Adverse reactions
6 ADVERSE REACTIONS The following serious 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 with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [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 )] Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy [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%) are nausea, diarrhea, vomiting, abdominal pain, and decreased appetite ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies 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. Adverse Reactions in the Clinical Trials in Adults with Type 2 Diabetes Mellitus Pool of Adult Placebo-Controlled Trials for TRULICITY 0.75 mg and 1.5 mg Doses The data in Table 1 are derived from a pool of placebo-controlled trials and include 1,670 adult patients with type 2 diabetes mellitus exposed to TRULICITY with a mean duration of exposure of 23.8 weeks [see Clinical Studies ( 14 )] . The mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8 years, a mean HbA1c of 8.0%, and 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m 2 ) in 96%. Table 1 shows adverse reactions, excluding hypoglycemia, occurring in ≥5% of TRULICITY treated adult patients and more commonly than placebo in a pool of placebo-controlled trials. Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials That Occurred in ≥5% of TRULICITY-Treated Adult Patients with Type 2 Diabetes Mellitus a Includes diarrhea, fecal volume increased, frequent bowel movements. b Includes retching, vomiting, vomiting projectile. c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain. d Includes fatigue, asthenia, malaise. Note: Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. Adverse Reaction Placebo (N=568) % TRULICITY 0.75 mg (N=836) % TRULICITY 1.5 mg (N=834) % Nausea 5.3 12.4 21.1 Diarrhea a 6.7 8.9 12.6 Vomiting b 2.3 6.0 12.7 Abdominal Pain c 4.9 6.5 9.4 Decreased Appetite 1.6 4.9 8.6 Dyspepsia 2.3 4.1 5.8 Fatigue d 2.6 4.2 5.6 Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal (GI) adverse reactions occurred more frequently among patients who received TRULICITY compared to patients who received placebo (placebo 21%, 0.75 mg 32%, 1.5 mg 41%). A higher percentage of patients who received TRULICITY 0.75 mg (1.3%) and TRULICITY 1.5 mg (3.5%) discontinued treatment due to GI adverse reactions than patients who received placebo (0.2%). Investigators graded the severity of GI adverse reactions that occurred in those treated with 0.75 mg and 1.5 mg of TRULICITY as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of cases, respectively, or “severe” in 7% and 11% of cases, respectively. The following GI adverse reactions were reported more frequently in TRULICITY-treated patients than placebo -treated patients (frequencies listed, respectively, as: placebo; 0.75 mg; 1.5 mg): constipation (0.7%, 3.9%, 3.7%), flatulence (1.4%, 1.4%, 3.4%), abdominal distension (0.7%, 2.9%, 2.3%), gastroesophageal reflux disease (0.5%, 1.7%, 2.0%), and eructation (0.2%, 0.6%, 1.6%). Adult Dose Ranging Trial for TRULICITY 3 mg and 4.5 mg Doses Table 2 shows adverse reactions occurring ≥5% in any of the treatment groups through 36 weeks in a clinical trial with 1842 adult patients with type 2 diabetes mellitus treated with TRULICITY 1.5 mg, 3 mg, or 4.5 mg subcutaneously once weekly as an add-on to metformin [see Clinical Studies ( 14.3 )] . The adverse reaction profile is consistent with previous clinical trials in adults. Table 2: Adverse Reactions That Occurred in ≥5% of TRULICITY-treated Adult Patients with Type 2 Diabetes Mellitus in a Clinical Trial through 36 Weeks a a Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. Adverse Reaction TRULICITY 1.5 mg (N=612) % TRULICITY 3 mg (N=616) % TRULICITY 4.5 mg (N=614) % Nausea 13.4 15.6 16.4 Diarrhea 7.0 11.4 10.7 Vomiting 5.6 8.3 9.3 Dyspepsia 2.8 5.0 2.6 Other Adverse Reactions in Adults Hypoglycemia Table 3 summarizes the incidence of hypoglycemia in the placebo-controlled clinical studies in adult patients with type 2 diabetes mellitus: episodes with a glucose level <54 mg/dL with or without symptoms, and severe hypoglycemia, defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Table 3: Incidence (%) of Hypoglycemia in Adult Patients with Type 2 Diabetes Mellitus in Placebo-Controlled Trials Placebo TRULICITY 0.75 mg TRULICITY 1.5 mg Add-on to Metformin (26 weeks) N=177 N=302 N=304 Hypoglycemia with a glucose level <54 mg/dL 0 0.3 0.7 Severe hypoglycemia 0 0 0 Add-on to Metformin + Pioglitazone (26 weeks) N=141 N=280 N=279 Hypoglycemia with a glucose level <54 mg/dL 1.4 2.1 0 Severe hypoglycemia 0 0 0 Add-on to Glimepiride (24 weeks) N=60 - N=239 Hypoglycemia with a glucose level <54 mg/dL 0 - 3.3 Severe hypoglycemia 0 - 0 In Combination with Insulin Glargine ± Metformin (28 weeks) N=150 - N=150 Hypoglycemia with a glucose level <54 mg/dL 9.3 - 14.7 Severe hypoglycemia 0 - 0.7 Add-on to SGLT2i ± Metformin (24 weeks) N=140 N=141 N=142 Hypoglycemia with a glucose level <54 mg/dL 0.7 0.7 0.7 Severe hypoglycemia 0 0.7 0 Hypoglycemia was more frequent when TRULICITY was used in combination with a sulfonylurea or insulin than when used with non-secretagogues. In a 78-week adult clinical trial, hypoglycemia (glucose level <54 mg/dL) occurred in 20% and 21% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea. Severe hypoglycemia occurred in 0% and 0.7% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea. In a 52-week adult clinical trial, hypoglycemia (glucose level <54 mg/dL) occurred in 77% and 69% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with prandial insulin. Severe hypoglycemia occurred in 2.7% and 3.4% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with prandial insulin. Refer to Table 3 for the incidence of hypoglycemia in patients treated in combination with basal insulin glargine. In the clinical trial with adult patients on TRULICITY 1.5 mg, TRULICITY 3 mg, or TRULICITY 4.5 mg once weekly, as add-on to metformin, incidences of hypoglycemia (glucose level <54 mg/dL) through 36 weeks were 1.1%, 0.3%, and 1.1%, respectively, and incidences of severe hypoglycemia were 0.2%, 0%, and 0.2%, respectively. Cholelithiasis and Cholecystitis In a cardiovascular outcomes trial in adult patients with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple cardiovascular risk factors with a median follow up of 5.4 years [see Clinical Studies 14.5 ] , cholelithiasis occurred at a rate of 0.62/100 patient-years in TRULICITY-treated patients and 0.56/100 patient-years in placebo-treated patients after adjusting for prior cholecystectomy. Serious events of acute cholecystitis were reported in 0.5% and 0.3% of patients on TRULICITY and placebo respectively. Heart Rate Increase and Tachycardia-Related Adverse Reactions In adult patients, TRULICITY 0.75 mg and 1.5 mg resulted in a mean increase in heart rate (HR) of 2-4 beats per minute (bpm). Adverse reactions of sinus tachycardia were reported more frequently in patients exposed to TRULICITY. Sinus tachycardia was reported in 3.0%, 2.8%, and 5.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Persistence of sinus tachycardia (reported at more than 2 visits) was reported in 0.2%, 0.4% and 1.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Episodes of sinus tachycardia, associated with a concomitant increase from baseline in heart rate of ≥15 beats per minute, were reported in 0.7%, 1.3% and 2.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Hypersensitivity Systemic hypersensitivity adverse reactions, sometimes severe (e.g., severe urticaria, systemic rash, facial edema, lip swelling), occurred in 0.5% of adult patients on TRULICITY in clinical studies. Injection-site Reactions In the placebo-controlled studies in adults, injection-site reactions (e.g., injection-site rash, erythema) were reported in 0.5% of TRULICITY-treated patients and in 0.0% of placebo-treated patients. PR Interval Prolongation and Adverse Reactions of First-Degree Atrioventricular (AV) Block A mean increase from baseline in PR interval of 2-3 milliseconds was observed in TRULICITY-treated adult patients in contrast to a mean decrease of 0.9 milliseconds in placebo-treated patients. The adverse reaction of first-degree AV block occurred more frequently in patients treated with TRULICITY than placebo (0.9%, 1.7% and 2.3% for placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively). On electrocardiograms, a PR interval increase to at least 220 milliseconds was observed in 0.7%, 2.5% and 3.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Acute Pancreatitis In a pooled analysis from the original registration studies, 12 (3.4 cases per 1,000 patient years) pancreatitis-related adverse reactions were reported in patients exposed to TRULICITY versus 3 in non-incretin comparators (2.7 cases per 1000 patient years). An analysis of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to TRULICITY (1.4 cases per 1,000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1,000 patient years). Based on an analysis of adjudicated events in a clinical trial evaluating Trulicity 1.5 mg, 3 mg, or 4.5 mg once weekly, pancreatitis occurred in 1 patient exposed to TRULICITY 1.5 mg (0.2%), in 2 patients exposed to TRULICITY 3 mg (0.3%), and 3 patients exposed to TRULICITY 4.5 mg (0.5%). Amylase and Lipase Increase Adult patients exposed to TRULICITY had mean increases from baseline in lipase and/or pancreatic amylase of 14% to 20%, while placebo-treated patients had mean increases of up to 3%. Adverse Reactions in the Clinical Trial of Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus TRULICITY was administered to 150 pediatric patients 10 years of age and older with type 2 diabetes mellitus for a mean duration of 41.3 weeks [ see Clinical Studies ( 14.6 ) ]. The mean age was 14.5 years and 71% of patients were female. Overall, 55% were White, 15% were Black or African American, 12% were Asian, 10% were American Indian or Alaska Native, 5% were other races, and 3% had unknown race. Additionally, 55% were Hispanic or Latino, 42% were not Hispanic or Latino, and 3% had unknown ethnicity. At baseline, the mean duration of type 2 diabetes mellitus was 2 years, mean HbA1c was 8.1%, mean weight was 90.5 kg and mean BMI was 34.1 kg/m 2 . The safety profile in pediatric patients treated with TRULICITY 0.75 mg and 1.5 mg subcutaneously once-weekly was consistent with that described above for adult patients with type 2 diabetes mellitus with the exception of injection site reactions. In pediatric patients, the incidence of injection site reactions was 3.9% (2 patients) in the TRULICITY 0.75 mg group, 3.8% (2 patients) in the TRULICITY 1.5 mg group, and 2.0% (1 patient) in the placebo group. 6.2 Postmarketing Experience The following additional adverse reactions have been reported during post-approval use of TRULICITY. 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 Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy, cholestasis, elevation of liver enzymes, hepatitis Hypersensitivity: anaphylactic reactions, angioedema Neurologic : dysgeusia, 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 Skin and Subcutaneous Tissue: alopecia
Clinical studies
14 CLINICAL STUDIES 14.1 Overview of Clinical Trials TRULICITY has been studied in adults as monotherapy and in combination with metformin, sulfonylurea, metformin and sulfonylurea, metformin and thiazolidinedione, sodium-glucose co-transporter-2 inhibitors (SGLT2i) with or without metformin, basal insulin with or without metformin, and prandial insulin with or without metformin. TRULICITY has also been studied in patients with type 2 diabetes mellitus and moderate to severe renal impairment. Dose escalation was performed in one trial in adults with TRULICITY doses up to 4.5 mg added to metformin. All other clinical studies in adults evaluated TRULICITY 0.75 mg and 1.5 mg without dose escalation; patients were initiated and maintained on either 0.75 mg or 1.5 mg for the duration of the trials [see Clinical Studies ( 14.2 , 14.3 , 14.4 )] . TRULICITY 0.75 mg and 1.5 mg was studied in pediatric patients 10 years of age and older with type 2 diabetes in combination with or without metformin and/or basal insulin treatment [see Clinical Studies ( 14.6 )] . In patients with type 2 diabetes mellitus, TRULICITY produced reductions from baseline in HbA1c compared to placebo. No overall differences in glycemic effectiveness were observed across demographic subgroups (age, gender, race/ethnicity, duration of diabetes). A cardiovascular outcomes trial was conducted in adult patients with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple cardiovascular risk factors. Patients were randomized to TRULICITY 1.5 mg or placebo both added to standard of care. TRULICITY significantly reduced the risk of first occurrence of primary composite endpoint of CV death, non-fatal MI, or non-fatal stroke [see Clinical Studies ( 14.5 )] . 14.2 Glycemic Control Monotherapy Trials in Adults with Type 2 Diabetes Mellitus In a double-blind trial with primary endpoint at 26 weeks, 807 adult patients inadequately treated with diet and exercise, or with diet and exercise and one antidiabetic agent used at submaximal dose, were randomized to TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or metformin 1500 to 2000 mg/day following a two-week washout. Seventy-five percent (75%) of the randomized population were treated with one antidiabetic agent at the screening visit. Most patients previously treated with an antidiabetic agent were receiving metformin (~90%) at a median dose of 1000 mg daily and approximately 10% were receiving a sulfonylurea. Patients had a mean age of 56 years and a mean duration of type 2 diabetes of 3 years. Forty-four percent were male. The White, Black and Asian race accounted for 74%, 7% and 8% of the population, respectively. Twenty-nine percent of the trial population were from the US. Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in reduction in HbA1c from baseline at 26-weeks ( Table 4 ). The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and metformin excluded the pre-specified non-inferiority margin of 0.4%. Table 4: Results at Week 26 in a Trial of TRULICITY as Monotherapy in Adult Patients with Type 2 Diabetes Mellitus a Abbreviation: HbA1c = hemoglobin A1c. a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 26, primary efficacy was missing for 10%, 12% and 14% of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and metformin, respectively. b Least-squares mean adjusted for baseline value and other stratification factors. ‡ Patients included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 265 individuals in each of the treatment arms. 26-Week Primary Time Point TRULICITY 0.75 mg TRULICITY 1.5 mg Metformin 1500-2000 mg Intent-to-Treat (ITT) Population (N) ‡ 270 269 268 HbA1c (%) (Mean) Baseline 7.6 7.6 7.6 Change from baseline b -0.7 -0.8 -0.6 Fasting Serum Glucose (mg/dL) (Mean) Baseline 161 164 161 Change from baseline b -26 -29 -24 Body Weight (kg) (Mean) Baseline 91.8 92.7 92.4 Change from baseline b -1.4 -2.3 -2.2 14.3 Glycemic Control Combination Therapy Trials in Adults with Type 2 Diabetes Mellitus Sitagliptin-Controlled Trial (Add-on to Metformin) In this placebo-controlled, double-blind trial with primary endpoint at 52 weeks, 972 adult patients were randomized to placebo, TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or sitagliptin 100 mg/day (after 26 weeks, patients in the placebo treatment group received blinded sitagliptin 100 mg/day for the remainder of the trial), all as add-on to metformin. Randomization occurred after an 11-week lead-in period to allow for a metformin titration period, followed by a 6-week glycemic stabilization period. Patients had a mean age of 54 years; mean duration of type 2 diabetes of 7 years; 48% were male; race: White, Black and Asian were 53%, 4% and 27%, respectively; and 24% of the trial population were in the US. At the 26-week placebo-controlled time point, the HbA1c change was 0.1%, -1.0%, -1.2%, and -0.6% for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively. The percentage of patients who achieved HbA1c <7.0% was 22%, 56%, 62% and 39% for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively. At 26 weeks, there was a mean weight reduction of 1.4 kg, 2.7 kg, 3.0 kg, and 1.4 kg for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively. There was a mean reduction of fasting glucose of 9 mg/dL, 35 mg/dL, 41 mg/dL, and 18 mg/dL for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively. Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo (at 26 weeks) and compared to sitagliptin (at 26 and 52 weeks), all in combination with metformin ( Table 5 and Figure 3 ). Table 5: Results at Week 52 of TRULICITY Compared to Sitagliptin used as Add-On to Metformin in Adult Patients with Type 2 Diabetes Mellitus a Abbreviations: HbA1c = hemoglobin A1c. a All ITT patients randomized after the dose-finding portion of the trial. Last observation carried forward (LOCF) was used to impute missing data. At Week 52 primary efficacy was missing for 15%, 19%, and 20% of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and sitagliptin, respectively. b Least-squares (LS) mean adjusted for baseline value and other stratification factors. ‡ Patients included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 276, 277, and 270 individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and sitagliptin, respectively. †† Multiplicity adjusted 1-sided p-value <0.001, for superiority of TRULICITY compared to sitagliptin, assessed only for HbA1c. ## p<0.001 TRULICITY compared to sitagliptin, assessed only for HbA1c <7.0%. 52-Week Primary Time Point TRULICITY 0.75 mg TRULICITY 1.5 mg Sitagliptin 100 mg Intent-to-Treat (ITT) Population (N) ‡ 281 279 273 HbA1c (%) (Mean) Baseline 8.2 8.1 8.0 Change from baseline b -0.9 -1.1 -0.4 Difference from sitagliptin b (95% CI) -0.5 (-0.7, -0.3) †† -0.7 (-0.9, -0.5) †† - Percentage of patients HbA1c <7.0% 49 ## 59 ## 33 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 174 173 171 Change from baseline b -30 -41 -14 Difference from sitagliptin b (95% CI) -15 (-22, -9) -27 (-33, -20) - Body Weight (kg) (Mean) Baseline 85.5 86.5 85.8 Change from baseline b -2.7 -3.1 -1.5 Difference from sitagliptin b (95% CI) -1.2 (-1.8, -0.6) -1.5 (-2.1, -0.9) - Mean HbA1c adjusted for baseline HbA1c and country. Number of patients with observed data Placebo 139 108 TRULICITY 0.75 mg 281 258 238 TRULICITY 1.5 mg 279 249 225 Sitagliptin 273 241 219 Figure 3: Adjusted Mean HbA1c at each Time Point (ITT, MMRM) and at Week 52 (ITT, LOCF) in Adult Patients with Type 2 Diabetes Mellitus Figure 3 Dosage Ranging Trial of TRULICITY 1.5, 3 mg, and 4.5 mg (Add-on to Metformin) In this parallel-arm, double-blind trial with primary endpoint at 36 weeks, a total of 1842 adult patients were randomized 1:1:1 to TRULICITY 1.5 mg, TRULICITY 3 mg, or TRULICITY 4.5 mg once weekly, all as add-on to metformin (NCT03495102). Following randomization, all patients received TRULICITY 0.75 mg once weekly. The dose was increased every 4 weeks to the next higher dose until the patients reached their assigned dose (1.5 mg, 3 mg, or 4.5 mg). Patients were to remain on the assigned study dose for the duration of the trial. Patients had a mean age of 57.1 years; a mean duration of type 2 diabetes of 7.6 years; 51.2% were male; race: White, Black, and Asian were 85.8%, 4.5%, and 2.4%, respectively; and 27.6% of the trial population was in the US. At 36 weeks, treatment with TRULICITY 4.5 mg resulted in a statistically significant reduction in HbA1c and in body weight compared to TRULICITY 1.5 mg ( Table 6 and Figure 4 ). Table 6. Results at Week 36 of TRULICITY 1.5 mg Compared to 3 mg and 4.5 mg as Add-On to Metformin in Adult Patients with Type 2 Diabetes Mellitus a Abbreviations: HbA1c = hemoglobin A1c a Intent-to-treat population. At Week 36, primary efficacy was missing for 7%, 7%, and 6% of individuals treated with TRULICITY 1.5 mg, TRULICITY 3 mg, and TRULICITY 4.5 mg, respectively. b Least-squares mean adjusted for baseline value and other stratification factors. Missing data were imputed using multiple imputation. c Patients with missing HbA1c data at Week 36 were considered as not achieving HbA1c target. ^ p=0.0001 for superiority compared to TRULICITY 1.5 mg, overall type I error controlled. ^^ p<0.0001 for superiority compared to TRULICITY 1.5 mg, overall type I error controlled. 36-Week Primary Time Point TRULICITY 1.5 mg TRULICITY 3 mg TRULICITY 4.5 mg Intent-to-Treat (ITT) Population (N) 612 616 614 HbA1c (%) (Mean) Baseline 8.6 8.6 8.6 Change from baseline b -1.5 -1.6 -1.8 Difference from 1.5 mg b (95% CI) -0.1 (-0.2, 0.0) -0.2 (-0.4, -0.1) ^ Percentage of patients HbA1c <7.0% c 50 56 62 Fasting Serum Glucose (mg/dL) (Mean) Baseline 185 184 183 Change from baseline b -45 -46 -51 Difference from 1.5 mg b (95% CI) - 2 (-7, 3) -6 (-11, -2) Body Weight (kg) (Mean) Baseline 95.5 96.3 95.4 Change from baseline b -3.0 -3.8 -4.6 Difference from 1.5 mg b (95% CI) -0.9 (-1.4, -0.4) -1.6 (-2.2, -1.1) ^^ Number of patients with observed data TRULICITY 1.5 mg 612 567 TRULICITY 3 mg 616 572 TRULICITY 4.5 mg 614 575 Observed mean HbA1c at scheduled visits and retrieved dropout multiple imputation (MI) based estimate at week 36. Figure 4: Mean HbA1c at each Time Point (ITT) and at Week 36 (ITT, MI) Figure 4 Placebo-Controlled Trial (Add-on to Sulfonylurea) In this 24-week placebo-controlled, double-blind trial, 299 adult patients were randomized to and received placebo or once weekly TRULICITY 1.5 mg, both as add-on to glimepiride. Patients had a mean age of 58 years; mean duration of type 2 diabetes of 8 years; 44% were male; race: White, Black, and Asian were 83%, 4%, and 2%, respectively; and 24% of the trial population were in the US. At 24 weeks, treatment with once weekly TRULICITY 1.5 mg resulted in a statistically significant reduction in HbA1c compared to placebo ( Table 7 ). Table 7: Results at Week 24 of TRULICITY Compared to Placebo as Add-On to Glimepiride in Adult Patients with Type 2 Diabetes Mellitus a Abbreviations: HbA1c = hemoglobin A1c. a Intent-to-treat population. Data post-onset of rescue therapy are treated as missing. At Week 24 primary efficacy was missing for 10% and 12% of individuals randomized to TRULICITY 1.5 mg and placebo, respectively. b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. Placebo multiple imputation, with respect to the baseline values, was used to model a wash-out of the treatment effect for patients having missing Week 24 data. c Patients with missing HbA1c data at Week 24 were considered as non-responders. †† p<0.001 for superiority of TRULICITY 1.5 mg compared to placebo, overall type I error controlled. 24-Week Primary Time Point Placebo TRULICITY 1.5 mg Intent-to-Treat (ITT) Population (N) 60 239 HbA1c (%) (Mean) Baseline 8.4 8.4 Change from baseline b -0.3 -1.3 Difference from placebo b (95% CI) -1.1 (-1.4, -0.7) †† Percentage of patients HbA1c <7.0% c 17 50 †† Fasting Serum Glucose (mg/dL) (Mean) Baseline 175 178 Change from baseline b 2 -28 Difference from placebo b (95% CI) -30 (-44, -15) †† Body Weight (kg) (Mean) Baseline 89.5 84.5 Change from baseline b -0.2 -0.5 Difference from placebo b (95% CI) -0.4 (-1.2, 0.5) Placebo- and Exenatide-Controlled Trial (Add-on to Metformin and Thiazolidinedione) In this placebo-controlled trial with primary endpoint at 26 weeks, 976 adult patients were randomized to and received placebo, TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or exenatide 10 mcg BID, all as add-on to maximally tolerated doses of metformin (≥1500 mg per day) and pioglitazone (up to 45 mg per day). Exenatide treatment group assignment was open-label while the treatment assignments to placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg were blinded. After 26 weeks, patients in the placebo treatment group were randomized to either TRULICITY 0.75 mg once weekly or TRULICITY 1.5 mg once weekly to maintain blinding. Randomization occurred after a 12-week lead-in period; during the initial 4 weeks of the lead-in period, patients were titrated to maximally tolerated doses of metformin and pioglitazone; this was followed by an 8-week glycemic stabilization period prior to randomization. Patients randomized to exenatide started at a dose of 5 mcg BID for 4 weeks and then were escalated to 10 mcg BID. Patients had a mean age of 56 years; mean duration of type 2 diabetes of 9 years; 58% were male; race: White, Black and Asian were 74%, 8% and 3%, respectively; and 81% of the trial population were in the US. Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo (at 26 weeks) and compared to exenatide at 26 weeks ( Table 8 and Figure 5 ). Over the 52-week trial period, the percentage of patients who required glycemic rescue was 8.9% in the TRULICITY 0.75 mg once weekly + metformin and pioglitazone treatment group, 3.2% in the TRULICITY 1.5 mg once weekly + metformin and pioglitazone treatment group, and 8.7% in the exenatide BID + metformin and pioglitazone treatment group. Table 8: Results at Week 26 of TRULICITY Compared to Placebo and Exenatide, All as Add-On to Metformin and Thiazolidinedione in Adult Patients with Type 2 Diabetes Mellitus a Abbreviations: BID = twice daily; HbA1c = hemoglobin A1c. a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 26, primary efficacy was missing for 23%, 10%, 7% and 12% of individuals randomized to placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and exenatide, respectively. b Least-squares (LS) mean adjusted for baseline value and other stratification factors. ‡ Patients included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 119, 269, 271 and 266 individuals randomized to placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and exenatide, respectively. ‡‡ Multiplicity adjusted 1-sided p-value <0.001, for superiority of TRULICITY compared to placebo, assessed only for HbA1c. †† Multiplicity adjusted 1-sided p-value <0.001, for superiority of TRULICITY compared to exenatide, assessed only for HbA1c. ** p<0.001 TRULICITY compared to placebo, assessed only for HbA1c <7.0%. ## p<0.001 TRULICITY compared to exenatide, assessed only for HbA1c <7.0%. 26-Week Primary Time Point Placebo TRULICITY 0.75 mg TRULICITY 1.5 mg Exenatide 10 mcg BID Intent-to-Treat (ITT) Population (N) ‡ 141 280 279 276 HbA1c (%) (Mean) Baseline 8.1 8.1 8.1 8.1 Change from baseline b -0.5 -1.3 -1.5 -1.0 Difference from placebo b (95% CI) - -0.8 (-1.0, -0.7) ‡‡ -1.1 (-1.2, -0.9) ‡‡ - Difference from exenatide b (95% CI) - -0.3 (-0.4, -0.2) †† -0.5 (-0.7, -0.4) †† - Percentage of patients HbA1c <7.0% 43 66** , ## 78** , ## 52 Fasting Serum Glucose (mg/dL) (Mean) Baseline 166 159 162 164 Change from baseline b -5 -34 -42 -24 Difference from placebo b (95% CI) - -30 (-36, -23) -38 (-45, -31) - Difference from exenatide b (95% CI) - -10 (-15, -5) -18 (-24, -13) - Body Weight (kg) (Mean) Baseline 94.1 95.5 96.2 97.4 Change from baseline b 1.2 0.2 -1.3 -1.1 Difference from placebo b (95% CI) - -1.0 (-1.8, -0.3) -2.5 (-3.3, -1.8) - Difference from exenatide b (95% CI) - 1.3 (0.6, 1.9) -0.2 (-0.9, 0.4) - Mean HbA1c adjusted for baseline HbA1c and country. Number of patients with observed data Placebo 141 108 TRULICITY 0.75 mg 280 251 TRULICITY 1.5 mg 279 259 Exenatide 276 242 Figure 5: Adjusted Mean HbA1c at Each Time Point (ITT, MMRM) and at Week 26 (ITT, LOCF) Figure 5 Placebo-Controlled Trial (Add-on to SGLT2i, with or without Metformin) In this 24-week placebo-controlled, double-blind trial, 423 adult patients were randomized to and received TRULICITY 0.75 mg, TRULICITY 1.5 mg, or placebo, as add-on to sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy (96% with and 4% without metformin). Trulicity was administered once weekly, and SGLT2i was administered according to the local country label. Patients had a mean age of 57 years; mean duration of type 2 diabetes of 9.4 years; 50% were male; race: White, Black, and Asian were 89%, 3%, and 0.2%, respectively; and 21% of the trial population was in the US. At 24 weeks, treatment with once weekly TRULICITY 0.75 mg and 1.5 mg resulted in a statistically significant reduction from baseline in HbA1c compared to placebo ( Table 9 ). The mean baseline body weight was 90.5, 91.1, and 92.9 kg in the placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg groups, respectively. The mean changes from baseline in body weight at Week 24 were -2.0, -2.5, and -2.9 kg for placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg, respectively. The difference from placebo (95% CI) was -0.9 kg (-1.7, -0.1) for TRULICITY 1.5 mg. Table 9: Results at Week 24 of TRULICITY as Add-on to SGLT2i in Adult Patients with Type 2 Diabetes Mellitus a Abbreviations: HbA1c = hemoglobin A1c; SGLT2i = sodium-glucose co-transporter-2 inhibitors. a Intent-to-treat population. At Week 24, primary efficacy was missing for 3%, 4%, and 6% of individuals treated with placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg, respectively. b Least-squares mean adjusted for baseline value and other stratification factors. Placebo multiple imputation, using baseline and 24-week values from the placebo arm, was applied to model a washout of the treatment effect for patients missing 24-week values (HbA1c, fasting serum glucose, and body weight). c Patients with missing HbA1c data at Week 24 were considered as non-responders. †† p<0.001 for superiority of TRULICITY compared to placebo, overall type I error controlled. 24-Week Primary Time Point Placebo TRULICITY 0.75 mg TRULICITY 1.5 mg Intent-to-Treat (ITT) Population (N) 140 141 142 HbA1c (%) (Mean) Baseline 8.1 8.1 8.0 Change from baseline b -0.6 -1.2 -1.3 Difference from placebo b (95% CI) - -0.7 (-0.8, -0.5) †† -0.8 (-0.9, -0.6) †† Percentage of patients HbA1c <7.0% c 31 59 †† 67 †† Fasting Serum Glucose (mg/dL) (Mean) Baseline 153 162 161 Change from baseline b -6 -25 -30 Difference from placebo b (95% CI) - -19 (-25, -13) -24 (-30, -18) †† Insulin Glargine Controlled Trial (Add-on to Metformin and Sulfonylurea) In this open-label comparator trial (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 52 weeks, 807 adult patients were randomized to and received TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or insulin glargine once daily, all as add-on to maximally tolerated doses of metformin and glimepiride. Randomization occurred after a 10-week lead-in period; during the initial 2 weeks of the lead-in period, patients were titrated to maximally tolerated doses of metformin and glimepiride. This was followed by a 6- to 8-week glycemic stabilization period prior to randomization. Patients randomized to insulin glargine were started on a dose of 10 units once daily. Insulin glargine dose adjustments occurred twice weekly for the first 4 weeks of treatment based on self-measured fasting plasma glucose (FPG), followed by once weekly titration through Week 8 of treatment, utilizing an algorithm that targeted a fasting plasma glucose of <100 mg/dL. Only 24% of patients were titrated to goal at the 52-week primary endpoint. The dose of glimepiride could be reduced or discontinued after randomization (at the discretion of the investigator) in the event of persistent hypoglycemia. The dose of glimepiride was reduced or discontinued in 28%, 32%, and 29% of patients randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg, and glargine. Patients had a mean age of 57 years; mean duration of type 2 diabetes of 9 years; 51% were male; race: White, Black and Asian were 71%, 1% and 17%, respectively; and 0% of the trial population were in the US. Treatment with TRULICITY once weekly resulted in a reduction in HbA1c from baseline at 52 weeks when used in combination with metformin and sulfonylurea ( Table 10 ). The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%. Table 10: Results at Week 52 of TRULICITY Compared to Insulin Glargine, Both as Add-on to Metformin and Sulfonylurea in Adult Patients with Type 2 Diabetes Mellitus a Abbreviations: HbA1c = hemoglobin A1c. a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 52, primary efficacy was missing for 17%, 13% and 12% of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and glargine, respectively. b Least-squares (LS) mean adjusted for baseline value and other stratification factors. ‡ Patients included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 267, 263 and 259 individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg, and glargine, respectively. 52-Week Primary Time Point TRULICITY 0.75 mg TRULICITY 1.5 mg Insulin Glargine Intent-to-Treat (ITT) Population (N) ‡ 272 273 262 HbA1c (%) (Mean) Baseline 8.1 8.2 8.1 Change from baseline b -0.8 -1.1 -0.6 Fasting Serum Glucose (mg/dL) (Mean) Baseline 161 165 163 Change from baseline b -16 -27 -32 Difference from insulin glargine b (95% CI) 16 (9, 23) 5 (-2, 12) - Body Weight (kg) (Mean) Baseline 86.4 85.2 87.6 Change from baseline b -1.3 -1.9 1.4 Difference from insulin b (95% CI) -2.8 (-3.4, -2.2) -3.3 (-3.9, -2.7) - Placebo-Controlled Trial (Add-on to Basal Insulin, with or without Metformin) In this 28-week placebo-controlled, double-blind trial, 300 adult patients were randomized to placebo or once weekly TRULICITY 1.5 mg, as add-on to titrated basal insulin glargine (with or without metformin). Patients had a mean age of 60 years; mean duration of type 2 diabetes of 13 years; 58% were male; race: White, Black, and Asian were 94%, 4%, and 0.3%, respectively; and 20% of the trial population was in the US. The mean starting dose of insulin glargine was 37 units/day for patients receiving placebo and 41 units/day for patients receiving TRULICITY 1.5 mg. At randomization, the initial insulin glargine dose in patients with HbA1c <8.0% was reduced by 20%. At 28 weeks, treatment with once weekly TRULICITY 1.5 mg resulted in a statistically significant reduction in HbA1c compared to placebo ( Table 11 ). Table 11: Results at Week 28 of TRULICITY Compared to Placebo as Add-On to Basal Insulin in Adult Patients with Type 2 Diabetes Mellitus a Abbreviations: HbA1c = hemoglobin A1c. a Intent-to-treat population. At Week 28, primary efficacy was missing for 12% and 8% of individuals randomized to placebo and TRULICITY 1.5 mg, respectively. b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. Placebo multiple imputation, with respect to baseline values, was used to model a wash-out of the treatment effect for patients having missing Week 28 data. c Patients with missing HbA1c data at Week 28 were considered as non-responders. †† p<0.001 for superiority of TRULICITY 1.5 mg compared to placebo, overall type I error controlled. † p≤0.005 for superiority of TRULICITY 1.5 mg compared to placebo, overall type I error controlled. 28-Week Primary Time Point Placebo TRULICITY 1.5 mg Intent-to-Treat (ITT) Population (N) 150 150 HbA1c (%) (Mean) Baseline 8.3 8.4 Change from baseline b -0.7 -1.4 Difference from placebo b (95% CI) -0.7 (-0.9, -0.5) †† Percentage of patients HbA1c <7.0% c 33 67 †† Fasting Serum Glucose (mg/dL) (Mean) Baseline 156 157 Change from baseline b -30 -44 Difference from placebo b (95% CI) -14 (-23, -4) † Body Weight (kg) (Mean) Baseline 92.6 93.3 Change from baseline b 0.8 -1.3 Difference from placebo b (95% CI) -2.1 (-2.9, -1.4) †† Insulin Glargine-Controlled Trial (Combination with Prandial Insulin, with or without Metformin) In this open-label comparator trial (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 26 weeks, 884 adult patients on 1 or 2 insulin injections per day were enrolled. Randomization occurred after a 9-week lead-in period; during the initial 2 weeks of the lead-in period, patients continued their pre-trial insulin regimen but could be initiated and/or up-titrated on metformin, based on investigator discretion; this was followed by a 7-week glycemic stabilization period prior to randomization. At randomization, patients discontinued their pre-trial insulin regimen and were randomized to TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or insulin glargine once daily, all in combination with prandial insulin lispro 3 times daily, with or without metformin. Insulin lispro was titrated in each arm based on preprandial and bedtime glucose, and insulin glargine was titrated to a fasting plasma glucose goal of <100 mg/dL. Only 36% of patients randomized to glargine were titrated to the fasting glucose goal at the 26-week primary timepoint. Patients had a mean age of 59 years; mean duration of type 2 diabetes of 13 years; 54% were male; race: White, Black and Asian were 79%, 10% and 4%, respectively; and 33% of the trial population were in the US. Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a reduction in HbA1c from baseline. The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4% ( Table 12 ). Table 12: Results at Week 26 of TRULICITY Compared to Insulin Glargine, Both in Combination with Insulin Lispro in Adult Patients with Type 2 Diabetes Mellitus a Abbreviation: HbA1c = hemoglobin A1c a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 26, primary efficacy was missing for 14%, 15%, and 14% of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and glargine, respectively. b Least-squares (LS) mean adjusted for baseline value and other stratification factors. ‡ Patients included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 275, 273 and 276 individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg, and glargine, respectively. 26-Week Primary Time Point TRULICITY 0.75 mg TRULICITY 1.5 mg Insulin Glargine Intent-to-Treat (ITT) Population (N) ‡ 293 295 296 HbA1c (%) (Mean) Baseline 8.4 8.5 8.5 Change from baseline b -1.6 -1.6 -1.4 Fasting Serum Glucose (mg/dL) (Mean) Baseline 150 157 154 Change from baseline b 4 -5 -28 Difference from insulin glargine b (95% CI) 32 (24, 41) 24 (15, 32) - Body Weight (kg) (Mean) Baseline 91.7 91.0 90.8 Change from baseline b 0.2 -0.9 2.3 Difference from insulin glargine b (95% CI) -2.2 (-2.8, -1.5) -3.2 (-3.8, -2.6) - 14.4 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus and Moderate to Severe Chronic Kidney Disease In this open-label comparator trial (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 26 weeks, a total of 576 adult patients with type 2 diabetes were randomized and treated to compare TRULICITY 0.75 mg and 1.5 mg with insulin glargine (NCT01621178). Patients on insulin and other antidiabetic therapy (e.g., oral antidiabetic drugs, pramlintide) had non-insulin therapies discontinued and had their insulin dose adjusted for 12 weeks prior to randomization. Patients on insulin therapy alone maintained a stable insulin dose for 3 weeks prior to randomization. At randomization, patients discontinued their pre-trial insulin regimen and patients were randomized to TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or insulin glargine once daily, all in combination with prandial insulin lispro. For patients randomized to insulin glargine, the initial insulin glargine dose was based on the basal insulin dose prior to randomization. Insulin glargine was allowed to be titrated with a fasting plasma glucose goal of ≤150 mg/dL. Insulin lispro was allowed to be titrated with a preprandial and bedtime glucose goal of ≤180 mg/dL. Patients had a mean age of 65 years; a mean duration of type 2 diabetes of 18 years; 52% were male; race: White, Black, and Asian were 69%, 16%, and 3%, respectively; and 32% of the trial population were in the US. At baseline, overall mean eGFR was 38 mL/min/1.73 m 2 , 30% of patients had eGFR <30 mL/min/1.73 m 2 , and 45% of patients had macroalbuminuria. Patients on over 70 units/day of basal insulin were excluded from the trial. Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a reduction in HbA1c at 26-weeks from baseline. The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%. Mean fasting plasma glucose increased in the TRULICITY arms ( Table 13 ). Mean baseline body weight was 90.9 kg, 88.1 kg, and 88.2 kg in the TRULICITY 0.75 mg, TRULICITY 1.5 mg, and insulin glargine arms, respectively. The mean changes from baseline at Week 26 were -1.1, -2, and 1.9 kg in the TRULICITY 0.75 mg, TRULICITY 1.5 mg, and insulin glargine arms, respectively. Table 13: Results at Week 26 of TRULICITY Compared to Insulin Glargine, Both in Combination with Insulin Lispro, in Patients with Moderate to Severe Chronic Kidney Disease in Adult Patients with Type 2 Diabetes Mellitus a Abbreviation: HbA1c = hemoglobin A1c a Intent-to-treat population (all randomized and treated patients) was used in the analysis regardless of discontinuation of study drug or initiation of rescue therapy. At Week 26, primary efficacy was missing for 12%, 15%, and 9% of individuals randomized to and treated with TRULICITY 0.75 mg, TRULICITY 1.5 mg, and insulin glargine, respectively. Missing data were imputed using multiple imputation within treatment group. b Least-squares (LS) mean from ANCOVA pattern mixture model adjusted for baseline value and other stratification factors. 26-Week Primary Time Point TRULICITY 0.75 mg TRULICITY 1.5 mg Insulin Glargine Intent-to-Treat Population (N) 190 192 194 HbA1c (%) (Mean) Baseline 8.6 8.6 8.6 Change from baseline b -0.9 -1.0 -1.0 Difference from insulin glargine b (95% CI) 0.0 (-0.2, 0.3) -0.1 (-0.3, 0.2) Percentage of patients HbA1c <8.0% 73 75 74 Fasting Serum Glucose (mg/dL) (Mean) Baseline 167 161 170 Change from baseline b 6 14 -23 Difference from insulin glargine b (95% CI) 30 (16, 43) 37 (24, 50) 14.5 Cardiovascular Outcomes Trial in Adults with Type 2 Diabetes Mellitus and Cardiovascular Disease or Multiple Cardiovascular Risk Factors The REWIND trial (NCT01394952) was a multi-national, multi-center, randomized, placebo-controlled, double-blind trial. In this trial, 9901 adult patients with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple cardiovascular risk factors were randomized to TRULICITY 1.5 mg or placebo both added to standard of care. The median follow-up duration was 5.4 years. The primary endpoint was the time to the first occurrence of a composite 3-component Major Adverse Cardiovascular Events (MACE) outcome, which included CV death, non-fatal myocardial infarction (MI), and non-fatal stroke. Patients eligible to enter the trial were 50 years of age or older who had type 2 diabetes mellitus, had an HbA1c value ≤9.5% with no lower limit at screening, and had either established CV disease, or did not have established CV disease but had multiple CV risk factors. Patients who were confirmed to have established CV disease (31.5% of randomized patients) had a history of at least one of the following: MI (16.2%); myocardial ischemia by a stress test or with cardiac imaging (9.3%); ischemic stroke (5.3%); coronary, carotid, or peripheral artery revascularization (18.0%); unstable angina (5.9%); or hospitalization for unstable angina with at least one of the following: ECG changes, myocardial ischemia on imaging, or a need for percutaneous coronary intervention (12.0%). Patients confirmed to be without established CV disease, but with multiple CV risk factors, comprised 62.8% of the randomized trial population. At baseline, demographic and disease characteristics were balanced between treatment groups. Patients had a mean age of 66 years; 46% were female; race: White, Black, and Asian were 76%, 7%, and 4%, respectively. The median baseline HbA1c was 7.2%. The mean duration of type 2 diabetes was 10.5 years and the mean BMI was 32.3 kg/m 2 . At baseline, 50.5% of patients had mild renal impairment (eGFR ≥60 but <90 mL/min/1.73m 2 ), 21.6% had moderate renal impairment (eGFR ≥30 but <60 mL/min/1.73m 2 ), and 1.1% of patients had severe renal impairment (eGFR <30 mL/min/1.73m 2 ) out of 9713 patients whose eGFR were available. At baseline, 94.7% of patients were taking antidiabetic medication, with 10.5% of patients taking three or more antidiabetic drugs. The most common background antidiabetic drugs used at baseline were metformin (81.2%), sulfonylurea (46.0%), and insulin (23.9%). At baseline, CV disease and risk factors were managed with ACE inhibitors or angiotensin receptor blockers (81.5%), beta blockers (45.6%), calcium channel blockers (34.4%), diuretics (46.5%), statin therapy (66.1%), antithrombotic agents (58.7%), and aspirin (51.7%). During the trial, investigators were to modify anti-diabetic and cardiovascular medications to achieve local standard of care treatment targets with respect to blood glucose, lipids, 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 superiority. Type I error was controlled across multiple tests. TRULICITY significantly reduced the risk of first occurrence of primary composite endpoint of CV death, non-fatal MI, or non-fatal stroke (HR: 0.88, 95% CI 0.79, 0.99). Refer to Figure 6 and Table 14 . Vital status was available for 99.7% of patients in the trial. A total of 1128 deaths were recorded during the REWIND trial. A majority of the deaths in the trial were adjudicated as CV deaths, and non-CV deaths were comparable between the treatment groups (4.4% in patients treated with TRULICITY and 5.0% in patients treated with placebo). There were 536 all-cause deaths (10.8%) in the dulaglutide group compared to 592 deaths (12.0%) in the placebo group. Number of patients at risk Placebo 4952 4791 4625 4437 4275 3575 742 Dulaglutide 4949 4815 4670 4521 4369 3686 741 Figure 6. KAPLAN MEIER CURVE: Time to First Occurrence of MACE in the REWIND Trial Table 14: Treatment Effect for MACE and the Individual Components in the REWIND Trial, Median Trial Observation Time of 5.4 years in Adult Patients with Type 2 Diabetes Mellitus a a All randomized patients. b Cox-proportional hazards model with treatment as a factor. Type I error was controlled for the primary and secondary endpoints. c p=0.026 for superiority (2-sided). d Number and percentage of patients with events. e Results for components of MACE, fatal and non-fatal stroke, and fatal and non-fatal MI are listed descriptively for supportive purposes. No statistical significance should be inferred since these CIs are not adjusted for multiplicity. Time to First Occurrence of: TRULICITY N=4949 Placebo N=4952 Hazard Ratio (95% CI) b Composite of non-fatal myocardial infarction, non-fatal stroke, cardiovascular death (MACE) d 594 (12.0%) 663 (13.4%) 0.88 (0.79, 0.99) c Cardiovascular death d,e 317 (6.4%) 346 (7.0%) 0.91 (0.78, 1.06) Non-fatal myocardial infarction d,e 205 (4.1%) 212 (4.3%) 0.96 (0.79, 1.16) Non-fatal stroke d,e 135 (2.7%) 175 (3.5%) 0.76 (0.61, 0.95) Fatal or non-fatal myocardial infarction d,e 223 (4.5%) 231 (4.7%) 0.96 (0.79, 1.15) Fatal or non-fatal stroke d,e 158 (3.2%) 205 (4.1%) 0.76 (0.62, 0.94) Figure 6 14.6 Glycemic Control Trial in Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus In this 26-week randomized, double-blind, placebo-controlled, parallel-arm, multicenter trial with an open-label extension for an additional 26 weeks,154 pediatric patients 10 years of age and older with type 2 diabetes mellitus, who had inadequate glycemic control despite diet and exercise, were randomized to subcutaneous TRULICITY once weekly (0.75 mg and 1.5 mg) or subcutaneous placebo once weekly in combination with or without metformin and/or basal insulin treatment (NCT02963766). Overall, in this trial demographic and baseline disease characteristics were comparable across the treatment groups. At baseline, 71% of patients were female, and the mean age was 14.5 years (ranging from 10 to 17 years). Overall, 55% were White, 15% were Black or African American, 12% were Asian, 10% were American Indian or Alaska Native, 5% were other races, and 3% had unknown race. Additionally, 55% were Hispanic or Latino, 42% were not Hispanic or Latino, and 3% had unknown ethnicity. At baseline, the mean duration of type 2 diabetes mellitus was 2 years, mean HbA1c was 8.1%, mean weight was 90.5 kg and mean BMI was 34.1 kg/m 2 . In this trial, once weekly TRULICITY (0.75 mg and 1.5 mg, pooled) (with or without metformin and/or basal insulin) was superior to placebo (p<0.001) in the change from baseline at Week 26 in HbA1c in pediatric patients 10 years of age and older with type 2 diabetes mellitus (see Table 15 ). Table 15: Glycemic Results at Week 26 in Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus with Inadequate Glycemic Control Despite Diet and Exercise (With or Without Metformin and/or Basal Insulin) Abbreviations: HbA1c = hemoglobin A1c. a Combined results for TRULICITY 0.75 mg and 1.5 mg. The comparison of the two dosages together and individually with placebo was prespecified with overall type I error controlled. b The change from baseline and difference from placebo were analyzed using analysis of covariance with effects for treatment, the baseline value as a covariate, and stratification factors which were HbA1c at screening (< 8% vs >= 8%), insulin use at baseline (yes/no), metformin use at baseline (yes/no). c For HbA1c and Fasting Blood Glucose, multiple imputation was performed for missing data guided by washout method. At Week 26 primary efficacy (HbA1c) was missing for 8%, 6%, and 10% of patients on placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg respectively. d For percentage of patients HbA1c < 7%, missing data was imputed as not achieving the target. Placebo TRULICITY 0.75 mg once weekly TRULICITY 1.5 mg once weekly TRULICITY once weekly Pooled a Intent-to-Treat Population (N) 51 51 52 103 HbA1c (%) (Mean) c Baseline Change from baseline at Week 26 b Difference from placebo (95% CI) b 8.1 0.6 - 7.9 -0.6 -1.2 (-1.8, -0.6) 8.2 -0.9 -1.5 (-2.1, -0.9) 8.0 -0.8 -1.4 (-1.9, -0.8) Percentage of Patients with HbA1c <7.0% at Week 26 d 14% 55% 48% 52% Fasting Blood Glucose (mg/dL) (Mean) c Baseline Change from baseline at Week 26 b Difference from placebo (95% CI) b 159 17.1 - 149 -12.8 -29.9 (-50.7, -9.1) 163 -24.9 -42.0 (-63.0, -20.9) 156 -18.9 -35.9 (-54.2, -17.6)