DOSE-RESPONSE CHARACTERISTICS OF CHOLESTEROL-LOWERING DRUG THERAPIES - IMPLICATIONS FOR TREATMENT

Purpose: To develop an optimal treatment strategy that reduces low-den sity lipoprotein (LDL) cholesterol levels and improves adherence to th erapy by reviewing clinical trials that define the dose-response chara cteristics for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibit ors (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 bibli ography review. Study Selection: Controlled, clinical trials were revi ewed if they evaluated 1) the effectiveness and toxicity of one LDL ch olesterol-lowering agent (statins, bile acid sequestrants, or niacin, at two or more doses) or 2) monotherapy with two LDL cholesterol-lower ing agents at defined doses used alone and in combination. Studies tha t had fewer than 10 patients in a treatment group or that selected pat ients on the basis of previous response to therapy were not included. Data Extraction: Trials were reviewed for overall methodology, inclusi on and exclusion criteria, sources of bias, and outcomes. Data Synthes is: 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 tha t have been done suggest that most of niacin's high-density lipoprotei n cholesterol-increasing effect can also be achieved with relatively l ow doses, but higher doses are needed to substantially reduce LDL chol esterol levels. If bile acid sequestrants or niacin are added to stati n 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 cholestero l-lowering effect when used together suggest a strategy for treating h ypercholesterolemia that may optimize effectiveness while minimizing a dverse effects and cost.