SELECT: Semaglutide provides CV benefits for adults with obesity, regardless of HbA1c
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Key takeaways:
- Adults with overweight or obesity plus preexisting CVD had a reduction in CV event risk with semaglutide in SELECT.
- Reduced CV risk was observed among all baseline HbA1c groups and regardless of HbA1c change.
ORLANDO — Semaglutide reduces risk for cardiovascular events among adults with overweight or obesity and preexisting cardiovascular disease, regardless of baseline HbA1c or change in HbA1c, according to data from the SELECT trial.
As Healio previously reported, adults with preexisting CVD and overweight or obesity in the SELECT trial receiving once-weekly semaglutide 2.4 mg (Wegovy, Novo Nordisk) had a 20% lower risk for CV events compared with placebo. In new data presented at the American Diabetes Association Scientific Sessions and simultaneously published in Diabetes Care, researchers found CV risk reduction with semaglutide was consistent across all baseline HbA1c groups.
“In this prespecified analysis of SELECT, we demonstrated CV benefits of semaglutide in people with overweight or obesity and established CVD, but without diabetes, are independent of baseline HbA1c and the magnitude of change in HbA1c,” Ildiko Lingvay, MD, MPH, MSCS, professor of medicine at the University of Texas Southwestern Medical Center in Dallas, said during a presentation. “It means that these beneficial effects of semaglutide would be anticipated across the glycemic continuum. Even if a patient has a completely normal HbA1c, they will still benefit from semaglutide for CV risk reduction.”
The SELECT trial enrolled 17,604 adults aged 45 years or older with overweight or obesity and established CVD, which was defined as prior myocardial infarction, stroke or symptomatic peripheral artery disease. Participants were randomly assigned, 1:1, to once-weekly semaglutide 2.4 mg or placebo. HbA1c was measured at baseline and 20 weeks. Participants were divided into three groups: a normoglycemia group with an HbA1c less than 5.7% at baseline, a low-range prediabetes group with an HbA1c of 5.7% to 5.9%, and a high-range prediabetes group with an HbA1c of 6% to 6.4%. Change in baseline HbA1c was assessed from baseline to 20 weeks. HbA1c improvement was defined as more than 0.3 percentage point reduction, and worsening of HbA1c was defined as at least 0.3 percentage points increase from baseline to 20 weeks. Time to first major adverse CV event (MACE) was the primary endpoint of the analysis. MACE was a composite of CV mortality, nonfatal MI or nonfatal stroke.
Semaglutide benefits all HbA1c groups
Of the study participants, 33.5% had normoglycemia at baseline, 34.6% had low-range prediabetes, and 31.9% had high-range prediabetes.
Adults receiving semaglutide in the normoglycemia (HR = 0.82; 95% CI, 0.68-1), low-range prediabetes (HR = 0.77; 95% CI, 0.64-0.93) and high-range prediabetes groups (HR = 0.81; 95% CI, 0.67-0.98) all had reduced risk for MACE compared with placebo. Reduced risk for all individual CV endpoints was seen for adults receiving semaglutide vs. placebo in all HbA1c subgroups. Semaglutide lowered risk for all-cause mortality, with greater risk reduction observed for adults with baseline HbA1c of 6% to 6.4% (HR = 0.64; 95% CI, 0.51-0.8) compared with the other two HbA1c groups.
There was no difference in MACE risk between adults with improved HbA1c from baseline to 20 weeks, those with unchanged HbA1c and those with worsened HbA1c. Of those receiving semaglutide, 54% had a reduction in HbA1c of 0.3 percentage points, whereas 86% of the placebo group had no change in HbA1c.
More research needed
The findings were similar to what was observed in an analysis of change in body weight. Data from another SELECT analysis presented at the European Congress on Obesity in May found adults receiving semaglutide had a reduction in CV risk regardless of body weight change.
“The CV benefits of semaglutide in these people with overweight or obesity who have preexisting CVD are due to pleiotropic factors other than weight or glucose-lowering effects,” Lingvay said.
During a Q&A session, Lingvay stated the findings are not an indication that providers should ignore HbA1c when treating people with overweight or obesity and preexisting CVD.
“The [CV] event rates were higher with higher baseline HbA1c,” Lingvay said. “That means [HbA1c] is still an independent risk of CVD and predicts future events. Semaglutide reduces that risk, irrespective of these glycemic parameters.”
Shivani Misra, MD, PhD, FRCP, a Wellcome Trust fellow, senior clinical lecturer and honorary consultant diabetologist at Imperial College London, noted the findings differed from results of previously published trials among adults with type 2 diabetes that found reductions in HbA1c with other medications were a mediator for CV risk reduction.
“What would be very welcome now is to undertake a mediation analysis to account for additional changes in cardiometabolic risk factors to see if they are mediating these outcomes,” Misra said during a presentation.
Misra said there are several questions that remain unanswered, including whether CV benefits extend to people without preexisting CVD and whether the findings were generalizable since most participants in SELECT were men and non-Hispanic white adults. Misra said more research is also needed to investigate the variability of weight-loss outcomes observed in SELECT to understand which people would most benefit from semaglutide.
“Right now, we’re only seeing our field of vision,” Misra said. “We need to extend our field of vision, diversify who we are studying to really fully understand the benefits of these agents for our patients.”
Reference:
Lingvay I, et al. Diabetes Care. 2024;doi:10.2337/dc24-0764.
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Ryan DH, et al. SELECT Trial – New looks at glycemia, inflammation and heart failure. Presented at: American Diabetes Association Scientific Sessions; June 21-24, 2024; Orlando.
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