New Insights on Simvastatin and Ezetimibe in a Single Tablet

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Evidence spanning from the pathogenesis of atherosclerosis to epidemiological studies consistently support the direct association of elevated plasma low-density lipoprotein-cholesterol (LDL-C) with the increased risk of cardiovascular disease (CVD). Meta-analysis of 14 trials of statin therapy, with more than 90,000 participants, has shown that each 1mmol/l (39mg/dl) of LDL-C reduction results in a 20–25% reduction in coronary heart disease (CHD) and stroke over five years. Finally, from the many outcome studies it has been established that for each 1% reduction in LDL-C, independent of mode of therapy, there was at least a 1% reduction in CVD events. On the basis of these premises, the Adult Treatment Panel (ATP) III and European guidelines have both recommended an LDL-C goal of <100mg/dl for patients at high risk of CHD. More recently, based on the later trials with statins, the ATP III has established LDL-C lowering as a primary goal in cholesterol treatment and has considered a more aggressive LDL-C goal of <70mg/dl in the highest risk CHD patients.

Despite the benefit of statin therapy and recommendations from international guidelines, LDL management remains suboptimal and many patients do not achieve recommended target goals. Several reasons could explain the failure of statin monotherapy to achieve the recommended LDL-C goal, including extrinsic (e.g. poor compliance, time and uptitration of the dose, concomitant drug therapy, diet) and intrinsic (genetic of lipoprotein metabolism/pharmacokinetics, poor responders) factors. The significant gap between guideline recommended treatment goals and the lipid levels actually achieved in clinical practice highlights the urgent need for new management strategies, particularly for high-risk patients.

Safety Issue

The more recent clinical trials addressing the benefits of high doses of statins versus standard lipid-lowering therapy in high CHD risk patients have shown additional clinical benefits in terms of reduction of cardiovascular risk as related to LDL-C lowering, but also have pointed out an increased risk of side effects including liver toxicity, myopathy and non-cardiovascular deaths. It is important to mention also the PRIMO (Prediction of Muscular Risk in Observational) study, a countrywide observational survey conducted in 7,924 hyperlipidaemic patients receiving high doses of statins in a usual care, outpatient setting in France. Patients were included if they were taking a high dosage of statins (fluvastatin 80mg, simvastatin 40 or 80mg, atorvastatin 40 or 80mg, pravastatin 40mg) for at least three months.

Overall, 832 patients (10.5%) have reported muscular symptoms with a median onset of one month after the beginning of statin therapy. Altogether, the PRIMO trial demonstrated that mild to moderate muscular symptoms with high dosage of statin therapy are more common and exert a greater impact on daily life than previously appreciated. Based on this evidence, the safety issue has become a major concern in terms of the potential use of high-dose statins in CHD patients, and strongly supports the use of combination therapy.

Figure 1 represents the pharmacological effect of statins as related to the doses. As shown in the figure, at the recommended clinical doses of statins, when doubling the dose you can achieve only a 6% additional reduction of LDL-C (i.e. the additional pharmacological benefits are minimal, getting close to the steady state), while the toxicity is increasing from minor to major.

The failure of statin monotherapy to achieve LDL-C goals, as well as the safety issue, a major concern in the potential use of high-dose statins in CHD patients, strongly support the use of combination therapy as a practical, effective and safe option to bring more patients to their LDL-C goal.

Pharmacological Issues

The rationale for developing a combination drug product involves the following standards: enhanced efficacy in treating the target condition, enhanced safety or tolerability (e.g. dose-sparing of the active component/s) relative to single-drug therapy, frequency and convenience, which may be reasonably anticipated to enhance compliance with complex drug regimens. In addition, an important step for designing an ideal combination therapy should have a strong pharmacological rationale either from a pharmacokinetic or from a pharmacodynamic point of view. The ezetimibe/simvastatin combination (single tablet) has all the ingredients to meet the above criteria. In humans, ezetimibe is rapidly absorbed and primarily metabolised in the small intestine and liver to the pharmacologically active glucuronide, with little oxidative cytochrome P450-mediated metabolism. Since ezetimibe does not influence the activities of cytochrome P450 enzymes, significant pharmacokinetic interactions with many medications – including statins, digoxin, glipizide, warfarin and oral contraceptives – have not been noted. Among the pharmacodynamic properties, knowledge of the mechanism of action is one of the more relevant because it could allow rational combination with statins.

Cholesterol homeostasis in the body is critically dependent on the interplay between two specific processes: the intestinal cholesterol absorption and liver cholesterol production. The cholesterol in the body mainly results from these two equipollent sources and, therefore, both pathways are potential targets for pharmacological control of hypercholesterolaemia. Among inhibitors of cholesterol absorption, ezetimibe acts at the brush border of the small intestine to selectively inhibit the absorption of cholesterol by interfering with the Niemann-Pick-C1-like 1 protein (NPC1L1), a critical mediator of cholesterol absorption. In humans, ezetimibe inhibits cholesterol absorption by 50% and promotes a compensatory increase of cholesterol production, followed by clinically relevant reductions of 17–20% in LDL-C. Another important pharmacodynamic property of the combination is the efficacy on lipid profile. As the mechanism of action of ezetimibe is complementary to that of a statin, combining these agents results in incremental decreases in LDL-C and favourable effects on high-density lipoprotein (HDL) and triglycerides. Indeed, in clinical trials, ezetimibe 10mg alone reduces LDL-C by approximately 18% and enhances the LDL-Clowering effect of statin by 20–25%. Therefore, ezetimibe may affect statin dose and exposure sparing, enhance tolerance and, in the meantime, ezetimibe can reduce the increased cholesterol absorption induced by statin monotherapy and vice versa. Statin may reduce the increased cholesterol production induced by ezetimibe monotherapy. The administration of ezetimibe with a statin, therefore, is not only additive but also co-operative.

Clinical Efficacy of Ezetimibe Co-administered with a Statin

Studies in patients with hypercholesterolaemia show that ezetimibe co-administered with a statin increases the number of patients reaching their LDL-C goal without increasing adverse events.

This had already been demonstrated in the Ezetimibe Add-on to Statin for Effectiveness (EASE) Trial where ezetimibe added to statin therapy consistently produced significant additional improvements in LDL-C levels and goal attainment. In this multicentre, randomised, double-blind, placebo-controlled, six-week parallel-group study, 3,030 hypercholesterolaemic patients with LDL-C levels exceeding National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III goals were randomised to receive ezetimibe (10mg/day) or placebo in addition to their ongoing statin therapy. Ezetimibe added to statin therapy significantly reduced LDL-C by an additional 25.8% in the total population compared with an additional 2.7% reduction with placebo plus statin.

A significantly greater proportion of patients treated with statin-ezetimibe reached their NCEP ATP III LDL-C goal than patients who received statin plus placebo (71% versus 20.6%, p<0.01). The addition of ezetimibe also resulted in improvement in other lipid parameters and high-sensitive C-reactive protein (CRP). These benefits were consistent across sex, age, race, statin brand and dose subgroups. Ezetimibe plus statin was well tolerated, with a safety profile similar to placebo with statin. The tolerability of ezetimibe in clinical trials so far has generally been excellent. However, an interaction between ezetimibe and statin-associated myopathy has been reported. Moreover, a number of patients treated with ezetimibe in whom myalgia occurred had previously experienced myalgia (with or without elevated serum creatinine kinase concentrations) with statin therapy.

Clinical Efficacy of Ezetimibe/Simvastatin as a Single Tablet

Further benefits in terms of lipid lowering are expected to be obtained with the use of ezetimibe/simvastatin in a single tablet because of better adherence to treatment. Indeed, a single pill form of ezetimibe and simvastatin therapy is available at various doses based on 10mg ezetimibe and 10–80mg simvastatin. The safety and efficacy of all doses of an ezetimibe/simvastatin single tablet were recently compared with either drug alone in a multicentre, randomised, double-blind trial in 1,528 patients with primary hypercholesterolaemia. Pooled ezetimibe/simvastatin was associated with greater reduction in LDL-C than pooled simvastatin or ezetimibe alone. The results of this study are comparable with previous studies in which ezetimibe was co-administered with simvastatin. Ezetimibe/simvastatin was generally well tolerated, with a safety profile similar to simvastatin monotherapy. The efficacy of ezetimibe/simvastatin in a single tablet has also been compared with atorvastatin in the Vytorin Versus Atorvastatin (VYVA) study. This multicentre, double-blind, six-week parallel-group study randomised 1,902 patients with LDL-C above ATP III goal to atorvastatin (10, 20, 40 or 80mg) or to ezetimibe/simvastatin (10/10, 10/20, 10/40 or 10/80mg). This study tested the hypothesis that ezetimibe/simvastatin provides greater LDL-C reductions than atorvastatin across dose ranges. At each milligram-equivalent statin dose comparison, and averaged across doses, ezetimibe/simvastatin provided greater LDL-C reductions (47–59%) than atorvastatin (36–53%) (see Figure 2). Ezetimibe/simvastatin 10/40 and 10/80mg also provided significantly greater HDL-C increases than atorvastatin 40 and 80mg. Triglyceride reductions were similar for all comparisons.

More ezetimibe/simvastatin than atorvastatin patients with coronary heart disease (CHD) or CHD risk equivalents attained the ATP III LDL-C goal of <100mg/dl and the optional LDL-C target of <70mg/dl. CRP reductions were similar between treatment groups. Consecutive elevations in alanine aminotransferase and/or aspartate aminotransferase occurred in significantly more atorvastatin patients than ezetimibe/simvastatin patients. No myopathy or liver-related adverse events led to study discontinuation with either drug. Ezetimibe/simvastatin is a highly efficacious, well-tolerated treatment option for hypercholesterolaemic patients.

The Recent Vytorin versus Atorvastatin in Patients With Type 2 Diabetes Mellitus and Hypercholesterolemia (VYTAL) study, a double-blind, multicentre trial, compares the efficacy and safety of the recommended usual starting (ezetimibe/simvastatin, 10/20mg/d, versus atorvastatin, 10 or 20mg/d) or next highest dose (ezetimibe/simvastatin, 10/40mg/d, versus atorvastatin 40mg/d) in 1,229 patients with type 2 diabetes. Efficacy end-points included percentage changes from baseline in LDL-C levels (primary) and proportion of patients attaining LDL-C levels lower than 70mg/dl (secondary). Significantly greater mean reductions were found in LDL-C levels with ezetimibe/simvastatin 10/20mg/d (-53.6%) than with atorvastatin 10mg/d (-38.3%, p<0.001) or 20mg/d (-44.6%, p<0.001), and with ezetimibe/simvastatin 10/40mg/d (-57.6%) versus atorvastatin 40mg/d (-50.9%, p<0.001). Ezetimibe/simvastatin was also superior to atorvastatin in attainment of LDL-C levels less than 70mg/dl (p<0.001 for all dose comparisons) (see Figure 3).

Significantly better improvements with ezetimibe/simvastatin than with atorvastatin (p≤0.001) were observed for total cholesterol, HDL-C and non-HDL-C. Ezetimibe/simvastatin 10/20mg/d reduced high-sensitivity CRP and triglyceride levels significantly more than atorvastatin 10mg/d (p=0.02), with comparable reductions at other doses. Incidences of clinical adverse events were similar for both treatments. Thus, inhibition of cholesterol absorption and production with ezetimibe/simvastatin provides an effective and well-tolerated therapy for patients with type 2 diabetes and hypercholesterolaemia.

Hildemann et al. have chosen a real-life, non-interventional study to evaluate the actual treatment benefits of ezetimibe/simvastatin in a single tablet and outcomes in typical primary care. Two open-label, prospective non-randomised, observational cohorts (study 1 with n=19,194 patients, predominantly with CHD; study 2 with n=19,484 patients, predominantly with diabetes mellitus) were investigated. Patients received – almost all after statin pre-treatment – ezetimibe 10mg plus simvastatin 10mg (study 1: 15%, study 2: 16%), 20mg (in 68% each), 40mg (12%/10%) or 80mg (1%/1%) as a single tablet over three months. Mean LDL-C was reduced by 28%/27% (study 1/study 2) compared with baseline values (on statin monotherapy). Mean total cholesterol was decreased by 22% in each study, mean triglycerides by 16/17%, and mean HDL-C was increased by 9/10%. Adverse events were reported in 0.3% and 0.2% of patients, respectively. Inhibition of cholesterol absorption and production with ezetimibe/ simvastatin was effective and well tolerated under real practice conditions in high-risk patients with CHD and/or diabetes mellitus. The cholesterol and triglyceride lowering effect of the combination in these statin-pre-treated patients with diverse characteristics was substantial.

Catapano et al. assess the efficacy and safety of ezetimibe/simvastatin single tablet product compared with rosuvastatin at the approved usual starting, next highest and maximum doses. A double-blind, multicentre, six-week parallel-group study in hypercholesterolaemic patients (n=2,959) was conducted. At all doses and across doses, ezetimibe/simvastatin reduced LDL-C levels significantly more (52–61%) than rosuvastatin (46–57%; p≤ 0.001) (see Figure 4). Significantly greater percentages of all patients (p<0.001) and high-risk patients (p≤0.005) attained LDL-C levels <70mg/dl following ezetimibe/simvastatin treatment compared with rosuvastatin. Ezetimibe/simvastatin also produced significantly greater reductions in total cholesterol (p<0.001), and non-HDL-C (p<0.001). Reductions in triglycerides were significantly greater with ezetimibe/simvastatin than with rosuvastatin at the usual starting (p=0.004), next highest (p=0.006) doses and across all doses (p<0.001). Increases in HDL, and decreases in CRP were similar between treatment groups. Safety profiles were comparable for both treatments; however, the percentage of patients with proteinuria was significantly higher following rosuvastatin treatment than ezetimibe/ simvastatin, respectively, at 10mg versus 10/20mg/day (p=0.004) and 40mg versus 10/80mg/day (p<0.001). Both treatments were generally well tolerated. Overall, ezetimibe/simvastatin as a single tablet offers an effective and tolerable treatment option for lipid management and it is a valuable new option to help patients to achieve optimal LDL-C target levels with the final aim of reducing the risk for CHD.

Clinical Outcomes Studies with Ezetimibe/Simvastatin in a Single Tablet

Despite the robust LDL-C lowering data with ezetimibe/simvastatin in a single tablet, it is important to realise that no clinical end-point data are yet available on cardiovascular events, although several trials are underway to address this issue (see Table 1).

Finally, it is important to mention the recently published Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial addressing, in 2,287 patients with stable coronary artery disease, the question of whether an initial management strategy of percutaneous coronary intervention (PCI) with intensive pharmacological therapy and lifestyle intervention (optimal medical therapy) is superior to optimal medical therapy alone in reducing the risk of cardiovascular events. All patients received the optimal medical therapy consisting of antiplatelet (aspirin and clopidogrel), anti-ischaemic drugs (metoprolol, isosorbide mononitrate, amlodipine, lisinopril and losartan, alone or in combination) and an aggressive therapy to lower LDL-C levels (simvastatin alone or in combination with ezetimibe) with a target level of 60–85mg/dl. The primary outcome was death from any cause and non-fatal myocardial infarction during a follow-up period of 2.5–7.0 years (median, 4.6). The results of the study have shown that in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction or other major cardiovascular events when added to optimal medical therapy. It is important to mention that at the end of the study ~50% of the patients received the combination simvastatin/ other lipid-lowering agents – including Ezetimibe – to achieve the optimal target level of LDL-C, thus confirming the concept that aggressive reduction of LDL-C, independent of mode of therapy, is indeed related to a significant protection against cardiovascular events in patients with stable CHD. This is the first study showing the clinical benefits of ezetimibe and simvastatin co-administration therapy.

In conclusion, based on the epidemiological, pharmacological and clinical evidence, it is obvious that the use of ezetimibe/simvastatin in a single tablet for lipid-lowering therapy has, at least theoretically, potential advantages in terms of enhanced efficacy in treating the target condition (i.e. dyslipidaemia) and of enhanced safety and tolerability. The final aim of ezetimibe/simvastatin in a single tablet for lipid management is to reduce the cardiovascular risk of patients and, ultimately, the incidence of cardiovascular events.


Further Reading
  1. Ballantyne CM, Abate N, Yuan Z, et al., Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study, Am Heart J, 2005;149(3):464–73.
    Crossref | PubMed
  2. Boden WE, O'Rourke RA, Teo KK, et al.: COURAGE Trial Research Group, Optimal medical therapy with or without PCI for stable coronary disease, N Engl J Med, 2007356(15):1503–16.
    Crossref | PubMed
  3. Bruckert E, Hayem G, Dejager S, et al., Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study, Cardiovasc Drugs Ther, 2005;19(6):403–14.`
    Crossref | PubMed
  4. Catapano AL, Davidson MH, Ballantyne CM, et al., Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients, Curr Med Res Opin, 2006;22(10):2041–53.
    Crossref | PubMed
  5. Davidson MH, Maccubbin D, Stepanavage M, et al., Striated muscle safety of ezetimibe/simvastatin (Vytorin), Am J Cardiol, 2006;97(2):223–8.
    Crossref | PubMed
  6. Goldberg RB, Guyton JR, Mazzone T, et al., Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia: the VYTAL study, Mayo Clin Proc, 2006;81(12):1579–88.
    Crossref | PubMed
  7. Hildemann SK, Barho C, Karmann B, et al., Dual cholesterol inhibition with ezetimibe/simvastatin in pre-treated hypercholesterolaemic patients with coronary heart disease or diabetes mellitus: prospective observational cohort studies in clinical practice, Curr Med Res Opin, 2007;23(4):713–19.
    Crossref | PubMed
  8. Pearson TA, Denke MA, McBride PE, et al., A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial, Mayo Clin Proc, 2005;80(5):587–95.
    Crossref | PubMed