Coadministration Of Ezetimibe Research Articles

Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia

ObjectivesThe purpose of this study was to assess the efficacy and safety of ezetimibe administered with simvastatin in patients with primary hypercholesterolemia. BackgroundDespite the availability of statins, many patients do not achieve lipid targets. Combination therapy with lipid-lowering agents that act via a complementary pathway may allow additional patients to achieve recommended cholesterol goals. MethodsAfter dietary stabilization, a 2- to 12-week washout period, and a 4-week, single-blind, placebo lead-in period, patients with baseline low-density lipoprotein cholesterol (LDL-C) ≥145 mg/dl to ≤250 mg/dl and triglycerides (TG) ≤350 mg/dl were randomized to one of the following 10 groups administered daily for 12 consecutive weeks: ezetimibe 10 mg; simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg plus simvastatin 10, 20, 40, or 80 mg; or placebo. The primary efficacy variable was percentage reduction from baseline to end point in direct LDL-C for the pooled ezetimibe plus simvastatin groups versus pooled simvastatin groups. ResultsEzetimibe plus simvastatin significantly improved LDL-C (p < 0.01), high-density lipoprotein cholesterol (HDL-C) (p = 0.03), and TG (p < 0.01) compared with simvastatin alone. Ezetimibe plus simvastatin (pooled doses) provided an incremental 13.8% LDL-C reduction, 2.4% HDL-C increase, and 7.5% TG reduction compared with pooled simvastatin alone. Coadministration of ezetimibe and simvastatin provided LDL-C reductions of 44% to 57%, TG reductions of 20% to 28%, and HDL-C increases of 8% to 11%, depending on the simvastatin dose. Ezetimibe 10 mg plus simvastatin 10 mg and simvastatin 80 mg alone each provided a 44% LDL-C reduction. The coadministration of ezetimibe with simvastatin was well tolerated, with a safety profile similar to those of simvastatin and of placebo. ConclusionsWhen coadministered with simvastatin, ezetimibe provided significant incremental reductions in LDL-C and TG, as well as increases in HDL-C. Coadministration of ezetimibe with simvastatin was well tolerated and comparable to statin alone.

Pharmacology of ezetimibe

Ezetimibe is the first of the cholesterol absorption inhibitors, a novel class of lipid modifying drugs, which potently inhibit the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Ezetimibe localizes in the brush border of the small intestinal enterocytes and reduces the uptake of cholesterol into the enterocytes. This has the net effect of inhibiting cholesterol absorption by keeping the cholesterol in the intestinal lumen, allowing it to be excreted. Pre-clinical studies demonstrated that ezetimibe was glucuronidated to a single metabolite localized at the intestinal wall, where it prevented cholesterol absorption. It was found that enterohepatic re-circulation of ezetimibe and/or its glucuronide ensured repeated delivery to the site of action and limited peripheral exposure. Ezetimibe had no effect on the activity of major drug metabolizing enzymes (CYP450), which reduces any potential drug-drug interactions with other medications. Pre-clinical models also demonstrated the lipid-lowering and anti-atherosclerosic properties of ezetimibe as a single agent, and showed its synergistic effect in combination with HMG CoA reductase inhibitors (‘statins‘). In cholesterol-fed rhesus monkeys, ezetimibe reduced both plasma cholesterol (ED50 = 0·0005 mg. kg−1. day−1) and LDL cholesterol in a dose-dependent manner. Plasma cholesterol levels were also reduced in dogs (ED50 = 0·007 mg.kg−1.day−1) and in hamsters (ED50 = 0·04 mg . kg−1 . day−1) fed cholesterol-containing diets. In apo E knockout mice, a model of atherosclerosis, ezetimibe reduced plasma cholesterol levels over 60% primarily through the reduction in VLDL and LDL cholesterol. Ezetimibe inhibited the development of carotid artery (decrease of 97%) and aortic (decrease of 71–87%) atherosclerosis. In non-cholesterol fed dogs, co-administration of ezetimibe with statins resulted in a synergistic reduction in plasma cholesterol levels that was significantly lower than with monotherapy with either agent. Clinically, ezetimibe (10 mg .day−1) was found to inhibit cholesterol absorption by an average of 54% in hypercholesterolemic individuals (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(P {<} 0{\cdot}001\) \end{document}). Plasma total and LDL cholesterol levels were significantly reduced and cholesterol synthesis was increased. These results suggest that in patients with hypercholesterolemia, ezetimibe, in combination with a statin, may produce clinically important additional reductions in plasma cholesterol levels.

Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia

Ezetimibe is a lipid-lowering drug that inhibits the intestinal absorption of dietary and biliary cholesterol by blocking passage across the intestinal wall. The efficacy and safety of adding ezetimibe to ongoing statin therapy in patients with primary hypercholesterolemia was evaluated in a randomized, double-blind, placebo-controlled study. The study group included 769 adults (aged ≥18 years) with primary hypercholesterolemia who had not achieved National Cholesterol Education Program (NCEP) Adult Treatment Panel II goals with dietary alteration and statin monotherapy. Patients receiving a stable dose of a statin for ≥6 weeks were randomized to receive concurrent treatment with placebo (n = 390) or ezetimibe (n = 379), 10 mg/day, in addition to continuing their open-label statin for 8 weeks. The primary efficacy variable was the percent change in low-density lipoprotein (LDL) cholesterol from baseline with statin monotherapy to end point after intervention (secondary variables: high-density lipoprotein [HDL] cholesterol and triglycerides). Ongoing statin therapy plus ezetimibe led to changes of −25.1% for LDL cholesterol (HDL cholesterol +2.7%; triglycerides −14.0%) compared with LDL cholesterol −3.7% (p <0.001), HDL cholesterol +1.0% (p <0.05), and triglycerides −2.9% (p <0.001) for placebo added to ongoing statin therapy. Among patients not at LDL cholesterol goal at on-statin baseline, 71.5% receiving statin plus ezetimibe versus 18.9% receiving statin plus placebo reached goal at end point (odds ratio 23.7; p <0.001). The co-administration of statin and ezetimibe was generally well tolerated. Adding ezetimibe to ongoing statin therapy led to substantial additional reduction in LDL cholesterol levels, facilitating attainment of NCEP goals. Ezetimibe offers a new therapeutic option for patients receiving statins who require further reduction in LDL cholesterol.

Cholesterol absorption inhibitors for the treatment of hypercholesterolaemia.

The benefits of lipid lowering therapy on coronary heart disease have been clearly established in many clinical trials on primary and secondary prevention. Despite the availability of potent lipid lowering drugs, many patients do not reach the current treatment goals. This paper reviews new therapeutic approaches in lipid lowering drugs focusing on compounds which lower cholesterol absorption. The role of plant sterols and stanols, new acyl-CoA:cholesterol O-acyl transferase (ACAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, and ezetimibe are summarised. Although the lipid lowering effect of plant sterols and plant stanols is only moderate, their use as functional foods is beneficial for patients with mild hypercholesterolaemia and is able to enhance the lipid lowering effect of HMG-CoA reductase inhibitors (statins). The role of ACAT inhibitors that might also inhibit cholesterol absorption remains unclear. Avasimibe, the first oral bioavailable ACAT inhibitor, has entered phase III trials. However, the presently available data in humans do not indicate a clear clinical benefit. The role of MTP inhibitors, which exhibit remarkable effects on all plasma lipids, also remains unclear, as safety concerns must first be addressed. Ezetimibe, the first available 2-azetidinone, succeeded in phase III trials showing remarkable effects in inhibition of cholesterol absorption as well as cholesterol lowering. The synergistic effect of co-administration of ezetimibe with statins seemingly offers a new approach in reaching the therapeutic goals.

Cholesterol absorption inhibition: filling an unmet need in lipid-lowering management

International guidelines specify target concentrations of low-density lipoprotein cholesterol (LDL-C) to reduce the risk of coronary heart disease. Although statins are the most widely prescribed cholesterol-lowering drugs, they have a number of limitations. A significant number of statin-treated patients do not reach recommended LDL-C target levels, even with high-dose therapy. Each doubling of the statin dose results in only a 6% reduction in LDL-C. Elevation of liver transaminase levels and muscle toxicity have been associated with high statin doses. Currently available agents that are co-administered with statins are not well tolerated due to gastrointestinal intolerance or are associated with an increased risk of myopathy. The limitations of statin monotherapy and currently available combination therapy warrant the need for more safe, effective and convenient approaches to combination therapy. Co-administration of statins and cholesterol absorption inhibitors may overcome some of these limitations and effectively target both the endogenous and exogenous pathways of cholesterol metabolism. Ezetimibe, a novel selective cholesterol absorption inhibitor, has demonstrated an excellent safety and tolerability profile and a LDL-C-lowering effect that is additive with statins. Co-administration of ezetimibe and a statin may therefore fill an unmet need in lipid-lowering management and provide broader lipid control.

Ezetimibe: a selective inhibitor of cholesterol absorption

Ezetimibe is a novel selective cholesterol absorption inhibitor that effectively blocks intestinal absorption of dietary and biliary cholesterol. Ezetimibe undergoes glucuronidation to a single metabolite and is localized in the intestinal wall, where it prevents cholesterol absorption. Enterohepatic recirculation of ezetimibe and the glucoronide ensures repeated delivery to the site of action and limits peripheral exposure. Ezetimibe does not affect the absorption of fat-soluble vitamins or triglycerides. Results from pre-clinical studies in various animal models have shown the lipid-lowering and anti-atherosclerotic properties of ezetimibe as a single agent, and a synergistic effect when combined with a statin. In cholesterol-fed rhesus monkeys, ezetimibe reduced both plasma cholesterol (ED50 = 0·0005 mg.kg−1.day−1) and low-density lipoprotein cholesterol levels in a dose-dependent manner. In apo F knockout mice, ezetimibe reduced serum cholesterol more than 50% and decreased carotid (97%) and aortic (47–87%) atherosclerosis. Ezetimibe inhibited the rise of plasma cholesterol in cholesterol-fed dogs (ED50 = 0·007 mg.kg−1.day−1). Co-administration of ezetimibe and lovastatin in chow-fed dogs synergistically reduced plasma cholesterol to levels lower than those achieved with either agent alone (⁠ \(P{<}0{\cdot}05\) ⁠). These results suggest that ezetimibe combined with a statin may similarly reduce plasma cholesterol levels in patients with hypercholesterolaemia.

Coadministration of ezetimibe and fenofibrate leads to favorable effects on Apo CIII and LDL subfractions

Coadministration of ezetimibe and fenofibrate leads to favorable effects on Apo CIII and LDL subfractions

Substitutes for Morphine and Heroin

Vitamin K (VK) is a micronutrient that facilitates blood coagulation. VK antagonists, such as warfarin, are used in the clinic to prevent thromboembolism. Because VK is not synthesized in the body, its intestinal absorption is crucial for maintaining whole-body VK levels. However, the molecular mechanism of this absorption is unclear. We demonstrate that Niemann-Pick C1-like 1 (NPC1L1) protein, a cholesterol transporter, plays a central role in intestinal VK uptake and modulates the anticoagulant effect of warfarin. In vitro studies using NPC1L1-overexpressing intestinal cells and in vivo studies with Npc1l1-knockout mice revealed that intestinal VK absorption is NPC1L1-dependent and inhibited by ezetimibe, an NPC1L1-selective inhibitor clinically used for dyslipidemia. In addition, in vivo pharmacological studies demonstrated that the coadministration of ezetimibe and warfarin caused a reduction in hepatic VK levels and enhanced the pharmacological effect of warfarin. Adverse events caused by the coadministration of ezetimibe and warfarin were rescued by oral VK supplementation, suggesting that the drug-drug interaction effects observed were the consequence of ezetimibe-mediated VK malabsorption. This mechanism was supported by a retrospective evaluation of clinical data showing that, in more than 85% of warfarin-treated patients, the anticoagulant activity was enhanced by cotreatment with ezetimibe. Our findings provide insight into the molecular mechanism of VK absorption. This new drug-drug interaction mechanism between ezetimibe (a cholesterol transport inhibitor) and warfarin (a VK antagonist and anticoagulant) could inform clinical care of patients on these medications, such as by altering the kinetics of essential, fat-soluble vitamins.