Semaglutide’s Cardioprotective Effects Extend Beyond Weight Loss, SELECT Trial Confirms

Key Takeaways:

• Semaglutide significantly reduced major adverse cardiovascular events (MACE) in adults with overweight or obesity and established cardiovascular disease, regardless of baseline body weight.
  
• Reductions in waist circumference contributed partly – but not fully – to the observed cardioprotective benefits, suggesting mechanisms beyond weight loss.
  
• Early divergence in cardiovascular outcomes between the semaglutide and placebo groups indicates that benefits emerge rapidly after treatment initiation.
  
  
  

Semaglutide’s impact on heart health goes beyond weight loss

A landmark study published in The Lancet has revealed that semaglutide, a Glucagon-Like Peptide 1 Receptor Agonist (GLP-1RA), offers cardiovascular protection in people with overweight and obesity that cannot be explained by weight loss alone. The findings come from the large-scale SELECT trial, which explored the drug’s effect on major adverse cardiovascular events (MACE) in individuals without diabetes but with established cardiovascular disease.

GLP-1 receptor agonists were originally developed for glycaemic control in type 2 diabetes but have since demonstrated additional benefits, including weight reduction and decreased cardiovascular risk. Obesity itself increases cardiovascular mortality and morbidity through metabolic, inflammatory, and haemodynamic pathways. However, simple measures such as body weight fail to differentiate between fat and lean mass or between subcutaneous and visceral fat – the latter being more strongly associated with cardiovascular disease.

Until now, the relationship between changes in adiposity induced by GLP-1RAs and subsequent cardiovascular outcomes has remained unclear.

About the SELECT trial

The SELECT trial was a randomised, double-blind, placebo-controlled, phase 3 study evaluating whether semaglutide, used alongside standard care, could reduce cardiovascular events in adults with overweight or obesity. The trial enrolled 17,604 participants aged 45 years or older with a body mass index (BMI) of at least 27 kg/m² and established cardiovascular disease (defined as a history of myocardial infarction, stroke, or symptomatic peripheral artery disease).

Participants were randomly assigned to receive either once-weekly semaglutide injections or a placebo, with a gradual 16-week dose escalation to a target of 2.4 mg from week 17 onwards. The primary endpoint was MACE – a composite measure including non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death.

Researchers analysed both baseline measures of adiposity (including waist circumference and body weight) and treatment-induced changes over time. Associations between these factors and MACE were assessed using a Cox proportional hazards model, with additional analyses distinguishing early (week 20) and long-term (week 104) effects.

Key findings

The mean follow-up period was nearly 40 months, with participants exposed to semaglutide for an average of 33.3 months and placebo for 35.1 months. Across all baseline body habitus measures, semaglutide reduced MACE incidence compared with placebo.

Higher baseline BMI was associated with female sex, younger age, non-Asian nationality, higher blood pressure, prediabetes, and greater inflammatory burden. Within both study arms, individuals with lower baseline adiposity had a lower MACE risk. In the semaglutide group, MACE risk fell by approximately 4% for every 5 kg reduction in baseline weight, although this trend was not significant in the placebo group. For waist circumference, both groups showed a 4% lower risk per 5 cm smaller baseline measurement.

By week 20, the rate of first MACE events had already diverged between the groups (hazard ratio [HR] 0.58), demonstrating an early cardioprotective effect.

At this point, mean changes in body weight and waist circumference were −6.4% and −5.0 cm in the semaglutide group, compared with −0.8% and −1.1 cm in the placebo group. These early changes accounted for about 70% of the total reductions seen at week 104. Importantly, 11% of all MACE events occurred within the first 20 weeks of treatment.

In the semaglutide group, greater reductions in waist circumference were associated with a lower subsequent MACE risk (HR 0.91; 95% CI 0.84–0.98; p = 0.02), while weight loss alone was not linearly linked to reduced risk. Among placebo recipients, those who lost at least 5% of their weight experienced higher MACE incidence and all-cause mortality, possibly reflecting unintentional or illness-related weight loss.

At week 104, semaglutide recipients who achieved the greatest weight loss had the lowest MACE incidence, whereas placebo recipients with comparable weight loss had the highest.

Waist circumference emerged as a stronger predictor

Analyses indicated that waist circumference reduction was a partial mediator of semaglutide’s cardiovascular benefits. Accounting for early changes in waist circumference reduced the treatment hazard ratio from 0.80 to 0.86 – suggesting that about one-third (33%) of the cardioprotective effect could be attributed to reduced abdominal fat, while the remainder likely involves other physiological mechanisms.

Crucially, time-varying changes in overall weight did not mediate the observed cardiovascular outcomes, underscoring that semaglutide’s heart-protective properties extend beyond simple weight loss.

Implications and limitations

The authors concluded that semaglutide was superior to placebo in reducing cardiovascular risk across all baseline weight and waist circumference levels, and that its benefits became evident early in treatment. They emphasised that early body weight reductions did not independently explain these benefits.

They cautioned, however, that analyses performed after randomisation were exploratory and not causal. The predominantly White, male study population also limits generalisability to broader groups, including women and ethnically diverse populations.

Despite these caveats, the findings strengthen the evidence that semaglutide’s cardioprotective effects go beyond adiposity reduction, pointing to additional metabolic, vascular, or anti-inflammatory mechanisms.

The SELECT trial was funded by Novo Nordisk, and is registered under ClinicalTrials.gov identifier NCT03574597.