Efficacy and Safety of Novel Diabetes Drugs for Stroke Prevention: Systematic Review, Meta-analysis, and Meta-regression
Cecelia Barry1, Gabriela Trifan2, Fernando Testai3
1University of Illinois College of Medicine, 2UIC, Department of Neurology, 3University of Illinois at Chicago
Objective:
Investigate efficacy and safety of sodium–glucose cotransporter 2 inhibitors (SGLT2i) as well as glucagon-like peptide 1 receptor (GLP-1RA) and peroxisome proliferator-activated receptor-γ agonists (PPAR-γ) on stroke prevention.
Background:
Data from randomized clinical trials (RCT) show that novel diabetic drugs (NDD) reduce the risk of major cardiovascular events. Clinical equipoise remains on their effect on stroke risk.
Design/Methods:
We performed a systematic database search from inception to September 30, 2023, to identify RCTs that investigated the efficacy of NDD on stroke outcomes. The primary outcome was total stroke rate, and the safety outcome was overall mortality rate, as defined in each trial. Effect size was represented by risk ratio (RR), and analyses were done using random-effects models. Heterogeneity was assessed by I2 statistics. In meta-regression analysis, we investigated the association of glycated hemoglobin levels (HbA1c) with stroke risk.
Results:
We analyzed 27 RCTs (9 studies- GLP-1RA, 6 studies- PPAR- γ and 12 studies- SGLT2i), comprising 166,991 patients. The mean±SD age was 64.3±3.4 years, and the average time on study drug was 114 weeks. The NDD had a reduction in the stroke risk of 12% (RR=0.88, 95% CI 0.81-0.95, I2=29%) and a reduction in mortality risk of 13% (RR=0.87, 95% CI 0.81-0.93; I2=72%), relative to placebo. The average±SD least-squares mean differences for HbA1c levels were lower by 0.6± 0.3% for treatment group compared to placebo. In meta-regression analyses, HbA1c levels did not significantly affect stroke risk (β=-0.01, 95% CI -0.48-0.47).
Conclusions:
NDD reduce the risk of stroke compared to placebo and this effect seems to be independent of HbA1c levels. Mortality risk had high heterogeneity, suggesting a need for carefully designed trials investigating the effect of NDD on stroke outcomes specifically.