Low HDL and Cardiovascular Disease

Overview

A low HDL-C level is a major causative risk factor for CHD, but some members of the medical community remain unconvinced. Several decades ago, many practitioners held the same doubts about a high LDL-C level. Early cross-sectional studies demonstrated that both a high LDL-C level and a low HDL-C level were CHD risks; and subsequent major prospective, observational studies (eg, Framingham) supported these relationships. When statins became available, dramatically lower LDL-C levels could be achieved with few adverse effects, and large randomized trials began to be performed. These studies proved conclusively that LDL is not merely correlated with, or a marker for, CHD but is a major cause of the disease. A medication with comparable HDL-raising impact has yet to be developed. Despite this obstacle, randomized interventional studies using fibrates or niacin have proven that raising HDL-C levels slows progression and speeds regression of coronary atherosclerosis in addition to achieving a reduction in the number of total coronary events. Moreover, multiple mechanisms have been identified, including antioxidant and anti-inflammatory actions, by which HDL slows the disease process. Niacin raises HDL more effectively than the fibrates and also reliably lowers LDL-C levels. Both niacin and fibrates lower triglyceride levels. Cardioprotective lifestyle changes (smoking cessation, frequent aerobic exercise, weight loss) exert favorable changes in both HDL-C and triglyceride levels.

In spite of accumulating evidence to the contrary, some practitioners still consider the HDL-C level to be merely a marker for CHD or believe that triglyceride levels, which are usually elevated when HDL-C levels are low, are responsible for higher disease rates. An understanding of the interaction of HDL with triglyceride-rich chylomicrons and VLDL makes such an argument questionable. Until highly effective, easily tolerated agents that raise the HDL-C level are available, doubts regarding HDL’s importance will probably persist; but a glimpse of the role HDL plays in reverse cholesterol transport may be enlightening.

HDL and Reverse Cholesterol Transport

Atherogenesis depends upon the transport of cholesterol to peripheral sites. Hepatic cholesterol and intestinal dietary cholesterol are packaged into lipoproteins (VLDL and chylomicrons, respectively) after which lipoprotein lipase hydrolyzes triglycerides to free fatty acids and transforms the lipoproteins to remnants. Hepatic lipase converts VLDL remnants to LDL, which is the primary mechanism for delivery of cholesterol to arterial endothelium. LDL also returns cholesterol to the liver, as do the remnants. Reverse cholesterol transport refers to the movement of cholesterol from peripheral sites back to the liver, where it can be safely eliminated as a component of bile.

HDL is essential for this process. Immature HDL particles take up cholesterol from chylomicrons and VLDL during the latter's transformation to remnants. HDL also removes cholesterol from peripheral sites in arterial walls. This process is facilitated by HDL’s critically important apolipoprotein, apoA-I. This protein binds to the ATP-binding cassette transporter 1 (ABCA1) gene in macrophages and other peripheral cells and facilitates cholesterol efflux to the nascent HDL. As increasing amounts of cholesterol accumulate, HDL matures from HDL3 to HDL2. Cholesterol can then be returned to the liver either directly via uptake by scavenger receptor B1 (SR-B1) or indirectly by transfer back to VLDL in exchange for triglycerides. The VLDL pathway is mediated by cholesterol ester transfer protein (CETP), an enzyme that has become the focus of intense research and drug development. The VLDL pathway facilitates reverse cholesterol transport only if LDL and VLDL remnants return to the hepatocytes. If the remnant lipoproteins transfer the cholesterol formerly carried by HDL back to peripheral sites, then the CETP-meditated pathway may be proatherogenic. Study of CETP in humans and in animal models has shown that both the proatherogenic and antiatherogenic actions are possible.

Clinical GUIDELINES

In 1987, a low HDL-C level was declared 1 of 6 major risk factors for CHD by the first National Cholesterol Education Program Adult Treatment Panel (ATP I). Low was defined as less than 35 mg/dL. An HDL-C level of 60 mg/dL or more was selected as the sole negative (ie, protective) risk factor. In 1993, the somewhat arbitrary nature of these cutoffs became apparent when the ATP II redefined the high-risk HDL-C value, raising it to less than 40 mg/dL. The global risk estimate introduced at the same time refined the HDL risk level by adding 1 point for an HDL-C level of 40-49 mg/dL and 2 points if less than 40 mg/dL and subtracting 1 point for an HDL-C level of more than 60 mg/dL. The ATP III did not change these HDL cut points but added a new target for treatment, the metabolic syndrome. Five components (HDL, triglycerides, BP, FBS, and weight) were chosen, only 3 of which are necessary for the diagnosis of the syndrome. The HDL-C levels for risk were made gender-specific (men, <40 mg/dL; women, <50 mg/dL), for the first time reflecting women’s higher average HDL-C levels. Also, African Americans have significantly higher HDL-C levels than Caucasians, but risk levels have not been adjusted to reflect this difference.

The ATP III does not specify a goal HDL-C level but suggests the following 4-step approach to management of levels less than 40 mg/dL:

• Reach the LDL-C goal.
• Intensify lifestyle intervention.
• If triglyceride levels are 200-499 mg/dL, achieve the non–HDL-C level (either by lowering the LDL-C level further or by lowering the triglyceride level).
• High-risk patients (ie, those with CHD or CHD risk equivalents) who have isolated low HDL-C levels may be treated with nicotinic acid or a fibrate.

Recent IMPORTANT STUDIES

In the Diabetes Atherosclerosis Intervention Study (DAIS), a randomized trial using fenofibrate in patients with diabetes, angiographic progression of coronary artery disease was reduced. All lipid parameters improved significantly in this trial, but the earlier Veterans Affairs HDL Intervention Trial (VA-HIT), which used gemfibrozil to treat men with CHD and low HDL-C levels, showed a statistical and clinically significant reduction in coronary events despite a lack of improvement in LDL-C levels. Both trials increased HDL-C levels approximately 6.3%.

In the HDL Atherosclerosis Treatment Study (HATS), a combined statin-niacin study of patients with CHD and low HDL-C levels, greater improvement in both regression and clinical end points was noted compared to the results obtained in statin-only trials. Clinical events were reduced but were not statistically significant because of the small study size. HDL-C levels increased 26%, while LDL-C and triglyceride levels decreased 42% and 36%, respectively.

Much interest has focused on raising HDL-C levels with CETP inhibitors. In a small placebo-controlled study of the inhibitor torcetrapib, HDL-C levels increased from 34 mg/dL to 70 mg/dL, with reductions of LDL-C and triglyceride levels. At a lower dose, HDL-C levels increased 46%; with the addition of a statin, HDL-C levels rose 61%.

References

Barter P. HDL: a recipe for longevity. Atheroscler Suppl. 2004 May;5(2):25-31.

Brousseau ME, Schaefer EJ, Wolfe ML, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med. 2004 Apr 8;350(15):1505-15.

Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001 Nov 29;345(22):1583-92.

Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet. 2001 Mar 24;357(9260):905-10. Erratum in: Lancet. 2001 Jun 9;357(9271):1890.

Elam MB, Hunninghake DB, Davis KB, et al. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: A randomized trial. Arterial Disease Multiple Intervention Trial. JAMA. 2000 Sep 13;284(10):1263-70.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001 May 16;285(19):2486-97.

Gotto AM Jr, Brinton EA. Assessing low levels of high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report and update. J Am Coll Cardiol. 2004 Mar 3;43(5):717-24.

Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003 Nov 5;290(17):2292-300.

Szapary PO, Rader DJ. The triglyceride-high-density lipoprotein axis: an important target of therapy? Am Heart J. 2004 Aug;148(2):211-21.