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

Study Overview
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Brief Summary
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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.

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

Conditions
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Diabetes Mellitus, Stroke

Intervention / Treatment
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* Drug: Metformin plus Pioglitazone plus an SGLT2 inhibitor


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active arm<br>metformin+pioglitazone+an SGLT2 inhibitor | Drug: Metformin plus Pioglitazone plus an SGLT2 inhibitor<br>* 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.<br>|
| Active Comparator: Control arm<br>metformin + DPP4 inhibitors | Drug: Metformin plus Pioglitazone plus an SGLT2 inhibitor<br>* 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.<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stroke, diabetes mellitus, sodium-glucose transport protein 2 inhibitor, pioglitazone