Risk of major adverse cardiovascular events and stroke associated with treatment with GLP-1 or the dual GIP/GLP-1 receptor agonist tirzepatide for type 2 diabetes: A systematic review and meta-analysis
Maria‐Ioanna Stefanou, Aikaterini Theodorou, Konark Malhotra, Diana Aguiar de Sousa, Mira Katan, Lina Palaiodimou, Aristeidis H. Katsanos, Ioanna Koutroulou, Vaia Lambadiari, Robin Lemmens, Sotirios Giannopoulos, Andrei V. Alexandrov, Gerasimos Siasos, Georgios Tsivgoulis
Abstract
Abstract Introduction: Mounting evidence suggests that glucagon-like-peptide-1 receptor-agonists (GLP-1 RAs) attenuate cardiovascular-risk in type-2 diabetes (T2DM). Tirzepatide is the first-in-class, dual glucose-dependent-insulinotropic-polypeptide GIP/GLP-1 RA approved for T2DM. Patients and methods: A systematic review and meta-analysis of randomized-controlled clinical trials (RCTs) was performed to estimate: (i) the incidence of major adverse cardiovascular events (MACE); and (ii) incidence of stroke, fatal, and nonfatal stroke in T2DM-patients treated with GLP-1 or GIP/GLP-1 RAs (vs placebo). Results: Thirteen RCTs (9 and 4 on GLP-1 RAs and tirzepatide, respectively) comprising 65,878 T2DM patients were included. Compared to placebo, GLP-1RAs or GIP/GLP-1 RAs reduced MACE (OR: 0.87; 95% CI: 0.81–0.94; p < 0.01; I 2 = 37%), all-cause mortality (OR: 0.88; 95% CI: 0.82–0.96; p < 0.01; I 2 = 21%) and cardiovascular-mortality (OR: 0.88; 95% CI: 0.80–0.96; p < 0.01; I 2 = 14%), without differences between GLP-1 versus GIP/GLP-1 RAs. Additionally, GLP-1 RAs reduced the odds of stroke (OR: 0.84; 95% CI: 0.76–0.93; p < 0.01; I 2 = 0%) and nonfatal stroke (OR: 0.85; 95% CI: 0.76–0.94; p < 0.01; I 2 = 0%), whereas no association between fatal stroke and GLP-1RAs was uncovered (OR: 0.80; 95% CI: 0.61–1.05; p = 0.105; I 2 = 0%). In secondary analyses, GLP-1 RAs prevented ischemic stroke (OR: 0.74; 95% CI: 0.61–0.91; p < 0.01; I 2 = 0%) and MACE-recurrence, but not hemorrhagic stroke (OR: 0.92; 95% CI: 0.51–1.66; p = 0.792; I 2 = 0%). There was no association between GLP-1RAs or GIP/GLP-1 RAs and fatal or nonfatal myocardial infarction. Discussion and conclusion: GLP-1 and GIP/GLP-1 RAs reduce cardiovascular-risk and mortality in T2DM. While there is solid evidence that GLP-1 RAs significantly attenuate the risk of ischemic stroke in T2DM, dedicated RCTs are needed to evaluate the efficacy of novel GIP/GLP-1 RAs for primary and secondary stroke prevention.