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Dose-Response Characteristics of Cholesterol-Lowering Drug Therapies: Implications for Treatment

Gordon Schectman, MD; and Jan Hiatt, PharmD
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From Medical College of Wisconsin and the Milwaukee Veterans Administration Medical Center. Acknowledgments: The authors thank Ms. Sue Goodman for her careful and thorough efforts to ensure proper completion of technical portions of this manuscript and Jerry VanRuiswyk, MD, for his careful review of the manuscript and assistance with the quantitative aspects of the data synthesis. Requests for Reprints: Gordon Schectman, MD, Division of General Internal Medicine, Medical College of Wisconsin, Froedtert Lutheran Memorial Hospital East, Box 135, 9200 West Wisconsin Avenue, Milwaukee, WI 53226. Current Author Addresses: Dr. Schectman: Division of General Internal Medicine, Medical College of Wisconsin, Froedtert Lutheran Memorial Hospital East, Box 135, 9200 West Wisconsin Avenue, Milwaukee, WI 53226.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1996;125(12):990-1000. doi:10.7326/0003-4819-125-12-199612150-00011
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Purpose: To develop an optimal treatment strategy that reduces low-density lipoprotein (LDL) cholesterol levels and improves adherence to therapy by reviewing clinical trials that define the dose-response characteristics for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), bile acid sequestrants, and niacin.

Data Sources: Data were obtained from a MEDLINE search of the English-language literature published from 1975 through November 1995 and from an extensive bibliography review.

Study Selection: Controlled, clinical trials were reviewed if they evaluated 1) the effectiveness and toxicity of one LDL cholesterol-lowering agent [statins, bile acid sequestrants, or niacin, at two or more doses] or 2) monotherapy with two LDL cholesterol-lowering agents at defined doses used alone and in combination. Studies that had fewer than 10 patients in a treatment group or that selected patients on the basis of previous response to therapy were not included.

Data Extraction: Trials were reviewed for overall methodology, inclusion and exclusion criteria, sources of bias, and outcomes.

Data Synthesis: Dose-response relations for bile acid sequestrants and statins are nonlinear, and most of their LDL cholesterol-lowering effects can be obtained with lower doses. The few dose-response studies of niacin that have been done suggest that most of niacin's high-density lipoprotein cholesterol-increasing effect can also be achieved with relatively low doses, but higher doses are needed to substantially reduce LDL cholesterol levels. If bile acid sequestrants or niacin are added to statin therapy, the effect of combined therapy on LDL cholesterol levels is additive.

Conclusion: The nonlinear dose-response relation of statins, bile acid sequestrants, and niacin and their additive LDL cholesterol-lowering effect when used together suggest a strategy for treating hypercholesterolemia that may optimize effectiveness while minimizing adverse effects and cost.


Grahic Jump Location
Figure 1. Open circles represent responses to combinations of statin and sequestrants; closed circles represent responses to combinations of statin and niacin (correlation coefficient, 0.92; < 0.001).
Observed response to combination drug therapy compared with the response predicted, assuming that the low-density lipoprotein cholesterol-lowering effects of each drug are independent and additive.P
Grahic Jump Location




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