Polyvascular disease, type 2 diabetes, and long-term vascular risk: a secondary analysis of the IMPROVE-IT trial

Background Polyvascular disease and type 2 diabetes are each associated with increased cardiovascular risk, but whether these risks are additive is unknown. In this exploratory analysis of a randomised trial, we explored the long-term cardiovascular risk associated with polyvascular disease, type 2 diabetes, and their combination in patients with acute coronary syndrome, and assessed the effect of ezetimibe given on top of statin therapy in patients with these concomitant conditions. Methods IMPROVE-IT was a multicentre, double-blind, randomised, placebo-controlled trial assessing the effect of ezetimibe added to statin therapy after acute coronary syndrome. Recruitment was from Oct 26, 2005, to July 8, 2010, and the trial was done at 1158 sites in 39 countries. 18 144 patients aged 50 years and older who had been stabilised after an acute coronary syndrome were randomly assigned to 40 mg per day simvastatin plus either 10 mg per day ezetimibe or matched placebo, for a median duration of 6 years. In this post-hoc exploratory analysis, we assessed the prespecified endpoints of the trial, including the primary composite endpoint (cardiovascular death, a major coronary event [non-fatal myocardial infarction, documented unstable angina requiring hospital admission, or coronary revascularisation occurring at least 30 days after randomisation], or stroke [ischaemic or haemorrhagic]) by concomitant polyvascular disease at baseline (peripheral artery disease or previous stroke or transient ischaemic attack) and stratified by concomitant type 2 diabetes. Efficacy analyses were done according to intention to treat and event rates. IMPROVE-IT is registered with ClinicalTrials.gov, number NCT00202878. Findings 1005 patients (6%) had peripheral artery disease and 1071 (6%) had stroke or transient ischaemic attack at baseline. Of these, 388 (39%) and 409 (38%) also had concomitant type 2 diabetes, respectively. At 7 years, patients with either polyvascular disease or type 2 diabetes had similar rates of the primary endpoint (39.8% and 39.9%, respectively), which were higher than patients without polyvascular disease or diabetes (29.6%). Polyvascular disease with concomitant type 2 diabetes was associated with further heightened risk (60.0% 7-year Kaplan-Meier rate, adjusted hazard ratio versus those with polyvascular disease 1.60, 95% CI 1.38-1.85; p<0.0001). Ezetimibe reduced cardiovascular risk consistently across groups with greater numerical absolute risk reductions in the highest-risk subgroups. Interpretation In patients with coronary artery disease, concomitant polyvascular disease or type 2 diabetes are associated with increased long-term cardiovascular risk. The combination of polyvascular disease and diabetes is additive, resulting in very high risk. The benefit of ezetimibe is consistent in patients with and without polyvascular disease and type 2 diabetes; however, by nature of their higher risk patients with one, or especially both, of these diseases might derive the greatest absolute benefits. Copyright (c) 2018 Elsevier Ltd. All rights reserved.