treated with VICTOZA and 3.6% in patients treated with placebo). The estimated hazard ratio of time to all-cause death for VICTOZA compared to placebo was 0.85 (0.74, 0.97). Figure 5. Kaplan-Meier: Time to First Occurrence of a MACE in the LEADER Trial (Patients with Type 2 Diabetes Mellitus and Atherosclerotic CVD) Table 13. Treatment Effect for the Primary Composite Endpoint, MACE, and its Components in the LEADER Trial (Patients with Type 2 Diabetes Mellitus and Atherosclerotic CVD) a VICTOZA N=4668 Placebo N=4672 Hazard Ratio (95% CI) b Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (MACE) (time to first occurrence) c 608 (13.0%) 694 (14.9%) 0.87 (0.78; 0.97) Non-fatal myocardial infarction d 281 (6.0%) 317 (6.8%) 0.88 (0.75;1.03) Non-fatal stroke d 159 (3.4%) 177 (3.8%) 0.89 (0.72;1.11) Cardiovascular death d 219 (4.7%) 278 (6%) 0.78 (0.66;0.93) a Full analysis set (all randomized patients) b Cox-proportional hazards model with treatment as a factor c p-value for superiority (2-sided) 0.011 d Number and percentage of first events figure-5

1 INDICATIONS AND USAGE XULTOPHY 100/3.6 is a combination of insulin degludec and liraglutide and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use: • XULTOPHY 100/3.6 contains liraglutide. Coadministration with any other product containing liraglutide or another glucagon-like peptide-1 (GLP-1) receptor agonist is not recommended [see Warnings and Precautions ( 5.5 )]. • XULTOPHY 100/3.6 is not recommended for the treatment of diabetic ketoacidosis. • XULTOPHY 100/3.6 has not been studied in combination with prandial insulin. XULTOPHY 100/3.6 is a combination of insulin degludec, a long-acting human insulin analog, and liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use : ( 1 ) • Coadministration with any other product containing liraglutide or another GLP-1 receptor agonist is not recommended. • Not recommended for the treatment of diabetic ketoacidosis. • Has not been studied in combination with prandial insulin.

2 DOSAGE AND ADMINISTRATION • Administer once-daily at same time each day with or without food. ( 2.1 ) • XULTOPHY 100/3.6 pen delivers doses from 10 to 50 units with each injection ( 2.1 , 2.2 ); each XULTOPHY 100/3.6 dosage unit contains 1 unit of insulin degludec and 0.036 mg of liraglutide. ( 2.1 ) • Maximum daily dosage is 50 units (50 units of insulin degludec and 1.8 mg of liraglutide). ( 2.1 ) • Recommended starting dosage in patients naïve to basal insulin or GLP-1 receptor agonist is 10 units (10 units of insulin degludec and 0.36 mg of liraglutide) injected subcutaneously once-daily. (2.2 ) • Discontinue therapy with liraglutide or basal insulin prior to initiation of XULTOPHY 100/3.6. ( 2.2 ) • Recommended starting dosage in patients currently on basal insulin or GLP-1 receptor agonist is 16 units (16 units of insulin degludec and 0.58 mg of liraglutide) injected subcutaneously once-daily. ( 2.2 ) • See Full Prescribing Information for titration recommendations. ( 2.3 ) • Inject XULTOPHY 100/3.6 subcutaneously into the thigh, upper arm, or abdomen. ( 2.5 ) • Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.5 ) • Do not administer intravenously or by an infusion pump. ( 2.5 ) • Do not dilute or mix with any other insulin products or solutions. ( 2.5 ) 2.1 Important Dosage Information • XULTOPHY 100/3.6 is a combination of insulin degludec and liraglutide. • Administer XULTOPHY 100/3.6 by subcutaneous injection once-daily at the same time each day with or without food. • The XULTOPHY 100/3.6 pen delivers doses from 10 to 50 units with each injection. Table 1 presents the units of insulin degludec and the milligrams of liraglutide in each dosage of XULTOPHY 100/3.6 [see Dosage and Administration ( 2.2 )]. • The maximum dosage of XULTOPHY 100/3.6 is 50 units daily (50 units of insulin degludec and 1.8 mg of liraglutide) [see Warnings and Precautions ( 5.5 )] . 2.2 Recommended Starting Dosage In patients naïve to basal insulin or a GLP-1 receptor agonist • The recommended starting dosage of XULTOPHY 100/3.6 is 10 units (10 units of insulin degludec and 0.36 mg of liraglutide) injected subcutaneously once-daily (see Table 1 ). In patients currently on basal insulin or a GLP-1 receptor agonist • Discontinue therapy with basal insulin or GLP-1 receptor agonist prior to initiation of XULTOPHY 100/3.6. • The recommended starting dosage of XULTOPHY 100/3.6 is 16 units (16 units of insulin degludec and 0.58 mg of liraglutide) injected subcutaneously once-daily (see Table 1 ). Table 1. Units of Insulin Degludec and Milligrams of Liraglutide in Each Dosage of XULTOPHY 100/3.6 XULTOPHY 100/3.6 (dose counter display) * insulin degludec component dose liraglutide component dose Comment ▪▪ ─ --- --- Priming symbol 10 10 units 0.36 mg Recommended starting dose for patients naïve to basal insulin or GLP-1 receptor agonist 11 11 units 0.4 mg 12 12 units 0.43 mg 13 13 units 0.47 mg 14 14 units 0.5 mg 15 15 units 0.54 mg 16 16 units 0.58 mg Recommended starting dose for patients currently on basal insulin or GLP-1 receptor agonist 17 17 units 0.61 mg 18 18 units 0.65 mg 19 19 units 0.68 mg 20 20 units 0.72 mg 21 21 units 0.76 mg 22 22 units 0.79 mg 23 23 units 0.83 mg 24 24 units 0.86 mg 25 25 units 0.9 mg 26 26 units 0.94 mg 27 27 units 0.97 mg 28 28 units 1.01 mg 29 29 units 1.04 mg 30 30 units 1.08 mg 31 31 units 1.12 mg 32 32 units 1.15 mg 33 33 units 1.19 mg 34 34 units 1.22 mg 35 35 units 1.26 mg 36 36 units 1.3 mg 37 37 units 1.33 mg 38 38 units 1.37 mg 39 39 units 1.4 mg 40 40 units 1.44 mg 41 41 units 1.48 mg 42 42 units 1.51 mg 43 43 units 1.55 mg 44 44 units 1.58 mg 45 45 units 1.62 mg 46 46 units 1.66 mg 47 47 units 1.69 mg 48 48 units 1.73 mg 49 49 units 1.76 mg 50 50 units 1.8 mg Maximum daily dosage [see Warnings and Precautions (5.5)] * The dose counter on the XULTOPHY 100/3.6 pen displays numbers for the even units and displays lines for the odd units. 2.3 Titration of XULTOPHY 100/3.6 • After starting the recommended starting dosage of XULTOPHY 100/3.6 [see Dosage and Administration ( 2.2 )] , titrate the dosage upwards or downwards by two units (see Table 2 ) once weekly or twice weekly (every three to four days), based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal until the desired fasting plasma glucose is achieved. • To minimize the risk of hypoglycemia or hyperglycemia, additional titration may be needed with changes in physical activity, meal patterns (i.e., macronutrient content or timing of food intake), or renal or hepatic function; during acute illness; or when used with other medications [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 )]. Table 2. Recommended Titration of XULTOPHY 100/3.6 (Once or Twice Weekly) Self-Monitored Fasting Plasma Glucose XULTOPHY 100/3.6 Dosage Adjustment Above target range + 2 units (2 units of insulin degludec and 0.072 mg of liraglutide) Within target range 0 units Below target range - 2 units (2 units of insulin degludec and 0.072 mg of liraglutide) 2.4 Recommendations Regarding Missed Doses • Instruct patients who miss a dose of XULTOPHY 100/3.6 to resume the once-daily dosage regimen as prescribed with the next scheduled dose. Do not administer an extra dose or increase the dose to make up for the missed dose. • If more than three days have elapsed since the last XULTOPHY 100/3.6 dose, reinitiate XULTOPHY 100/3.6 at the recommended starting dose to mitigate the risk of gastrointestinal adverse reactions associated with reinitiation of treatment [see Dosage and Administration ( 2.1 , 2.2 , 2.3 )] . 2.5 Important Administration Instructions • The XULTOPHY 100/3.6 pen is for single-patient-use only [see Warnings and Precautions ( 5.3 )]. • Train patients on proper use and injection technique before initiating XULTOPHY 100/3.6. • Always check the label on the XULTOPHY 100/3.6 pen before administration [see Warnings and Precautions ( 5.5 )]. • Inspect visually for particulate matter and discoloration prior to administration. Only use XULTOPHY 100/3.6 if the solution appears clear and colorless. • Inject XULTOPHY 100/3.6 subcutaneously into the thigh, upper arm, or abdomen. • Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.1 , 6.3 )] . • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.4 )]. • Use XULTOPHY 100/3.6 with caution in patients with visual impairment who may rely on audible clicks to dial their dose. • The XULTOPHY 100/3.6 pen dials in one-unit increments. • Do not administer XULTOPHY 100/3.6 intravenously or in an insulin infusion pump. • Do not dilute or mix XULTOPHY 100/3.6 with any other insulin or solutions. • Do not split the dose of XULTOPHY 100/3.6.

5 WARNINGS AND PRECAUTIONS • Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including liraglutide. Discontinue if pancreatitis is suspected. ( 5.2 ) • Never share a XULTOPHY 100/3.6 pen between patients, even if the needle is changed. ( 5.3 ) • Hyperglycemia or hypoglycemia with changes in insulin regimen : Make changes to a patient’s insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. ( 5.4 ) • Overdose due to medication errors : XULTOPHY 100/3.6 contains two drugs. Instruct patients to check label before injection since accidental mix-ups with insulin containing products can occur. Do not exceed the maximum dose or administer with other GLP-1 receptor agonists. ( 5.5 ) • Hypoglycemia: May be life-threatening. Increase monitoring with changes to : dosage, concomitant drugs, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness. ( 5.6 ) • Acute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.7 ) • Severe Gastrointestinal Adverse Reactions : Use has been associated with gastrointestinal adverse reactions, sometimes severe. XULTOPHY 100/3.6 is not recommended in patients with severe gastroparesis. ( 5.8 ) • Hypersensitivity Reactions : Severe, life-threatening, generalized allergy, including anaphylaxis, angioedema, bronchospasm, hypotension, and shock can occur. If a hypersensitivity reaction occurs, discontinue and treat per standard of care. ( 5.9 ) • Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.10 ) • Hypokalemia : May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated. ( 5.11 ) • Fluid retention and congestive heart failure with use of thiazolidinediones (TZDs) : Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. ( 5.12 ) • Pulmonary Aspiration During General Anesthesia or Deep Sedation : Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.13 ) 5.1 Risk of Thyroid C-cell Tumors Liraglutide, one of the components of XULTOPHY 100/3.6, causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical Toxicology ( 13.1 )] . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether XULTOPHY 100/3.6 will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. XULTOPHY 100/3.6 is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of XULTOPHY 100/3.6 and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with XULTOPHY 100/3.6. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including liraglutide, one of the components of XULTOPHY 100/3.6 [see Adverse Reactions ( 6 )]. After initiation of XULTOPHY 100/3.6, observe patients carefully for signs and symptoms of acute pancreatitis, which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue XULTOPHY 100/3.6 and initiate appropriate management. 5.3 Never Share a XULTOPHY 100/3.6 Pen Between Patients XULTOPHY 100/3.6 pen must never be shared between patients, even if the needle is changed. Sharing of the pen poses a risk for transmission of blood-borne pathogens. 5.4 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions ( 5.6 )] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions ( 6.1 , 6.3 )]. Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. Adjustments in concomitant oral anti-diabetic treatment may be needed. When initiating XULTOPHY 100/3.6, follow dosing recommendations [see Dosage and Administration ( 2.1 , 2.2 , 2.3 )] . 5.5 Overdose due to Medication Errors XULTOPHY 100/3.6 contains two drugs: insulin degludec and liraglutide. Administration of more than 50 units of XULTOPHY 100/3.6 daily can result in overdose of the liraglutide component. Do not exceed the 1.8 mg maximum recommended dose of liraglutide or use with other GLP-1 receptor agonists. Accidental mix-ups between insulin products have been reported. To avoid medication errors between XULTOPHY 100/3.6 (an insulin containing product) and other insulin products, instruct patients to always check the label before each injection. 5.6 Hypoglycemia Hypoglycemia is the most common adverse reaction of insulin containing products, including XULTOPHY 100/3.6 [see Adverse Reactions ( 6.1 )] . Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). XULTOPHY 100/3.6 (an insulin-containing product) or any insulin, should not be used during episodes of hypoglycemia [see C ontraindications ( 4 ) ] . Hypoglycemia can happen suddenly and symptoms may differ in each patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, in patients using drugs that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions ( 7.1 ) ] , or who experience recurrent hypoglycemia. The long-acting effect of insulin degludec may delay recovery from hypoglycemia compared to shorter acting insulins. Risk Factors for Hypoglycemia The risk of hypoglycemia generally increases with intensity of glycemic control. The risk of hypoglycemia after an injection is related to the duration of action of the insulin [see Clinical Pharmacology ( 12.2 )] and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin containing products, the glucose lowering effect time course of XULTOPHY 100/3.6 may vary among different patients or at different times in the same patients and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature. Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to concomitant drugs [see Drug Interactions ( 7.1 )] . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations ( 8.6 , 8.7 )] . Risk Mitigation Strategies for Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. 5.7 Acute Kidney Injury Due to Volume Depletion There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with liraglutide, one of the components of XULTOPHY 100/3.6 [see Adverse Reactions ( 6.2 )] . The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea [see Adverse Reactions ( 6.1 )]. Monitor renal function in patients reporting adverse reactions to XULTOPHY 100/3.6 that could lead to volume depletion, especially during dosage initiation and escalation of XULTOPHY 100/3.6. 5.8 Severe Gastrointestinal Adverse Reactions Use of GLP-1 receptor agonists, including liraglutide, one of the components of XULTOPHY 100/3.6, has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions ( 6 )]. In a XULTOPHY 100/3.6 clinical trial severe gastrointestinal adverse reactions were reported among patients receiving XULTOPHY 100/3.6 (0.8 %) and patients receiving the active comparators liraglutide (2.9%) and insulin degludec (0.2%) [see Clinical Studies ( 14.2 )] . Severe gastrointestinal adverse reactions have also been reported postmarketing with GLP-1 receptor agonists. XULTOPHY 100/3.6 is not recommended in patients with severe gastroparesis. 5.9 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, angioedema, bronchospasm, hypotension, and shock can occur with insulins, including XULTOPHY 100/3.6. Allergic reactions (manifested with signs and symptoms such as urticaria, rash, pruritus) have been reported with XULTOPHY 100/3.6. There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with liraglutide, one of the components of XULTOPHY 100/3.6 [see Adverse Reactions ( 6.2 )] . If a hypersensitivity reaction occurs, discontinue XULTOPHY 100/3.6; treat promptly per standard of care, and monitor until signs and symptoms resolve. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with XULTOPHY 100/3.6. XULTOPHY 100/3.6 is contraindicated in patients who have had hypersensitivity reactions to insulin degludec, liraglutide or one of the excipients of these products [see Contraindications (4) ]. 5.10 Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In a cardiovascular outcomes trial (LEADER trial) [see Clinical Studies ( 14.4 )] , 3.1% of patients treated with liraglutide, one of the components of XULTOPHY 100/3.6, versus 1.9% of placebo treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis [see Adverse Reactions ( 6.1 )] . If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated. 5.11 Hypokalemia All insulin-containing products, including XULTOPHY 100/3.6, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations). 5.12 Fluid Retention and Congestive Heart Failure with Concomitant Use of a PPAR Gamma Agonist Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists can cause dose related fluid retention, when used in combination with insulin containing products, including XULTOPHY 100/3.6. Fluid retention may lead to or exacerbate congestive heart failure. Patients treated with insulin containing products, including XULTOPHY 100/3.6 and a PPAR-gamma agonist should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of the PPAR-gamma agonist must be considered. 5.13 Pulmonary Aspiration During General Anesthesia or Deep Sedation XULTOPHY 100/3.6 delays gastric emptying [see Clinical Pharmacology ( 12.1 )] . There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking XULTOPHY 100/3.6, including whether modifying preoperative fasting recommendations or temporarily discontinuing XULTOPHY 100/3.6 could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking XULTOPHY 100/3.6.

7 DRUG INTERACTIONS • Drugs that affect glucose metabolism : Adjustment of XULTOPHY 100/3.6 dosage may be needed; closely monitor blood glucose. ( 7.1 ) • Anti-Adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Hypoglycemia signs and symptoms may be reduced or absent. ( 7.1 ) • Effects of delayed gastric emptying on oral medications : May impact absorption of concomitantly administered oral medications. ( 7.2 ) 7.1 Medications that Can Affect Glucose Metabolism A number of medications affect glucose metabolism and may require dose adjustment of XULTOPHY 100/3.6 and particularly close monitoring [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.6 )]. Drugs That May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics Intervention: Dosage reductions and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is coadministered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of XULTOPHY 100/3.6 Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: Dosage increases and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is coadministered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of XULTOPHY 100/3.6 Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dosage adjustment and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is coadministered with these drugs. Drugs That May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine Intervention: Increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is coadministered with these drugs. 7.2 Effects of Delayed Gastric Emptying on Oral Medications Liraglutide-containing products, including XULTOPHY 100/3.6, cause a delay of gastric emptying, and thereby have the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide did not affect the absorption of the tested orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide containing products.

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] • Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] • Hypoglycemia [see Warnings and Precautions ( 5.6 )] • Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.7 )] • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.8 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.9 )] • Acute Gallbladder Disease [see Warnings and Precautions ( 5.10 )] • Hypokalemia [see Warnings and Precautions ( 5.11 )] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.13 )] • Most common adverse reactions (incidence ≥5%) in clinical trials are nasopharyngitis, headache, nausea, diarrhea, increased lipase and upper respiratory tract infection. ( 6 ) • Immunogenicity-related events, including urticaria, were more common among liraglutide-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. ( 12.6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. XULTOPHY 100/3.6 The data in Table 3 reflect the exposure of 1881 patients to XULTOPHY 100/3.6 and a mean duration of exposure of 33 weeks in trials NCT01336023, NCT01618162, NCT02773368, NCT01676116, NCT01392573, NCT01952145 [see Clinical Studies ( 14.2 and 14.3 )] . The mean age was 57 years and 3% were older than 75 years; 53% were male, 75% were White, 6% were Black or African American and 16% were Hispanic or Latino. The mean body mass index (BMI) was 31.8 kg/m 2 . The mean duration of diabetes was 9 years and the mean HbA 1c at baseline was 8.2%. A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported in 25%, 12%, 7% and 6% respectively. The mean estimated glomerular filtration rate (eGFR) at baseline was 88.3 mL/min/1.73 m 2 and 6% of the patients had an eGFR less than 60 mL/min/1.73 m 2 . Table 3: Adverse Reactions Occurring in ≥5% of XULTOPHY 100/3.6-Treated Patients with Type 2 Diabetes Mellitus XULTOPHY 100/3.6 N = 1881 % Nasopharyngitis 10 Headache 9 Nausea 8 Diarrhea 8 Increased Lipase 7 Upper respiratory tract infection 6 Hypoglycemia Hypoglycemia was the most commonly observed adverse reaction in patients treated with insulin and insulin containing products, including XULTOPHY 100/3.6 [see Warnings and Precautions ( 5.6 )]. The number of reported hypoglycemia episodes depended on the definition of hypoglycemia used, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for XULTOPHY 100/3.6 with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice. In the phase 3 clinical program [see Clinical Studies ( 14 )] , events of severe hypoglycemia were defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions ( Table 4 ). Hypoglycemia episodes with a glucose level below 54 mg/dL associated with or without symptoms is shown in Table 4 . No clinically important differences in risk of severe hypoglycemia between XULTOPHY 100/3.6 and comparators were observed in clinical trials. Table 4. Hypoglycemia Episodes Reported in XULTOPHY 100/3.6-Treated Patients with T2DM † Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Patients naïve to basal insulin or GLP-1 receptor agonist Patients currently on GLP-1 receptor agonist Patients currently on basal insulin XULTOPHY 100/3.6 NCT01336023 XULTOPHY 100/3.6 NCT01618162 XULTOPHY 100/3.6 NCT02773368 XULTOPHY 100/3.6 NCT01676116 XULTOPHY 100/3.6 NCT01392573 XULTOPHY 100/3.6 NCT01952145 Total Subjects (N) 825 288 209 291 199 278 Severe Hypoglycemia (%)† 0.2 0.7 0.5 0.3 0.5 0 Hypoglycemia with a glucose level <54 mg/dL (%)* 27.6 37.2 14.4 27.1 22.1 24.8 * Episodes of hypoglycemia with a glucose level below 54 mg/dL that are associated with or without symptoms of hypoglycemia. Gastrointestinal Adverse Reactions Gastrointestinal adverse reactions including nausea, diarrhea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, flatulence, eructation, gastroesophageal reflux disease, abdominal distension and decreased appetite have been reported in patients treated with XULTOPHY 100/3.6. In a XULTOPHY 100/3.6 clinical trial severe gastrointestinal adverse reactions were reported among patients receiving XULTOPHY 100/3.6 (0.8%) and patients receiving the active comparators liraglutide (2.9%) and insulin degludec (0.2%) [see Clinical Studies ( 14.2 )] . Gastrointestinal adverse reactions may occur more frequently at the beginning of XULTOPHY 100/3.6 therapy and diminish within a few days or weeks on continued treatment. Papillary thyroid carcinoma Liraglutide In glycemic control trials of liraglutide, there were 7 reported cases of papillary thyroid carcinoma in patients treated with liraglutide and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1,000 patient years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Pancreatitis Liraglutide In glycemic control trials of liraglutide, there have been 13 cases of pancreatitis among liraglutide-treated patients and 1 case in a comparator (glimepiride) treated patient (2.7 vs. 0.5 cases per 1,000 patient-years). Nine of the 13 cases with liraglutide were reported as acute pancreatitis and four were reported as chronic pancreatitis. In one case in a liraglutide-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. Cholelithiasis and cholecystitis Liraglutide In glycemic control trials of liraglutide, the incidence of cholelithiasis was 0.3% in both liraglutide-treated and placebo-treated patients. The incidence of cholecystitis was 0.2% in both liraglutide treated and placebo-treated patients. In a cardiovascular outcomes trial (LEADER trial) [see Clinical Studies ( 14.4 )] , the incidence of cholelithiasis was 1.5% (3.9 cases per 1,000 patient years of observation) in liraglutide-treated and 1.1% (2.8 cases per 1,000 patient years of observation) in placebo-treated patients, both on a background of standard of care. The incidence of acute cholecystitis was 1.1% (2.9 cases per 1,000 patient years of observation) in liraglutide-treated and 0.7% (1.9 cases per 1,000 patient years of observation) in placebo-treated patients. The majority of events required hospitalization or cholecystectomy. Initiation of insulin containing products and intensification of glucose control Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. Lipodystrophy Long-term use of insulin containing products, including XULTOPHY 100/3.6, can cause lipodystrophy at the site of repeated injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect absorption [see Dosage and Administration ( 2.5 )] . Peripheral Edema XULTOPHY 100/3.6 may cause sodium retention and edema, particularly if previously poor metabolic control is improved rapidly by intensified therapy. Weight Gain Weight gain can occur with insulin containing products, including XULTOPHY 100/3.6, and has been attributed to the anabolic effects of insulin. In study A, after 26 weeks of treatment, patients converting to XULTOPHY 100/3.6 from liraglutide had a mean increase in body weight of 2 kg. Injection Site reactions As with any insulin and GLP-1 receptor agonist-containing products, patients taking XULTOPHY 100/3.6 may experience injection site reactions, including injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass. In the clinical program, the proportion of injection site reactions occurring in patients treated with XULTOPHY 100/3.6 was 2.6%. These reactions were usually mild and transitory and they normally disappear during continued treatment. Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock have occurred with insulin, including XULTOPHY 100/3.6 and may be life threatening [see Warnings and Precautions ( 5.8 )] . Hypersensitivity (manifested with swelling of tongue and lips, diarrhea, nausea, tiredness, and itching) and urticaria were reported. Laboratory tests Bilirubin Liraglutide In the five glycemic control trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of liraglutide-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. Calcitonin XULTOPHY 100/3.6 Calcitonin, a biological marker of MTC, was measured throughout the XULTOPHY 100/3.6 clinical development program. Among patients with pretreatment calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of XULTOPHY 100/3.6-treated patients, 0.7% of placebo-treated patients, and 1.1% and 0.7% of active-comparator-treated patients (basal insulins and GLP-1s respectively). The clinical significance of these findings is unknown. Liraglutide Calcitonin, a biological marker of MTC, was measured throughout the liraglutide clinical development program. At the end of the glycemic control trials, adjusted mean serum calcitonin concentrations were higher in liraglutide-treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. Between group differences in adjusted mean serum calcitonin values were approximately 0.1 ng/L or less. Among patients with pretreatment calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of liraglutide-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients. The clinical significance of these findings is unknown. Lipase and Amylase Liraglutide In one glycemic control trial in renal impairment patients, a mean increase of 33% for lipase and 15% for amylase from baseline was observed for liraglutide-treated patients while placebo-treated patients had a mean decrease in lipase of 3% and a mean increase in amylase of 1%. In a cardiovascular outcomes trial (LEADER trial) [see Clinical Studies ( 14.4 )] , serum lipase and amylase were routinely measured. Among liraglutide-treated patients, 7.9% had a lipase value at any time during treatment of greater than or equal to 3 times the upper limit of normal compared with 4.5% of placebo-treated patients, and 1% of liraglutide-treated patients had an amylase value at any time during treatment of greater than or equal to 3 times the upper limit of normal versus 0.7% of placebo-treated patients. The clinical significance of elevations in lipase or amylase with liraglutide is unknown in the absence of other signs and symptoms of pancreatitis [see Warnings and Precautions ( 5.2 )] . Vital signs Mean increases from baseline in heart rate of 2 to 3 beats per minute have been observed with XULTOPHY 100/3.6 which is attributable to the liraglutide component. 6.2 Postmarketing Experience The following additional adverse reactions have been reported during post-approval use. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Insulin degludec Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site. Liraglutide • Gastrointestinal: Acute pancreatitis; hemorrhagic and necrotizing pancreatitis sometimes resulting in death; ileus, and nausea, vomiting and diarrhea leading to dehydration, intestinal obstruction, severe constipation including fecal impaction • Hepatobiliary: Elevations of liver enzymes, hyperbilirubinemia, cholestasis, cholecystitis, cholelithiasis requiring cholecystectomy, hepatitis • Hypersensitivity: Angioedema, anaphylactic reactions, rash, pruritus • Neoplasms: Medullary thyroid carcinoma • Neurologic: Dysgeusia, dysesthesia, dizziness • Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation. • Renal: Acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis; and increased serum creatinine • Skin and subcutaneous tissue: Cutaneous amyloidosis, alopecia

14 CLINICAL STUDIES 14.1 Overview of Clinical Studies A total of 3908 patients with type 2 diabetes mellitus participated in 6 randomized, parallel and active or placebo-controlled phase 3 trials of 26 weeks duration. Three studies were conducted in patients inadequately controlled on one or more OADs (e.g. metformin, pioglitazone, sulfonylurea, or sodium-glucose cotransporter-2 inhibitors (SGLT2i) ( Tables 5-7 ). Three studies were conducted in patients converting from liraglutide or basal insulin: one study was conducted in patients converting from liraglutide (with doses up to 1.8 mg), ( Table 8 ), one study was conducted in patients converting from any basal insulin ( Table 9 ), and one study was conducted in patients converting from insulin glargine U-100 ( Table 10 ). In all trials, XULTOPHY 100/3.6 was titrated twice weekly by increments or decrements of 2 units (2 units insulin degludec/0.072 mg liraglutide), towards a pre-specified fasting blood glucose target. The same titration algorithm was applied for basal insulin comparators. 14.2 Patients with Type 2 Diabetes Mellitus Uncontrolled on OAD Treatment NCT01336023: The efficacy and safety of XULTOPHY 100/3.6 compared to insulin degludec and liraglutide, all administered once-daily, was studied in a 26-week randomized, open-label, three-arm parallel trial in 1,660 patients with type 2 diabetes mellitus inadequately controlled on 1-2 OADs (metformin or metformin with or without pioglitazone). The mean age of the trial population was 55 years and mean duration of diabetes was 7 years. 51% were male. 62% were White, 7% were Black or African American and 15% were Hispanic or Latino ethnicity, 5% of patients had eGFR <60 mL/min/1.73 m 2 ; no patients had eGFR <30 mL/min/1.73 m 2 . The mean BMI was 31.2 kg/m 2 . The starting dose of XULTOPHY 100/3.6 was 10 units (10 units insulin degludec/0.36 mg liraglutide). The starting dose of insulin degludec was 10 units. XULTOPHY 100/3.6 and insulin degludec were titrated twice weekly towards a target fasting blood glucose goal of 72 to 90 mg/dL. Patients in the liraglutide arm followed a fixed dose escalation scheme with a starting dose of 0.6 mg and a dose increase of 0.6 mg weekly until a daily dose of 1.8 mg was reached. Patients continued on pre-trial treatment with metformin or metformin and pioglitazone throughout the trial. At the end of 26 weeks, treatment with XULTOPHY 100/3.6, insulin degludec, and liraglutide resulted in a reduction in HbA 1c from baseline of 1.81%, 1.35% and 1.21%, respectively, (see Table 5 ). The end of trial dose of XULTOPHY 100/3.6 was 38 units (38 units insulin degludec/1.37 mg liraglutide). Table 5. Results of a 26-Week Trial with XULTOPHY 100/3.6 in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin Alone or in Combination with Pioglitazone XULTOPHY 100/3.6 + metformin ± pioglitazone Insulin degludec + metformin ± pioglitazone Liraglutide + metformin ± pioglitazone Total (N) 833 413 414 HbA 1c (%) Baseline 8.3 8.3 8.3 End of Trial (LS Mean) # 6.5 6.9 7.1 Change from baseline (LS Mean) # -1.81 -1.35 -1.21 Estimated treatment difference [95% CI] # -- -0.46% [-0.59; -0.34] A -0.6% [-0.72; -0.47] A Percentage of patients achieving HbA 1c <7% ## 74.1% 60.5% 56% Fasting Plasma Glucose (FPG) (mg/dL) Baseline 166 169 163 End of Trial (LS Mean) # 104 107 133 Change from baseline (LS Mean) # -61.8 -59.2 -32.4 A p<0.01. Primary endpoint was tested for non-inferiority of XULTOPHY 100/3.6 to insulin degludec based on pre-specified non-inferiority margin of 0.3% and for superiority of XULTOPHY 100/3.6 to liraglutide. # Estimated using an ANCOVA with treatment, baseline HbA 1c stratum, sub-study, concomitant diabetes treatment and country as factors and baseline response as covariate. Multiple imputation modeled “return to baseline” of the treatment effect for subjects having missing week 26 data. ## Patients with missing HbA 1c value at week 26 data were considered non-responders. There were 11.8% of subjects in the XULTOPHY 100/3.6 arm, 12.3% in the insulin degludec arm and 15.5% in the liraglutide arm for whom HbA 1c data was missing at week 26. NCT01618162: The efficacy and safety of XULTOPHY 100/3.6 compared to placebo were studied in a 26-week randomized, double-blind, treat-to-target trial in 435 patients with type 2 diabetes mellitus inadequately controlled on sulfonylurea alone or in combination with metformin. The mean age of the trial population was 60 years, and mean duration of diabetes was 9 years. 52% were male. 75% were White, 7% were Black or African American and 9% were Hispanic or Latino ethnicity, 11% of patients had eGFR < 60 mL/min/1.73 m 2 ; no patients had eGFR <30 mL/min/1.73 m 2 . The mean BMI was 31.5 kg/m 2 . XULTOPHY 100/3.6 was started at 10 units (10 units insulin degludec/0.36 mg liraglutide) and titrated twice weekly towards a target fasting blood glucose goal of 72 to108 mg/dL. Patients continued on pre-trial treatment with sulfonylurea, with or without metformin throughout the trial. Treatment with XULTOPHY 100/3.6 for 26 weeks resulted in a statistically significant reduction in mean HbA 1c compared to placebo (see Table 6 ). The end of trial dose of XULTOPHY 100/3.6 was 28 units (28 units insulin degludec/1.01 mg liraglutide). Table 6. Results of a 26-Week Trial with XULTOPHY 100/3.6 in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Sulfonylurea Alone or in Combination with Metformin XULTOPHY 100/3.6 + sulfonylurea ### ± metformin Placebo + sulfonylurea ### ± metformin Total (N) 289 146 HbA 1c (%) Baseline 7.9 7.9 End of Trial (LS Mean) # 6.5 7.3 Change from baseline (LS Mean) # -1.42 -0.62 Estimated treatment difference [95% CI] # -0.81% [-0.98; -0.63] A Percentage of patients achieving HbA 1c <7% ## 70.9% 26.7% FPG (mg/dL) Baseline 164 165 End of Trial (LS Mean) # 118 152 Change from baseline (LS Mean) # -46.2 -12.1 A p<0.01. Primary endpoint was tested for superiority of XULTOPHY 100/3.6 to placebo. # Estimated using an ANCOVA with treatment, region and pre-trial medication as fixed factors and baseline response as covariate. Multiple imputation modeled “jump-to-control” of the treatment effect for subjects having missing week 26 data. ## Patients with missing HbA 1c value at week 26 data were considered non-responders. There were 12.8% of subjects in the XULTOPHY 100/3.6 arm and 24.7% in the placebo arm for whom HbA 1c data was missing at week 26. ### Dose of sulfonylurea was ≥ half of the maximum approved dose. NCT02773368: The efficacy and safety of XULTOPHY 100/3.6 compared to insulin glargine U-100, both administered once-daily, were studied in a 26-week randomized, open-label, two-arm parallel trial in 420 patients with type 2 diabetes mellitus inadequately controlled on a SGLT2i alone or in combination with other OADs [with or without metformin, pioglitazone, and/or dipeptidyl peptidase-4 9DPP-4) inhibitor]. At randomization, the DPP-4 inhibitor was discontinued. The mean age of the trial population was 57 years and mean duration of diabetes was 10 years. 59% were male. 82% were White, 1% were Black or African American and 16% were Hispanic or Latino ethnicity, 3% of patients had eGFR <60 mL/min/1.73 m 2 ; none of the patients had eGFR <30 mL/min/1.73 m 2 . The mean BMI was 31.2 kg/m 2 . The starting dose of XULTOPHY 100/3.6 was 10 units (10 units insulin degludec/0.36 mg liraglutide). The starting dose of insulin glargine U-100 was 10 units. XULTOPHY 100/3.6 and insulin glargine U-100 were titrated twice weekly to target a fasting blood glucose goal of 72 to 90 mg/dL. Patients could not increase the dose of XULTOPHY 100/3.6 and insulin glargine U-100 by more than 4 units per week, and there was no maximum allowed dose of insulin glargine. The patients continued on pretrial treatment with SGLT2i, with or without other OADs throughout the entire trial. The targeted fasting blood glucose goal was achieved by 49% of patients randomized to XULTOPHY 100/3.6 and 41.9% of patients randomized to insulin glargine at 26 weeks. At the end of 26 weeks, XULTOPHY 100/3.6 resulted in a reduction in HbA 1c from baseline of 1.97% and insulin glargine U-100 resulted in a reduction of 1.59% (see Table 7 ). At the end of trial, the average dose of XULTOPHY 100/3.6 was 36 units (36 units insulin degludec/1.3 mg liraglutide) and the dose of insulin glargine was 54 units; it is unclear that these observed differences in insulin doses are clinically important. The difference in HbA 1c effect observed at 26 weeks may not necessarily reflect the effect in the care setting where insulin glargine may be more rapidly titrated. Table 7. Results of a 26-Week Trial in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on SGLT2i Alone or in Combination with Metformin, Pioglitazone and/or DPP4 Inhibitor XULTOPHY 100/3.6 + SGLT2i ± metformin± pioglitazone Insulin Glargine U-100 + SGLT2i ± metformin± pioglitazone Total (N) 210 210 HbA 1c (%) Baseline 8.2 8.4 End of Trial (LS Mean) # 6.3 6.7 Change from baseline (LS Mean) # -1.97 -1.59 Estimated treatment difference [95% CI] # -0.38% [-0.54; -0.23] A Percentage of patients achieving HbA 1c <7% ## 79.5% 68.6% FPG (mg/dL) Baseline 171 172 End of Trial (LS Mean) ### 108 112 Change from baseline (LS Mean) ### -63.8 -59.9 A Primary endpoint was tested for non-inferiority of XULTOPHY 100/3.6 to insulin glargine U-100 on a non-inferiority margin of 0.3%. # Estimated using an ANCOVA with treatment, pretrial OAD group and region as factors and corresponding baseline value as covariate. For HbA 1c (%), missing week 26 measurements from subjects who discontinued early were multiply-imputed using information from subjects who also discontinued early but still had a week 26 measurement (retrieved dropouts). ## Patients with missing HbA 1c value at week 26 data were considered non-responders. There were 6.2% of subjects in the XULTOPHY 100/3.6 arm and 2.4% in the insulin glargine U-100 arm for whom HbA 1c data was missing at week 26. ### Missing week 26 FPG measurements from subjects who discontinued early were imputed using multiple imputation with a mean for each subject equal to their respective baseline value. 14.3 Patients Currently on Basal Insulin or GLP-1 Receptor Agonist Converting to XULTOPHY 100/3.6 from GLP-1 receptor agonist NCT01676116: The efficacy and safety of XULTOPHY 100/3.6 (once-daily) compared to unchanged pretrial liraglutide up to a dose of 1.8 mg daily, were studied in a 26-week randomized, open-label, treat-to-target (fasting blood glucose goal of 72 to 90 mg/dL) trial. The trial included 348 patients with type 2 diabetes mellitus inadequately controlled on liraglutide and metformin alone or in combination with pioglitazone, sulfonylurea or both. Oral anti-diabetic drugs (OADs) were continued at pretrial doses throughout the trial, and 22% of subjects were treated with sulfonylureas (SU) in combination with metformin with or without pioglitazone. The mean age of the population was 58 years, and mean duration of diabetes was 10 years. 49% were male. 91% were White, 8% Black or African American. 11% were Hispanic or Latino ethnicity, 6% of patients had eGFR <60 mL/min/1.73 m 2 ; no patient had eGFR <30 mL/min/1.73 m 2 . The mean BMI was 33.1 kg/m 2 . The starting dose of XULTOPHY 100/3.6 was 16 units (16 units insulin degludec/0.58 mg liraglutide), and the average starting dose of liraglutide was 1.7 mg. XULTOPHY 100/3.6 was titrated twice weekly to target a fasting blood glucose goal of 72 to 90 mg/dL. The end of trial dose of XULTOPHY 100/3.6 was 44 units (44 units insulin degludec/1.58 mg liraglutide). The primary endpoint, change in HbA 1c , was tested for superiority of XULTOPHY 100/3.6 to unchanged liraglutide therapy. At the end of 26 weeks, there was a reduction in HbA 1c from baseline of 1.31% for XULTOPHY 100/3.6 and 0.36% for liraglutide (see Table 8 ). Table 8. Results of a 26-Week Trial with XULTOPHY 100/3.6 in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Liraglutide up to 1.8 mg Daily XULTOPHY 100/3.6 + metformin±pioglitazone±SU liraglutide 1.8 mg+ metformin±pioglitazone±SU Total (N) 232 116 HbA 1c (%) Baseline 7.8 7.8 End of Trial (LS Mean) # 6.4 7.4 Change from baseline (LS Mean) # -1.31 -0.36 Estimated treatment difference [95% CI] -0.95 [-1.15; -0.75] A Percentage of patients achieving HbA 1c <7% ## 74.6% 30.2% FPG (mg/dL) Baseline 161 169 End of Trial (LS Mean) # 112 153 Change from baseline (LS Mean) # -51.1 -10.9 A Test for superiority evaluated at 5.0% level for significance, (p<0.0001) # Estimated using an ANCOVA with treatment, pretrial liraglutide and region as fixed factors and baseline response as covariate. Multiple imputation modeled “return to baseline” of the treatment effect for subjects having missing week 26 data. ## Patients with missing HbA 1c data at week 26 were considered as non-responders. There were 5.2% of subjects in the XULTOPHY 100/3.6 arm and 19m% in the liraglutide arm for whom HbA 1c data was missing at week 26. Figure 3. Mean HbA 1c (%) By Treatment Week in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Liraglutide IDegLira=XULTOPHY 100/3.6 Converting from basal insulin NCT01392573: The efficacy and safety of XULTOPHY 100/3.6 compared to insulin degludec, both once-daily and added on to metformin, were studied in a 26-week randomized, double-blind, trial in 398 patients with type 2 diabetes mellitus inadequately controlled on basal insulin and metformin alone or in combination with sulfonylurea/glinides. Basal insulin and sulfonylurea/glinides were discontinued at randomization. The mean age of the trial population was 57 years, and mean duration of diabetes was 11 years. 55% were male. 77% were White, 5% Black or African American. 10% were Hispanic or Latino ethnicity, 7% of patients had eGFR < 60 mL/min/1.73 m 2 ; no patient had eGFR <30 mL/min/1.73 m 2 . The mean BMI was 33.7 kg/m 2 . The mean dose of metformin and basal insulin in patients entering the trial was approximately 2 g and 29 units, respectively. The starting dose of XULTOPHY 100/3.6 and insulin degludec was 16 units (16 units insulin degludec/0.58 mg liraglutide) and 16 units, respectively. XULTOPHY 100/3.6 and degludec were to be titrated twice weekly to target a fasting blood glucose goal of 72 to 90 mg/dL. Patients could not increase their dose by more than 4 units per week, and the maximum dose of insulin degludec was limited to 50 units. The targeted fasting blood glucose goal was achieved in 24% of patients randomized to insulin degludec and in 31.6% of the patients randomized to XULTOPHY 100/3.6 at 26 weeks. At the end of 26 weeks, reductions in HbA 1c from baseline of 1.94% for XULTOPHY 100/3.6 and 1.05% for insulin degludec limited to 50 units daily were observed (see Table 9 ). The mean difference (95% CI) in HbA 1c reduction between XULTOPHY 100/3.6 and insulin degludec was -0.89 [-1.10; -0.68] and statistically significant. The trial was designed to show the contribution of the liraglutide component to glycemic lowering and the insulin degludec dosing algorithm was selected to isolate the effect of the GLP-1 component. At the end of the trial, the doses of insulin degludec were equivalent between treatment groups. The mean final dose of XULTOPHY 100/3.6 and insulin degludec was 46 units (for XULTOPHY 100/3.6: 46 units insulin degludec/1.66 mg liraglutide). The difference in glucose lowering effect observed in the trial may not necessarily reflect the effect that will be observed in the care setting where insulin degludec dosage can be different than that used in the trial. Table 9. Results of a 26-Week Trial in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Basal Insulin XULTOPHY 100/3.6 + metformin Insulin degludec* + metformin Total (N) 199 199 HbA 1c (%) Baseline 8.7 8.8 End of Trial (LS Mean) # 6.9 7.7 Change from baseline (LS Mean) # -1.94 -1.05 Estimated treatment difference [95% CI] # -0.89 [-1.10; -0.68] A Percentage of patients achieving HbA 1c <7% ## 57.3% 22.6% FPG (mg/dL) Baseline 175 172 End of Trial (LS Mean) # 110 118 Change from baseline (LS Mean) # -63.5 -55.5 A p<0.01. The trial was designed to show the contribution of the liraglutide component to glycemic lowering and the insulin degludec dosing algorithm was selected to isolate the effect of the GLP-1 component. At the end of the trial, the doses of insulin degludec were equivalent between treatment groups. The mean final dose of XULTOPHY 100/3.6 and insulin degludec was 46 units (for XULTOPHY 100/3.6: 46 units insulin degludec/1.66 mg liraglutide). The difference in glucose lowering effect observed in the trial may not necessarily reflect the effect that will be observed in the care setting where alternative insulin degludec dosage can be used. * Maximum dose 50 units # Estimated using an ANCOVA with treatment, country, and previous antidiabetic treatment as fixed factors and baseline response as covariate. Multiple imputation modeled “jump to control” of the treatment effect for subjects having missing week 26 data. ## Patients with missing HbA 1c data at week 26 were considered non-responders. There were 11.1% of subjects in the XULTOPHY 100/3.6 arm and 13.1% in the insulin degludec arm for whom HbA 1c data was missing at week 26. NCT01952145 : The efficacy and safety of XULTOPHY 100/3.6 compared to insulin glargine U-100, both once-daily and added on to metformin, were studied in a 26-week randomized, open-label, two-arm parallel trial in 557 patients with type 2 diabetes mellitus inadequately controlled on insulin glargine U-100 and metformin. The mean age of the trial population was 59 years and mean duration of diabetes was 12 years. 50% were male. 95% were White, 2% Black or African American. 43% were Hispanic or Latino ethnicity, 6% of patients had eGFR < 60mL/min/1.73m 2 ; one patient had eGFR < 30mL/min/1.73m 2 . The mean BMI was 32 kg/m 2 . The mean dose of insulin glargine U-100 in patients entering the trial was 32 units. XULTOPHY 100/3.6 and insulin glargine were to be titrated twice weekly to target a fasting blood glucose goal of 72 to 90 mg/dL. The starting dose of XULTOPHY 100/3.6 was 16 units (16 units insulin degludec/0.58 mg liraglutide). The average starting dose of insulin glargine U-100 was 32 units. Patients could not increase the dose of the two products by more than 4 units per week and there was no maximum allowed dose of insulin glargine. The targeted fasting plasma blood glucose goal was achieved in 39.6% of patients randomized to insulin glargine and 32.9% of the patients randomized to XULTOPHY 100/3.6 at 26 weeks. At the end of 26 weeks, treatment with XULTOPHY 100/3.6 resulted in a reduction in HbA 1c from baseline of 1.67% and was 1.16% for insulin glargine U-100 (see Table 10 ) and excluded the pre-specified non-inferiority margin of 0.3%. At the end of the trial, the average dose of XULTOPHY 100/3.6 was 41 units (41 units insulin degludec/1.48 mg liraglutide) and the dose of glargine was 66 units, it is unclear that these observed differences in insulin doses are clinically important. The difference in HbA 1c effect observed at 26 weeks may not necessarily reflect the effect in the care setting where insulin glargine may be more rapidly titrated. Table 10. Results of a 26-Week Trial in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Insulin Glargine U-100 XULTOPHY 100/3.6 + metformin Insulin glargine U-100 + metformin Total (N) 278 279 HbA 1c (%) Baseline 8.4 8.2 End of Trial (LS Mean) # 6.6 7.1 Change from baseline (LS Mean) # -1.67 -1.16 Estimated treatment difference [95% CI] -0.51 [-0.67; -0.34] A Percentage of patients achieving HbA 1c <7% ## 68.3% 46.2% FPG (mg/dL) Baseline 161 160 End of Trial (LS Mean) # 110 110 Change from baseline (LS Mean) # -49.9 -49.6 A p<0.01. Primary endpoint was tested for noninferiority of XULTOPHY 100/3.6 to insulin glargine U-100. The difference in glucose lowering effect observed in the trial may not necessarily reflect the effect that will be observed in the care setting where alternative insulin glargine dosage can be used. # Estimated using an ANCOVA with treatment and region as fixed factors and baseline response as covariate. Multiple imputation modeled “return to baseline” of the treatment effect for subjects having missing week 26 data. ## Patients with missing HbA 1c value at week 26 data were considered non-responder. There were 10.1% of subjects in the XULTOPHY 100/3.6 arm and 4.7% in the insulin glargine U-100 arm for whom HbA 1c data was missing at week 26. figure_3 14.4 Cardiovascular Outcomes Trials in Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Conducted with Liraglutide 1.8 mg and Insulin Degludec The effect of XULTOPHY 100/3.6 on the risk of cardiovascular outcomes in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease has not been established. The studies below were conducted with liraglutide 1.8 mg and insulin degludec, individually. Liraglutide 1.8 mg The LEADER trial (NCT01179048) randomized 9,340 patients with inadequately controlled type 2 diabetes mellitus and cardiovascular disease to liraglutide 1.8 mg or placebo in addition to standard of care treatments for type 2 diabetes mellitus for a median follow up of 3.5 years. Patients either were 50 years of age or older with established, stable cardiovascular, cerebrovascular, peripheral artery disease, chronic kidney disease or chronic heart failure (80% of patients) or were 60 years of age or older and had other specified risk factors for cardiovascular disease (20% of patients). The population was 64% male, 78% White, 10% Asian, and 8% Black or African American; 12% of the population was Hispanic or Latino. The mean duration of type 2 diabetes mellitus was 13 years, the mean HbA 1c was 8.7% and the mean BMI was 33 kg/m 2 ; the mean eGFR at baseline was 79 mL/min/1.73 m 2 . In total, 96.8% of the patients completed the trial; vital status was available for 99.7%. The primary endpoint was the time from randomization to first occurrence of a major adverse cardiovascular event (MACE) defined as: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. No increased risk for MACE was observed with liraglutide 1.8 mg. The total number of primary component MACE endpoints was 1302 (608[13.0%] with liraglutide 1.8 mg and 694 [14.9%] with placebo). Insulin degludec The DEVOTE trial (NCT01959529) randomized 7,637 patients with inadequately controlled type 2 diabetes mellitus and cardiovascular disease to either insulin degludec or insulin glargine U-100. Each was administered once-daily in addition to standard of care treatments for diabetes for a median duration of follow up of 2 years. Patients either were 50 years of age or older and had established, stable cardiovascular, cerebrovascular, peripheral artery disease, chronic kidney disease or chronic heart failure (85% of patients) or were 60 years of age or older and had other specified risk factors for cardiovascular disease (15% of patients). The population was 63% male, 76% White 11% Black or African American, and 10% Asian; 15% of the population was Hispanic or Latino. The mean HbA 1c was 8.4% and the mean BMI was 33.6 kg/m 2 . The baseline mean eGFR was 68 mL/min/1.73m 2 . In total, 98% of the patients completed the trial; vital status was known at the end of the trial for 99%. The primary endpoint was the time from randomization to the first occurrence of MACE, defined as: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. No increased risk for MACE was observed with insulin degludec when compared to insulin glargine U-100. The total number of primary MACE endpoints was 681 (325 [8.5%] with insulin degludec and 356 [9.3%] with insulin glargine).