For modeling purposes in this study, only the first event was considered in patients experiencing multiple events. MACE generally included nonfatal MI, stroke, and cardiovascular death (including acute MI, heart failure, stroke, pulmonary embolism, and cardiovascular procedure-related) the definition of MACE is essentially equivalent to the UKPDS definition of coronary heart disease (which includes nonfatal MI, and death from MI, heart failure, and others) and stroke ( Appendix 1). Citation5, Citation11 In each of these studies, specific cardiovascular outcomes were combined into a common descriptor as major adverse cardiac events (MACE), either as the primary safety end point or key safety end point. Several recently completed and published large outcome studies were included in this analysis, namely ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation), Citation10, Citation21 VADT (Veterans Affairs Diabetes Trial), Citation4, Citation9 ACCORD (Action to Control Cardiovascular Risk in Diabetes), Citation3, Citation6 RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes), Citation8 PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events), Citation22, Citation23 and BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes). The definition of stroke included fatal and nonfatal stroke. Coronary heart disease was defined as the occurrence of fatal or nonfatal myocardial infarction (MI) or sudden death, verified by two independent clinical assessors. The UKPDS risk engine included two risk equations for coronary heart disease Citation19 and stroke Citation18 ( Appendix 2A). UKPDS and selected outcome studies: harmonization of event definitions The results provided herein suggest that event rate prediction based on the modified UKPDS model could be used as a benchmark for more accurate prediction of event rates in prospectively designed clinical trials. A model modification strategy for improving the predictability of the UKPDS risk engine to allow for differences in duration of diabetes and risk factors for cardiovascular disease was also evaluated. Accordingly, the purpose of the present study was to explore the hypothesis that the UKPDS risk engine, when applied across a broad population of subjects with T2DM derived from several major outcomes studies, would generate a more consistent prediction of event rates. While the inconsistency of prediction of the UKPDS model has been observed within individual studies, the pattern of prediction across different studies including a broader spectrum of patient populations has not been evaluated. Citation15 Furthermore, overestimation of rates tended to vary between outcomes studies, rendering prospective risk prediction modeling a challenge. Citation18, Citation19 However, the generalizability of the UKPDS model for use in the broader population of subjects with T2DM may be limited, because utilization of the UKPDS risk engine, when applied to other individual outcomes studies, tended to overestimate the macrovascular event rate. The UKPDS risk engine has been considered a useful tool for assessing cardiovascular risk and identifying high-risk individuals among newly diagnosed patients having no previous history of cardiovascular disease. The United Kingdom Prospective Diabetes Study (UKPDS) was the first to examine cardiovascular risk in subjects with T2DM. Predictive measures of macrovascular risk for use in prospectively designed studies have been generated based on cardiovascular risk models developed from epidemiologic studies, such as the Framingham Heart, Citation14 Hoorn, Citation15 DECODE (Diabetes Epidemiology: Collaborative analysis of Diagnostic criteria in Europe), Citation16 and Fremantle Diabetes Citation17 studies, as well as from prospectively designed outcomes studies. Citation3 – Citation12 Further, various regulatory agencies, including the United States Food and Drug Administration, have generated guidelines for the development of novel medications in the treatment of T2DM to ensure that these agents, in addition to improving indices of glycemic control, provide adequate evidence for cardiovascular safety. Several recently published outcomes studies have evaluated macrovascular events for various treatment options. Citation1, Citation2 Accordingly, the goals of lifestyle modification, and therapeutic intervention when required, are to improve those risk factors known to be important in improving macrovascular outcomes. Type 2 diabetes mellitus (T2DM) confers a 2–4-fold increased risk of macrovascular disease relative to nondiabetic individuals.
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