Relationship between baseline LDL cholesterol levels and cardiovascular outcomes in adults with cardiovascular disease and overweight or obesity: an exploratory analysis of the SELECT trial

Background In the SELECT trial, semaglutide reduced the risk of major adverse cardiovascular events (MACE) in patients with established cardiovascular (CV) disease (CVD) and obesity without diabetes. The impact of baseline low-density lipoprotein cholesterol (LDL-C) levels on the effects of semaglutide in SELECT is yet to be explored. Purpose To evaluate whether the effect of semaglutide on MACE varies as a function of baseline LDL-C levels in SELECT. Methods SELECT was a double-blind, randomised, placebo-controlled trial that compared the effect of once-weekly subcutaneous semaglutide 2.4 mg versus placebo in patients aged ≥45 years with established CVD and a body mass index (BMI) of ≥27 kg/m² without diabetes. In this exploratory analysis, the primary endpoint of time to first occurrence of a three-component MACE (CV death, non-fatal myocardial infarction and non-fatal stroke) was evaluated according to tertiles of LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) at baseline. Data were analysed using a Cox proportional hazards model with treatment (semaglutide, placebo), subgroup and treatment-by-subgroup interaction as fixed factors. Results Of the 17,113 patients with LDL-C data available for this analysis, median LDL-C tertiles were 54.4 mg/dL (Tertile 1, n=5692), 78.0 mg/dL (Tertile 2, n=5685) and 116.2 mg/dL (Tertile 3, n=5736). Patients in Tertile 1 were more often male, non-smokers and were more likely to have had coronary revascularisation compared with patients in Tertiles 2 and 3. Patients in Tertile 1 also exhibited the lowest median value for high-sensitivity C-reactive protein. Additionally, patients in Tertiles 1 and 2 had lower median triglyceride levels and a higher proportion were receiving lipid-lowering therapies and statins compared with those in Tertile 3. Over a mean follow-up of 39.8 months, semaglutide consistently reduced the risk of MACE versus placebo, irrespective of baseline LDL-C tertile: Tertile 1 (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.61, 0.95), Tertile 2 (HR 0.74, 95% CI 0.61, 0.90) and Tertile 3 (HR 0.87, 95% CI 0.73, 1.04) (p for interaction=0.44) (Figure 1). Similar results were observed when baseline LDL-C was evaluated as a continuous variable (Figure 2A). Semaglutide also consistently reduced the risk of MACE versus placebo, irrespective of baseline non-HDL-C tertiles: Tertile 1 (HR 0.75, 95% CI 0.61, 0.93), Tertile 2 (HR 0.78, 95% CI 0.64, 0.95) and Tertile 3 (HR 0.86, 95% CI 0.72, 1.02) (p for interaction=0.63) and when baseline non-HDL-C was evaluated as a continuous variable (Figure 2B). Conclusions Semaglutide treatment reduced the risk of MACE versus placebo in patients with established CVD and a BMI of ≥27 kg/m² without diabetes, irrespective of baseline LDL-C and non-HDL-C levels. These findings support the use of semaglutide to improve CV outcomes in this high-risk population, across a broad spectrum of LDL-C.