Clinical Scorecard: Frailty may not limit semaglutide benefits

At a Glance

Key Highlights

• The primary composite cardiovascular outcome occurred less often with semaglutide than placebo in each frailty category, but there was no statistically significant interaction between frailty and treatment.
• Cardiovascular event incidence increased with greater baseline frailty, irrespective of treatment assignment.
• Patients with greater frailty had larger improvements in health-related quality of life, primarily in mobility, self-care, and usual activities.
• Frailty category improved over 104 weeks in 34% of semaglutide recipients versus 18% of placebo recipients, and worsened in 10% versus 19%.
• Serious adverse events were less frequent with semaglutide, while adverse events leading to permanent discontinuation were more frequent; gastrointestinal events were the most common reason for discontinuation.

Guideline-Based Recommendations

Diagnosis

• Frailty was classified using a 31-item index based on accumulated health deficits: 5,432 participants were classified as not frail, 8,349 as more frail, and 3,823 as most frail.

Management

• The authors stated that baseline frailty should not necessarily preclude consideration of semaglutide in otherwise eligible patients with cardiovascular disease and overweight or obesity.
• The analysis does not establish cardiovascular benefit independently in the least- and most-frail subgroups.

Monitoring & Follow-up

• Assess adverse events leading to permanent treatment discontinuation; these were more frequent with semaglutide across all frailty categories.
• The study assessed frailty-status changes over 104 weeks; frailty category improved in 34% with semaglutide versus 18% with placebo.

Risks

• Permanent treatment discontinuation occurred in 15.5% versus 5.5% of patients without frailty, 16.8% versus 8.3% with intermediate frailty, and 17.6% versus 11.7% with the greatest frailty, for semaglutide versus placebo.
• Gastrointestinal events were the most common reason for discontinuation.
• The subgroup analysis may have been underpowered, did not account for multiple comparisons, and used a deficit-based frailty measure without systematically collected physical characteristics.

Patient & Prescribing Data

SELECT enrolled patients aged 45 years or older with established cardiovascular disease, BMI of at least 27, and no diabetes. The analysis excluded patients with diabetes or end-stage kidney disease and those without established cardiovascular disease or with BMI below 27.

Participants were randomly assigned to semaglutide 2.4 mg once weekly or placebo. Serious adverse events were less frequent with semaglutide across frailty categories, but treatment discontinuation due to adverse events was more frequent.

Clinical Best Practices

• Interpret the frailty subgroup findings as hypothesis-generating; SELECT was not designed specifically to test whether frailty modified cardiovascular treatment effects.
• Do not infer that cardiovascular benefit was independently established in the least- or most-frail subgroups.
• Consider the study's eligibility criteria and frailty measurement when applying its findings to other patient populations.

Related Resources & Content

• SELECT frailty subgroup analysis, JAMA Cardiology (as described in the supplied article)