Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a promising class of medications for type 2 diabetes (T2D) management. While their glucose-lowering effects are well-established, their long-term impact on cardiovascular outcomes remains a subject of ongoing research and debate. This systematic review aims to assess the long-term cardiovascular effects of GLP-1 RAs in adults with T2D compared to placebo, standard care, or other glucose-lowering medications. We systematically searched PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) and observational studies published from database inception to April 2024. Two independent reviewers screened the studies and extracted the data. The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke. Secondary outcomes included individual components of MACE, hospitalization for heart failure, and all-cause mortality. We included 15 studies (eight RCTs and seven observational studies) involving over 180,000 participants. GLP-1 RAs were associated with a significant reduction in MACE compared to placebo or standard care (risk ratio: 0.88, 95% CI: 0.82-0.94, p<0.001). GLP-1 RAs also demonstrated superior cardiovascular protection compared to DPP-4 inhibitors and sulfonylureas. The benefits were particularly pronounced in reducing the risk of stroke and MI. Notably, some studies found larger cardiovascular benefits in frail patients. The effects on heart failure outcomes were mixed, with potential attenuated benefits in patients with baseline heart failure. GLP-1 RAs also showed promising effects on renal outcomes and metabolic parameters. The quality of evidence ranged from moderate to high across outcomes. This systematic review provides strong evidence that GLP-1 RAs offer significant cardiovascular benefits in adults with T2D, particularly in reducing MACE, stroke, and MI. The findings support current guidelines recommending GLP-1 RAs as preferred agents in patients with established cardiovascular disease or high cardiovascular risk. However, the variability in effects across different patient subgroups underscores the need for personalized treatment approaches. Future research should focus on head-to-head comparisons between different GLP-1 RAs, long-term follow-up studies, and investigation of combination therapies to further optimize the use of these agents in clinical practice.
