Study reveals how semaglutide not only aids in weight loss but also offers a surprising defense against severe infections, including COVID-19, in at-risk populations.

Study: The Effect of Semaglutide on Mortality and COVID-19–Related Deaths: An Analysis From the SELECT Trial. Image Credit: MillaF / Shutterstock

In a recent study published in The Journal of The American College of Cardiology, researchers assessed the effects of semaglutide on mortality.

The obesity epidemic has led to a global increase in obesity-related complications. Besides, obesity is associated with a heightened risk of all-cause mortality across populations. It aggravates various cardiovascular (CV) risk factors and is, per se, an independent risk factor for CV mortality. Improving obesity-related mortality is challenging as fewer interventions yield clinically meaningful, safe, and sustained weight loss.

While observational studies report associations between bariatric surgery or intentional weight loss and reduced mortality, no randomized clinical trials show that weight loss therapies augment CV outcomes. The Semaglutide Effects on CV Outcomes in Patients with Obesity or Overweight (SELECT) trial found a statistically significant reduction in the rate of all-cause mortality among patients receiving semaglutide compared to placebo recipients.

Besides, semaglutide also reduced the primary composite endpoint (CV death, non-fatal myocardial infarction, or non-fatal stroke). However, it is important to note that the reduction in CV deaths did not reach the prespecified threshold for statistical significance, meaning subsequent analyses should be viewed as hypothesis-generating rather than confirmatory.

The coronavirus disease 2019 (COVID-19) pandemic ensued after the SELECT trial commenced. The most severe COVID-19 periods were concurrent with the trial, thus allowing for studying the effects of COVID-19 in patients at risk of COVID-19 complications and mortality and whether semaglutide could modify the risk.

About the study

In the present study, researchers evaluated the effects of semaglutide on CV, non-CV, and all-cause mortality. The SELECT trial investigated semaglutide in decreasing the risk of the primary composite endpoint in 17,604 patients with overweight/obesity and CV disease but without diabetes. Eligible participants were aged ≥ 45 and had a body mass index (BMI) ≥ 27 kg/m² and CV disease (symptomatic peripheral artery disease, prior myocardial infarction, or prior stroke).

Patients were randomized to receive 2.4 mg semaglutide or placebo once weekly for 16 weeks. Randomization occurred between October 2018 and March 2021, thus overlapping with COVID-19 periods. The present study assessed the effects of semaglutide on all-cause death, non-CV and CV death, and COVID-19 death.

A clinical events committee independently reviewed deaths to determine the cause. The SELECT trial prospectively collected clinical information on COVID-19 treatment, outcomes, and death shortly after the pandemic began. Time-to-event outcomes were examined using hazard ratios estimated from a Cox proportional hazards model. However, it is essential to acknowledge that competing risks, such as non-CV death during the pandemic, could have influenced the observed effects on CV death rates, as non-CV deaths might have ‘competed’ with CV deaths as causes of mortality. The study employed the Aalen-Johansen estimator to account for these competing risks, which is more accurate than traditional methods in such scenarios.

Findings

In the SELECT trial, 833 deaths occurred over a median of 3.3 years of follow-up. Of these, 58% were CV deaths, and 42% were non-CV deaths. Lower rates of all-cause death, non-CV death, and CV mortality were noted among semaglutide recipients than in the placebo group. However, it is crucial to note that the lower rate of non-CV death with semaglutide was largely due to fewer infection-related deaths, especially those due to COVID-19, rather than a broad reduction across all non-CV death causes.

In general, consistently lower mortality rates were observed in the semaglutide group across subgroups (age, race, sex, heart failure, renal function) compared to placebo subjects.

Notably, there was a trend toward a higher treatment effect with semaglutide in patients with glycated hemoglobin levels ≥ 6% for non-CV and all-cause death compared to placebo. The most common cause of CV death was sudden cardiac death. Infections and malignancy were the most common causes of non-CV death. Overall, 24.2% of patients reported COVID-19 diagnosis.

Semaglutide did not decrease the number of patients with COVID-19 compared to placebo. However, among patients with COVID-19, fewer semaglutide recipients had serious adverse events related to COVID-19. Patients with COVID-19 were more likely to have a non-CV cause of death. However, an inverse relationship was observed in those without COVID-19. The study highlighted that this unexpected pattern might be due to the unique circumstances of the pandemic, which increased the prominence of non-CV deaths as competing risks.

Throughout the trial, 137 non-CV deaths were reported among those with COVID-19. Fewer deaths were adjudicated as COVID-19-related in the semaglutide arm. Numerically, fewer deaths occurred in the semaglutide arm in COVID-19 subgroups. Most non-CV deaths occurred after COVID-19 onset. Rates of CV death were lower before and after the pandemic in both arms and did not increase during the pandemic.

Conclusions

Together, once-weekly 2.4 mg semaglutide reduced all-cause mortality by 19%, CV deaths by 15%, and non-CV deaths by 23% among non-diabetic obese or overweight patients with CV disease. However, it is important to recognize that the reduction in non-CV deaths was primarily due to fewer deaths from infections, particularly COVID-19, and not necessarily from a broader reduction across all causes of non-CV death. Further, non-CV death may have been a competing risk for CV death during the pandemic.

Subjects with COVID-19 were more likely to have a non-CV death, while those without COVID-19 were more likely to die from CV causes. The study’s findings are significant, but they should be interpreted cautiously, considering the limitations, including the potential for misclassification of causes of death and the unique circumstances of the COVID-19 pandemic. Overall, the findings underscore the mortality benefit of semaglutide and reinforce that obesity and overweight elevate mortality risks through several etiologies, which can be modified with potent therapies like semaglutide.