A Study of Tirzepatide in Participants With Type 2 Diabetes Mellitus (T2DM)

The Effect of Tirzepatide on α and β Cell Function and Insulin Sensitivity in Patients With Type 2 Diabetes Mellitus

This is a study for participants with type 2 diabetes mellitus. The main purpose of this study is to learn more about how tirzepatide, semaglutide and placebo affect the body's ability to respond to blood sugar levels after a meal. The study will last up to 40 weeks, including a 28-week treatment period.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Tirzepatide; Drug: Placebo; Drug: Semaglutide

• Study Type: Interventional
• Enrollment (Actual): 117
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Nordrhein-Westfalen
    • Neuss, Nordrhein-Westfalen, Germany, 41460
      • Profil Institut für Stoffwechselforschung
  • Rheinland-Pfalz
    • Mainz, Rheinland-Pfalz, Germany, 55116
      • Profil Mainz GmbH & Co. KG

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Have T2DM for at least 6 months
• Treated with diet and exercise and stable dose(s) of metformin, with or without 1 additional stable dose of oral antihyperglycemia medication other than metformin, 3 months prior to study entry
• Have a hemoglobin A1c (HbA1c) value at screening of ≥7% and ≤ 9.5 % if on metformin only; or ≥6.5% and ≤9.0% if on metformin in combination with oral antihyperglycemia medications other than metformin
• Have a body mass index (BMI) between 25 and 45 kilograms per square meter (kg/m² ) inclusive, at screening; are of stable weight (±5%) >3 months prior to screening

Exclusion Criteria:

• Have a history of proliferative retinopathy or maculopathy as determined by the investigator based on a recent (<1.5 years) ophthalmologic examination
• Impaired renal estimated glomerular filtration rate (eGFR) <45 milliliters per minute per 1.73 square meters (mL/min/1.73 m²) calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
• Have a history or current cardiovascular, respiratory, hepatic, renal, GI,endocrine, hematological or neurological disorders capable of significantly altering the absorption, metabolism or elimination of drugs; of constituting a risk when taking the study drug; or of interfering with the interpretation of data

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tirzepatide 15 mg; Participants received 15 milligram (mg) tirzepatide administered subcutaneously (SC) once weekly for 28 weeks.	Drug: Tirzepatide; Administered SC; Other Names: LY3298176
Active Comparator: Semaglutide 1 mg; Participants received 1 mg Semaglutide administered SC once weekly for 28 weeks.	Drug: Semaglutide; Administered SC
Placebo Comparator: Placebo; Participants received Placebo administered SC once weekly for 28 weeks.	Drug: Placebo; Administered SC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Total Clamp Disposition Index (cDI)	cDI is defined as the product of the M-value derived from the hyperinsulinemic euglycemic clamp over the last 30 minutes and total insulin secretion (ISR AUC0-120min) derived from the insulin secretion rate based on C-peptide using the using the deconvolution technique divided by the total glucose AUC0-120min from the hyperglycemic clamp portion of the study. Least squares (LS) mean was determined by analysis of covariance (ANCOVA) model for endpoint measures: log(Actual Measurement/Baseline) = log(Baseline) + Treatment (Type III sum of squares).	Baseline, Week 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Fasting Glucose	Fasting glucose is a test to determine sugar levels in blood sample after an overnight fast. Fasting glucose was measured prior to standardized mixed-meal tolerance tests (sMMTT). LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline + Treatment (Type III sum of squares).	Baseline, Week 28
Change From Baseline in Postmeal Glucose	Total AUC from time zero to 240 minutes after start of the meal [AUC0-240min]) during sMMTT was evaluated. LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline + Treatment (Type III sum of squares) and ANOVA model for baseline measures: Variable = Treatment (Type III sum of squares).	Baseline, Week 28
Change From Baseline in Hemoglobin A1c (HbA1c)	HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. LS mean was determined by mixed model repeated measures; (MMRM) model for post-baseline measures: Variable = Baseline + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 28
Change From Baseline in Total Insulin Secretion Rate During the 120-Minute Hyperglycemic Clamp (ISR0-120min)	Total Insulin Secretion Rate During the 120-Minute Hyperglycemic Clamp (ISR0-120min) will be determined from C-peptide concentrations using the deconvolution technique. LS mean was determined by ANCOVA model for endpoint measures: log(Actual Measurement/Baseline) = log(Baseline) + Treatment (Type III sum of squares).	Baseline and Week 28
Change From Baseline in Hyperinsulinemic Euglycemic Clamp M-value	Hyperinsulinemic euglycemic clamp M-value is calculated from glucose infusion rate (GIR) over the last 30 minutes, corresponding to steady-state (+150 to +180 minutes), corrected for urine loss and space. LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline + Treatment (Type III sum of squares).	Baseline, Week 28
Change From Baseline in Glucagon Concentration at Fasting	Glucagon concentration was measured prior to sMMTT. LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline + Treatment (Type III sum of squares).	Baseline and Week 28
Change From Baseline in Glucagon Concentration at Postmeal	Total AUC from time zero to 240 minutes after start of the meal [AUC0-240min]) during sMMTT. LS mean was determined by ANCOVA model for endpoint measures: Variable = Baseline + Treatment (Type III sum of squares).	Baseline and Week 28
Change From Baseline in Food Intake During Ad Libitum Meal	Ad libitum meal served buffet-style. Food intake was recorded during a 45 minute period. The sum of the caloric breakdown (carbohydrates, protein, and fats) was calculated from the respective nutritional information of the food items. LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 28

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Publications and helpful links

General Publications

• Heise T, Mari A, DeVries JH, Urva S, Li J, Pratt EJ, Coskun T, Thomas MK, Mather KJ, Haupt A, Milicevic Z. Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial. Lancet Diabetes Endocrinol. 2022 Jun;10(6):418-429. doi: 10.1016/S2213-8587(22)00085-7. Epub 2022 Apr 22.

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2019
• Primary Completion (Actual): April 8, 2021
• Study Completion (Actual): April 8, 2021

Study Registration Dates

• First Submitted: May 14, 2019
• First Submitted That Met QC Criteria: May 14, 2019
• First Posted (Actual): May 15, 2019

Study Record Updates

• Last Update Posted (Actual): March 20, 2023
• Last Update Submitted That Met QC Criteria: June 8, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Tirzepatide
• Other Study ID Numbers: 17091; I8F-MC-GPGT (Other Identifier: Eli Lilly and Company); 2018-003343-37 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes