Pioglitazone and SGLT2 Inhibitors vs. DPP4 Inhibitors in Patients With Stroke

Comparison of Combined Pioglitazone and SGLT2 Inhibitors vs. DPP4 Inhibitors in Diabetic Patients With Ischemic Stroke: Rationale and Study Design

Introduction: An optimal combination of antidiabetic drugs for diabetic patients with ischemic stroke is not well-established. The objective of this randomized trial is to evaluate whether combination of pioglitazone and a sodium glucose cotransporter 2 (SGLT-2) inhibitor, compared with a dipeptidyl peptidase-4 (DPP-4) inhibitor, reduces recurrent stroke in diabetic patients with recent ischemic stroke.

Methods and analysis: The trial is a randomized, parallel-group study conducted at 7 hospitals in Taiwan. Inclusion criteria are adult patients with a history of ischemic stroke within 3 months, diabetes mellitus with Hba1C > 7%, taking metformin currently or previously, and estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2. Eligible patients who sign the informed consent forms will be randomly assigned in a 1:1 ratio to receive either combination of pioglitazone and an SGLT2 inhibitor (empagliflozin or dapagliflozin or canagliflozin) vs. a DPP4 inhibitor. Primary outcome is change in HbA1C between 6 months and baseline in active vs comparator groups. Additional biomarker outcomes are change in hs-CRP insulin resistance, B type natriuretic peptide, and urine albumin creatinine ratio between 6 months and baseline.

Ethics and dissemination Study protocol was approved by the Institutional Review Board of Chang Gung Memorial Hospital, Chiayi Branch, Taiwan (201702353A3, 201802340A3 and 201902176A3). All participants will be required to sign and date an informed consent form. Study findings will be disseminated via a peer-reviewed journal.

Study Overview

• Status: Recruiting
• Conditions: Stroke; Diabetes Mellitus
• Intervention / Treatment: Drug: Metformin plus Pioglitazone plus an SGLT2 inhibitor

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 2

Contacts and Locations

Study Locations

• Taiwan
  • Chiayi City, Taiwan, 613
    • Recruiting
    • Chang Gung Memorial Hospital, Chiayi Branch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Ischemic stroke within 3 months of randomization
2. Type 2 diabetes mellitus and Hba1C > 7.0% and under metformin therapy currently or previously
3. Estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2
4. Age ≥ 20 y at study entry
5. Ability and willingness to provide informed consent

Exclusion Criteria:

1. History of congestive heart failure (NYHA class 1-4)
2. History of bladder cancer
3. History of repeated (> 2 episodes) urinary tract infection or genital tract infection
4. Irreversible medical conditions with predicted survival < 1 years
5. Current use of an insulin
6. Current use of a glucagon-like peptide-1 receptor agonist
7. Current use of pioglitazone or an SGLT-2 inhibitor

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: Active arm; metformin+pioglitazone+an SGLT2 inhibitor	Drug: Metformin plus Pioglitazone plus an SGLT2 inhibitor; Patients assigned to active group will stop their prior oral antidiabetic drugs and receive combination of metformin, pioglitazone, and an SGLT2 inhibitor (empagliflozin or dapagliflozin or canagliflozin) and dose will be adjusted by their physicians.
Active Comparator: Control arm; metformin + DPP4 inhibitors	Drug: Metformin plus Pioglitazone plus an SGLT2 inhibitor; Patients assigned to active group will stop their prior oral antidiabetic drugs and receive combination of metformin, pioglitazone, and an SGLT2 inhibitor (empagliflozin or dapagliflozin or canagliflozin) and dose will be adjusted by their physicians.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HbA1C	blood test to evaluate glycemic control	6 months from baseline in active vs control arms

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NT-proBNP	to evaluate NT-proBNP in active vs control arms	6 months from randomization
insulin resistance	Insulin resistance will be evaluated by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)	6 months from randomization
UACR	to evaluate microalbuminuria	6 months from randomization in active vs control arms
hs-CRP	to evaluate hs-CRP in active vs control arms	6 months from randomization

Collaborators and Investigators

• Sponsor: Chang Gung Memorial Hospital
• Collaborators: National Taiwan University Hospital; Chiayi Christian Hospital; Tainan Sin-lau Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2019
• Primary Completion (Anticipated): July 31, 2023
• Study Completion (Anticipated): January 31, 2024

Study Registration Dates

• First Submitted: February 26, 2020
• First Submitted That Met QC Criteria: June 3, 2020
• First Posted (Actual): June 5, 2020

Study Record Updates

• Last Update Posted (Actual): March 30, 2023
• Last Update Submitted That Met QC Criteria: March 28, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: stroke; pioglitazone; diabetes mellitus; sodium-glucose transport protein 2 inhibitor
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Stroke; Diabetes Mellitus; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Metformin; Pioglitazone; Sodium-Glucose Transporter 2 Inhibitors
• Other Study ID Numbers: MOST 108-2314-B-182-017-

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