Comparative Effectiveness of Two Initial Combination Therapies in Patients With Recent Onset Diabetes

Comparative Effectiveness of Two Initial Combination Therapies in Patients With New Onset Diabetes

The primary purpose of this study is to evaluate the efficacy, durability, and mechanism of HbA1c reduction produced by the combination of pioglitazone plus tirzepatide compared to metformin plus sitagliptin in patients with recently diagnosed type 2 diabetes mellitus.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes (Adult Onset)
• Intervention / Treatment: Drug: Tirzepatide; Drug: Pioglitazone; Drug: Sitagliptin; Drug: Metformin HCI XR

Detailed Description

This is a randomized open label controlled 2 arm study (with one of the arms containing 3 sub-groups) which aims to examine the effectiveness and long term effects on HbA1c reduction produced by the combination of pioglitazone plus tirzepatide versus metformin plus sitagliptin in recently diagnosed type 2 diabetes mellitus (T2DM) patients.

A subgroup of patients from group 1 will be invited to participate in a sub-study which lasts for 6 months and aims at exploring the metabolic/molecular mechanisms responsible for the study results. The selection of subjects to each subgroup will be done randomly and the end of sub-study, subjects will continue therapy and follow-up from month 6 on in the main study.

• Study Type: Interventional
• Enrollment (Estimated): 256
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Muhammad Abdul-Ghani, MD; Phone Number: 210-567-6691; Email: abdulghani@uthscsa.edu
• Study Contact Backup: Name: Gozde Baskoy, PhD; Phone Number: 210-358-7200; Email: baskoy@uthscsa.edu

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78207
      • Recruiting
      • University Health System Texas Diabetic Institute
      • Contact: Muhammad Abdul-Ghani, MD; Phone Number: 210-567-2391; Email: abdulghani@uthscsa.edu
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • UT Health Science Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Ability of subject to understand and the willingness to sign a written informed consent document.
2. Males and females; Age 18-75 years
3. Recently (within 5 years) diagnosed Type 2 Diabetes Mellitus (T2DM) patients
4. Drug naïve or receiving metformin monotherapy
5. HbA1c >6.5% (no limit on upper HbA1c value);
6. Willingness to adhere to the investigational product regimen
7. Good general health
8. Stable body weight over the preceding 3 months
9. Agreement to adhere to Lifestyle Considerations throughout study duration.

Exclusion Criteria:

1. positive anti-GAD (antibodies to glutamic acid decarboxylase)
2. pregnancy or plan of becoming pregnant
3. evidence of proliferative diabetic retinopathy,
4. plasma creatinine >1.4 females or >1.5 males;
5. presence of congestive heart failure (CHF);
6. history of cancer (<5 years);
7. prior history of pancreatitis,
8. bladder cancer or family history of thyroid tumors;
9. presence of hematuria in the urine analysis.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group IC; Tirzepatide starting at 2.5mg weekly titrated to 15mg weekly (2.5 month 1, 5mg month 2, 10mg month 3 and 15mg at month 4) with Pioglitazone beginning at 15mg daily and ending at 45mg daily (15mg month 1, 30mg month 2 and 45mg at month 3 onwards).	Drug: Tirzepatide; Tirzepatide:Participants will be initiated on 2.5mg weekly and increase their dose to 5mg at week 4, 10mg at week 8 and 15mg at week 12 as tolerated.; Other Names: Mounjaro; Drug: Pioglitazone; Pioglitazone: Participants will begin therapy at 15mg daily for the first 4 weeks then increase dose to 30mg at week 4 and to 45 mg at week 8, as tolerated.; Other Names: Actos
Active Comparator: Group II; Metformin starting at 1000mg XR daily and Sitagliptin 100mg daily at week 4, Metformin will be increased to 200mg.	Drug: Sitagliptin; Sitagliptin: will be administered as a 100mg dose once daily.; Other Names: Januvia; Drug: Metformin HCI XR; Metformin will be administered at a dose of 1000mg for the first 4 weeks and then the dose increased to 2000mg.; Other Names: Extended Release Metformin
Active Comparator: Group IA; Tirzepatide will be started at 2.5mg and increased to 15mg by month 4. At month 6, Pioglitazone will be added to the Tirzepatide, 15 mg daily.	Drug: Tirzepatide; Tirzepatide:Participants will be initiated on 2.5mg weekly and increase their dose to 5mg at week 4, 10mg at week 8 and 15mg at week 12 as tolerated.; Other Names: Mounjaro; Drug: Pioglitazone; Pioglitazone: Participants will begin therapy at 15mg daily for the first 4 weeks then increase dose to 30mg at week 4 and to 45 mg at week 8, as tolerated.; Other Names: Actos
Active Comparator: Group 1B; Pioglitazone will be started at 15mg and increased to 45 mg by month 3. At month 6, tirzepatide 2.5mg will be started and increased weekly as tolerated.	Drug: Tirzepatide; Tirzepatide:Participants will be initiated on 2.5mg weekly and increase their dose to 5mg at week 4, 10mg at week 8 and 15mg at week 12 as tolerated.; Other Names: Mounjaro; Drug: Pioglitazone; Pioglitazone: Participants will begin therapy at 15mg daily for the first 4 weeks then increase dose to 30mg at week 4 and to 45 mg at week 8, as tolerated.; Other Names: Actos

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
number of subjects achieving HbA1c <6.5% at 6 months (Efficacy)	Therapy failure will be determined as HbA1c >6.5% in two consecutive HbA1c measurements 3 months apart. Time to cumulative incidence of therapy failure curves will be created in subjects receiving pioglitazone/tirzepatide versus subjects receiving metformin/sitagliptin	6 months
Number of subjects failing to achieving HbA1c <6.5% Long-term	The failure to achieving HbA1c <6.5% (Durability) at the end of study in subjects receiving pioglitazone/tirzepatide (Group I) versus metformin/sitagliptin (Group II) in two consecutive HbA1c measurements 3 months apart.	month 60

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in insulin sensitivity	Matsuda Index of insulin sensitivity or total glucose disposal measured with the clamp.These are the gold standard methods for quantification insulin sensitivity with the OGTT or a euglycemic clamp	from baseline to end of study (60 months)
Change in Beta Cell Function	A calculated value using plasma glucose, insulin and C-peptide concentrations during the Oral Glucose Tolerance Test (OGTT) test.	Baseline to end of study (60 months)
Change in body weight	Change from study beginning to end, measured in kilograms (kg)	Baseline to end of study (60 months)

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)
• Investigators: Principal Investigator: Muhammad Abdul-Ghani, MD, The University of Texas Health Science Center at San Antonio

Study record dates

Study Major Dates

• Study Start (Actual): November 7, 2024
• Primary Completion (Estimated): April 30, 2029
• Study Completion (Estimated): June 30, 2029

Study Registration Dates

• First Submitted: January 30, 2024
• First Submitted That Met QC Criteria: January 30, 2024
• First Posted (Actual): February 7, 2024

Study Record Updates

• Last Update Posted (Actual): March 10, 2026
• Last Update Submitted That Met QC Criteria: March 9, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Amino Acids, Peptides, and Proteins; Proteins; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thiazoles; Azoles; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide Receptors; Receptors, G-Protein-Coupled; Receptors, Cell Surface; Membrane Proteins; Receptors, Gastrointestinal Hormone; Receptors, Peptide; Pyrazines; Triazoles; Thiazolidinediones; Pioglitazone; Sitagliptin Phosphate; Tirzepatide
• Other Study ID Numbers: STUDY00000139; R01DK097554 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data will be shared with other researchers at study completion when all data are analyzed and as summary results in ClinicalTrials.gov.
• IPD Sharing Time Frame: At study completion at the time of publication.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

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.: No