Fig. 3.1
Molecular formula of Ezetimibe (C24H21F2NO3)
Fig. 3.2
Mechanism of Ezetimibe. Both dietary cholesterol consumption and intestinal cholesterol absorption contribute to plasma cholesterol concentrations. Ezetimibe lowers cholesterol absorption and plasma cholesterol by blocking Niemann-Pick C1-like protein 1 (NPC1L1) in the small intestine
The primary mechamism of ezetimibe is blocking the function of the protein encoded by the Niemann-Pick C1Like 1(NPC1 L1) gene that plays a critical role in the absorption of intestinal cholesterol. NPC1L1 expression is enriched in the brush border membrane of enterocytes of the small intestine [2]. Additional effects are not fully understood and may include inhibition of NPC1L1 in hepatocytes, blocking of aminopeptidase N, or interruption of the calveolon-1/annexin-1 complex that is involved in trafficking cholesterol [3].
After oral administration, ezetimibe is absorbed and conjugated to a pharmacologically active phenolic glucuronide (Table 3.1). Within 4–12 h of the oral administration of a 10-mg dose to fasting adults, the attained mean ezetimibe peak plasma concentration (C max) is 3.4–5.5 ng/ml. Mean C max (45–71 ng/ml) of ezetimibe-glucuronide is attained within 1–2 h. The concomitant administration of food (high-fat vs. nonfat meals) has no effect on the extent of absorption of ezetimibe. However, coadministration with a high-fat meal increases the C max of ezetimibe by 38 %. The absolute bioavailability cannot be determined, since ezetimibe is insoluble in aqueous media suitable for injection. Ezetimibe and its active metabolite are highly bound to human plasma proteins (90 %) (Zetia label: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021445s033lbl.pdf). Ezetimibe is primarily metabolized in the liver and the small intestine via glucuronide conjugation with subsequent renal and biliary excretion. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 h. Ezetimibe lacks significant effects on cytochrome P-450 isoenzymes, which explains its limited number of drug interactions (Zetia label: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021445s033lbl.pdf).
Table 3.1
Properties of ezetimibe
Bioavailability | 35–65 % |
Molecular weight | 409.4 |
Protein binding | >90 % |
Half-life | 19–30 h |
Excretion | Renal 11 %, faecal 78 % |
Inhibition of intestinal cholesterol absorption reduces LDL- and total cholesterol concentrations but promotes a compensatory increase of hepatic cholesterol synthesis. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols sitosterol and campesterol [4]. Sitosterolemia is a very rare inherited disorder that results in increased absorption and decreased excretion of plant sterols (sitosterol, campesterol) and severe premature atherosclerosis. Ezetimibe is able to decrease the elevated plasma concentrations of sitosterol [5].
Ezetimibe undergoes glucuronidation in the intestinal wall and the liver. The elimination half-life for ezetimibe and ezetimibeglucuronide is approximately 22 h, which allows for once-daily dosing [6]. Pharmacokinetics of ezetimibe do not depend on sex, age, and renal or hepatic function [7]. The LDL-C lowering effect of ezetimibe correlates with dose and plasma concentration. A pooled analysis of 399 patients receiving either placebo or ezetimibe 0.25, 1, 5, or 10 mg once daily showed a median percentage reduction of LDL-C of 0 %, 12.7 %, 14.7 %, 15.8 %, and 19.4 %, respectively [7]. Ezetimibe 10 mg a day reduces cholesterol absorption by 54 % compared with placebo. This leads to a decrease of LDL-C of 20.4 % and a compensatory increase of 89 % in cholesterol synthesis [4, 6]. Therefore, the combination of statins and ezetimibe exerts a synergistic effect on LDL-C lowering.
Genetic Association of Mutations of NPC1L1 with LDL-C and CV Risk
The principle of Mendelian randomization tests how genetically determined changes of a biomarker, e.g., a laboratory parameter, correlates with clinical events. With respect to HDL-cholesterol concentrations, individuals with genetically determined changes of this lipoprotein have an unchanged myocardial infarction risk compared to the general population. Therefore, the genetic data suggest that HDL-C is a cardiovascular risk marker but not a true causal risk factor [8]. With respect to gene-induced changes of the serum LDL-cholesterol concentration, a linear association for the risk of myocardial infarction has been shown [8, 9]. A large meta-analysis in over 300,000 individuals demonstrated that lifelong exposure to LDL-C serum concentrations is linearly associated with a lower cardiovascular risk. Lifelong reduction of LDL-C by 1 mmol/L (39 mg/dl) by genetic determination translates to a 55 % reduction of CV risk [10]. New data presented by Brian Ference at the AHA Scientific Sessions 2014 showed that this relationship also holds true for mutations of NPC1L1 (the molecular target of ezetimibe) and for genetic variations of PCSK9 (the molecular targets of the novel PCSK9 inhibitors) [11].
Recently, several inactivating mutations of NPC1L1 were identified (Fig. 3.3) [12]. One of 650 individuals is a heterozygous carrier of an inactivating NPC1L1 mutation which is associated with an average LDL-C reduction by 12 mg/dl and accompanied by a 53 % coronary artery disease risk reduction. This NPC1L1-associated risk reduction appears to be greater than what was observed in other genetic studies [10]. NPC1L1 not only mediates the intestinal transport of cholesterol but also of plant sterols. Experimental evidence has suggested that plant sterols cause endothelial dysfunction and accelerate atherogenesis in mice [13]. One could speculate whether inhibition of sterol uptake by NPC1L1 may contribute to the preventive effect.
Fig. 3.3
Inactivating Mutations of NPC1L1Inactivating Mutations of NPC1L1 (Niemann-Pick C1-like protein 1) as identified by the Myocardial Infarction Genetics Consortium, adapted from [8]. The 15 circles represent the identified mutations. Red: insertion/deletion mutations; blue: splice site mutations; yellow: single nucleotide variants. NH2 denotes the N-terminus and COOH the C-terminus of the NPC1L1 protein, which contains 13 transmembrane domains and 3 extracellular domains
Examples of Clinical Studies with Ezetimibe and Statins
In a double-blind study, Ballantyne et al. randomized 628 patients with baseline LDL-C 145–250 mg/dL to receive one of the following for 12 weeks: ezetimibe (10 mg/d); atorvastatin (10, 20, 40, or 80 mg/d); ezetimibe (10 mg) plus atorvastatin (10, 20, 40, or 80 mg/d); or placebo [14] (Fig. 3.4). Coadministration of ezetimibe provided an additional 12 % LDL-C reduction, 3 % HDL-C increase, 8 % triglyceride reduction, and 10 % hs-CRP reduction versus atorvastatin alone. Ezetimibe plus atorvastatin provided LDL-C reductions of 50–60 %, triglyceride reductions of 30–40 %, and HDL-C increases of 5–9 %, depending on atorvastatin dose. LDL-C reductions with ezetimibe plus 10 mg atorvastatin (50 %) and 80 mg atorvastatin alone (51 %) were similar [14].
Leiter et al. studied the change of LDL-C after the addition of ezetimibe 10 mg to atorvastatin 40 mg compared with uptitration to atorvastatin 80 mg in hypercholesterolemic patients [15]. In this double-blind, parallel-group study, atorvastatin 40 mg plus ezetimibe reduced LDL-C by 27 % versus atorvastatin 80 mg by 11 % (p < 0.001). Both treatments were generally well tolerated [15].
The INFORCE study assessed the lipid-altering efficacy and safety profile of switching to Eze⁄Simva 10⁄40 mg vs. doubling the dose of statin in n = 424 high-risk patients recently hospitalized for a recent coronary event [16]. LDL-C values were 1.74 mmol/l in the Eze⁄Simva group and 2.22 mmol/l in the statin group resulting in a significant between-group difference of 0.49 mmol/l.
The IN-CROSS study [17] evaluated the efficacy of switching from a previous statin monotherapy to ezetimibe⁄simvastatin vs. rosuvastatin in n = 618 patients with hypercholesterolemia and high cardiovascular risk. Ezetimibe⁄simvastatin 10⁄20 mg produced greater reductions in LDL-C (−27.7 % vs.−16.9 %) and total cholesterol and apolipoprotein B compared with rosuvastatin 10 mg, while both treatments were equally effective at increasing HDL-C.
The TEMPO study was a 6-week, randomized, parallel-group study on 196 patients treated with atorvastatin 20 mg that received atorvastatin 20 mg plus ezetimibe 10 mg oratorvastatin 40 mg for 6 weeks [18]. Adding ezetimibe 10 mg to atorvastatin 20 mg produced greater reductions in LDL cholesterol than increasing atorvastatin to 40 mg (−31 % vs −11 %, p < 0.001). The two treatment groups had comparable results for high-density lipoprotein cholesterol, triglycerides, apolipoprotein A-I, and high-sensitivity C-reactive protein. The incidences of clinical and laboratory adverse experiences were similar between groups [18].
The ezetimibe add-on to statin for effectiveness (EASE) trial showed in 3030 randomized patients that ezetimibe added to statin therapy significantly reduced the LDL-C level by an additional 23 % in the total population; the treatment difference ranged from −19.9 to −24.0 % (p < 0.001) in all NCEP ATP III risk category subgroups [19] (Fig. 3.5).
Fig. 3.5
Ezetimibe 10 mg (EZE) plus Atorvastatin versus Atorvastatin-Monotherapy on LDL-C lowering (Modified from Ballantyne et al. [34])
In the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, ultrasonographic imaging in patients with familial hypercholesterolemia (FH) and combined therapy with ezetimibe and simvastatin did not result in a significant difference in intima–media thickness (IMT) compared with simvastatin alone [20], a result that was explained by Kastelein et al. by the normal IMT in the specific FH population studied. The Stop Atherosclerosis in Native Diabetics Study (SANDS) in patients with type 2 diabetes suggested that reducing LDL-C to aggressive targets results in similar regression of CIMT in patients who attained equivalent LDL-C reductions from a statin alone or statin plus ezetimibe [21].
The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial was designed to study the effects of long-term, intensive cholesterol lowering with daily use of simvastatin and ezetimibe in n = 1873 patients with asymptomatic, mild-to-moderate aortic-valve stenosis and no other indication for lipid-lowering treatment [22]. During a median follow-up of 52.2 months, the primary outcome occurred in 333 patients in the simvastatin–ezetimibe group and in 355 patients in the placebo group (hazard ratio in the simvastatin–ezetimibe group p = 0.59). Aortic-valve replacement did not differ between groups. Fewer patients experience ischemic cardiovascular events in the simvastatin–ezetimibe group (148 patients) than in the placebo group (187 patients) (p = 0.02).
The SHARP (Study of Heart and Renal Protection) trial aimed to assess the safety and efficacy of reducing LDL cholesterol in more than 9000 patients with chronic kidney disease. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0.85 mmol/L during a median follow-up of 4.9 years and produced a 17 % proportional reduction in major atherosclerotic events (526 [11·3 %] simvastatin plus ezetimibe vs 619 [13.4 %] placebo; p = 0.0021). The results showed that reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease [23].
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