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

Sponsor

Chang Gung Memorial Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT04419337

Collaborator

National Taiwan University Hospital (Other), Chiayi Christian Hospital (Other)

550

Enrollment

Location

Arms

25.5

Anticipated Duration (Months)

21.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 recurrent stroke and the key secondary outcome is occurrence of major cardiovascular events by trial end. 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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus Stroke	Drug: Metformin plus Pioglitazone plus an SGLT2 inhibitor	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

550 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 15, 2021

Anticipated Primary Completion Date :

Jul 31, 2023

Anticipated Study Completion Date :

Jan 31, 2024

Arms and Interventions

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.

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

Outcome Measures

Primary Outcome Measures

recurrent stroke [Each participant will be followed up to 60 months]
first event of ischemic or hemorrhagic stroke

Secondary Outcome Measures

major adverse cardiovascular event [Each participant will be followed up to 60 months]
nonfatal stroke, nonfatal myocardial infarction, cardiovascular death
All-cause mortality [Each participant will be followed up to 60 months]
any cause of death
UACR [6 months from randomization]
to evaluate microalbuminuria
hs-CRP [6 months from randomization]
to evaluate hs-CRP
NT-proBNP [6 months from randomization]
to evaluate NT-proBNP in active vs control arms
insulin resistance [6 months from randomization]
Insulin resistance will be evaluated by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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