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Efficacy of Extended-Release Niacin With Lovastatin for Hypercholesterolemia
Assessing All Reasonable Doses With Innovative Surface Graph Analysis
William Insull, Jr, MD;
Mark E. McGovern, MD;
Helmut Schrott, MD;
Paul Thompson, MD;
J. Robin Crouse, MD;
Franklin Zieve, MD;
John Corbelli, MD
Arch Intern Med. 2004;164:1121-1127.
Background Combination therapy to improve the total lipid profile may achieve greater coronary risk reductions than lowering low-density lipoprotein cholesterol (LDL-C) alone. A new extended-release niacin (niacin ER)/lovastatin tablet substantially lowers LDL-C, triglyceride, and lipoprotein(a) levels and raises high-density lipoprotein cholesterol (HDL-C) level. We evaluated these serum lipid responses to niacin ER/lovastatin at all clinically reasonable doses.
Methods Men (n = 85) and women (n = 79) with type IIa or IIb primary hyperlipidemia after diet were randomized among 5 parallel treatment arms. Each arm had 5 sequential 4-week treatment periods: niacin ER (starting at 500 mg/d, increasing in 500-mg increments to 2500 mg/d); lovastatin (starting at 10 mg, increasing to 20 mg, then 40 mg/d); and 3 combinations arms, each with a constant lovastatin dose and escalating niacin ER doses.
Results For primary comparisons, mean LDL-C level reductions from baseline were greater with niacin ER/lovastatin (1500/20 mg) than with lovastatin (20 mg) (35% vs 22%, P<.001) and with niacin ER/lovastatin (2000/40 mg) than with lovastatin (40 mg) (46% vs 24%, P<.001). Each 500-mg increase in niacin ER, on average, decreased LDL-C levels an additional 4% and increased HDL-C levels 8%. The maximum recommended dose (2000/40 mg/d) increased HDL-C levels 29% and decreased LDL-C levels 46%, triglyceride levels 38%, and lipoprotein(a) levels 14%. All lipid responses were dose dependent and generally additive. Graphs of the dose-response relationships as 3-dimensional surfaces documented the strength and consistency of these responses.
Conclusions Niacin ER/lovastatin combination therapy substantially improves 4 major lipoprotein levels associated with atherosclerotic disease. Dose-response surfaces provide a practical guide for dose selection.
From the Lipid Research Clinic, Baylor College of Medicine, Houston, Tex (Dr Insull); Kos Pharmaceuticals, Inc, Weston, Fla (Dr McGovern); Lipid Research Clinic, University of Iowa, Iowa City (Dr Schrott); Hartford Hospital, Hartford, Conn (Dr Thompson); Department of Medicine/Endocrinology, Wake Forest University, Winston-Salem, NC (Dr Crouse); McGuire VA Medical Center, Richmond, Va (Dr Zieve); and Buffalo Cardiology & Pulmonary Associates, Williamsville, NY (Dr Corbelli). Dr Insull has received support for performing other clinical trials for Kos Pharmaceuticals Inc by contract to Baylor College of Medicine and has performed occasional lecturing and consulting. Dr McGovern is a senior vice president and chief medical officer for Kos Pharmaceuticals Inc, the sponsor of this trial. Dr Thompson has received grant funds to Hartford Hospital to perform this research. Dr Zieve has received grant funds to the McGuire VA Medical Center to perform this research.
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