Risk-based thresholds enable efficient allocation of GLP-1 receptor agonists in atherosclerotic cardiovascular disease without diabetes
S H J Hageman, F L J VisserenAbstract
Background
GLP-1 receptor agonists (GLP-1RA) reduce cardiovascular events in patients with type 2 diabetes and the SELECT trial recently demonstrated benefit in individuals with established atherosclerotic cardiovascular disease (ASCVD) without diabetes. However, criteria to guide initiation of GLP-1RA in secondary prevention are lacking, potentially limiting widespread implementation.
Purpose
To determine the optimal CVD risk-based treatment threshold for initiating GLP-1RA therapy in individuals with established ASCVD without diabetes.
Methods
Patients with symptomatic ASCVD without diabetes were included from the UCC-SMART cohort (1996–2023). SELECT-trial based eligibility was defined as age ≥45 years, established ASCVD, and BMI ≥27 kg/m². In addition to a no-threshold strategy, treatment initiation was evaluated at 10-year predicted recurrent CVD risk thresholds of 10%, 20%, 30%, and 40%, using the SMART2 algorithm. Treatment effects were estimated by applying hazard ratios from SELECT to predicted risks for recurrent CVD, which as defined as myocardial infarction, stroke or CVD death, (HR 0.80, 95%CI 0.72–0.90) and from the SMART2-HF model for incident heart failure (HR 0.82, 95%CI 0.71–0.96).
Results
Among 6,586 patients with coronary, cerebrovascular, or peripheral artery disease, 1,268 recurrent CVD events occurred during a median follow-up of 9.4 years (IQR 5.0–14.2). Of these individuals, 2,969 (41%) had a BMI of ≥27 kg/m2, meeting the SELECT inclusion criteria. Incorporating SMART2-based risk thresholds markedly reduced the number of treatment-eligible individuals. At a 20% 10-year predicted recurrent CVD risk threshold, 1,125 patients (17%) would be treated, representing a substantial reduction compared with the no-threshold approach. Further restriction to 30% and 40% thresholds reduced eligibility to 399 (6%) and 146 (2%) patients, respectively. Over 10 years, GLP-1RA therapy at 20%, 30%, and 40% thresholds would prevent 56, 25, and 10 recurrent CVD events and 29, 13, and 6 incident HF events, respectively, versus 98 CVD and 48 HF events if everyone meeting the SELECT inclusion criteria would be treated Treatment efficiency improved with increasing thresholds, with the number needed to treat decreasing from 13 at 20% risk to 10 and 9 at 30% and 40%, respectively. Events prevented per 1,000 treated increased accordingly, indicating greater benefit among higher-risk individuals.
Conclusion
SMART2-based initiation of GLP-1RA in ASCVD without diabetes improves treatment efficiency compared with a no-threshold strategy. A 20% 10-year risk threshold substantially reduces treatment volume while preserving meaningful reductions in recurrent CVD and incident heart failure. Higher thresholds further increase efficiency, but reduce overall population impact. Cost-effectiveness analyses may help define the optimal threshold for implementation in secondary prevention.Figure 1:Distribution of recurrent CVD riskFigure 2:Comparison or risk thresholds