Statin-Ezetimibe Combination Therapy In Diabetic Individuals.

Abstract

Statins are the cornerstone of lipid-lowering treatment in patients with or without type 2 diabetes. Prospective randomized clinical trials and meta-analyses have shown that the statin-mediated decrease in plasma low-density lipoprotein cholesterol (LDL-C) is associated with a significant decrease in cardiovascular (CV) morbidity and mortality. Furthermore, high-intensity statin treatment in high-risk individuals is followed by a significantly greater decrease in CV events compared with moderate dose statin treatment. However, the majority of high-risk individuals do not attain the LDL-C targets set by the guidelines even if high-intensity statin therapy is used. This is especially relevant in diabetic patients who need aggressive lipid management to decrease macrovascular complications. To further decrease this residual CV risk associated with suboptimal reduction in LDL-C levels, combination lipid-lowering treatment (eg, statin þ ezetimibe) is an attractive option. Ezetimibe targets the Niemann-Pick C1-like 1 (NPC1L1) protein and thus decreases cholesterol absorption from the gastrointestinal tract leading to a further fall in plasma LDL-C concentration by 20% to 25% when added to ongoing statin therapy. The recently published results of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) study showed, for the first time, that the additional ezetimibe-induced decrease in LDL-C levels (compared with simvastatin monotherapy) is associated with a significant further decrease in major CV events in very high-risk patients with acute coronary syndrome. Thus, the IMPROVE-IT trial confirms the LDL-C story. A lower LDL-C concentration is better for the reduction in CV events. These findings also refute any hypothesis that focuses on LDL-C–independent pleiotropic effects of statins. Additionally, a recently published meta-analysis of randomized controlled trials showed that adding ezetimibe to statin therapy not only decreases LDL-C concentration but also reduces CV events (relative risk: 0.92, P 1⁄4 .004). The IMPROVE-IT trial showed that elderly individuals and diabetic patients gain greater benefit from the addition of ezetimibe (Table 1). Interestingly, the addition of ezetimibe to ongoing statin therapy may induce a greater reduction in plasma LDL-C levels in diabetic patients compared with nondiabetic individuals. It is worth mentioning that the incidence of side effects (including cancer) in the IMPROVE-IT trial was not different between the statin and the statin þ ezetimibe combination groups. This finding not only confirms the long-term safety of ezetimibe but also that of very low LDL-C levels. Furthermore, recently published Mendelian randomization studies have also confirmed the benefits of decreased cholesterol absorption, which is associated with reduction in LDL-C concentration, in terms of CV disease. These studies showed that genetic polymorphisms of the NPC1L1 gene, which can be used as a proxy of ezetimibe therapy that targets the NPC1L1 protein, are not only associated with a reduction in LDL-C levels but also with a reduction in CV events (Table 2). Thus, combination therapy of statins with ezetimibe is a reasonable, effective, and safe option to treat diabetic dyslipidemia. Nowadays, fixed-dose combinations of a statin with ezetimibe are currently, or awaiting to be, marketed. The fixed-dose atorvastatin þ ezetimibe combination is especially attractive, since it can substantially increase adherence to statin therapy, while atorvastatin (the most commonly used statin in many countries) has the unique properties of lower renal excretion and fewer interactions with other commonly used drugs compared with simvastatin. Further analysis of the results of the IMPROVE-IT trial will clarify the role of ezetimibe (and of statin þ ezetimibe combination therapy) in carbohydrate homeostasis. Some recently published preliminary data hint that ezetimibe might favorably affect insulin resistance and carbohydrate metabolism, in part due to its ability to stimulate intestinal glucagon-like peptide 1 secretion via the mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase signaling pathway. It is worth mentioning that ezetimibe can also exhibit pleiotropic effects,