The following is a summary of “GLP-1 Receptor Agonists and Risk of Adverse Cerebrovascular Outcomes in Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials,” published in the July 2023 issue of Endocrinology & Metabolism by Banerjee, et al.
The impact of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on stroke and transient ischemic attacks (TIA) in individuals with type 2 diabetes mellitus (T2DM) has not been definitively established. For a study, researchers sought to combine the effects of GLP-1RAs on adverse cerebrovascular outcomes and explore how baseline factors influence these effects.
A comprehensive search was conducted on PubMed, Embase, Web of Science, Cochrane Library, and clinical trial registry websites for randomized controlled trials (RCTs) lasting ≥24 weeks involving adults with T2DM (PROSPERO: CRD42022331547). Adjudicated cerebrovascular events in the GLP-1RA treatment and control arms were pooled to calculate risk ratios (RR) using a fixed-effects model. Subgroup analyses were conducted based on individual GLP-1RA drugs, treatment duration, and baseline patient characteristics. The quality of evidence was evaluated using the GRADE framework.
A total of 28 RCTs comprising 74,148 patients (57% male; median [range] age 58 [52-67] years, BMI 32 [25.4-37.2] kg/m2, T2DM duration 9 [3.5-15.4] years, treatment duration 52 [24-259] weeks) were included. GLP-1RAs in T2DM were associated with a significantly reduced risk of adverse cerebrovascular outcomes compared to placebo/active comparator (RR, 0.83; 95% CI, 0.76-0.91; I2 = 0%). GLP-1RA therapy was associated with a decreased incidence of nonfatal stroke (RR, 0.85; 95% CI, 0.76-0.94; I2 = 0%) but not a fatal stroke (RR, 0.80; 95% CI, 0.61-1.05; I2 = 0%) when data from cardiovascular outcome trials (n = 8) were analyzed. Utilization of GLP-1RA was not linked to an increased risk of hemorrhagic stroke (3 RCTs; RR, 0.92; 95% CI, 0.51-1.64; I2 = 0%), but it was linked to a lower risk of ischemic stroke (12 RCTs; RR, 0.73; 95% CI, 0.60-0.89; I2 = 0%), and a composite of ischemic stroke/TIA (16 RCTs; RR, 0.76; 95% CI, 0.65-0.90; I2 = 0%). Treatment benefits were influenced by baseline estimated glomerular filtration rate (eGFR) and diabetes duration (P interaction < .1). Statistically significant benefits were observed for dulaglutide and subcutaneous/oral semaglutide (P < .05). Excluding the shorter-acting lixisenatide in sensitivity analysis reduced heterogeneity between individual GLP-1RA effects.
GLP-1RAs, particularly longer-acting formulations, were associated with a reduced risk of ischemic cerebrovascular events in individuals with T2DM. The observed benefits were more pronounced in patients with shorter T2DM duration and higher eGFR.