Semaglutide was associated with favorable cardiovascular outcomes without statistically significant variation by baseline frailty status among patients with established cardiovascular disease and overweight or obesity but without diabetes. Patients with greater frailty also appeared to experience larger improvements in health-related quality of life.
Researchers analyzed data from 17,604 patients enrolled in the global, double-blind, placebo-controlled SELECT trial. Eligible patients were aged 45 years or older, had established cardiovascular disease, and had a body mass index of at least 27 without diabetes. Patients were randomly assigned to receive once-weekly semaglutide 2.4 mg or placebo. Using a 31-item frailty index based on accumulated health deficits, the researchers classified 5,432 patients (31%) as not frail, 8,349 (47%) as more frail, and 3,823 (22%) as most frail. The mean age was 61.6 years.
The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included heart failure events, all-cause hospitalization, all-cause mortality, kidney outcomes, progression to biochemical diabetes, and health-related quality of life. The researchers also assessed changes in frailty status over 104 weeks and adverse events leading to permanent treatment discontinuation.
The primary cardiovascular outcome occurred in 4.1% of semaglutide recipients vs 4.9% of placebo recipients without frailty, 5.7% vs 8.1% among those with intermediate frailty, and 11.3% vs 12.2% among those with the greatest frailty. These differences corresponded to relative reductions in the hazard of the primary outcome of 16%, 30%, and 8%, respectively. However, the researchers found no statistically significant interaction between baseline frailty and semaglutide treatment. The cardiovascular benefit was not independently established in the least and most frail subgroups.
The incidence of cardiovascular events increased with greater baseline frailty, irrespective of treatment assignment. Among placebo recipients, incidence rates increased from 1.5 events per 100 person-years in patients without frailty to 3.9 events per 100 person-years among those with the greatest frailty. Researchers also observed favorable treatment effects on the composite heart failure outcome, all-cause hospitalization, and all-cause mortality without statistically significant variation across frailty categories.
Semaglutide was associated with larger improvements in health-related quality of life among patients with greater frailty. These differences were primarily driven by improvements in mobility, self-care, and usual activities. Patients receiving semaglutide were also more likely to experience improvements in frailty status over 104 weeks. Frailty category improved in 34% of semaglutide recipients vs 18% of placebo recipients, representing approximately 2.5 times the odds of improvement. Conversely, frailty category worsened in 10% vs 19%, respectively.
Treatment effects on several cardiovascular, kidney, and metabolic risk factors were generally similar or greater among patients with higher baseline frailty. Semaglutide reduced body weight across frailty categories, while reductions in progression to biochemical diabetes were greater among patients with higher frailty scores.
Serious adverse events were less frequent with semaglutide than placebo across all frailty categories. Among patients with the greatest frailty, serious adverse events occurred in 43.8% of semaglutide recipients vs 49% of placebo recipients. However, adverse events leading to permanent treatment discontinuation were more frequent with semaglutide across all frailty categories, occurring in 15.5% vs 5.5% of patients without frailty, 16.8% vs 8.3% of those with intermediate frailty, and 17.6% vs 11.7% of those with the greatest frailty. The relative excess risk of discontinuation with semaglutide decreased as baseline frailty increased. Gastrointestinal events were the most common reason for discontinuation.
The researchers noted that SELECT was not designed specifically to evaluate whether frailty modified semaglutide's cardiovascular effects, and the exploratory subgroup analyses may have been underpowered. Frailty was measured using accumulated health deficits rather than physical characteristics such as muscle weakness, gait speed, or falls, which were not systematically collected. The analysis also did not account for multiple comparisons. Additionally, the exclusion of patients with diabetes or end-stage kidney disease, as well as those without established cardiovascular disease or with a body mass index below 27, also limits generalizability. Researchers cautioned that the findings should be considered hypothesis-generating.
Baseline frailty should not necessarily preclude consideration of semaglutide in otherwise eligible patients with cardiovascular disease and overweight or obesity. Although the researchers found no definitive evidence that baseline frailty modified cardiovascular treatment effects, they observed greater improvements in health-related quality of life among patients with higher frailty scores. “These findings enhance understanding and reassurance around the benefit-risk balance of semaglutide for people with cardiovascular disease and overweight or obesity,” wrote lead study author John W. Ostrominski, MD, of Brigham and Women’s Hospital and Harvard Medical School, and colleagues.
Disclosures: The SELECT trial was sponsored by Novo Nordisk. Several authors reported financial relationships with pharmaceutical companies, including Novo Nordisk, and some were Novo Nordisk employees or shareholders. Ostrominski reported personal fees from Bayer, Corcept Therapeutics, and Viking Therapeutics outside the submitted work. Full disclosures are available in the published study.
Source: JAMA Cardiology
