Have we learnt all from Improve-It? Part I. Core results and subanalyses on the effects of ezetimibe added to statin therapy related to age, gender and selected chronic diseases (kidney disease, diabetes mellitus and non- alcoholic fatty liver disease)

: IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) was a randomized clini- cal trial (18,144 patients) that evaluated the efficacy of the combination of ezetimibe with simvastatin vs simvastatin mono- therapy in patients with acute coronary syndrome (ACS) and moderately increased low-density lipoprotein cholesterol (LDL-C) levels (of up to 2.6-3.2 mmol/L; 100-120 mg/dL). After 7 years of follow-up, combination therapy resulted in an additional LDL-C decrease [1.8 mmol/L, or 70 mg/dL, within the simvastatin (40 mg/day) monotherapy arm and 1.4 mmol/L, or 53 mg/dL for simvastatin (40 mg/day) + ezetimibe (10 mg/day)] and showed an incremental clinical benefit (composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary re- vascularization (≥30 days after randomization), or nonfatal stroke; hazard ratio (HR) of 0.936, and 95% CI 0.887-0.996, p=0.016). Therefore, for very high cardiovascular risk patients “even lower is even better” regarding LDL-C, independently of the LDL-C reducing strategy. These findings confirm ezetimibe as an option to treat very-high-risk patients who cannot achieve LDL-C targets with statin monotherapy. Additional analyses of the IMPROVE-IT (both prespecified and post-hoc) include specific very-high-risk subgroups of patients (those with previous acute events and/or coronary revascularization, older than 75 years, as well as patients with diabetes mellitus, chronic kidney disease or non-alcoholic fatty liver disease). The data from IMPROVE-IT also provide reassurance regarding longer-term safety and efficacy of the intensification of li- pid-lowering therapy in very-high-risk patients resulting in very low LDL-C levels. We comment on the results of several (sub) analyses of IMPROVE-IT.