Adverse reactions
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) ] • Diabetic Retinopathy Complications [see Warnings and Precautions ( 5.3 )] • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [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 )] • Acute Gallbladder Disease [see Warnings and Precautions ( 5.9 )] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.10 )] The most common adverse reactions reported in ≥5% of patients treated with OZEMPIC are: nausea, vomiting, diarrhea, abdominal pain and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc., at 1-888-693-6742 or FDA at 1-800-FDA-1088 or http://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. Pool of Placebo-Controlled Trials The data in Table 1 are derived from 2 placebo-controlled trials (1 monotherapy trial and 1 trial in combination with basal insulin) in patients with type 2 diabetes [see Clinical Studies ( 14 )] . These data reflect exposure of 521 patients to OZEMPIC and a mean duration of exposure to OZEMPIC of 32.9 weeks. Across the treatment arms, the mean age of patients was 56 years, 3.4% were 75 years or older and 55% were male. In these trials 71% were White, 7% were Black or African American, and 19% were Asian; 21% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 8.8 years and had a mean HbA 1c of 8.2%. At baseline, 8.9% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 57.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 35.9% and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 6.9% of patients. Pool of Placebo- and Active-Controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 7 placebo- and active-controlled glycemic control trials [see Clinical Studies ( 14 )] including two trials in Japanese patients evaluating the use of OZEMPIC as monotherapy and add-on therapy to oral medications or insulin. In this pool, a total of 3150 patients with type 2 diabetes were treated with OZEMPIC for a mean duration of 44.9 weeks. Across the treatment arms, the mean age of patients was 57 years, 3.2% were 75 years or older and 57% were male. In these trials, 60% were White, 6% were Black or African American, and 31% were Asian; 16% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 8.2 years and had a mean HbA 1c of 8.2%. At baseline, 7.8% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 63.1%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 34.3%, and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 2.5% of the patients. Common Adverse Reactions Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of OZEMPIC in the pool of placebo-controlled trials. These adverse reactions occurred more commonly on OZEMPIC than on placebo and occurred in at least 5% of patients treated with OZEMPIC. Table 1. Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of OZEMPIC-Treated Patients with Type 2 Diabetes Mellitus Adverse Reaction Placebo (N=262) % OZEMPIC 0.5 mg (N=260) % OZEMPIC 1 mg (N=261) % Nausea 6.1 15.8 20.3 Vomiting 2.3 5 9.2 Diarrhea 1.9 8.5 8.8 Abdominal pain 4.6 7.3 5.7 Constipation 1.5 5 3.1 In the pool of placebo- and active-controlled trials and in the 2-year cardiovascular outcomes trial, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1 . In a clinical trial with 959 patients treated with OZEMPIC 1 mg or OZEMPIC 2 mg as add-on to metformin with or without sulfonylurea treatment for 40 weeks, no new safety signals were identified. In the FLOW trial [see Clinical Studies ( 14.3 )] in patients with type 2 diabetes mellitus and chronic kidney disease, safety data collection was limited to serious adverse events and selected predefined categories of adverse events regardless of seriousness. There were no new serious or severe adverse reactions identified in this trial. Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving OZEMPIC than placebo (placebo 15.3%, OZEMPIC 0.5 mg 32.7%, OZEMPIC 1 mg 36.4%). The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation. More patients receiving OZEMPIC 0.5 mg (3.1%) and OZEMPIC 1 mg (3.8%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.4%). In the trial with OZEMPIC 1 mg and 2 mg, gastrointestinal adverse reactions occurred more frequently among patients receiving OZEMPIC 2 mg (34%) vs OZEMPIC 1 mg (30.8%). In addition to the reactions in Table 1 , the following gastrointestinal adverse reactions with a frequency of <5% were associated with OZEMPIC (frequencies listed, respectively, as: placebo; 0.5 mg; 1 mg): dyspepsia (1.9%, 3.5%, 2.7%), eructation (0%, 2.7%, 1.1%), flatulence (0.8%, 0.4%, 1.5%), gastroesophageal reflux disease (0%, 1.9%, 1.5%), and gastritis (0.8%, 0.8%, 0.4%). Other Adverse Reactions Hypoglycemia Table 2 summarizes the incidence of events related to hypoglycemia by various definitions in the placebo-controlled trials. Table 2. Hypoglycemia Adverse Reactions in Placebo-Controlled Trials in Patients with Type 2 Diabetes Mellitus Placebo OZEMPIC 0.5 mg OZEMPIC 1 mg Monotherapy (30 weeks) N=129 N=127 N=130 Severe † 0% 0% 0% Documented symptomatic (≤70 mg/dL glucose threshold) 0% 1.6% 3.8% Severe † or Blood Glucose Confirmed Symptomatic (≤56 mg/dL glucose threshold) 1.6% 0% 0% Add-on to Basal Insulin with or without Metformin (30 weeks) N=132 N=132 N=131 Severe † 0% 0% 1.5% Documented symptomatic (≤70 mg/dL glucose threshold) 15.2% 16.7% 29.8% Severe † or Blood Glucose Confirmed Symptomatic (≤56 mg/dL glucose threshold) 5.3% 8.3% 10.7% † “Severe” hypoglycemia adverse reactions are episodes requiring the assistance of another person. Hypoglycemia was more frequent when OZEMPIC was used in combination with a sulfonylurea [see Warnings and Precautions ( 5.5 ), Clinical Studies ( 14 )]. Severe hypoglycemia occurred in 0.8% and 1.2% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was coadministered with a sulfonylurea. Documented symptomatic hypoglycemia occurred in 17.3% and 24.4% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was coadministered with a sulfonylurea. Severe or blood glucose confirmed symptomatic hypoglycemia occurred in 6.5% and 10.4% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was coadministered with a sulfonylurea. Injection Site Reactions In placebo-controlled trials, injection site reactions (e.g., injection-site discomfort, erythema) were reported in 0.2% of OZEMPIC-treated patients. Increases in Amylase and Lipase In placebo-controlled trials, patients exposed to OZEMPIC had a mean increase from baseline in amylase of 13% and lipase of 22%. These changes were not observed in placebo-treated patients. Acute Pancreatitis In glycemic control trials, acute pancreatitis was confirmed by adjudication in 7 OZEMPIC-treated patients (0.3 cases per 100 patient years) versus 3 in comparator-treated patients (0.2 cases per 100 patient years). Cholelithiasis In placebo-controlled trials, cholelithiasis was reported in 1.5% and 0.4% of patients-treated with OZEMPIC 0.5 mg and 1 mg, respectively. Cholelithiasis was not reported in placebo-treated patients. Increases in Heart Rate In placebo-controlled trials, OZEMPIC 0.5 mg and 1 mg resulted in a mean increase in heart rate of 2 to 3 beats per minute. There was a mean decrease in heart rate of 0.3 beats per minute in placebo-treated patients. Fatigue, Dysgeusia and Dizziness Other adverse reactions with a frequency of >0.4% were associated with OZEMPIC include fatigue, dysgeusia and dizziness. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient of OZEMPIC. 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 and necrotizing pancreatitis, sometimes resulting in death; ileus, intestinal obstruction, severe constipation including fecal impaction Hypersensitivity : anaphylaxis, angioedema, rash, urticaria Hepatobiliary : cholecystitis, cholecystectomy 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 Skin and Subcutaneous Tissue : alopecia
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. Pool of Placebo-Controlled Trials The data in Table 1 are derived from 2 placebo-controlled trials (1 monotherapy trial and 1 trial in combination with basal insulin) in patients with type 2 diabetes [see Clinical Studies ( 14 )] . These data reflect exposure of 521 patients to OZEMPIC and a mean duration of exposure to OZEMPIC of 32.9 weeks. Across the treatment arms, the mean age of patients was 56 years, 3.4% were 75 years or older and 55% were male. In these trials 71% were White, 7% were Black or African American, and 19% were Asian; 21% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 8.8 years and had a mean HbA 1c of 8.2%. At baseline, 8.9% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 57.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 35.9% and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 6.9% of patients. Pool of Placebo- and Active-Controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 7 placebo- and active-controlled glycemic control trials [see Clinical Studies ( 14 )] including two trials in Japanese patients evaluating the use of OZEMPIC as monotherapy and add-on therapy to oral medications or insulin. In this pool, a total of 3150 patients with type 2 diabetes were treated with OZEMPIC for a mean duration of 44.9 weeks. Across the treatment arms, the mean age of patients was 57 years, 3.2% were 75 years or older and 57% were male. In these trials, 60% were White, 6% were Black or African American, and 31% were Asian; 16% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes for an average of 8.2 years and had a mean HbA 1c of 8.2%. At baseline, 7.8% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m 2 ) in 63.1%, mildly impaired (eGFR 60 to 90 mL/min/1.73m 2 ) in 34.3%, and moderately impaired (eGFR 30 to 60 mL/min/1.73m 2 ) in 2.5% of the patients. Common Adverse Reactions Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of OZEMPIC in the pool of placebo-controlled trials. These adverse reactions occurred more commonly on OZEMPIC than on placebo and occurred in at least 5% of patients treated with OZEMPIC. Table 1. Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of OZEMPIC-Treated Patients with Type 2 Diabetes Mellitus Adverse Reaction Placebo (N=262) % OZEMPIC 0.5 mg (N=260) % OZEMPIC 1 mg (N=261) % Nausea 6.1 15.8 20.3 Vomiting 2.3 5 9.2 Diarrhea 1.9 8.5 8.8 Abdominal pain 4.6 7.3 5.7 Constipation 1.5 5 3.1 In the pool of placebo- and active-controlled trials and in the 2-year cardiovascular outcomes trial, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1 . In a clinical trial with 959 patients treated with OZEMPIC 1 mg or OZEMPIC 2 mg as add-on to metformin with or without sulfonylurea treatment for 40 weeks, no new safety signals were identified. In the FLOW trial [see Clinical Studies ( 14.3 )] in patients with type 2 diabetes mellitus and chronic kidney disease, safety data collection was limited to serious adverse events and selected predefined categories of adverse events regardless of seriousness. There were no new serious or severe adverse reactions identified in this trial. Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving OZEMPIC than placebo (placebo 15.3%, OZEMPIC 0.5 mg 32.7%, OZEMPIC 1 mg 36.4%). The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation. More patients receiving OZEMPIC 0.5 mg (3.1%) and OZEMPIC 1 mg (3.8%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.4%). In the trial with OZEMPIC 1 mg and 2 mg, gastrointestinal adverse reactions occurred more frequently among patients receiving OZEMPIC 2 mg (34%) vs OZEMPIC 1 mg (30.8%). In addition to the reactions in Table 1 , the following gastrointestinal adverse reactions with a frequency of <5% were associated with OZEMPIC (frequencies listed, respectively, as: placebo; 0.5 mg; 1 mg): dyspepsia (1.9%, 3.5%, 2.7%), eructation (0%, 2.7%, 1.1%), flatulence (0.8%, 0.4%, 1.5%), gastroesophageal reflux disease (0%, 1.9%, 1.5%), and gastritis (0.8%, 0.8%, 0.4%). Other Adverse Reactions Hypoglycemia Table 2 summarizes the incidence of events related to hypoglycemia by various definitions in the placebo-controlled trials. Table 2. Hypoglycemia Adverse Reactions in Placebo-Controlled Trials in Patients with Type 2 Diabetes Mellitus Placebo OZEMPIC 0.5 mg OZEMPIC 1 mg Monotherapy (30 weeks) N=129 N=127 N=130 Severe † 0% 0% 0% Documented symptomatic (≤70 mg/dL glucose threshold) 0% 1.6% 3.8% Severe † or Blood Glucose Confirmed Symptomatic (≤56 mg/dL glucose threshold) 1.6% 0% 0% Add-on to Basal Insulin with or without Metformin (30 weeks) N=132 N=132 N=131 Severe † 0% 0% 1.5% Documented symptomatic (≤70 mg/dL glucose threshold) 15.2% 16.7% 29.8% Severe † or Blood Glucose Confirmed Symptomatic (≤56 mg/dL glucose threshold) 5.3% 8.3% 10.7% † “Severe” hypoglycemia adverse reactions are episodes requiring the assistance of another person. Hypoglycemia was more frequent when OZEMPIC was used in combination with a sulfonylurea [see Warnings and Precautions ( 5.5 ), Clinical Studies ( 14 )]. Severe hypoglycemia occurred in 0.8% and 1.2% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was coadministered with a sulfonylurea. Documented symptomatic hypoglycemia occurred in 17.3% and 24.4% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was coadministered with a sulfonylurea. Severe or blood glucose confirmed symptomatic hypoglycemia occurred in 6.5% and 10.4% of patients when OZEMPIC 0.5 mg and 1 mg, respectively, was coadministered with a sulfonylurea. Injection Site Reactions In placebo-controlled trials, injection site reactions (e.g., injection-site discomfort, erythema) were reported in 0.2% of OZEMPIC-treated patients. Increases in Amylase and Lipase In placebo-controlled trials, patients exposed to OZEMPIC had a mean increase from baseline in amylase of 13% and lipase of 22%. These changes were not observed in placebo-treated patients. Acute Pancreatitis In glycemic control trials, acute pancreatitis was confirmed by adjudication in 7 OZEMPIC-treated patients (0.3 cases per 100 patient years) versus 3 in comparator-treated patients (0.2 cases per 100 patient years). Cholelithiasis In placebo-controlled trials, cholelithiasis was reported in 1.5% and 0.4% of patients-treated with OZEMPIC 0.5 mg and 1 mg, respectively. Cholelithiasis was not reported in placebo-treated patients. Increases in Heart Rate In placebo-controlled trials, OZEMPIC 0.5 mg and 1 mg resulted in a mean increase in heart rate of 2 to 3 beats per minute. There was a mean decrease in heart rate of 0.3 beats per minute in placebo-treated patients. Fatigue, Dysgeusia and Dizziness Other adverse reactions with a frequency of >0.4% were associated with OZEMPIC include fatigue, dysgeusia and dizziness.
6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient of OZEMPIC. 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 and necrotizing pancreatitis, sometimes resulting in death; ileus, intestinal obstruction, severe constipation including fecal impaction Hypersensitivity : anaphylaxis, angioedema, rash, urticaria Hepatobiliary : cholecystitis, cholecystectomy 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 Skin and Subcutaneous Tissue : alopecia
Clinical studies
14 CLINICAL STUDIES 14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus OZEMPIC has been studied as monotherapy and in combination with metformin, metformin and sulfonylureas, metformin and/or thiazolidinedione, and basal insulin in patients with type 2 diabetes mellitus. The efficacy of OZEMPIC was compared with placebo, sitagliptin, exenatide extended-release (ER), and insulin glargine. Most trials evaluated the use of OZEMPIC 0.5 mg, and 1 mg, with the exception of the trial comparing OZEMPIC and exenatide ER where only the 1 mg dose was studied. One trial evaluated the use of OZEMPIC 2 mg once weekly. In patients with type 2 diabetes mellitus, OZEMPIC produced clinically relevant reduction from baseline in HbA 1c compared with placebo. The efficacy of OZEMPIC was not impacted by age, gender, race, ethnicity, BMI at baseline, body weight (kg) at baseline, diabetes duration and level of renal function impairment. Monotherapy Use of OZEMPIC in Adults with Type 2 Diabetes Mellitus In a 30-week double-blind trial (NCT02054897), 388 patients with type 2 diabetes mellitus inadequately controlled with diet and exercise were randomized to OZEMPIC 0.5 mg or OZEMPIC 1 mg once weekly or placebo. Patients had a mean age of 54 years and 54% were men. The mean duration of type 2 diabetes was 4.2 years, and the mean BMI was 33 kg/m 2 . Overall, 64% were White, 8% were Black or African American, and 21% were Asian; 30% identified as Hispanic or Latino ethnicity. Monotherapy with OZEMPIC 0.5 mg and 1 mg once weekly for 30 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 3 ). Table 3. Results at Week 30 in a Trial of OZEMPIC as Monotherapy in Adult Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise Placebo OZEMPIC 0.5 mg OZEMPIC 1 mg Intent-to-Treat (ITT) Population (N) a 129 128 130 HbA 1c (%) Baseline (mean) 8 8.1 8.1 Change at week 30 b -0.1 -1.4 -1.6 Difference from placebo b [95% CI] -1.2 [-1.5, -0.9] c -1.4 [-1.7, -1.1] c Patients (%) achieving HbA 1c <7% 28 73 70 FPG (mg/dL) Baseline (mean) 174 174 179 Change at week 30 b -15 -41 -44 a The intent-to-treat population includes all randomized and exposed patients. At week 30 the primary HbA 1c endpoint was missing for 10%, 7% and 7% of patients and during the trial rescue medication was initiated by 20%, 5% and 4% of patients randomized to placebo, OZEMPIC 0.5 mg and OZEMPIC 1 mg, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. b Intent-to-treat analysis using ANCOVA adjusted for baseline value and country. c p <0.0001 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 89.1 kg, 89.8 kg, 96.9 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The mean changes from baseline to week 30 were -1.2 kg, -3.8 kg and -4.7 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The difference from placebo (95% CI) for OZEMPIC 0.5 mg was -2.6 kg (-3.8, -1.5), and for OZEMPIC 1 mg was -3.5 kg (-4.8, -2.2). Combination Therapy Use of OZEMPIC in Adults with Type 2 Diabetes Mellitus Combination with metformin and/or thiazolidinediones In a 56-week, double-blind trial (NCT01930188), 1231 patients with type 2 diabetes mellitus were randomized to OZEMPIC 0.5 mg once weekly, OZEMPIC 1 mg once weekly, or sitagliptin 100 mg once daily, all in combination with metformin (94%) and/or thiazolidinediones (6%). Patients had a mean age of 55 years and 51% were men. The mean duration of type 2 diabetes was 6.6 years, and the mean BMI was 32 kg/m 2 . Overall, 68% were White, 5% were Black or African American, and 25% were Asian; 17% identified as Hispanic or Latino ethnicity. Treatment with OZEMPIC 0.5 mg and 1 mg once weekly for 56 weeks resulted in a statistically significant reduction in HbA1c compared to sitagliptin (see Table 4 and Figure 5 ). Table 4. Results at Week 56 in a Trial of OZEMPIC Compared to Sitagliptin in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin and/or Thiazolidinediones OZEMPIC 0.5 mg OZEMPIC 1 mg Sitagliptin Intent-to-Treat (ITT) Population (N) a 409 409 407 HbA 1c (%) Baseline (mean) 8 8 8.2 Change at week 56 b -1.3 -1.5 -0.7 Difference from sitagliptin b [95% CI] -0.6 [-0.7, -0.4] c -0.8 [-0.9, -0.6] c Patients (%) achieving HbA 1c <7% 66 73 40 FPG (mg/dL) Baseline (mean) 168 167 173 Change at week 56 b -35 -43 -23 a The intent-to-treat population includes all randomized and exposed patients. At week 56 the primary HbA 1c endpoint was missing for 7%, 5% and 6% of patients and during the trial rescue medication was initiated by 5%, 2% and 19% of patients randomized to OZEMPIC 0.5 mg, OZEMPIC 1 mg and sitagliptin, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. b Intent-to-treat analysis using ANCOVA adjusted for baseline value and country. c p <0.0001 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 89.9 kg, 89.2 kg, 89.3 kg in the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and sitagliptin arms, respectively. The mean changes from baseline to week 56 were -4.2 kg, -5.5 kg, and -1.7 kg for the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and sitagliptin arms, respectively. The difference from sitagliptin (95% CI) for OZEMPIC 0.5 mg was -2.5 kg (-3.2, -1.8), and for OZEMPIC 1 mg was -3.8 kg (-4.5, -3.1). Figure 5. Mean HbA 1c (%) Over Time - Baseline to Week 56 Combination with metformin or metformin with sulfonylurea In a 56-week, open-label trial (NCT01885208), 813 patients with type 2 diabetes mellitus on metformin alone (49%), metformin with sulfonylurea (45%), or other (6%) were randomized to OZEMPIC 1 mg once weekly or exenatide 2 mg once weekly. Patients had a mean age of 57 years and 55% were men. The mean duration of type 2 diabetes was 9 years, and the mean BMI was 34 kg/m 2 . Overall, 84% were White, 7% were Black or African American, and 2% were Asian; 24% identified as Hispanic or Latino ethnicity. Treatment with OZEMPIC 1 mg once weekly for 56 weeks resulted in a statistically significant reduction in HbA1c compared to exenatide 2 mg once weekly (see Table 5 ). Table 5. Results at Week 56 in a Trial of OZEMPIC Compared to Exenatide 2 mg Once Weekly in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with Sulfonylurea OZEMPIC 1 mg Exenatide ER 2 mg Intent-to-Treat (ITT) Population (N) a 404 405 HbA 1c (%) Baseline (mean) 8.4 8.3 Change at week 56 b -1.4 -0.9 Difference from exenatide b [95% CI] -0.5 [-0.7, -0.3] c Patients (%) achieving HbA 1c <7% 62 40 FPG (mg/dL) Baseline (mean) 191 188 Change at week 56 b -44 -34 a The intent-to-treat population includes all randomized and exposed patients. At week 56 the primary HbA 1c endpoint was missing for 9% and 11% of patients and during the trial rescue medication was initiated by 5% and 10% of patients randomized to OZEMPIC 1 mg and exenatide ER 2 mg, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. b Intent-to-treat analysis using ANCOVA adjusted for baseline value and country. c p <0.0001 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 96.2 kg and 95.4 kg in the OZEMPIC 1 mg and exenatide ER arms, respectively. The mean changes from baseline to week 56 were -4.8 kg and -2 kg in the OZEMPIC 1 mg and exenatide ER arms, respectively. The difference from exenatide ER (95% CI) for OZEMPIC 1 mg was -2.9 kg (-3.6, -2.1). Combination with metformin or metformin with sulfonylurea In a 30-week, open-label trial (NCT02128932), 1089 patients with type 2 diabetes mellitus were randomized to OZEMPIC 0.5 mg once weekly, OZEMPIC 1 mg once weekly, or insulin glargine once daily on a background of metformin (48%) or metformin and sulfonylurea (51%). Patients had a mean age of 57 years and 53% were men. The mean duration of type 2 diabetes was 8.6 years, and the mean BMI was 33 kg/m 2 . Overall, 77% were White, 9% were Black or African American, and 11% were Asian; 20% identified as Hispanic or Latino ethnicity. Patients assigned to insulin glargine had a baseline mean HbA1c of 8.1% and were started on a dose of 10 U once daily. Insulin glargine dose adjustments occurred throughout the trial period based on self-measured fasting plasma glucose before breakfast, targeting 71 to <100 mg/dL. In addition, investigators could titrate insulin glargine at their discretion between study visits. Only 26% of patients had been titrated to goal by the primary endpoint at week 30, at which time the mean daily insulin dose was 29 U per day. Treatment with OZEMPIC 0.5 mg and 1 mg once weekly for 30 weeks resulted in a statistically significant reduction in HbA1c compared with the insulin glargine titration implemented in this study protocol (see Table 6 ). Table 6. Results at Week 30 in a Trial of OZEMPIC Compared to Insulin Glargine in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with Sulfonylurea OZEMPIC 0.5 mg OZEMPIC 1 mg Insulin Glargine Intent-to-Treat (ITT) Population (N) a 362 360 360 HbA 1c (%) Baseline (mean) 8.1 8.2 8.1 Change at week 30 b -1.2 -1.5 -0.9 Difference from insulin glargine b [95% CI] -0.3 [-0.5, -0.1] c -0.6 [-0.8, -0.4] c Patients (%) achieving HbA 1c <7% 55 66 40 FPG (mg/dL) Baseline (mean) 172 179 174 Change at week 30 b -35 -46 -37 a The intent-to-treat population includes all randomized and exposed patients. At week 30 the primary HbA 1c endpoint was missing for 8%, 6% and 6% of patients and during the trial rescue medication was initiated by 4%, 3% and 1% of patients randomized to OZEMPIC 0.5 mg, OZEMPIC 1 mg and insulin glargine, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. b Intent-to-treat analysis using ANCOVA adjusted for baseline value, country and stratification factors. c p <0.0001 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 93.7 kg, 94 kg, 92.6 kg in the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and insulin glargine arms, respectively. The mean changes from baseline to week 30 were -3.2 kg, -4.7 kg and 0.9 kg in the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and insulin glargine arms, respectively. The difference from insulin glargine (95% CI) for OZEMPIC 0.5 mg was -4.1 kg (-4.9, -3.3) and for OZEMPIC 1 mg was -5.6 kg (-6.4, -4.8). Combination with metformin or metformin with sulfonylurea In a 40-week, double-blind trial (NCT03989232), 961 patients with type 2 diabetes currently treated with metformin with or without sulfonylurea treatment were randomized to OZEMPIC 2 mg or OZEMPIC 1 mg once weekly. Patients had a mean age of 58 years and 58.6% were men. The mean duration of type 2 diabetes was 9.5 years and the mean BMI was 34.6 kg/m 2 . At randomization, 53.3% of patients were treated with sulfonylurea and metformin. Overall, 88.1% were White, 4.5% were Black or African American, and 7.2% were Asian; 11.6% identified as Hispanic or Latino ethnicity. Treatment with OZEMPIC 2 mg once weekly for 40 weeks resulted in a statistically significant reduction in HbA 1c compared with OZEMPIC 1 mg (see Table 7 ). Patients were stratified by region (Japan/outside Japan) at randomization. Table 7. Results at Week 40 in a Trial of OZEMPIC 2 mg Compared to OZEMPIC 1 mg in Adult Patients with Type 2 Diabetes Mellitus in Combination With Metformin or Metformin with Sulfonylurea OZEMPIC 1 mg OZEMPIC 2 mg Intent-to-Treat (ITT) Population (N) a 481 480 HbA 1c (%) Baseline (mean) 8.8 8.9 Change at week 40 b -1.9 -2.1 Difference from OZEMPIC 1 mg [95% CI] -0.2 [-0.31 ; -0.04] c Patients (%) achieving HbA 1c <7% a 56 64 FPG (mg/dL) Baseline (mean) 196 193 Change at week 40 b -55 -59 a The intent-to-treat population includes all randomized subjects. At week 40 the primary HbA 1c endpoint was missing for 3% and 5% of patients randomized to OZEMPIC 1 mg and OZEMPIC 2 mg, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. For calculation of proportions, imputed values are dichotomized and the denominator is the number of all randomized subjects. b Intent-to-treat analysis using ANCOVA adjusted for baseline value and stratification factor. c p <0.01 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 98.6 kg and 100.1 kg in the OZEMPIC 1 mg and OZEMPIC 2 mg arms, respectively. The mean changes from baseline to week 40 were -5.6 kg and -6.4 kg in the OZEMPIC 1 mg and OZEMPIC 2 mg arms, respectively. The difference between treatment arms in body weight change from baseline at week 40 was not statistically significant. Combination with basal insulin In a 30-week, double-blind trial (NCT02305381), 397 patients with type 2 diabetes mellitus inadequately controlled with basal insulin, with or without metformin, were randomized to OZEMPIC 0.5 mg once weekly, OZEMPIC 1 mg once weekly, or placebo. Patients with HbA 1c ≤8.0% at screening reduced their insulin dose by 20% at start of the trial to reduce the risk of hypoglycemia. Patients had a mean age of 59 years and 56% were men. The mean duration of type 2 diabetes was 13 years, and the mean BMI was 32 kg/m 2 . Overall, 78% were White, 5% were Black or African American, and 17% were Asian; 12% identified as Hispanic or Latino ethnicity. Treatment with OZEMPIC resulted in a statistically significant reduction in HbA 1c after 30 weeks of treatment compared to placebo (see Table 8 ). Table 8. Results at Week 30 in a Trial of OZEMPIC in Adult Patients with Type 2 Diabetes Mellitus in Combination with Basal Insulin with or without Metformin Placebo OZEMPIC 0.5 mg OZEMPIC 1 mg Intent-to-Treat (ITT) Population (N) a 133 132 131 HbA 1c (%) Baseline (mean) 8.4 8.4 8.3 Change at week 30 b -0.2 -1.3 -1.7 Difference from placebo b [95% CI] -1.1 [-1.4, -0.8] c -1.6 [-1.8, -1.3] c Patients (%) achieving HbA 1c <7% 13 56 73 FPG (mg/dL) Baseline (mean) 154 161 153 Change at week 30 b -8 -28 -39 a The intent-to-treat population includes all randomized and exposed patients. At week 30 the primary HbA 1c endpoint was missing for 7%, 5% and 5% of patients and during the trial rescue medication was initiated by 14%, 2% and 1% of patients randomized to placebo, OZEMPIC 0.5 mg and OZEMPIC 1 mg, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. b Intent-to-treat analysis using ANCOVA adjusted for baseline value, country and stratification factors. c p <0.0001 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 89.9 kg, 92.7 kg, and 92.5 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The mean changes from baseline to week 30 were -1.2 kg, -3.5 kg, and -6 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The difference from placebo (95% CI) for OZEMPIC 0.5 mg was -2.2 kg (-3.4, -1.1), and for OZEMPIC 1 mg was -4.7 kg (-5.8, -3.6). Figure 5. Mean HbA1c (%) Over Time - Baseline to Week 56 14.2 Cardiovascular Outcomes Trial of OZEMPIC in Adults with Type 2 Diabetes Mellitus and Cardiovascular Disease SUSTAIN 6 (NCT01720446) was a multi-center, multi-national, placebo-controlled, double-blind cardiovascular outcomes trial. In this trial, 3,297 patients with inadequately controlled type 2 diabetes and atherosclerotic cardiovascular disease were randomized to OZEMPIC (0.5 mg or 1 mg) once weekly or placebo for a minimum observation time of 2 years. The trial compared the risk of Major Adverse Cardiovascular Event (MACE) between semaglutide and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and cardiovascular disease. The primary endpoint, 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 NYHA class II and III heart failure or were 60 years of age or older and had other specified risk factors for cardiovascular disease. In total, 1,940 patients (58.8%) had established cardiovascular disease without chronic kidney disease, 353 (10.7%) had chronic kidney disease only, and 442 (13.4%) had both cardiovascular disease and kidney disease; 562 patients (17%) had cardiovascular risk factors without established cardiovascular disease or chronic kidney disease. In the trial 453 patients (13.7%) had peripheral artery disease. The mean age at baseline was 65 years, and 61% were men. The mean duration of diabetes was 13.9 years, and mean BMI was 33 kg/m 2 . Overall, 83% were White, 7% were Black or African American, and 8% were Asian; 16% identified as Hispanic or Latino ethnicity. Concomitant diseases of patients in this trial included, but were not limited to, heart failure (24%), hypertension (93%), history of ischemic stroke (12%) and history of a myocardial infarction (33%). In total, 98.0% of the patients completed the trial and the vital status was known at the end of the trial for 99.6%. For the primary analysis, a Cox proportional hazards model was used to test for non-inferiority of OZEMPIC to placebo for time to first MACE using a risk margin of 1.3. The statistical analysis plan pre specified that the 0.5 mg and 1 mg doses would be combined. Type-1 error was controlled across multiple tests using a hierarchical testing strategy. OZEMPIC significantly reduced the occurrence of MACE. The estimated hazard ratio for time to first MACE was 0.74 (95% CI: 0.58, 0.95). Refer to Figure 6 and Table 9 . Figure 6. Kaplan-Meier: Time to First Occurrence of a MACE in the SUSTAIN 6 Trial The treatment effect for the primary composite endpoint and its components in the SUSTAIN 6 trial is shown in Table 9 . Table 9. Treatment Effect for MACE and its Components, Median Study Observation Time of 2.1 Years Placebo N=1649 (%) OZEMPIC N=1648 (%) Hazard ratio vs Placebo (95% CI) a Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence) 146 (8.9) 108 (6.6) 0.74 (0.58, 0.95) Non-fatal Myocardial Infarction 64 (3.9) 47 (2.9) 0.74 (0.51, 1.08) Non-fatal Stroke 44 (2.7) 27 (1.6) 0.61 (0.38, 0.99) Cardiovascular Death 46 (2.8) 44 (2.7) 0.98 (0.65, 1.48) Fatal or Non-fatal Myocardial Infarction 67 (4.1) 54 (3.3) 0.81 (0.57, 1.16) Fatal or Non-fatal Stroke 46 (2.8) 30 (1.8) 0.65 (0.41, 1.03) a Cox-proportional hazards models with treatment as factor and stratified by evidence of cardiovascular disease, insulin treatment and renal impairment. figure_6 14.3 Kidney Outcomes Trial of OZEMPIC in Adults with Type 2 Diabetes Mellitus and Chronic Kidney Disease FLOW (NCT03819153) was a randomized, double-blind, placebo-controlled, event driven trial in adults with type 2 diabetes mellitus and chronic kidney disease (eGFR 25 to 75 mL/min/1.73m 2 with urine albumin-to- creatinine ratio [UACR] >100 mg/g and <5000 mg/g). All patients needed to have an HbA 1c ≤10% at screening and be receiving standard of care background therapy, including a maximum tolerated labeled dose of a renin- angiotensin-aldosterone system (RAAS) blocking agent including an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), unless such treatment was contraindicated or not tolerated. The trial excluded patients with congenital or hereditary kidney diseases including polycystic kidney disease, autoimmune kidney diseases including glomerulonephritis or congenital urinary tract malformations. A total of 3,533 patients were randomized to receive OZEMPIC 1 mg once weekly or placebo and were followed for a median of 41 months. The mean age of the study population was 67 years, and 70% of patients were male. Approximately 66% of the trial population was White, 24% Asian, and 5% Black or African American. At baseline, the mean eGFR was 47 mL/min/1.73m 2 , with 11% of patients having an eGFR <30 mL/min/1.73m 2 . Median baseline UACR was 568 mg/g with 69% of patients with a UACR >300 mg/g. At baseline, 95% of patients were treated with an ACE inhibitor or ARB, 16% were on sodium-glucose cotransporter 2 (SGLT2) inhibitors, 76% were on a statin, and 50% were on an antiplatelet agent. OZEMPIC was superior to placebo in reducing the incidence of the primary composite endpoint of a sustained decline in eGFR of ≥50%, sustained eGFR <15 mL/min/1.73m 2 , chronic renal replacement therapy, renal death, CV death (HR 0.76 [95% CI 0.66, 0.88], p=0.0003) as shown in Table 10 and Figure 7 . The treatment effect reflected a reduction in a sustained decline in eGFR of ≥50%, progression to kidney failure and CV death. There were few renal deaths during the trial. OZEMPIC also reduced the annual rate of change in eGFR ( Figure 9 ), the incidence of a composite cardiovascular endpoint, consisting of non-fatal myocardial infarction (MI), non-fatal stroke, and cardiovascular death, and the incidence of all-cause death ( Table 10 and Figure 8 ). The treatment effect on the primary composite endpoint was generally consistent across the pre-specified subgroups examined, including age, biological sex, eGFR and UACR. The treatment benefit on the primary composite endpoint was not evident in patients taking SGLT2 inhibitors at baseline, but there were few events in these patients. Table 10: Analyses of the Primary and Secondary Endpoints and their Individual Components in FLOW Trial Placebo N=1766 (%) OZEMPIC 1 mg N=1767 (%) Hazard Ratio vs Placebo (95% CI) 1 p-value 2 Number of Patients (%) Composite Endpoint (≥50% sustained eGFR decline, sustained eGFR <15 mL/min/1.73m 2 , chronic renal replacement therapy, or renal or cardiovascular death (time to first occurrence) 3 410 (23.2) 331 (18.7) 0.76 (0.66, 0.88) 0.0003 ≥50% sustained eGFR decline 3 213 (12.1) 165 (9.3) 0.73 (0.59, 0.89) Sustained eGFR <15mL/min/1.73m 2 3 110 (6.2) 92 (5.2) 0.8 (0.61, 1.06) Chronic renal replacement therapy 100 (5.7) 87 (4.9) 0.84 (0.63, 1.12) Renal death 5 (0.3) 5 (0.3) 0.97 (0.27, 3.49) Cardiovascular death 169 (9.6) 123 (7) 0.71 (0.56, 0.89) Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence) 254 (14.4) 212 (12) 0.82 (0.68, 0.98) 0.0289 All-cause death 279 (15.8) 227 (12.8) 0.8 (0.67, 0.95) 0.0104 1 Cox proportional hazards model with treatment as factor and stratified by baseline use of SGLT2-inhibitor at baseline (yes or no). 2 Two-sided p-value for the test of no difference. The significance level was 0.03224. 3 Sustained was defined as having 2 consecutive measurements ≥28 days apart fulfilling the criteria. Figure 7. Cumulative Incidence: Time to First Occurrence of the Primary Composite Endpoint - Sustained Decline in eGFR ≥50%, Sustained eGFR<15 mL/min/1.73m 2 , Chronic Renal Replacement Therapy, Renal Death or CV Death Cumulative incidence estimates are based on time from randomization to first composite renal event with non-CV and non-renal death modelled as competing risk. The x-axis is truncated at 52 months where approximately 5% of the population was in the trial. Sustained was defined as having 2 consecutive measurements ≥28 days apart fulfilling the criteria. Figure 8. Cumulative incidence: Time to First Occurrence of MACE in FLOW Trial Cumulative incidence estimates are based on time from randomization to first EAC-confirmed MACE with non-CV death modelled as competing risk. The x-axis is truncated at 52 months where approximately 5% of the population was in the trial. Figure 9. Observed Mean Plot: eGFR (mL/min/1.73m 2 ) by Week in FLOW Trial Observed data from the in-trial period until week 104. Error bars are +/- 1.96 *standard error of the mean eGFR, which was calculated using the CKD-EPI 2009 formula. CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration, eGFR: estimated glomerular filtration rate. figure_7 figure_8 figure_9
14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus OZEMPIC has been studied as monotherapy and in combination with metformin, metformin and sulfonylureas, metformin and/or thiazolidinedione, and basal insulin in patients with type 2 diabetes mellitus. The efficacy of OZEMPIC was compared with placebo, sitagliptin, exenatide extended-release (ER), and insulin glargine. Most trials evaluated the use of OZEMPIC 0.5 mg, and 1 mg, with the exception of the trial comparing OZEMPIC and exenatide ER where only the 1 mg dose was studied. One trial evaluated the use of OZEMPIC 2 mg once weekly. In patients with type 2 diabetes mellitus, OZEMPIC produced clinically relevant reduction from baseline in HbA 1c compared with placebo. The efficacy of OZEMPIC was not impacted by age, gender, race, ethnicity, BMI at baseline, body weight (kg) at baseline, diabetes duration and level of renal function impairment. Monotherapy Use of OZEMPIC in Adults with Type 2 Diabetes Mellitus In a 30-week double-blind trial (NCT02054897), 388 patients with type 2 diabetes mellitus inadequately controlled with diet and exercise were randomized to OZEMPIC 0.5 mg or OZEMPIC 1 mg once weekly or placebo. Patients had a mean age of 54 years and 54% were men. The mean duration of type 2 diabetes was 4.2 years, and the mean BMI was 33 kg/m 2 . Overall, 64% were White, 8% were Black or African American, and 21% were Asian; 30% identified as Hispanic or Latino ethnicity. Monotherapy with OZEMPIC 0.5 mg and 1 mg once weekly for 30 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 3 ). Table 3. Results at Week 30 in a Trial of OZEMPIC as Monotherapy in Adult Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise Placebo OZEMPIC 0.5 mg OZEMPIC 1 mg Intent-to-Treat (ITT) Population (N) a 129 128 130 HbA 1c (%) Baseline (mean) 8 8.1 8.1 Change at week 30 b -0.1 -1.4 -1.6 Difference from placebo b [95% CI] -1.2 [-1.5, -0.9] c -1.4 [-1.7, -1.1] c Patients (%) achieving HbA 1c <7% 28 73 70 FPG (mg/dL) Baseline (mean) 174 174 179 Change at week 30 b -15 -41 -44 a The intent-to-treat population includes all randomized and exposed patients. At week 30 the primary HbA 1c endpoint was missing for 10%, 7% and 7% of patients and during the trial rescue medication was initiated by 20%, 5% and 4% of patients randomized to placebo, OZEMPIC 0.5 mg and OZEMPIC 1 mg, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. b Intent-to-treat analysis using ANCOVA adjusted for baseline value and country. c p <0.0001 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 89.1 kg, 89.8 kg, 96.9 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The mean changes from baseline to week 30 were -1.2 kg, -3.8 kg and -4.7 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The difference from placebo (95% CI) for OZEMPIC 0.5 mg was -2.6 kg (-3.8, -1.5), and for OZEMPIC 1 mg was -3.5 kg (-4.8, -2.2). Combination Therapy Use of OZEMPIC in Adults with Type 2 Diabetes Mellitus Combination with metformin and/or thiazolidinediones In a 56-week, double-blind trial (NCT01930188), 1231 patients with type 2 diabetes mellitus were randomized to OZEMPIC 0.5 mg once weekly, OZEMPIC 1 mg once weekly, or sitagliptin 100 mg once daily, all in combination with metformin (94%) and/or thiazolidinediones (6%). Patients had a mean age of 55 years and 51% were men. The mean duration of type 2 diabetes was 6.6 years, and the mean BMI was 32 kg/m 2 . Overall, 68% were White, 5% were Black or African American, and 25% were Asian; 17% identified as Hispanic or Latino ethnicity. Treatment with OZEMPIC 0.5 mg and 1 mg once weekly for 56 weeks resulted in a statistically significant reduction in HbA1c compared to sitagliptin (see Table 4 and Figure 5 ). Table 4. Results at Week 56 in a Trial of OZEMPIC Compared to Sitagliptin in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin and/or Thiazolidinediones OZEMPIC 0.5 mg OZEMPIC 1 mg Sitagliptin Intent-to-Treat (ITT) Population (N) a 409 409 407 HbA 1c (%) Baseline (mean) 8 8 8.2 Change at week 56 b -1.3 -1.5 -0.7 Difference from sitagliptin b [95% CI] -0.6 [-0.7, -0.4] c -0.8 [-0.9, -0.6] c Patients (%) achieving HbA 1c <7% 66 73 40 FPG (mg/dL) Baseline (mean) 168 167 173 Change at week 56 b -35 -43 -23 a The intent-to-treat population includes all randomized and exposed patients. At week 56 the primary HbA 1c endpoint was missing for 7%, 5% and 6% of patients and during the trial rescue medication was initiated by 5%, 2% and 19% of patients randomized to OZEMPIC 0.5 mg, OZEMPIC 1 mg and sitagliptin, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. b Intent-to-treat analysis using ANCOVA adjusted for baseline value and country. c p <0.0001 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 89.9 kg, 89.2 kg, 89.3 kg in the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and sitagliptin arms, respectively. The mean changes from baseline to week 56 were -4.2 kg, -5.5 kg, and -1.7 kg for the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and sitagliptin arms, respectively. The difference from sitagliptin (95% CI) for OZEMPIC 0.5 mg was -2.5 kg (-3.2, -1.8), and for OZEMPIC 1 mg was -3.8 kg (-4.5, -3.1). Figure 5. Mean HbA 1c (%) Over Time - Baseline to Week 56 Combination with metformin or metformin with sulfonylurea In a 56-week, open-label trial (NCT01885208), 813 patients with type 2 diabetes mellitus on metformin alone (49%), metformin with sulfonylurea (45%), or other (6%) were randomized to OZEMPIC 1 mg once weekly or exenatide 2 mg once weekly. Patients had a mean age of 57 years and 55% were men. The mean duration of type 2 diabetes was 9 years, and the mean BMI was 34 kg/m 2 . Overall, 84% were White, 7% were Black or African American, and 2% were Asian; 24% identified as Hispanic or Latino ethnicity. Treatment with OZEMPIC 1 mg once weekly for 56 weeks resulted in a statistically significant reduction in HbA1c compared to exenatide 2 mg once weekly (see Table 5 ). Table 5. Results at Week 56 in a Trial of OZEMPIC Compared to Exenatide 2 mg Once Weekly in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with Sulfonylurea OZEMPIC 1 mg Exenatide ER 2 mg Intent-to-Treat (ITT) Population (N) a 404 405 HbA 1c (%) Baseline (mean) 8.4 8.3 Change at week 56 b -1.4 -0.9 Difference from exenatide b [95% CI] -0.5 [-0.7, -0.3] c Patients (%) achieving HbA 1c <7% 62 40 FPG (mg/dL) Baseline (mean) 191 188 Change at week 56 b -44 -34 a The intent-to-treat population includes all randomized and exposed patients. At week 56 the primary HbA 1c endpoint was missing for 9% and 11% of patients and during the trial rescue medication was initiated by 5% and 10% of patients randomized to OZEMPIC 1 mg and exenatide ER 2 mg, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. b Intent-to-treat analysis using ANCOVA adjusted for baseline value and country. c p <0.0001 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 96.2 kg and 95.4 kg in the OZEMPIC 1 mg and exenatide ER arms, respectively. The mean changes from baseline to week 56 were -4.8 kg and -2 kg in the OZEMPIC 1 mg and exenatide ER arms, respectively. The difference from exenatide ER (95% CI) for OZEMPIC 1 mg was -2.9 kg (-3.6, -2.1). Combination with metformin or metformin with sulfonylurea In a 30-week, open-label trial (NCT02128932), 1089 patients with type 2 diabetes mellitus were randomized to OZEMPIC 0.5 mg once weekly, OZEMPIC 1 mg once weekly, or insulin glargine once daily on a background of metformin (48%) or metformin and sulfonylurea (51%). Patients had a mean age of 57 years and 53% were men. The mean duration of type 2 diabetes was 8.6 years, and the mean BMI was 33 kg/m 2 . Overall, 77% were White, 9% were Black or African American, and 11% were Asian; 20% identified as Hispanic or Latino ethnicity. Patients assigned to insulin glargine had a baseline mean HbA1c of 8.1% and were started on a dose of 10 U once daily. Insulin glargine dose adjustments occurred throughout the trial period based on self-measured fasting plasma glucose before breakfast, targeting 71 to <100 mg/dL. In addition, investigators could titrate insulin glargine at their discretion between study visits. Only 26% of patients had been titrated to goal by the primary endpoint at week 30, at which time the mean daily insulin dose was 29 U per day. Treatment with OZEMPIC 0.5 mg and 1 mg once weekly for 30 weeks resulted in a statistically significant reduction in HbA1c compared with the insulin glargine titration implemented in this study protocol (see Table 6 ). Table 6. Results at Week 30 in a Trial of OZEMPIC Compared to Insulin Glargine in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with Sulfonylurea OZEMPIC 0.5 mg OZEMPIC 1 mg Insulin Glargine Intent-to-Treat (ITT) Population (N) a 362 360 360 HbA 1c (%) Baseline (mean) 8.1 8.2 8.1 Change at week 30 b -1.2 -1.5 -0.9 Difference from insulin glargine b [95% CI] -0.3 [-0.5, -0.1] c -0.6 [-0.8, -0.4] c Patients (%) achieving HbA 1c <7% 55 66 40 FPG (mg/dL) Baseline (mean) 172 179 174 Change at week 30 b -35 -46 -37 a The intent-to-treat population includes all randomized and exposed patients. At week 30 the primary HbA 1c endpoint was missing for 8%, 6% and 6% of patients and during the trial rescue medication was initiated by 4%, 3% and 1% of patients randomized to OZEMPIC 0.5 mg, OZEMPIC 1 mg and insulin glargine, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. b Intent-to-treat analysis using ANCOVA adjusted for baseline value, country and stratification factors. c p <0.0001 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 93.7 kg, 94 kg, 92.6 kg in the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and insulin glargine arms, respectively. The mean changes from baseline to week 30 were -3.2 kg, -4.7 kg and 0.9 kg in the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and insulin glargine arms, respectively. The difference from insulin glargine (95% CI) for OZEMPIC 0.5 mg was -4.1 kg (-4.9, -3.3) and for OZEMPIC 1 mg was -5.6 kg (-6.4, -4.8). Combination with metformin or metformin with sulfonylurea In a 40-week, double-blind trial (NCT03989232), 961 patients with type 2 diabetes currently treated with metformin with or without sulfonylurea treatment were randomized to OZEMPIC 2 mg or OZEMPIC 1 mg once weekly. Patients had a mean age of 58 years and 58.6% were men. The mean duration of type 2 diabetes was 9.5 years and the mean BMI was 34.6 kg/m 2 . At randomization, 53.3% of patients were treated with sulfonylurea and metformin. Overall, 88.1% were White, 4.5% were Black or African American, and 7.2% were Asian; 11.6% identified as Hispanic or Latino ethnicity. Treatment with OZEMPIC 2 mg once weekly for 40 weeks resulted in a statistically significant reduction in HbA 1c compared with OZEMPIC 1 mg (see Table 7 ). Patients were stratified by region (Japan/outside Japan) at randomization. Table 7. Results at Week 40 in a Trial of OZEMPIC 2 mg Compared to OZEMPIC 1 mg in Adult Patients with Type 2 Diabetes Mellitus in Combination With Metformin or Metformin with Sulfonylurea OZEMPIC 1 mg OZEMPIC 2 mg Intent-to-Treat (ITT) Population (N) a 481 480 HbA 1c (%) Baseline (mean) 8.8 8.9 Change at week 40 b -1.9 -2.1 Difference from OZEMPIC 1 mg [95% CI] -0.2 [-0.31 ; -0.04] c Patients (%) achieving HbA 1c <7% a 56 64 FPG (mg/dL) Baseline (mean) 196 193 Change at week 40 b -55 -59 a The intent-to-treat population includes all randomized subjects. At week 40 the primary HbA 1c endpoint was missing for 3% and 5% of patients randomized to OZEMPIC 1 mg and OZEMPIC 2 mg, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. For calculation of proportions, imputed values are dichotomized and the denominator is the number of all randomized subjects. b Intent-to-treat analysis using ANCOVA adjusted for baseline value and stratification factor. c p <0.01 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 98.6 kg and 100.1 kg in the OZEMPIC 1 mg and OZEMPIC 2 mg arms, respectively. The mean changes from baseline to week 40 were -5.6 kg and -6.4 kg in the OZEMPIC 1 mg and OZEMPIC 2 mg arms, respectively. The difference between treatment arms in body weight change from baseline at week 40 was not statistically significant. Combination with basal insulin In a 30-week, double-blind trial (NCT02305381), 397 patients with type 2 diabetes mellitus inadequately controlled with basal insulin, with or without metformin, were randomized to OZEMPIC 0.5 mg once weekly, OZEMPIC 1 mg once weekly, or placebo. Patients with HbA 1c ≤8.0% at screening reduced their insulin dose by 20% at start of the trial to reduce the risk of hypoglycemia. Patients had a mean age of 59 years and 56% were men. The mean duration of type 2 diabetes was 13 years, and the mean BMI was 32 kg/m 2 . Overall, 78% were White, 5% were Black or African American, and 17% were Asian; 12% identified as Hispanic or Latino ethnicity. Treatment with OZEMPIC resulted in a statistically significant reduction in HbA 1c after 30 weeks of treatment compared to placebo (see Table 8 ). Table 8. Results at Week 30 in a Trial of OZEMPIC in Adult Patients with Type 2 Diabetes Mellitus in Combination with Basal Insulin with or without Metformin Placebo OZEMPIC 0.5 mg OZEMPIC 1 mg Intent-to-Treat (ITT) Population (N) a 133 132 131 HbA 1c (%) Baseline (mean) 8.4 8.4 8.3 Change at week 30 b -0.2 -1.3 -1.7 Difference from placebo b [95% CI] -1.1 [-1.4, -0.8] c -1.6 [-1.8, -1.3] c Patients (%) achieving HbA 1c <7% 13 56 73 FPG (mg/dL) Baseline (mean) 154 161 153 Change at week 30 b -8 -28 -39 a The intent-to-treat population includes all randomized and exposed patients. At week 30 the primary HbA 1c endpoint was missing for 7%, 5% and 5% of patients and during the trial rescue medication was initiated by 14%, 2% and 1% of patients randomized to placebo, OZEMPIC 0.5 mg and OZEMPIC 1 mg, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts. b Intent-to-treat analysis using ANCOVA adjusted for baseline value, country and stratification factors. c p <0.0001 (2-sided) for superiority, adjusted for multiplicity. The mean baseline body weight was 89.9 kg, 92.7 kg, and 92.5 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The mean changes from baseline to week 30 were -1.2 kg, -3.5 kg, and -6 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The difference from placebo (95% CI) for OZEMPIC 0.5 mg was -2.2 kg (-3.4, -1.1), and for OZEMPIC 1 mg was -4.7 kg (-5.8, -3.6). Figure 5. Mean HbA1c (%) Over Time - Baseline to Week 56
14.3 Kidney Outcomes Trial of OZEMPIC in Adults with Type 2 Diabetes Mellitus and Chronic Kidney Disease FLOW (NCT03819153) was a randomized, double-blind, placebo-controlled, event driven trial in adults with type 2 diabetes mellitus and chronic kidney disease (eGFR 25 to 75 mL/min/1.73m 2 with urine albumin-to- creatinine ratio [UACR] >100 mg/g and <5000 mg/g). All patients needed to have an HbA 1c ≤10% at screening and be receiving standard of care background therapy, including a maximum tolerated labeled dose of a renin- angiotensin-aldosterone system (RAAS) blocking agent including an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), unless such treatment was contraindicated or not tolerated. The trial excluded patients with congenital or hereditary kidney diseases including polycystic kidney disease, autoimmune kidney diseases including glomerulonephritis or congenital urinary tract malformations. A total of 3,533 patients were randomized to receive OZEMPIC 1 mg once weekly or placebo and were followed for a median of 41 months. The mean age of the study population was 67 years, and 70% of patients were male. Approximately 66% of the trial population was White, 24% Asian, and 5% Black or African American. At baseline, the mean eGFR was 47 mL/min/1.73m 2 , with 11% of patients having an eGFR <30 mL/min/1.73m 2 . Median baseline UACR was 568 mg/g with 69% of patients with a UACR >300 mg/g. At baseline, 95% of patients were treated with an ACE inhibitor or ARB, 16% were on sodium-glucose cotransporter 2 (SGLT2) inhibitors, 76% were on a statin, and 50% were on an antiplatelet agent. OZEMPIC was superior to placebo in reducing the incidence of the primary composite endpoint of a sustained decline in eGFR of ≥50%, sustained eGFR <15 mL/min/1.73m 2 , chronic renal replacement therapy, renal death, CV death (HR 0.76 [95% CI 0.66, 0.88], p=0.0003) as shown in Table 10 and Figure 7 . The treatment effect reflected a reduction in a sustained decline in eGFR of ≥50%, progression to kidney failure and CV death. There were few renal deaths during the trial. OZEMPIC also reduced the annual rate of change in eGFR ( Figure 9 ), the incidence of a composite cardiovascular endpoint, consisting of non-fatal myocardial infarction (MI), non-fatal stroke, and cardiovascular death, and the incidence of all-cause death ( Table 10 and Figure 8 ). The treatment effect on the primary composite endpoint was generally consistent across the pre-specified subgroups examined, including age, biological sex, eGFR and UACR. The treatment benefit on the primary composite endpoint was not evident in patients taking SGLT2 inhibitors at baseline, but there were few events in these patients. Table 10: Analyses of the Primary and Secondary Endpoints and their Individual Components in FLOW Trial Placebo N=1766 (%) OZEMPIC 1 mg N=1767 (%) Hazard Ratio vs Placebo (95% CI) 1 p-value 2 Number of Patients (%) Composite Endpoint (≥50% sustained eGFR decline, sustained eGFR <15 mL/min/1.73m 2 , chronic renal replacement therapy, or renal or cardiovascular death (time to first occurrence) 3 410 (23.2) 331 (18.7) 0.76 (0.66, 0.88) 0.0003 ≥50% sustained eGFR decline 3 213 (12.1) 165 (9.3) 0.73 (0.59, 0.89) Sustained eGFR <15mL/min/1.73m 2 3 110 (6.2) 92 (5.2) 0.8 (0.61, 1.06) Chronic renal replacement therapy 100 (5.7) 87 (4.9) 0.84 (0.63, 1.12) Renal death 5 (0.3) 5 (0.3) 0.97 (0.27, 3.49) Cardiovascular death 169 (9.6) 123 (7) 0.71 (0.56, 0.89) Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence) 254 (14.4) 212 (12) 0.82 (0.68, 0.98) 0.0289 All-cause death 279 (15.8) 227 (12.8) 0.8 (0.67, 0.95) 0.0104 1 Cox proportional hazards model with treatment as factor and stratified by baseline use of SGLT2-inhibitor at baseline (yes or no). 2 Two-sided p-value for the test of no difference. The significance level was 0.03224. 3 Sustained was defined as having 2 consecutive measurements ≥28 days apart fulfilling the criteria. Figure 7. Cumulative Incidence: Time to First Occurrence of the Primary Composite Endpoint - Sustained Decline in eGFR ≥50%, Sustained eGFR<15 mL/min/1.73m 2 , Chronic Renal Replacement Therapy, Renal Death or CV Death Cumulative incidence estimates are based on time from randomization to first composite renal event with non-CV and non-renal death modelled as competing risk. The x-axis is truncated at 52 months where approximately 5% of the population was in the trial. Sustained was defined as having 2 consecutive measurements ≥28 days apart fulfilling the criteria. Figure 8. Cumulative incidence: Time to First Occurrence of MACE in FLOW Trial Cumulative incidence estimates are based on time from randomization to first EAC-confirmed MACE with non-CV death modelled as competing risk. The x-axis is truncated at 52 months where approximately 5% of the population was in the trial. Figure 9. Observed Mean Plot: eGFR (mL/min/1.73m 2 ) by Week in FLOW Trial Observed data from the in-trial period until week 104. Error bars are +/- 1.96 *standard error of the mean eGFR, which was calculated using the CKD-EPI 2009 formula. CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration, eGFR: estimated glomerular filtration rate. figure_7 figure_8 figure_9