The New England Journal of Medicine NOVEMBER 11, 2023

Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT)

A. Michael Lincoff, Kirstine Brown-Frandsen, Helen M. Colhoun, et al.

Bottom Line

In patients with overweight or obesity and established cardiovascular disease but without diabetes, weekly subcutaneous semaglutide 2.4 mg significantly reduced the risk of major adverse cardiovascular events (MACE) compared to placebo.

Key Findings

1. The primary composite outcome (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) occurred in 6.5% of the semaglutide group versus 8.0% of the placebo group, representing a 20% relative risk reduction (hazard ratio, 0.80; 95% CI, 0.72–0.90; P<0.001).

2. Treatment with semaglutide resulted in a mean body weight reduction of 9.4% compared to 0.9% in the placebo group over the course of the study.

3. The benefit in reducing MACE was observed regardless of baseline HbA1c levels or the magnitude of weight loss achieved, suggesting mechanisms beyond simple glycemic or weight-based control.

4. Adverse events leading to treatment discontinuation were more frequent in the semaglutide group (16.6%) compared to the placebo group (8.2%), primarily due to gastrointestinal symptoms.

Study Design

Design

RCT

Double-Blind

Sample

17,604

Patients

Duration

40 mo

Median

Setting

Multicenter, international

Population Adults aged 45 years or older with overweight or obesity (BMI >=27) and established cardiovascular disease, but without a history of diabetes.

Intervention Once-weekly subcutaneous semaglutide 2.4 mg as an adjunct to standard of care.

Comparator Once-weekly matching placebo as an adjunct to standard of care.

Outcome Time from randomization to the first occurrence of a major adverse cardiovascular event (MACE), defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

Study Limitations

• The trial was limited to patients with pre-existing cardiovascular disease and high body mass index, potentially limiting generalizability to broader obesity populations without established cardiovascular disease.

• The study used a targeted safety data collection approach, which may have resulted in underreporting of non-serious adverse events.

• The study did not evaluate long-term outcomes beyond the median follow-up of 40 months, and the influence of potential weight regain post-trial remains unknown.

Clinical Significance

The SELECT trial provides landmark evidence that pharmacotherapy targeting obesity with semaglutide 2.4 mg reduces hard cardiovascular endpoints in a high-risk population without diabetes, establishing weight management as a critical component of cardiovascular risk reduction strategy.

Historical Context

While GLP-1 receptor agonists were previously established to reduce cardiovascular events in patients with type 2 diabetes, the SELECT trial is the first large-scale randomized trial to demonstrate that this class of medication provides definitive cardiovascular protection in individuals with obesity who do not have diabetes, fundamentally changing the management approach to obesity-related cardiovascular risk.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Given that the SELECT trial participants did not have diabetes, what are the primary mechanisms by which a GLP-1 receptor agonist like semaglutide provides cardiovascular protection?

Key Response

GLP-1 receptors are found throughout the cardiovascular system, including on endothelial cells and cardiomyocytes. The benefits likely stem from pleiotropic effects such as reduced systemic inflammation (demonstrated by lower CRP levels), improved endothelial function, blood pressure reduction, and favorable changes in lipid profiles, rather than solely through glucose-lowering pathways.

Resident

For a patient who has a history of myocardial infarction and a BMI of 31 but a normal HbA1c, how does the SELECT trial change your standard of care for secondary prevention?

Key Response

Previously, semaglutide 2.4 mg was primarily indicated for chronic weight management. The SELECT trial demonstrates that in patients with established CVD and obesity/overweight, it provides a 20% relative risk reduction in MACE. This trial supports adding semaglutide to the standard 'four-pillar' therapy (aspirin, statin, ACE-i/ARB, beta-blocker) for secondary prevention in this specific phenotype.

Fellow

The Kaplan-Meier curves for the primary MACE endpoint in SELECT began to diverge significantly within the first 20 weeks of treatment. What does this early divergence imply regarding the relationship between weight loss and cardiovascular risk reduction?

Key Response

The early divergence suggests that the cardiovascular benefit is partially independent of total weight loss, as the reduction in MACE occurred before participants achieved their maximum weight reduction. This indicates that direct vascular effects or rapid anti-inflammatory benefits likely contribute significantly to the trial's positive outcome.

Attending

As we integrate the SELECT findings into practice, how should we navigate the high cost and long-term adherence challenges of GLP-1 RAs compared to established, lower-cost secondary prevention therapies like high-intensity statins?

Key Response

This trial redefines obesity as a modifiable cardiovascular risk factor rather than just a metabolic comorbidity. Clinicians must lead shared decision-making discussions that prioritize therapy based on absolute risk reduction, while advocating for broader insurance coverage by framing these agents as life-saving secondary prevention rather than elective weight-loss medications.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

In the context of the SELECT trial's double-blind design, how might the 'functional unblinding' caused by significant weight loss and common gastrointestinal side effects have influenced the adjudication of the primary endpoints?

Key Response

When a drug has a highly visible physiological effect (weight loss) and a distinct side-effect profile (nausea/vomiting), participants and investigators may correctly guess the treatment assignment. This risk of unblinding can introduce bias in the reporting of subjective symptoms or the frequency of clinical follow-up, which could potentially impact the adjudication of borderline clinical events.

Journal Editor

The SELECT trial utilized a hierarchical testing strategy for secondary endpoints. Since the first secondary endpoint (cardiovascular death) did not reach statistical significance (p=0.07), how does this affect the interpretation of the subsequent heart failure and all-cause mortality data?

Key Response

Under a hierarchical testing framework, once a primary or preceding secondary endpoint fails to meet the significance threshold, all subsequent p-values must be considered nominal or exploratory. A rigorous reviewer would insist that the benefits for heart failure and total mortality be described as such to avoid overstating the evidence for these outcomes.

Guideline Committee

How should the SELECT trial influence the next update of the ACC/AHA or ESC guidelines regarding the Class of Recommendation for GLP-1 RAs in patients with established ASCVD but without diabetes?

Key Response

The SELECT trial provides high-quality (Level A) evidence for a population previously not covered by GLP-1 RA recommendations. Guideline committees must decide if this warrants a Class I recommendation for all patients with CVD and BMI ≥27, which would represent a major shift from current guidelines (e.g., 2019 ACC/AHA Primary Prevention) that primarily emphasize these agents for those with type 2 diabetes.

Clinical Landscape

Noteworthy Related Trials

2015

EMPA-REG OUTCOME Trial

n = 7,020 · NEJM

Tested

Empagliflozin 10mg or 25mg daily

Population

T2DM patients with established CVD

Comparator

Placebo

Endpoint

3-point MACE

Key result: Empagliflozin significantly reduced the primary composite outcome of cardiovascular death, nonfatal MI, or nonfatal stroke compared to placebo.

2016

LEADER Trial

n = 9,340 · NEJM

Tested

Liraglutide 1.8mg daily

Population

T2DM patients with high CV risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Liraglutide significantly reduced the rate of first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

2016

SUSTAIN-6 Trial

n = 3,297 · NEJM

Tested

Semaglutide 0.5mg or 1.0mg weekly

Population

T2DM patients with high CV risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: The rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide.

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