Treatment of dyslipidemia: room for improvement?

Abstract

Low density lipoprotein cholesterol (LDL-C) is the appropriate focus of primary and secondary prevention of coronary heart disease (CHD) in patients with hypercholesterolemia. Basic investigation and evidence from animal models and epidemiological studies lend robust support to its role as a major risk factor for CHD. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors reduce plasma concentrations of LDL-C and have consistently shown substantial benefits in primary and secondary prevention. However, although treatment has dramatically reduced the risk of recurrent CHD in secondary prevention trials, it is becoming increasingly evident that even reduction of LDL-C to 100 mg/dL may not be adequate to restore the risk levels of such patients to the risk levels of those individuals free of CHD. Despite mean on-treatment LDL-C concentrations ranging from 97 to 113 mg/dL, recurrent CHD event rates in 3 secondary prevention trials were all ≈2% per year.1 2 3 The CHD event rate in the 40% subset of participants in the Scandinavian Simvastatin Survival Study who lowered their LDL-C levels to <100 mg/dL (mean 95 mg/dL) was also 2% per year.4 These event rates are unacceptably high, and 2 approaches are being explored to determine whether there is room for improvement: (1) more aggressive lowering of LDL-C and (2) treatment of the “lipoprotein complex.” Although the first of these appears intuitively attractive, careful examination of curves relating CHD event rates to on-treatment LDL-C in the trials outlined above suggests an asymptotic relationship. The CHD risk appears to “flatten out” at 2% per year for LDL-C levels <120 mg/dL. In addition, although there are no data to show that dramatic reduction of LDL-C (eg, <50 mg/dL) might lead to increased risk of adverse events, subgroup analysis from the Multiple Risk Factor Intervention Trial (MRFIT) suggests an increased risk of hemorrhagic stroke in individuals with …