Niacin extended-release with lovastatin for hypercholesterolemia

There is a growing consensus that treatment of the total lipid profile can reduce the burden of coronary artery disease (CAD) more effectively than lowering low-density lipoprotein (LDL) cholesterol alone.1-3 However, no single lipid-altering agent effectively modifies all lipid abnormalities. The HMG-CoA reductase inhibitors (statins) are the most powerful agents for lowering LDL cholesterol, but they have lesser effects on triglycerides and high-density lipoprotein (HDL) cholesterol levels. Niacin is the most effective agent for raising HDL cholesterol, and it further complements statin therapy by effectively lowering triglycerides and lipoprotein (a). Their combination has the advantage of controlling the four major components of the lipid profile influencing the development of atherosclerosis. Moreover, preliminary data suggest that this combination may produce substantial clinical benefits; in the HDL Atherosclerosis Treatment Study (HATS), CAD patients treated with simvastatin plus niacin experienced a 60% to 90% reduction in cardiovascular events compared with placebo.4

Extended-release (ER) niacin/lovastatin is the first combination agent approved for the treatment of primary hypercholesterolemia and mixed dyslipidemia.5 The present study compared the lipid-altering efficacy of coadministration of niacin ER and lovastatin with niacin ER alone and lovastatin alone using all clinically reasonable doses.6 The dose-response effects were also analyzed by innovative surface graphs.

Patients and methods

The study results have been previously published.6 In brief, this was a 26-week, randomized, double-blind, active-control study performed at multiple clinical centers in the United States. Men and women with type IIa or IIb hyperlipidemia were eligible if they had stable baseline LDL cholesterol levels of 130 mg/dL or higher with CAD or risk equivalents, 160 mg/dL or higher LDL cholesterol with two or more CAD risk factors, or 190 mg/dL or higher LDL cholesterol with fewer than two risk factors and fasting triglyceride levels less than 800 mg/dL during screening.

Patients were randomly assigned to one of five treatment arms: three arms tested coadministration of niacin ER/lovastatin, one tested niacin ER alone, and one tested lovastatin alone for 20 weeks. In each combination group, the lovastatin dose was fixed at 10, 20, or 40 mg, whereas the niacin ER dose was titrated by 500-mg increments every 4 weeks, up to 2,500 mg. In the monotherapy groups, the niacin ER dose was titrated similarly, whereas the lova-statin dose was doubled every 8 weeks, from 10 mg up to 40 mg. In total, this design included 23 different doses. Patients were counseled to take study medications once daily at bedtime with a low-fat snack. In addition, to reduce flushing, 325 mg of aspirin 30 minutes before dosing was recommended.

The two primary end points of efficacy were the mean percentage change in LDL cholesterol level for patients taking 1,500/20 mg niacin ER/lovastatin compared with those taking 20 mg of lovastatin alone

and the mean percentage change in LDL cholesterol for patients taking 2,000/40 mg of niacin ER/lovastatin compared with those taking 40 mg of lovastatin alone. Secondary end points of efficacy included mean percentage change in HDL cholesterol, triglyceride, and lipoprotein (a) levels. Blood was drawn to determine lipid levels every 4 weeks prior to scheduled dose escalation. Treatment-emergent adverse events and serum levels were evaluated

at each visit. For use in clinical practice, results are given for the FDA-approved niacin ER/lovastatin dosing range of from 500/20 mg to 2,000/40 mg. Three-dimensional surface graphs (figure) show all the results of the study, from 500/10 mg to 2,500/40 mg.

Results

A total of 164 patients were randomly assigned to one of the five treatment groups. Baseline characteristics were similar among the groups (table 1).6 Medication compliance was 96%, 96%, and 92% with the combination, lovastatin alone, and niacin ER alone, respectively.

Efficacy. Niacin ER/lovastatin produced favorable, dose-dependent changes in all four components of the lipid profile. For the two pri-mary end points, niacin ER/lova-statin at 1,500/20 mg and 2,000/40 mg lowered mean LDL cholesterol levels more effectively than lova-statin alone at 20 mg and 40 mg, respectively (P < .001 for both comparisons; table 2). Niacin ER/lova-statin at doses of 500/20 mg to 2,000/40 mg produced progressive decreases in LDL cholesterol of 29% to 46% from baseline. These reductions were approximately additive relative to those achieved with the individual components. Each combination of niacin ER (500 mg—2,000 mg) with lovastatin 20 mg also lowered LDL cholesterol more effectively than lovastatin alone at the 40-mg dose. In addition, LDL cholesterol decreased by approximately 4% for each 500-mg increase in the niacin ER dose.

For secondary end points, niacin ER/lovastatin at doses of 500/20 mg to 2,000/40 mg produced progressive increases in mean HDL cholesterol levels of 7% to 29% and decreases in triglycerides of 9% to 39% from baseline (table 1). The effects of combination treatment were generally additive. In addition, HDL cholesterol increased by approximately 8% for each 500-mg increase in the niacin ER dose. Lipoprotein (a) levels decreased progressively by 5% to 14% with combinations containing niacin ER doses of 1,000 mg or more.

The overall strength and consistency of the dose-response relationships for each lipid are shown in the surface graphs in the figure.6 They display the incremental efficacy on the four lipid components simultaneously across the 23 doses tested. The figure caption provides a detailed explanation of how to read the graphs.

Safety. Flushing was the most common side effect seen in patients treated with niacin ER regimens (62%), but it led to withdrawal in only 6% of patients on combination therapy and 10% of patients on niacin ER alone. Excluding flushing, the incidence of adverse events and withdrawals was similar among all five treatment groups. At recommended niacin ER/lovastatin doses less than 2,000/40 mg, one patient had transient increases in liver function test levels greater than three times normal. Three additional patients had increased liver function test levels with combination doses containing 2,500 mg of niacin ER.

No increases in creatine kinase levels greater than three times normal occurred. No cases of myopathy were reported.

Discussion

Optimal control of dyslipidemia is essential for the primary and secondary prevention of CAD. This study shows the complementary and incremental efficacy of niacin ER/

lovastatin on four lipid parameters independently correlated with CAD risk. In the recommended dosing range of 1,000/20 mg to 2,000/40 mg per day, niacin ER/lovastatin reduced LDL cholesterol levels by 32% to 46%, triglycerides by 24% to 38%, and lipoprotein (a) levels by 5% to 14%, and increased HDL cholesterol levels by 18% to 29%. Niacin ER/

lovastatin produced generally additive effects on LDL cholesterol, HDL cholesterol, and triglycerides. At the 2,000/40-mg dose, changes in lipids were similar to or greater than those seen in HATS.4 For LDL cholesterol lowering, combination therapy was more effective than doubling the dose of lovastatin alone. As a rule of thumb, LDL cholesterol was reduced by 4% and HDL cholesterol was increased by 8% for each 500-mg increment in niacin ER dose. Lipoprotein (a) levels also decreased with niacin ER doses of 1,000 mg or more.

Combination treatment was safe and generally well tolerated. Flushing induced by niacin ER was not a major clinical problem. Although 62% of patients experienced flushing, 38% of patients did not. Only 6% withdrew because of flushing over the 5 months of treatment. Adverse events other than flushing were similar among treatment groups.

The many beneficial effects of niacin ER/lovastatin therapy on lipid profiles in men and women are clinically applicable to the current evidence-based guidelines for lipid treatment and CAD prevention.3,7 The 2004 update to the National Cholesterol Education Program Adult Treatment Panel III guidelines reemphasized the importance of controlling LDL cholesterol in patients at higher risk, such as those with CAD, diabetes, and metabolic syndrome.7 The update cites new clinical trial data that clearly show for the first time the dependence

of CAD risk on LDL cholesterol

at treatment-induced levels less

than 100 mg/dL.8-11 Revisions to the guidelines include new optional LDL cholesterol goals of less than

70 mg/dL for patients at very high risk and less than 100 mg/dL for those at moderately high risk. They also emphasize the routine use of standard doses of statins or combination therapy to lower LDL cholesterol by 30% to 40% or more. For high-risk patients with high triglycerides or low HDL cholesterol levels, or both, the guidelines suggest combination therapy using niacin or a fibrate. Furthermore, the new American Heart Association guidelines for CAD prevention in women have raised the HDL cholesterol treatment goal from 40 mg/dL or greater to

50 mg/dL or greater.3

The broad endorsement of these two guidelines by leading professional groups and experts is setting new national standards of practice. To successfully achieve the increasingly aggressive and often multiple targets, clinicians need to become familiar with the lipid-altering profiles of combination therapies. The surface graphs (figure) show the multi-lipid dose-response effects of niacin ER/lovastatin and provide a practical guide for treating patients with more than one lipid abnormality.6 The graphs can be used to select the optimal dose for attaining LDL cholesterol, HDL cholesterol, triglyceride, and, in selected cases, lipo-protein (a) goals. This study design and efficacy summary by surface graphs can provide a useful standard model for the evaluations of other combinations of lipid drugs, and for orderly comparisons among the drugs.