Wegovy Benefits Heart Disease Patients Regardless of Frailty

Frailty did not appear to prevent adults with cardiovascular disease and overweight or obesity from reaping the benefits of semaglutide (Wegovy), a secondary analysis of SELECT trial data indicated.

By week 104, semaglutide’s risk reduction on the primary outcome — a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke — was consistent across all frailty statuses with no detectable heterogeneity (P=0.09 for interaction), reported John Ostrominski, MD, MPH, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues.

Findings were similar in models when frailty, defined as accumulated age-related deficits, was examined continuously (P=0.30 for interaction), the authors wrote in JAMA Cardiology.

Semaglutide also reduced a composite heart failure outcome (P=0.82 for interaction), all-cause hospitalization (P=0.71 for interaction), and all-cause mortality (P=0.28 for interaction), regardless of frailty category.

“This is an important message of reassurance,” Ostrominski told MedPage Today. “Despite high risks of adverse health outcomes, persons with frailty are often undertreated due to concerns around potentially attenuated benefits or excess safety risks. This analysis suggests that the benefit/risk balance may be favorable for semaglutide, even in persons with frailty.”

Prior research evaluating GLP-1 drugs in people with frailty has been limited but critically needed, he added. The findings align semaglutide with other established cardiometabolic therapies, such as SGLT2 inhibitors and finerenone (Kerendia), which have demonstrated reassuring safety and efficacy profiles across frailty categories.

Participants on semaglutide were more likely to see their frailty category improve (OR 2.46, 95% CI 1.80-3.37) and were less likely to see it worsen (OR 0.47, 95% CI 0.34-0.65), suggesting frailty may be preventable or modifiable, said Ostrominski.

“Obesity is an important risk factor for dysfunction across multiple organ systems, and, therein, is an important risk factor for premature disability and frailty,” he explained. “While further research is certainly needed, these findings suggest that optimal obesity management may improve markers of frailty over time.”

Although the main findings were largely expected, Ostrominski highlighted a key takeaway: frailer participants experienced greater gains in health-related quality of life as measured by EuroQol 5-Dimension 5-Level index scores (P=0.02 for interaction) than those who were not frail, largely driven by improvements in mobility, self-care, and usual activities.

They were also less likely to permanently discontinue semaglutide due to adverse events compared with those in the placebo group (P<0.001 for interaction).

Ultimately, decisions to use GLP-1-based therapies should always be individualized and made in collaboration with a healthcare professional irrespective of frailty status, Ostrominski emphasized. “I would recommend rigorous attention to optimal dietary and physical activity approaches in persons treated with GLP-1 therapies,” he advised.

The post-hoc analysis of the SELECT trial included 17,604 adults with a body mass index of 27 or higher and established cardiovascular disease without diabetes. The average age was 61.6 years and 72.3% were male.

Frailty was measured on a 31-item scale and stratified participants into three categories: not frail (frailty index [FI] score ≤0.210; 31% of cohort), more frail (FI 0.211-0.310; 47%), and most frail (FI ≥0.311; 22%). Frailer participants tended to have a higher body mass index, more obesity-related complications, and worse health-related quality of life. They were also more likely to be older, female, and current or former tobacco users.

Ostrominski emphasized two main limitations. “First, this was a secondary analysis of a clinical trial, so these findings should be cautiously interpreted,” he explained.

“Second, this analysis defined frailty using a frailty index, which reflects a total burden of age-related deficits. While this is a strongly validated approach, other frailty definitions exist, such as physical frailty phenotypes defined by weakness and slow gait speed, among other factors,” Ostrominski added.

The authors noted that despite the large trial size, exploratory frailty subgroups may have been underpowered, making the findings hypothesis-generating.

“Further studies of GLP-1 receptor agonists are needed in these groups, including those with low muscle mass or low muscle function,” Ostrominski concluded.