Glucagon-Like Peptide-1 Receptor Agonists and Major Adverse Cardiovascular Events in Patients With and Without Diabetes: A Meta-Analysis of Randomized-Controlled Trials

Abstract

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown encouraging results regarding cardiovascular outcomes mainly in patients with diabetes. In the present study, we compared the efficacy of GLP-1 RAs in cardiovascular events between patients with and without diabetes.

Methods: After finding eligible studies assessing the impact of GLP-1 RAs on cardiovascular events in patients with and without diabetes using a systematic search, we performed a meta-analysis on randomized-controlled trials (RCTs) comparing cardiovascular outcomes between patients taking GLP-1 RAs and placebo stratified by the presence or absence of diabetes. Relative risk (RR) and its 95% confidence interval (CI) were set as the reporting effect size using the random-effects model.

Results: A total of 24 RCTs (50 033 with GLP-1 RAs and 44 514 with placebo) were included. Patients on GLP-1 RAs had lower risk of major adverse cardiovascular events (MACE) (RR 0.87, 95% CI 0.82-0.93), cardiovascular death (RR 0.88, 95% CI 0.82-0.94), myocardial infarction (MI) (RR 0.87, 95% CI 0.77-0.97), stroke (RR 0.86, 95% CI 0.80-0.92), and hospitalization for heart failure (RR 0.90, 95% CI 0.83-0.98). Both subgroups were shown to be effective in terms of MACE and mortality. Nondiabetic patients had decreased risk of hospitalization for heart failure and MI, whereas the diabetic subgroup had marginally nonsignificant efficacy.

Conclusion: The findings of this meta-analysis indicated that patients who are overweight/obese but do not have diabetes have a comparable reduction in the risk of adverse cardiovascular events as those with diabetes. These results need to be confirmed further by large-scale randomized trials in the future.

Keywords: GLP‐1; glucagon‐like peptide‐1; major adverse cardiovascular events; meta‐analysis.

Figure 1

Flowchart showing the study selection process.

Figure 2

Traffic light of the risk of bias assessment (REWIND: the Researching Cardiovascular Events with a Weekly Incretin in Diabetes, AMPLITUDE‐O, Harmony, EXSCEL: the Exenatide Study of Cardiovascular Event Lowering, PIONEER 6: Peptide Innovation for Early Diabetes Treatment 6, STEP‐HFpEF: Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity, SELECT: the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity, LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results, SUSTAIN‐6: Trial to Evaluate Cardiovascular and Other Long‐term Outcomes With Semaglutide in Subjects With Type 2 Diabetes, ELIXA: Evaluation of Lixisenatide in Acute Coronary Syndrome, STEP: Semaglutide Treatment Effect in People with Obesity, SCALE: Satiety and Clinical Adiposity—Liraglutide Evidence in Nondiabetic and Diabetic Individuals).

Figure 3

Comparison between GLP‐1 receptor agonists and placebo stratified by comorbidity in terms of (A) MACE (RR), (B) MACE (HR), (C) all‐cause death, and (D) cardiovascular death. CI, confidence interval; GLP‐1, glucagon‐like peptide‐1; HR, hazard ratio; MACE, major adverse cardiovascular events; RR, relative risk.

Figure 4

Comparison between GLP‐1 receptor agonists and placebo stratified by comorbidity in terms of (A) myocardial infarction, (B) stroke, and (C) hospitalization for heart failure. CI, confidence interval; GLP‐1, glucagon‐like peptide‐1; RR, relative risk.