The SELECT Trial: How GLP-1s Became Heart Medications

What Was the SELECT Trial?

SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) was the largest cardiovascular outcomes trial ever conducted specifically in people with obesity. Published in the New England Journal of Medicine in December 2023, the trial was designed to answer a crucial question: Can a GLP-1 medication reduce heart attacks and strokes in people who don't have diabetes?

Previous trials like LEADER and SUSTAIN-6 had shown cardiovascular benefits of GLP-1 medications in diabetic populations, but it was unclear whether these benefits stemmed from glucose control or other mechanisms. SELECT removed diabetes from the equation entirely.

Who Was Enrolled

Participants had to meet all of the following criteria:

• Age 45 years or older
• BMI ≥27 kg/m² (overweight or obese)
• Established cardiovascular disease (prior heart attack, stroke, or symptomatic peripheral artery disease)
• No diabetes (HbA1c <6.5%)

This was a high-risk population: 76% had a prior heart attack, 24% had heart failure, and 18% had a prior stroke. Most participants (72%) were male, with a mean age of 62 years and mean BMI of 33 kg/m².

The Primary Results

Participants were randomized 1:1 to receive either semaglutide 2.4 mg once weekly (the Wegovy dose) or placebo, in addition to standard cardiovascular care including statins and blood pressure medications.

This 20% relative risk reduction was highly statistically significant and clinically meaningful. In absolute terms, this means treating 67 patients with semaglutide for approximately 3 years would prevent one major cardiovascular event.

All three components of the primary endpoint contributed to the benefit, though the reduction in nonfatal heart attack was most pronounced (28% relative risk reduction). Cardiovascular death was reduced by 15% but did not reach statistical significance due to the hierarchical testing framework.

Beyond the Primary Endpoint

The SELECT trial revealed benefits well beyond cardiovascular events. Several secondary analyses have demonstrated the breadth of semaglutide's effects.

Diabetes Prevention

At week 156, 69.5% of participants on semaglutide were normoglycemic compared to just 35.8% on placebo. This finding, published in Diabetes Care, represents a breakthrough for prediabetes treatment.

Metabolic Improvements

• Weight loss: -9.4% with semaglutide vs -0.9% with placebo at 104 weeks
• Blood pressure: -3.8 mmHg systolic with semaglutide vs -0.5 mmHg with placebo
• HbA1c: Sustained 0.32 percentage point reduction throughout study

Heart Failure Benefits

A prespecified analysis published in The Lancet examined the 4,286 participants with heart failure at baseline. Semaglutide reduced:

• MACE by 28% (HR 0.72)
• Heart failure composite by 21% (HR 0.79)
• Cardiovascular death by 24% (HR 0.76)

Benefits were consistent in both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF).

The Key Question: Why Does It Work?

One of the most intriguing findings from SELECT is that cardiovascular benefits appear largely independent of weight loss. A prespecified mediation analysis published in The Lancet in October 2025 found:

Cardiovascular benefits were consistent across all baseline weight categories and were similar regardless of how much weight participants lost. Even participants who lost minimal weight experienced cardiovascular protection.

Potential Mechanisms

Researchers theorize multiple pathways contribute to cardiovascular benefit:

• Anti-inflammatory effects: Significant reduction in high-sensitivity C-reactive protein (hsCRP)
• Direct vascular effects: GLP-1 receptors are expressed on endothelial cells
• Reduced visceral fat: Preferential loss of metabolically active visceral adipose tissue
• Improved lipid handling: Changes in cholesterol and triglyceride metabolism
• Glucose regulation: Prevention of hyperglycemia-related vascular damage

Safety Profile

The trial's safety findings were consistent with previous GLP-1 RA studies, though the discontinuation rate was notable:

Despite higher discontinuation rates with semaglutide, overall serious adverse events were actually lower in the treatment group. The higher discontinuation was driven almost entirely by gastrointestinal side effects (nausea, vomiting, diarrhea), which are known effects of GLP-1 RAs.

FDA Approval: A Historic Moment

The FDA's March 2024 approval was historic. In its announcement, the FDA stated:

The approval has significant implications for Medicare coverage. While Medicare is generally prohibited from covering weight-loss drugs, this cardiovascular indication opens a potential pathway for coverage when prescribed for heart disease prevention rather than weight loss alone.

How Many Americans Could Benefit?

Analysis of National Health and Nutrition Examination Survey data suggests millions of Americans would meet SELECT eligibility criteria. Research published in Circulation estimated:

However, the practical impact may be limited by drug cost, insurance coverage, supply constraints, and physician awareness. As Dr. Martha Gulati of Cedars-Sinai noted after the FDA approval, approximately 70% of her heart patients could potentially be eligible for treatment.

Context: GLP-1s and Cardiovascular Disease

SELECT built upon earlier cardiovascular outcomes trials with GLP-1 medications:

SELECT's importance lies in removing diabetes from the equation. The cardiovascular benefits appear to be a class effect of GLP-1 medications that extends beyond glycemic control—transforming these drugs from diabetes medications that happen to help with weight into cardiovascular medications that happen to cause weight loss.

What This Means for Patients

For patients with established heart disease and overweight or obesity:

• Proven benefit: A 20% reduction in heart attacks, strokes, and cardiovascular death is comparable to the benefit of statins
• Independent of diabetes: Benefits occur regardless of blood sugar status
• Independent of weight loss: Cardiovascular protection occurs even without substantial weight loss
• Additional benefits: 73% reduction in progression to diabetes, improvements in blood pressure, potential heart failure benefits
• FDA-approved indication: Wegovy is now specifically approved for cardiovascular risk reduction, which may improve insurance coverage

The evidence supports semaglutide as a disease-modifying treatment rather than simply a weight-loss drug—a medication that addresses cardiovascular risk through multiple mechanisms beyond weight reduction alone.