Section Review—Cardiovascular & Renal: Emerging Therapies in Atherosclerosis

Abstract

Elevated blood cholesterol is an established risk factor for coronary heart disease (CHD), and the basis for treatment is normalisation of LDL-cholesterol (LDL-C). If dietary measures fail, inhibitors of HMG-CoA reductase (HMGR) potently lower LDL-C, and have been shown to reduce morbidity and mortality for CHD. New investigational drugs, reviewed herein, will address other medical needs, such as inhibiting cholesterol synthesis without affecting the synthesis of other essential molecules (e.g., ubiquinone, dolichol, etc.), inhibiting biliary and dietary cholesterol absorption, lowering Lp(a), elevating HDL and/or stimulating reverse cholesterol transport, and directly interacting with numerous arterial wall proteins involved in atherogenesis. Potent and specific drugs can best answer important questions about whether elevating HDL-C (or other apoAl-containing particles) or lowering Lp(a) is beneficial, much in the same way that HMGR inhibitors have answered questions about the merits of LDL lowering. Arterial wall targets (e.g., ACAT, VCAM, 15-LO), aimed primarily at CHD patients with normal lipoprotein profiles, will likely be more challenging with regard to drug development. Theoretically, such drugs must achieve sufficient concentrations in the bloodstream so as to result in appreciable uptake/accumulation in arterial lesions, but yet possess an acceptable margin of safety. Moreover, surrogate markers for determining clinical effectiveness, which at present are limited to expensive, specialised techniques, must be identified. Whom and when to treat remain to be established, and drugs affecting targets at the arterial wall will likely have to demonstrate an additive or unique activity compared to HMGR inhibitors. Thus, refined methods of lesion assessment will become essential for all approaches, both lipoprotein and nonlipoprotein-based, to obtain a clinical indication for CHD in man.