A Study of LY2409021 in Participants With Type 2 Diabetes Mellitus

• LY2409021 (Drug): Administered orally
• Sitagliptin (Drug): Administered orally
• Placebo (Drug): Administered orally
• Metformin (Drug): Administered orally
• Sulfonylurea (Drug): Administered orally

Primary outcomes

• Change From Baseline to 6 Months in Hepatic Fat Fraction [Baseline, 6 months]: The hepatic fat fraction (HFF) was calculated by a core imaging laboratory from noncontrast magnetic resonance imaging (MRI) of the liver. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit.

Secondary outcomes

• Change From Baseline to 6 Months in Alanine Aminotransferase Levels [Baseline, 6 months]: Alanine aminotransferase (ALT) assessed by a central laboratory. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit.
• Number of Participants With Hepatobiliary Adverse Events of Special Interest (AESI) [Baseline, 6 months]: Number of participants with ALT or AST greater than 3 times the upper limit of normal at a post-baseline visit. A summary of other non-serious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section.
• Change From Baseline to 6 Months in Fasting Lipids Levels [Baseline, 6 months]: Lipid values (cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides) assessed by a central laboratory. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit.
• Change From Baseline to 6 Months in Fasting Blood Glucagon [Baseline, 6 months]: Glucagon values assessed by a central laboratory. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit.
• Change From Baseline to 6 Months in Body Weight [Baseline, 6 months]: Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit.
• Change From Baseline to 6 Months in Hemoglobin A1c (HbA1c) [Baseline, 6 months]: HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, visit, baseline score, and treatment-by-visit.
• Change From Baseline to 6 Months in Fasting Plasma Glucose [Baseline, 6 months]: Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit.
• Change From Baseline to 6 Months in Blood Pressure [Baseline, 6 months]: Seated systolic blood pressure (SBP) and seated diastolic blood pressure (DBP) were measured in triplicate throughout the study. At each visit, all available blood pressure measurements for a subject were averaged to provide the blood pressure for that visit. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit.
• Change From Baseline to 6 Months in Pulse Rate [Baseline, 6 months]: Seated pulse rate was measured in triplicate throughout the study. At each visit, all available pulse measurements for a subject were averaged to provide the pulse for that visit. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit.
• Change From Baseline to 6 Months in 7-Point Self-Monitoring of Blood Glucose (SMBG) [Baseline, 6 months]: 7-point profile consists of pre-meal and 2-hour postprandial SMBG measurements for the morning, midday, and evening meals in 1 day and at 3 AM (nocturnal blood glucose measurement). Pre-meal measurements were taken before the subject began eating the meal. Participants recorded their glucose measurements in their study diaries.
• Population Pharmacokinetics: Apparent Clearance of LY2409021 [Day 1 Month 1, 3, 6, 9, predose, 1 hour postdose,]: Reported as a Population Estimate with % Standard Errors of Estimation (SEE), 5th-95th confidence interval.
• Population Pharmacokinetics: Apparent Volume of Distribution of LY2409021 [Day 1 Month 1, 3, 6, 9, predose, 1 hour postdose,]
• Rate of Hypoglycemic Events Adjusted Per 30 Days [Baseline through 6 months]: Documented symptomatic hypoglycemia, an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration <=70 mg/dL (<=39 mmol/L),is presented. Rate: (30 days) is calculated as: (number of episodes during the time period divided by the number of days during the time period) multiplied by 30.
• Number of Participants With Hypoglycemic Events [Baseline through 6 months]: Documented symptomatic hypoglycemia, an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration <=70 mg/dL (<=39 mmol/L), is presented. The number of subjects with an event are subjects who had at least one episode of documented symptomatic hypoglycemia during the time period.

Sex: All, ages: 18 Years to 79 Years

Inclusion Criteria:

* Have been treated with a stable dose of metformin for at least 3 months and have been treated with an optimally effective and stable dose of an sulfonylurea for at least 6 months prior to screening.
* HbA1c value between 7.0% and 10.0%, inclusive.
* Body mass index (BMI) between 20 and 45 kilograms/square meter (kg/m\^2), inclusive.

Exclusion Criteria:

* Known type 1 diabetes mellitus.
* More than 1 episode of severe hypoglycemia within 6 months prior to screening.
* Two or more emergency room visits or hospitalizations due to poor glucose control in the 6 months prior to screening.
* Severe gastrointestinal disease that may significantly impact gastric emptying or motility or having undergone gastric bypass or gastric banding surgery.
* Previous history or active diagnosis of pancreatitis.
* Positive hepatitis B surface antigen or hepatitis C antibody.
* Clinical signs or symptoms of liver disease, or hepatic aminotransferases (aminotransferase or alanine aminotransferase) greater than 2.0× upper limit of normal (ULN) or elevated alkaline phosphatase (greater than ULN) unrelated to bone metabolic disease.
* Elevated total bilirubin level (greater than ULN), clinically suspicious signs/symptoms of cirrhosis or history of cirrhosis.
* Current diagnosis, personal history of neuroendocrine tumors, family history of any type of multiple endocrine neoplasia (MEN), or Von Hippel-Lindau.
* Contraindications for magnetic resonance imaging.

Participant flow

Outcome results

• Change From Baseline to 6 Months in Hepatic Fat Fraction (Primary), Least squares mean, percentage: LY2409021 3.65 (2.13 to 5.17); Sitagliptin -0.07 (-1.94 to 1.79); Placebo -0.79 (-2.28 to 0.70)
• Change From Baseline to 6 Months in Alanine Aminotransferase Levels (Secondary), Least squares mean, microgram per Liter (µ/L): LY2409021 9.4 (4.6 to 14.2); Sitagliptin 2.6 (-3.1 to 8.3); Placebo -1.3 (-6.0 to 3.4)
• Number of Participants With Hepatobiliary Adverse Events of Special Interest (AESI) (Secondary), Count of participants, Participants: LY2409021 0; Sitagliptin 1; Placebo 1
• Change From Baseline to 6 Months in Fasting Lipids Levels (Secondary), Least squares mean, millimol per liter (mmol/L): LY2409021 0.468 (0.222 to 0.714); Sitagliptin 0.006 (-0.282 to 0.295); Placebo 0.130 (-0.110 to 0.371)
• Change From Baseline to 6 Months in Fasting Blood Glucagon (Secondary), Least squares mean, picomol per liter (pmol/L): LY2409021 44.06 (36.36 to 51.76); Sitagliptin 3.38 (-5.64 to 12.41); Placebo 5.05 (-2.50 to 12.60)
• Change From Baseline to 6 Months in Body Weight (Secondary), Least squares mean, kilograms (kg): LY2409021 0.37 (0.12 to 0.63); Sitagliptin -0.08 (-0.39 to 0.22); Placebo -0.05 (-0.30 to 0.20)
• Change From Baseline to 6 Months in Hemoglobin A1c (HbA1c) (Secondary), Least squares mean, percent of HbA1c: LY2409021 -0.63 (-0.94 to -0.32); Sitagliptin -0.42 (-0.80 to -0.05); Placebo 0.14 (-0.15 to 0.45)
• Change From Baseline to 6 Months in Fasting Plasma Glucose (Secondary), Least squares mean, milligram per decililiter (mg/dL): LY2409021 -20.5 (-34.3 to -6.6); Sitagliptin -9.4 (-26.3 to 7.4); Placebo 6.6 (-7.0 to 20.2)
• Change From Baseline to 6 Months in Blood Pressure (Secondary), Least squares mean, millimeters of mercury (mm/Hg): LY2409021 6.1 (2.7 to 9.5); Sitagliptin 1.1 (-2.9 to 5.2); Placebo 1.8 (-1.5 to 5.1)
• Change From Baseline to 6 Months in Pulse Rate (Secondary), Least squares mean, beats per minutes (bpm): LY2409021 1.5 (-0.6 to 3.7); Sitagliptin 3.5 (0.9 to 6.0); Placebo 1.2 (-0.9 to 3.3)
• Change From Baseline to 6 Months in 7-Point Self-Monitoring of Blood Glucose (SMBG) (Secondary), Mean, mg/dL: LY2409021 -29.4 +/- 40.36; Sitagliptin -8.13 +/- 31.25; Placebo -4.31 +/- 26.69
• Population Pharmacokinetics: Apparent Clearance of LY2409021 (Secondary), Number, Liters per hour (L/h): LY2409021 0.526 (0.454 to 0.598)
• Population Pharmacokinetics: Apparent Volume of Distribution of LY2409021 (Secondary), Number, Liters (L): LY2409021 31.9 (24.5 to 39.3)
• Rate of Hypoglycemic Events Adjusted Per 30 Days (Secondary), Number, number of episodes per day: LY2409021 0.27; Sitagliptin 0.19; Placebo 0.12
• Number of Participants With Hypoglycemic Events (Secondary), Count of participants, Participants: LY2409021 20; Sitagliptin 40; Placebo 68

Adverse events

Serious adverse events by term

Other adverse events by term

9 more terms not shown.

Limitations and caveats: Terminated, The overall benefit-risk profile did not support continued development of LY2409021 for type 2 diabetes.

• Results publication: Kazda CM, Frias J, Foga I, Cui X, Guzman CB, Garhyan P, Heilmann C, Yang JA, Hardy TA. Treatment with the glucagon receptor antagonist LY2409021 increases ambulatory blood pressure in patients with type 2 diabetes. Diabetes Obes Metab. 2017 Aug;19(8):1071-1077. doi: 10.1111/dom.12904. Epub 2017 Mar 27. PMID 28191913

• Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Study director, Eli Lilly and Company