Guidelines for the Management of High Blood Cholesterol

The cholesterol hypothesis holds that high blood cholesterol is a major risk factor for atherosclerosis cardiovascular disease (ASCVD) and lowering cholesterol levels will reduce risk for ASCVD. This hypothesis is based on epidemiological evidence that both within and between populations higher cholesterol levels raise the risk for ASCVD; and conversely, randomized clinical trials (RCTs) show that lowering cholesterol levels will reduce risk. Cholesterol in the circulation is embedded in lipoproteins. The major atherogenic lipoproteins are low density lipoproteins (LDL) and very low-density lipoproteins (VLDL). Together they constitute non-high-density lipoproteins (non-HDL). Clinically these lipoproteins are identified by their cholesterol (C) content, i.e. LDL-C, VLDL-C, and non-HDL-C. Atherogenic lipoproteins can be reduced by both lifestyle intervention and cholesterol-lowering drugs. The efficacy of lifestyle intervention is best demonstrated in epidemiological studies, whereas efficacy of drugs is revealed through RCTs. Currently available cholesterol-lowering drugs are statins, ezetimibe, bile acid sequestrants, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, niacin, fibrates, and n-3 fatty acids (e.g., icosapent ethyl). The latter three generally are reserved for patients with hypertriglyceridemia; here they can be combined with statins that together lower non-HDL-C. Highest priority to cholesterol-lowering therapy goes to patients with established ASCVD (secondary prevention). RCTs in such patients show that “lower is better” for cholesterol reduction. The greatest risk reductions are attained by reducing LDL-C concentrations by at least 50% with a high intensity statin; and if necessary, to achieve LDL-C < 70 mg/dL, combining a statin with ezetimibe or PCSK9 inhibitor. For primary prevention, a decision to initiate statin therapy is made on multiple factors (i.e., presence of diabetes or severe hypercholesterolemia, estimated 10-year risk for ASCVD, presence of risk enhancing factors (e.g., metabolic syndrome and chronic kidney disease); and if in doubt, detection of subclinical atherosclerosis (e.g., coronary artery calcium [CAC]). A reasonable goal for primary prevention using moderate-intensity statin therapy is an LDL-C in the range of 70-99 mg/dL. Both population epidemiology and genetic epidemiology show that low serum cholesterol throughout life will minimize lifetime risk of ASCVD. For this reason, cholesterol-lowering intervention, preferably through lifestyle change, should be carried out as early as possible. If cholesterol concentrations are very high in younger adults, it sometimes may be judicious to introduce a cholesterol-lowering drug. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.