Association between intensity of glycemic control with GLP-1 receptor agonists and risk of atherosclerotic cardiovascular disease: a systematic review and meta-regression

Abstract

Abstract Background Several glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown to reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (DM). However, this reduction has not been consistent among different GLP-1 RAs. We conducted a systematic review and meta-regression analyses to evaluate the association between the intensity of glycemic control achieved byGLP-1 RAs therapy in patients with type 2 DM and the reduction of MACE as well as to identify potential mechanisms involved. Methods Electronic databases (MEDLINE, CENTRAL, SCOPUS) were searched through November 2022. Studies were considered eligible if they were cardiovascular outcomes randomized trials (CVOTs) comparing GLP-1 RAs versus placebo in type 2 DM patients. Trials including non-diabetic patients and GLP-1 RAs refused by European Medicines Agency or US Food and Drug Administration were excluded. The outcome of interest was 3-point MACE (CV death, MI, or stroke). Random-effects meta-analyses and meta-regression evaluated associations between glycemic control withGLP-1 RAs and study outcomes. Secondary meta-regression analyses were performed for body weight and blood pressure (BP) variation. Results Overall, 8 CVOTs were included, with a total of 60080 patients (30694 treated withGLP-1 RAs). GLP-1 RAs were associated with a lower incidence of 3P-MACE (RR 0.876; 95% CI 0.821-0.935, p<0.001). Mean HbA1C reduction was 0.57% in patients treated withGLP-1 RAs vs. placebo. Meta-regression showed that higher reductions of HbA1C levels were associated with lower risk of 3P-MACE (Log RR -0.286 [95% CI-0.512; -0.056], p=0.015), which translates into an estimated relative risk reduction of 25% for each 1% reduction in HbA1C (Figure 1A). There was a non-significant association between glycemic control and each of the 3P-MACE outcomes analysed separately. Body weight reduction was also associated with a lower risk of 3P-MACE (Log RR -0.067 [95% CI-0.134; 0.001], p=0.053), despite not meeting statistical significance (Figure 1B). Systolic BP decrease was not associated with reduced risk of 3P-MACE. Conclusions The better the glycemic control withGLP-1 RAs in type 2 DM patients, the greater the reduction in 3P-MACE. Body weight reduction may also play a potential role.Figure 1