Science

The SELECT Trial: What It Means for GLP-1 and Heart Health

GLP-1 Companion · 9 min read

In November 2023, results from the SELECT trial were published in the New England Journal of Medicine and simultaneously presented at the American Heart Association Scientific Sessions. The findings marked a pivotal moment in obesity medicine: for the first time, a weight-loss medication demonstrated a statistically significant reduction in major adverse cardiovascular events in patients without diabetes. The FDA subsequently approved semaglutide 2.4 mg (Wegovy) for cardiovascular risk reduction in March 2024, adding a new indication alongside its existing obesity approval.

SELECT Trial Design

The SELECT trial (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) was a double-blind, randomized, placebo-controlled trial conducted across 804 sites in 41 countries. The key design elements that made it landmark:

• Population: 17,604 adults aged 45 or older with a BMI of 27 or higher
• Cardiovascular inclusion requirement: All participants had established cardiovascular disease — prior heart attack, stroke, or symptomatic peripheral artery disease
• Critical exclusion: Patients with type 2 diabetes or type 1 diabetes were excluded — this was a non-diabetic population only
• Randomization: 1:1 to semaglutide 2.4 mg once weekly or matching placebo, both added to standard-of-care cardiovascular therapy
• Median follow-up: approximately 40 months (3.3 years)
• Primary endpoint: 3-point MACE — composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke

Primary Results: 20% Risk Reduction

The primary endpoint result was both statistically significant and clinically meaningful.

• Semaglutide group: 6.5% experienced a primary MACE event
• Placebo group: 8.0% experienced a primary MACE event
• Hazard ratio: 0.80 (95% CI: 0.72 to 0.90)
• P-value: less than 0.001, confirming statistical significance
• Relative risk reduction: 20%
• Absolute risk reduction: approximately 1.5 percentage points over ~40 months
• Number needed to treat: approximately 67 patients treated for ~40 months to prevent one MACE event

All three components of the composite endpoint showed consistent directional benefit: cardiovascular death (HR 0.85), non-fatal heart attack (HR 0.72), and non-fatal stroke (HR 0.67). The benefit on non-fatal MI and stroke was particularly pronounced.

Weight Loss Results in SELECT

Participants in SELECT lost an average of approximately 9.4 percent of body weight on semaglutide compared to 0.9 percent in the placebo group — a difference of approximately 8.5 percentage points. This is a meaningful but more modest weight loss than seen in the STEP 1 trial (14.9%), likely because SELECT participants were older, had established cardiovascular disease, and were on multiple concomitant medications that can limit weight loss. Despite the more modest weight reduction, the cardiovascular benefit remained robust.

Does the Cardiovascular Benefit Come from Weight Loss Alone?

One of the most scientifically important questions raised by SELECT is whether the cardiovascular benefit is simply a function of weight loss, or whether semaglutide has direct cardioprotective effects beyond its effect on body weight. Several lines of evidence suggest the benefit extends beyond weight loss alone.

• The cardiovascular benefit appeared early — within the first year — before substantial weight loss had accumulated in many participants
• Analyses across weight loss subgroups showed cardiovascular benefit even in participants who lost minimal weight on semaglutide
• Semaglutide produces reductions in C-reactive protein (CRP), interleukin-6, and other inflammatory markers independent of weight loss magnitude
• GLP-1 receptors are expressed in cardiac tissue, endothelial cells, macrophages, and arterial smooth muscle cells — direct receptor engagement may reduce inflammation and improve endothelial function
• Animal models show direct anti-atherosclerotic effects of GLP-1 agonism independent of body weight changes

Current scientific consensus is that the cardiovascular benefit from semaglutide in SELECT is likely mediated through a combination of weight loss and direct pleiotropic anti-inflammatory and cardiometabolic effects. The relative contribution of each pathway remains an active area of research.

FDA Approval for Cardiovascular Risk Reduction

Based on SELECT, the FDA approved a new indication for Wegovy in March 2024: reduction of the risk of serious cardiovascular events such as cardiovascular death, non-fatal heart attack, and non-fatal stroke in adults with established cardiovascular disease and either obesity (BMI ≥30) or overweight (BMI ≥27) with a weight-related comorbidity. This makes Wegovy the first weight-loss medication approved for a cardiovascular risk reduction indication. The practical implication is that insurers and payers now have a clearer medical necessity argument for coverage in patients with established CVD.

Significance for Non-Diabetic Patients

Before SELECT, cardiovascular outcome data for GLP-1 medications existed primarily in patients with type 2 diabetes (LEADER for liraglutide, SUSTAIN-6 for semaglutide 0.5/1 mg). These trials showed benefit, but it was impossible to determine how much was driven by glucose lowering versus direct GLP-1 effects, since diabetes itself is a major cardiovascular risk factor. SELECT was the first large trial to isolate the effect of semaglutide in a non-diabetic population. The finding that benefit persisted in the absence of diabetes-related glucose lowering is strong evidence for direct cardioprotective mechanisms.

Who Is Most Likely to Benefit Based on SELECT?

The SELECT population was specific, and the FDA indication reflects that specificity. The cardiovascular indication applies to patients who have all three of the following:

• Established cardiovascular disease: prior myocardial infarction, stroke, or symptomatic peripheral artery disease
• Overweight or obesity: BMI of 27 or higher
• No type 2 diabetes (or diabetes well-controlled — the indication is primarily for the non-diabetic CVD population)

Patients with obesity and established CVD but without diabetes represent a large clinical population that has historically been undertreated from a pharmacological standpoint. SELECT provides the first high-quality evidence base for treating this group with a GLP-1 agent as part of cardiovascular secondary prevention.

Limitations and Open Questions

• SELECT studied secondary prevention (patients with established CVD) — results may not extrapolate to primary prevention populations
• The trial excluded patients with diabetes, so SELECT findings do not apply directly to diabetic CVD patients (who have separate trials)
• Median follow-up of ~40 months may miss very long-term effects or potential risks
• All-cause mortality trended favorable (HR 0.81) but did not reach statistical significance — the trial was not powered for this endpoint
• Real-world populations may differ from the carefully selected SELECT participants

The Bottom Line

The SELECT trial is one of the most important cardiovascular outcomes studies in obesity medicine. Its demonstration of a robust, statistically significant 20 percent reduction in major adverse cardiovascular events with semaglutide 2.4 mg in patients with obesity but without diabetes changed how clinicians and payers view GLP-1 therapy. The treatment is no longer just about weight loss — for patients with established cardiovascular disease and overweight or obesity, semaglutide is now a cardiovascular risk-reduction medication in its own right.

SELECT showed us that semaglutide benefits the heart through mechanisms that extend beyond pounds lost. For patients with established cardiovascular disease and obesity, it has become part of the secondary prevention toolkit alongside statins, beta-blockers, and ACE inhibitors.

Sources

• Lincoff et al. (2023). Semaglutide and Cardiovascular Outcomes in Obesity. NEJM.
• Wilding et al. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity. NEJM.