Ezetimibe + statin

Combination drug therapy is an effective means to achieve greater reductions in LDL cholesterol (statin + ezetimibe or bile acid resin, bile acid resin + ezetimibe, or three-drug combinations) as well as raising HDL cholesterol and lowering serum triglycerides (statin + niacin or fibrate). 

Ezetimibe interferes with the absorption of cholesterol from the brush border of the intestine, a novel mechanism that makes it a good choice for adjunctive therapy. It is approved as both monotherapy and for use with a statin. The dose is 10 mg once daily, given with or without food. When used alone, it results in an approximate 18% reduction in LDL cholesterol. When added to a statin, ezetimibe lowers LDL by about an additional 12% to 20%. A combination product (Vytorin) containing ezetimibe 10 mg and simvastatin 10, 20, 40, or 80 mg is available. Ezetimibe is well tolerated approximately 4% of patients experience GI upset. Because cardiovascular outcomes with ezetimibe have not been evaluated, it should be reserved for patients unable to tolerate statin therapy or those who do not achieve satisfactory lipid lowering with a statin alone. 

Ezetimibe is the first compound approved for lowering total and LDL-C levels that inhibits cholesterol absorption by enterocytes in the small intestine. It lowers LDL-C levels by 15-20% and is used primarily as adjunctive therapy with statins. Ezetimibe does not affect intestinal triglyceride absorption. In human subjects, ezetimibe reduced cholesterol absorption by 54%, precipitating a compensatory increase in cholesterol synthesis, which can be inhibited with a cholesterol synthesis inhibitor such as a statin. The consequence of inhibiting intestinal cholesterol absorption is a reduction in the incorporation of cholesterol into chylomicrons. The reduced cholesterol content... 

Systematic reviews Differences between combination statin + ezetimibe therapy and statin monotherapy have been reviewed using 27 trials of fair quality but relatively short duration statin [7 ]. There were no statistically significant differences between the two types of treatment. 

Combination studies Statins+ ezetimibe A niacin See below under Nicotinic acid derivatives. 

Combination studies Triple combination therapy with a statin + ezetimibe + extended-release niacin (ER niacin) is being considered for patients who require intensive lowering of LDL cholesterol. In a 64-week study in 942 patients with hypercholesterolemia, with or without triglyceri-demia, combinations of up to 2 g of ER niacin, together with 20 mg/day simvastatin and 10 mg/day ezetimibe, were well tolerated, except for flushing due to niacin [35 ]. However, in others ER niacin was associated with rises in blood glucose concentrations, albeit slightly, and rises in liver enzymes, as reported in a 28-week study in which ER niacin up to 2g/day was... 

Ezetimibe + a statin The profiles of general safety and tolerability of statin monotherapy and statin+ezetiniibe combination therapy have been accumulated [3,4], A pooled analysis with over 22,000 subjects has confirmed the overall safety and tolerability profiles of ezetimibe added to a statin are generally comparable to statin monotherapy for up to 24 weeks [5]. Although the incidence was low, elevations in liver enzymes were observed more often with ezetimibe-statin combination treatment compared with statin monotherapy (consecutive aspartate aminotransferase (AST) or ALT elevation elevations 3 x upper limit of normal (statin 0.35%, statin + ezetimibe 0.56% p=0.017)). 

Runhua H, Anne Carol G. FACP. Lowering low-density Hpoprotein cholesterol statins, ezetimibe, bile add sequestrants, and combinations comparative efficacy and safety. End and Metab Chn North Am 2009 38 79-97. 

Ezetimibe 1 0 mg tablet 10 mg once daily The overall incidence of adverse events reported with ezetimibe alone was similar to that reported with placebo and generally similar between ezetimibe with a statin and statin alone. The frequency of increased transaminases was slightly higher in patients receiving ezetimibe plus a statin compared with those receiving statin monotherapy (1.3% versus 0.4%). 

Ezetimibe reduces LDL cholesterol by an average of 18% (Table 9-8). However, larger reductions can be seen in some individuals, presumably due to higher absorption of cholesterol. These individuals appear to have a blunted response to statin therapy. Ezetimibe lowers triglycerides by 7% to 9% and modestly increases HDL cholesterol. 

Once absorbed, ezetimibe undergoes extensive glucuronida-tion in the intestinal wall to the active metabolite (ezetimibe glucuronide). Ezetimibe and the active metabolite are entero-hepatically recirculated back to the site of action, which limits systemic exposure and may explain the low incidence of adverse effects (Table 9-9). Ezetimibe alone or with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in LFTs. Currently, clinical trials designed to determine ezetimibe s effects on CHD morbidity and mortality have not been completed. The time until maximum effect on lipids for ezetemibe is generally 2 weeks. 

A statin combined with a resin results in similar reductions in LDL cholesterol as those seen with ezetimibe. However, the magnitude of triglyceride reduction is less with a resin compared to ezetimibe, and this should be considered in patients with higher baseline triglyceride levels. In addition, gastrointestinal adverse events and potential drug interactions limit the utility of this combination. 

Combination therapy with a statin and ezetimibe is also rational because ezetimibe inhibits cholesterol absorption across the gut border and adds 12% to 20% further reduction when combined with a statin or other drugs. 

Primary hypercholesterolemia (familial hypercholesterolemia, familial combined hyperlipidemia, type Ila hyperlipoproteinemia) is treated with BARs, statins, niacin, or ezetimibe. 

Cholesterol Transport Protein Inhibitor Ezetimibe is the first hypolipidemic agent to act by blocking the absorption of dietary cholesterol at the intestinal level. It represents a novel treatment option for patients with hypercholesterolemia, alone or in combination with statins (Figure 8.60). 

Phillips PS. Ezetimibe and statin-associated myopathy. Ann Intern Med 2004 141(8) 649. 

In several studies of co-administration of ezetimibe with a statin there have been small numbers of patients with raised serum transaminase activities at or above three times the upper limit of the reference range. 

A recently developed antihyperlipidemic is ezetimibe (Zetia, A.113) (Figure A.31). Ezetimibe inhibits the absorption of cholesterol across the intestinal wall. Like fibrates, ezetimibe is often prescribed with statins, although the effectiveness of ezetimibe has recently been called into question. A compound that may soon be approved for the treatment of high cholesterol is anacetrapib (A.114). Anacetrapib, a product of Merck, is currently in phase III trials. The compound inhibits cholesteryl ester transfer protein (CETP). The net effect of CETP inhibition is elevated HDL cholesterol and lower LDL cholesterol levels. 

Ziajka, P. E., Reis, M., Kreul, S., and King., H. (2004) Initial low-density lipoprotein response to statin therapy predicts subsequent low-density lipoprotein response to the addition of ezetimibe. Am. J. Cardiol. 93, 779-780. 

The primary goal of therapy is the control of the hypercholesterolemia and prevention of atherosclerotic cardiovascular disease. Patients with heterozygous FH can usually be successfully treated with medications to lower the LDL cholesterol to acceptable levels (Table 14-2). They are generally responsive to treatment with statins, alone or in combination with other drugs, such as bile acid sequestrants (such as cholestyramine) or cholesterol absorption inhibitors (such as ezetimibe) that act additively to upregulate the expression of the functioning LDL receptor as described in the Biochemical Perspectives section. In a few cases, a more aggressive treatment with LDL apheresis (discussed in this section) may have to be considered in order to reach acceptable LDL cholesterol levels. 

What is the mechanism of action of commonly used lipid-lowering drugs, such as statins and ezetimibe ... 

The combination of a statin with an inhibitor of cholesterol absorption (e.g., ezetimibe) can lower LDL levels even further. 

Ezetimibe, either alone or in combination with a statin, rarely causes musculoskeletal effects [1]. 

A statin could be considered in this patient with appropriate monitoring. Fibrates, niacin or ezetimibe could be used with appropriate monitoring of LFTs. Colestyramine/colestipol and acipimox should be safe to use. 

Pravastatin is the statin of choice in this patient as it is least likely to accumulate, is hydrophilic, and is not highly protein bound. The starting dose should be low and should be increased cautiously. Monitoring of LFTs is required. Colestyramine and colestipol may be considered and may help the patient s pruritus. Niacin and acipimox could be used if the pruritus does not worsen. The fibrates should be avoided because of the risk of gallstone formation. Ezetimibe could be considered alone. 

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