Metabolic and Safety Outcomes of Statin–Ezetimibe Versus High‐Intensity Statin in Older Patients

Background High‐intensity statins are recommended for secondary prevention in atherosclerotic cardiovascular disease (ASCVD), but older adults frequently experience tolerability issues and adverse metabolic effects. Moderate‐intensity statin plus ezetimibe can achieve substantial low‐density lipoprotein cholesterol lowering, yet randomized data comparing metabolic and safety outcomes versus high‐intensity statins in older patients remain limited. Methods This subgroup analysis of the randomized SaveSAMS (Effects of High‐Dose Statin Versus Low‐Dose Statin Plus Ezetimibe on SAMS and on Reaching Target LDL‐Cholesterol Levels Among Older Patients With ASCVD) trial included patients aged ≥70 years with established ASCVD assigned to high‐intensity statin monotherapy (rosuvastatin 20 mg) or a moderate‐intensity statin plus ezetimibe (rosuvastatin 5 mg/ezetimibe 10 mg). Among 318 patients (monotherapy, n=168; combination, n=150), 6‐month changes in lipid parameters, metabolic biomarkers, and safety end points were compared. Results Both strategies significantly improved lipid profiles. Combination therapy achieved greater non–high‐density lipoprotein cholesterol reduction (Δ −76.0 versus −66.0 mg/dL; P =0.047) and attenuated statin‐associated increases in lipoprotein(a) (Δ +0.1 versus +1.2 mg/dL; P =0.033). Statin‐associated muscle symptoms occurred less frequently with combination therapy (0.7% versus 5.4%; P =0.021). New‐onset diabetes did not differ significantly between groups (5.1% versus 14.5%; P =0.065), while changes in glycemic markers were similar. Low‐density lipoprotein cholesterol target attainment (<70 and <55 mg/dL) was comparable between groups. Conclusions In older patients with ASCVD, a moderate‐intensity statin plus ezetimibe provided low‐density lipoprotein cholesterol lowering comparable with high‐intensity statin monotherapy, with a more favorable metabolic and safety profile, including greater non–high‐density lipoprotein cholesterol reduction, stable lipoprotein(a), and fewer muscle symptoms. Registration URL: https://www.clinicatrials.gov ; Unique Identifier: NCT04826354.