The multi-target effects of semaglutide make it a breakthrough therapy for managing diabetes and obesity, offering comprehensive benefits particularly for patients with cardiovascular disease. However, its clinical applications for patients with heart failure (HF) are still under active investigation.

To systematically review the efficacy and safety of subcutaneous semaglutide in the treatment of HF regardless of the presence of obesity or type 2 diabetes (T2DM).

We searched Cochrane Library, PubMed, Embase, CNKI, Wanfang Data and VIP database from inception to November 2, 2024 for randomized controlled trials about subcutaneous semaglutide in the treatment of HF, where the experimental group received subcutaneous semaglutide and the control group received placebo. Data on HF hospitalization rate, cardiovascular death rate, all-cause death rate, serious adverse events, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and 6-minute walk distance (6-MWD) were collected and analyzed by two investigators who independently screened the literature, extracted the data, and evaluated the risk of bias of the included studies. Subgroup analyses were performed based on comorbidities and different dosages, and data were statistically analyzed using Review Manager 5.3 software.

A total of 4 randomized controlled studies, with a total of 6 109 patients (3 070 in the experimental group and 3 039 in the control group). Meta-analysis results showed that compared with placebo, subcutaneous semaglutide reduced the risk of cardiovascular death (RR=0.75, 95%CI=0.61-0.92, P=0.005), all-cause death (RR=0.81, 95%CI=0.67-0.98, P=0.03) and serious adverse events (RR=0.53, 95%CI=0.41-0.68, P<0.000 01). Subgroup analysis found that subcutaneous semaglutide could increase KCCQ-CSS (MD=7.58, 95%CI=4.40-10.77, P<0.000 01) and 6-MWD (MD=16.91, 95%CI=8.98-24.83, P<0.000 1) and reduced the risk of HF hospitalization (RR=0.41, 95%CI=0.26-0.65, P=0.000 1) of patients in HF with preserved ejection fraction (HFpEF) with obesity. In patients without T2DM, semaglutide was superior to placebo in reducing the risk of HF hospitalization (RR=0.16, 95%CI=0.04-0.68, P=0.01) and cardiovascular death (RR=0.76, 95%CI=0.60-0.97, P=0.03); similarly, in patients with a weekly dose of 2.4 mg, semaglutide reduced the risk of HF hospitalization (RR=0.29, 95%CI=0.14-0.58, P=0.000 5) and cardiovascular death (RR=0.75, 95%CI=0.59-0.95, P=0.02) compared with placebo, but the efficacy of the weekly dose of 1.0 mg was not significant compared with placebo.

Current evidence shows that subcutaneous semaglutide can reduce the risk of cardiovascular death, all-cause death and serious adverse events of heart failure patients while improving quality of life and activity tolerance and reducing risk of HF hospitalization in patients with HFpEF and obesity. Due to limited quantity and populations of the included studies, more high-quality studies are needed to verify the above conclusion.