The impacts of new antidiabetic drugs on the risk of ischemic and hemorrhagic strokes: a comprehensive review and meta-analysis of clinical trials.

Introduction: New classes of antidiabetic drugs reportedly lower the risk of cardiovascular events. This review summarizes the evidence for the effects of these drugs on the risk of stroke in diabetic individuals. Methods: Multiple databases that report stroke outcome data were scrutinized for clinical trials (from inception to June 25, 2023), compared sodium-glucose cotransporter 2 inhibitors (SGLT2-Is), glucagon-like peptide-1 receptor agonists (GLP1-RAs), and dipeptidyl peptidase-4 inhibitors (DPP4-Is), vs. other antidiabetic drugs and placebo. Results: Among the 960 identified trials, 259 satisfied the eligibility criteria. Among these, 177 and 82 trials reported at least one or no stroke events, respectively. In total, 208, 19, and 32 trials had a low, unclear, and high risk of bias, respectively. SGLT2-Is use did not decrease the risk of non-fatal hemorrhagic or ischemic stroke (risk ratio (RR) 0.96; 95% CI 0.87 to 1.06; P = 0.42) vs. either active comparators or placebo. GLP1-RAs use significantly decreased stroke risk (RR: 0.84, 95% CI [0.77, 0.93], p = 0.0005) and ischemic stroke (RR: 0.85, 95% CI [0.77, 0.94], p = 0.002) vs. placebo. However, GLP1-RAs use did not decrease hemorrhagic events vs. active comparators or placebo. DPP4-Is use did not decrease the risk of non-fatal hemorrhagic or ischemic stroke (RR: 0.91; 95% CI [0.83, 1.01], p = 0.07) vs. active comparators or placebo. For all classes, fatal stroke risk did not decrease vs. active comparators or placebo, and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group scores were moderate. Discussion: The use of GLP1-RAs, but not SGLT2-Is or DPP4-Is, may decrease non-fatal stroke risk. Considering these results, the findings may inform the treatment of diabetic people at risk of stroke and the design of new antidiabetic interventional trials. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42017067889, identifier 42017067889.