Association of Semaglutide Therapy with Weight Loss and Cardiovascular and Heart Failure Risk in Patients with Type 2 Diabetes Mellitus

Abstract

Background: Semaglutide, a GLP-1RA, leads to significant weight reduction, and it has been shown to reduce cardiovascular outcomes through clinical outcome studies. However, evidence on the relationship between the degree of weight loss and the cardiovascular or heart failure outcomes of patients with T2DM is scarce.
Aims: To assess the relationship between treatment with semaglutide versus an active comparator for glucose lowering in terms of (1) body weight change, (2) MACE (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death), and (3) heart failure (HF) hospitalization in adults with T2DM and to identify whether the degree of weight loss impacts cardiovascular or HF risk.
Methods: Retrospective, new-user, active-comparator cohort study design was used where an integrated electronic health record and claims database were employed. Adults with T2DM who newly started on semaglutide were matched 1:1 with those starting on an active comparator (dipeptidyl peptidase-4 inhibitors, sulfonylurea, or basal insulin) through propensity scores based on demographic, clinical, and drug treatment history variables. Co-primary outcome measures included percentage change in body weight at 12 months and 24 months, incidence of MACE, and HF hospitalization, which were determined using Cox proportional hazards models. Subgroup analyses were prespecified to determine whether effect modification exists by age, baseline BMI, and ASCVD.
Results: Analytic cohort consisted of 10,500 patients (5,250 per group; median follow-up 21–22 months). At 12 months and 24 months, semaglutide users had significantly higher percentage weight loss (-10.6% vs -1.4% and -12.4% vs -1.7%, respectively). Incidence of MACE among semaglutide initiators was 4.3% compared to 7.1% in comparators (HR 0.72, 95% CI 0.60-0.87). Also, HF hospitalization risk was lower for semaglutide (HR 0.69, 95% CI 0.52-0.92). The amount of weight lost was inversely related to the risk of HF in a dose-related manner, with the cardiovascular effects of semaglutide being more pronounced in those individuals having BMI ≥35 kg/m² and a history of ASCVD.
Conclusions: This real-world study shows that patients with T2DM on semaglutide treatment experienced clinically significant weight loss and had reduced risk of MACE and HF hospitalization compared to patients on glucose lowering comparator drugs, with patients having the largest weight loss experiencing the greatest cardiovascular benefit from the use of semaglutide. The results of this study further reinforce evidence from randomized clinical trials in support of semaglutide use as a preferred glucose lowering drug in patients with T2DM and cardiovascular disease.