Ezetimibe Coadministered With Lovastatin in Patients With Primary Hypercholesterolemia - Ezetimibe Coadministered With Lovastatin in Patients With Primary Hypercholesterolemia

Description:

The goal of the Ezetimibe Coadministered With Lovastatin in Patients With Primary Hypercholesterolemia trial was to evaluate a novel cholesterol absorption inhibitor given with lovastatin versus lovastatin alone for the reduction of low-density lipoprotein cholesterol (LDL-C) in patients with primary hypercholesterolemia.

Hypothesis:

Coadministration of ezetimibe with lovastatin would result in a significantly greater reduction in LDL-C than lovastatin alone.

Study Design

Study Design:

Patients Screened: 2,335
Patients Enrolled: 548
Mean Follow Up: 12 weeks

Patient Populations:

Patients age ≥18 years with primary hypercholesterolemia, defined as calculated LDL-C of 145-250 mg/dl with no single value <145 mg/dl or >250 mg/dl, and triglyceride levels ≤350 mg/dl, with no single value >400 mg/dl

Exclusions:

Congestive heart failure defined as New York Heart Association class III or IV; uncontrolled cardiac arrhythmias; myocardial infarction, CABG surgery, or angioplasty within six months of study entry; history of unstable or severe peripheral artery disease within three months of study entry; unstable angina; uncontrolled or newly diagnosed (within one month of study entry) diabetes mellitus; unstable endocrine or metabolic diseases known to influence serum lipids and lipoproteins; known impairment of renal function; active or chronic hepatic or hepatobiliary disease; and known coagulopathy

Primary Endpoints:

Percentage decrease in LDL-C from baseline to endpoint for pooled ezetimibe plus lovastatin versus pooled lovastatin alone

Secondary Endpoints:

Change from baseline to final assessment for calculated LDL-C, total cholesterol, triglyceride, HDL-C, HDL2-C, HDL3-C, non–HDL-C, lipoprotein(a), apo A-I, apo B, and total cholesterol:HDL-C and direct LDL-C:HDL-C ratios

Drug/Procedures Used:

Patients were randomized to 1 of 10 treatments: placebo (n=64); ezetimibe alone (10 mg, n=72); lovastatin alone (10, 20, or 40 mg); or ezetimibe (10 mg) plus lovastatin (10, 20, or 40 mg). Patients were treated with the study drug for 12 weeks.

Principal Findings:

LDL-C was significantly reduced from baseline to final assessment with ezetimibe plus lovastatin (pooled treatment groups; -39%) compared with either lovastatin alone (-25% for pooled treatment groups; p<0.01) or ezetimibe alone (-19%; p<0.01). A reduction of LDL-C ≥50% occurred in 23% of patients who received combination therapy versus 2% of patients who received lovastatin monotherapy.

LDL-C reduction with coadministration (all doses) was generally consistent across all subgroups. Total cholesterol:high-density lipoprotein cholesterol (HDL-C) ratio was also significantly reduced with ezetimibe plus lovastatin (-34%) compared with lovastatin alone (-21%, p<0.01) or ezetimibe alone (-15%, p<0.01), as were triglycerides (-22% with combination therapy vs. -11% with lovastatin, p<0.01; and vs. -3% with ezetimibe alone, p<0.01), and HDL-C values were higher with combination therapy (9% with combination therapy vs. 4% with lovastatin, p<0.01; and vs. 3% with ezetimibe alone, p<0.01).

Combination therapy at the lowest dose of lovastatin (10 mg) provided similar reductions to results seen with the maximum dose of lovastatin (40 mg) alone for LDL-C (-33% vs. -29%, p=0.10). Adverse events that were treatment-related occurred in 16% of patients receiving lovastatin monotherapy and 17% of patients receiving combination therapy. There were no cases of hepatitis, jaundice, or other clinical signs of liver dysfunction, and no deaths during the study.

Interpretation:

Among patients with primary hypercholesterolemia, treatment with ezetimibe plus lovastatin was associated with a greater reduction in LDL-C compared with lovastatin alone or ezetimibe alone. Ezetimibe plus the lowest dose of lovastatin (10 mg) was associated with reductions in direct LDL-C that were similar to results seen with the maximum dose of lovastatin (40 mg) alone. Ezetimibe plus lovastatin appeared safe, with no excess treatment-related adverse events, and no increase in hepatitis or jaundice indicating liver dysfunction.

The authors note that ezetimibe inhibits the intestinal absorption of cholesterol, suggesting that the cholesterol-lowering effect of ezetimibe may be complementary to that of agents that inhibit the endogenous production of cholesterol such as statins, which may in part explain the larger improvements in the combination arms compared with either of the monotherapy arms.

The overall duration of the study was relatively short (12 weeks), and additional follow-up is needed to determine if the efficacy is maintained and if the safety profile is similar with longer therapy. Ezetimibe plus lovastatin may prove to be an alternative for patients in whom maximal dose statin monotherapy is inefficient.

Similar results were also observed in trials of ezetimibe plus simvastatin (Davidson MH, McGarry T, Bettis R. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002;40:2125–34) and ezetimibe plus atorvastatin (Ballantyne CM, Houri J, Notarbartolo A, et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003;107:2409-15).

References:

Kerzner B, Corbelli J, Sharp S, et al. Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia. Am J Cardiol 2003;91:418–24.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Intestinal Absorption, Follow-Up Studies, Lovastatin, Cholesterol, LDL, Hepatitis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Heptanoic Acids, Simvastatin, Hypercholesterolemia, Pyrroles, Azetidines, Jaundice, Cholesterol, HDL, Triglycerides


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