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Jump to Key Points Some reassuring news for cardiologists who hesitate to treat older patients who have frailty with GLP-1 receptor agonists: In addition to tolerating semaglutide, these patients appear to derive greater functional and symptomatic benefits.
The findings, from a secondary analysis of the SELECT trial published online in JAMA Cardiology, highlight a possible therapy as the US is aging at a historic pace.
The study evaluated whether baseline frailty influences cardiovascular efficacy, safety, and health outcomes of weekly semaglutide (2.4 mg) in adults with overweight or obesity and cardiovascular disease without diabetes.
How Frailty Was Measured
In the double-blind, randomized SELECT trial (17,604 participants aged 45 years or older; mean age, 61.6 years; 72.3% men), researchers evaluated frailty using a 31-item frailty index (FI) constructed via the Rockwood cumulative deficit approach.
- Semaglutide reduced MACE across frailty strata; no significant heterogeneity.
- Higher baseline frailty = higher CV event, hospitalization, mortality, kidney risk.
- Frail patients had greater HRQoL gains; mobility/self-care/usual activities improved.
- Semaglutide improved frailty trajectory: +33.7% vs 18.0% category improvement.
- GI discontinuation ↑ overall; serious AEs ↓, including cardiac/infectious/respiratory.
Rather than measuring physical weakness or gait speed alone, the FI quantified accumulated age-related deficits across four domains: medical history, vital signs, lab biomarkers (eg, low hemoglobin or abnormal estimated glomerular filtration rate), and self-reported health-related quality of life.
Participants were categorized into three baseline frailty strata:
- Not Frail: (FI ≤ 0.210). Few or no health deficits (31% of study population)
- More Frail (FI, 0.211-0.310). Moderate accumulation of chronic conditions and functional limitations (47% of study population)
- Most Frail (FI ≥ 0.311). High burden of accumulated deficits and significantly reduced physiologic reserve (22% of study population)
Big Wins Across the Spectrum
Over a mean follow-up of 39 months, the risk for cardiovascular events rose steeply with higher baseline frailty. However, semaglutide consistently reduced the primary composite outcome — cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke — across all frailty categories with no significant heterogeneity (P for interaction = .09).
Secondary outcomes demonstrated similarly consistent benefits regardless of baseline frailty, including reductions in composite heart failure outcomes (P for interaction = .82), all-cause hospitalization (P for interaction = .71), all-cause mortality (P for interaction = .28), and composite kidney outcomes (P for interaction = .09).
Additionally, semaglutide was associated with greater reductions in new-onset biochemical diabetes among participants with higher frailty (P for interaction = .006).
Quality of Life and Frailty Trajectory
Patients with higher baseline frailty experienced significantly greater improvements in health-related quality of life, measured by EuroQol 5-Dimension 5-Level index scores (P for interaction = .02), particularly across mobility (P = .05), self-care (P = .049), and usual activities (P = .03).
By week 104, semaglutide significantly improved overall frailty trajectories.
- Odds of improvement. Patients had 2.46 times higher odds of improving their FI category vs placebo (33.7% vs 18.0%; P < .001).
- Odds of worsening. Patients had 53% lower odds of frailty progression vs placebo (10.0% vs 19.3%; odds ratio, 0.47; P < .001).
Safety and Tolerability Profiles
Serious adverse events occurred less frequently with semaglutide than with placebo across all frailty subgroups, driven by lower rates of serious cardiac, infectious, and respiratory disorders. Serious bone and joint injuries were rare and did not increase with semaglutide therapy, even among the most frail patients.
While overall drug discontinuations due to adverse events (primarily gastrointestinal) were higher with semaglutide, the relative risk of stopping treatment due to adverse events decreased as baseline frailty increased (P for interaction = .001).
Customizing Treatment
The study findings were consistent with expected clinical event reductions, and the magnitude of quality-of-life improvements was noteworthy, said lead author John W. Ostrominski, MD, MPH, preventive cardiologist and obesity medicine specialist at Brigham and Women’s Hospital and Harvard Medical School in Boston.
Researchers didn’t expect patients with frailty to derive greater benefits on how they felt and functioned, and compared with placebo, patients with greater frailty were less likely to discontinue semaglutide because of safety events, Ostrominski said.
“However, decisions to initiate and maintain GLP-1RA-based therapies in persons with frailty should remain individualized,” he added.
Dennis Bruemmer, MD, PhD, cardiologist at the Cleveland Clinic in Cleveland, emphasized the need for a tailored clinical approach.
“The average age in the SELECT trial was 61 years, and this study was not specifically designed to assess whether the muscle loss seen with GLP-1 receptor agonists increases frailty or, for example, fall risk in the elderly population,” Bruemmer pointed out.
“Assessing the extent of obesity and comorbidities, baseline muscle mass, functional tolerance, nutrition, and fall risk in the elderly population all should contribute to the development of an individualized weight-loss management approach and dosing regimen of a GLP-1 receptor agonist,” Bruemmer added.
Ostrominski reported receiving grant support from AstraZeneca and serving on advisory boards or having speaker engagements with Bayer AG, Corcept Therapeutics, and Viking Therapeutics.
Bruemmer is a consultant for Bayer Healthcare Pharmaceuticals, Inc.
Lois Anzelowitz Levine is a lifestyle and medical writer in Lawrenceville, New Jersey.
