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Is it time to reconsider combination lipid therapy in high-risk diabetic patients?

DOI:10.1097/MOL.0000000000000306 Diabetic patients are among the highest risk populations for atherosclerosis-related cardiovascular events [1] and LDL cholesterol (LDL-C) remains, the most effective target for pharmacological intervention in these patients. The American Diabetic Association recommends moderate-intensity statin therapy in addition to lifestyle modification for diabetic patients aged at least 40 or those less than 40 with additional cardiac risk factors, and high-intensity statin therapy for diabetic patients aged at least 40 with additional cardiac risk factors [2]. These guidelines do not currently recommend combination therapy due to the failures of prior trials examining add-on therapy, including the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial [3]. Furthermore, clinicians are generally reluctant to prescribe multidrug regimens due to concerns about drug–drug interactions and the potential negative impact on patient compliance. Despite the accepted benefits of lifestyle modification and statin therapy, the yearly cardiovascular event rate in diabetic patients remains upward of 3% [4]. Although statins effectively lower LDL-C, they also upregulate proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations, which may lessen the extent of therapeutic benefit [5,6,7 & ]. Circulating PCSK9 levels closely correlate with atherogenic dyslipidemia analyzed by NMR in diabetic patients [8 & ]. This provides further impetus to reconsider combination therapy in diabetic patients, particularly those at highest risk for clinical events, such as following an acute coronary syndrome. Recent studies have shown that adding ezetimibe improves LDL-C levels in diabetic patients compared with simply increasing statin dose alone. Ezetimibe also improves lipoprotein subclass profile and lipoprotein-associated phospholipase A2 levels more than statin therapy alone [9 & ], as well as potentially offsetting statin-related elevation in plasma PCSK9 levels [10]. The recently published Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated that ezetimibe and simvastatin were more successful