Durability of Combination Therapy With Exenatide/Pioglitazone/Metformin vs. Conventional Therapy in New Onset T2DM

Durability of Early Initial Combination Therapy With Exenatide/Pioglitazone/Metformin vs Conventional Therapy in New Onset Type 2 Diabetes

Type 2 diabetes is a systemic metabolic disease with significant morbidity and mortality due to damaging blood vessels. Increased blood sugar level is a hallmark of diabetes and is an contributes to the development of many of its complications. Multiple defects, e.g. impaired insulin secretion and impaired insulin action, contribute to the development of the disease. The aim of this study is to test the efficacy and durability of combination of drugs which correct the defects that lead to the development of diabetes on achieving adequate and durable control of blood sugar levels. Achieving adequate and durable control of blood sugar will prevent many of diabetes complications.

Study Overview

• Status: Completed
• Conditions: Diabetes
• Intervention / Treatment: Drug: metformin\pioglitazone\exenatide; Drug: metformin, glyburide and glargine

Detailed Description

Subjects will be randomized (using a table of random numbers) to receive, in open label fashion, one of the following treatment regimens: (i) Group I will be started on pioglitazone (15 mg/day) plus metformin (1000 mg/day) with the supper meal and exenatide (5 mcg s.c. bid 30 min before breakfast and supper) and up-titrated to 45 pioglitazone plus 2000 metformin and 10 mcg s.c. bid exenatide to achieve HbA1c <6.0%; (II) Group II will be started on metformin, 1000 mg with breakfast and 1000 mg with supper, glyburide and basal insulin will be added and up titrated to achieve HbA1c <6.0% The study team will compare the efficacy of two therapeutic regimens: (i) triple therapy (pioglitazone, metformin, exenatide) at the time of diagnosis of T2DM versus (ii) stepwise therapy starting with metformin and subsequent addition of sulfonylurea and basal insulin (i.e., the "standard" approach) in achieving this goal. The first intervention is based on the novel concept of initiating therapy at the time of diagnosis with combination therapy using agents that correct specific pathophysiologic defects that are characteristic of T2DM (insulin resistance and beta cell failure). The second intervention is based upon stepwise addition of antidiabetic agents to reduce the HbA1C according to the current ADA therapeutic recommendation.

• Study Type: Interventional
• Enrollment (Actual): 318
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229-3900
      • Texas Diabetes Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• subjects with type 2 diabetes diagnosed during the past 2 years,
• above 18 years of age,
• drug naive, or have been on metformin less than 3 months

Exclusion Criteria:

• subjects with type 1 diabetes or GAD positive subjects or subjects with long standing diabetes (>2 years) or subjects who are not drug naive or have been on metformin more than 3 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Triple Therapy; initiation a combination of metformin (1000 mg), pioglitazone (15 mg) and exenatide (5 microgram bid) at the time diabetes is diagnosed	Drug: metformin\pioglitazone\exenatide; metformin (1000 mg), pioglitazone (15 mg) and exenatide (5 microgram bid) are started and dose is up titrated to achieve HbA1c < 6.5%
Active Comparator: conventional therapy; sequential addition of metformin, glyburide and basal insulin	Drug: metformin, glyburide and glargine; subjects are started on metformin 500 mg bid and dose is up titrated and glyburide (up to 5 mg) and glargine are sequentially added to maintain HbA1c < 6.5%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HbA1c Level	subjects will be followed for 3 years and the HbA1c measured at this time to provide the values for each arm as defined for the primary outcome of the study	at the end of the study (3 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Failure	Number of participants with HbA1c>6.5% at 3 years	3 years
Percentage of Patients With Reported Hypoglycemic Events	asymptomatic hypoglycemic events with documented PGC < 60 mg/dl and sympotomatic hypoglycemia	during the entire study (3 years)

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); American Diabetes Association; Amylin Pharmaceuticals, LLC.
• Investigators: Principal Investigator: Ralph DeFronzo, MD, The University of Texas Health Science Center at San Antonio

Publications and helpful links

General Publications

• Abdul-Ghani M, Puckett C, Adams J, Khattab A, Baskoy G, Cersosimo E, Triplitt C, DeFronzo RA. Durability of Triple Combination Therapy Versus Stepwise Addition Therapy in Patients With New-Onset T2DM: 3-Year Follow-up of EDICT. Diabetes Care. 2021 Feb;44(2):433-439. doi: 10.2337/dc20-0978. Epub 2020 Dec 3.

Helpful Links

• Publication

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): February 3, 2023
• Study Completion (Actual): February 3, 2023

Study Registration Dates

• First Submitted: April 19, 2010
• First Submitted That Met QC Criteria: April 20, 2010
• First Posted (Estimated): April 21, 2010

Study Record Updates

• Last Update Posted (Actual): September 5, 2024
• Last Update Submitted That Met QC Criteria: August 13, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: type 2 diabetes; combination therapy; new onset; new onset type 2 diabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Obesity Agents; Incretins; Glucagon-Like Peptide-1 Receptor Agonists; Metformin; Pioglitazone; Exenatide; Glyburide
• Other Study ID Numbers: HSC20080456H; 5R01DK103841-03 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified data will be shared with local investigators
• IPD Sharing Time Frame: At study completion after publication in a peer review journal
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP