What is the robustness of improvement in all-cause mortality for obese patients on Glucagon-like peptide-1 (GLP-1) agonists?

From the Guidelines

The use of GLP-1 agonists, such as semaglutide, in obese patients is associated with a significant reduction in all-cause mortality, primarily due to a decrease in cardiovascular events, as evidenced by the SELECT trial, which showed a hazard ratio of 0.80 for cardiovascular death, MI, or stroke 1. The improvement in all-cause mortality for obese patients on GLP-1 agonists appears promising, with current evidence suggesting a modest mortality benefit. Medications like semaglutide have demonstrated reductions in major adverse cardiovascular events in patients with overweight or obesity without diabetes. Some key points to consider include:

• The SELECT trial showed a significant reduction in the incidence of cardiovascular death, MI, or stroke in patients with pre-existing CVD who were overweight or obese, but without diabetes, treated with weekly subcutaneous semaglutide 1.
• The STEP trials examined the efficacy of semaglutide in individuals with obesity without diabetes, resulting in mean weight loss of 14.9% and 16.0% at 68 weeks, respectively 1.
• The use of GLP-1 agonists is recommended for further weight reduction in patients who have not reached their weight targets through lifestyle modifications alone, as part of a comprehensive weight management plan 1. The mortality benefit likely stems from multiple mechanisms, including weight reduction, improved glycemic control, reduced blood pressure, improved lipid profiles, and potential direct anti-inflammatory effects on blood vessels. For patients considering GLP-1 agonists primarily for mortality benefit, it's essential to understand that the strongest evidence currently exists for those with both obesity and established cardiovascular disease, while data specifically on mortality in otherwise healthy obese individuals remains limited. Key considerations for the use of GLP-1 agonists in clinical practice include:
• Patient selection: identifying individuals who are most likely to benefit from treatment with GLP-1 agonists, such as those with established cardiovascular disease or multiple cardiovascular risk factors.
• Dosing and administration: ensuring that patients receive the recommended dose and administration schedule for the specific GLP-1 agonist being used.
• Monitoring and follow-up: regularly monitoring patients for efficacy and safety, and adjusting treatment as needed to optimize outcomes.

From the Research

Robustness of Improvement in All-Cause Mortality

The robustness of improvement in all-cause mortality for obese patients on Glucagon-like peptide-1 (GLP-1) agonists is supported by several studies:

• A study published in 2025 2 found that patients with hypertrophic cardiomyopathy (HCM) and obesity who received GLP-1 agonists had a significant reduction in all-cause mortality compared to those who did not receive GLP-1 agonists.
• The SELECT trial, published in 2024 3, demonstrated that semaglutide, a GLP-1 receptor agonist, reduced the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in obese and overweight non-diabetic patients with preexisting cardiovascular disease.
• A review article published in 2023 4 summarized the benefits and challenges associated with lifestyle changes, bariatric surgery, and pharmacologic interventions in the treatment of obesity, and highlighted the efficacy and safety of GLP-1 receptor agonists in the management of obesity and potential reduction of cardiovascular disease risk.

Key Findings

Key findings from the studies include:

• GLP-1 agonists are associated with improved survival and lower rates of heart failure hospitalization in patients with obesity and HCM 2.
• Semaglutide reduces the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in obese and overweight non-diabetic patients with preexisting cardiovascular disease 3.
• GLP-1 receptor agonists have been shown to achieve substantial weight loss and improve cardiometabolic risk factors, including glycemic control and blood pressure 5.

Cardiovascular Effects

The cardiovascular effects of GLP-1 receptor agonists have been assessed in several studies:

• A review published in 2018 6 found that GLP-1 RAs have positive effects on weight loss, blood pressure, hyperlipidemia, and glycemic control, and exhibit a broad range of effects on the cardiovascular system that are independent of changes in blood glucose.
• The use of GLP-1 RAs was associated with relative risk reduction in cardiovascular mortality and all-cause mortality, with no significant differences for the incidence of severe hypoglycemia, pancreatitis, pancreatic cancer, or medullary thyroid cancer when compared to placebo 6.