The “Other” Cholesterol: HDL and the importance of lowering overall cardiovascular disease risk

The management of Coronary Artery Disease has traditionally focused on the reduction of LDL cholesterol or on the total lipid profile for management of patients with CHD. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) established a low-density lipoprotein (LDL) cholesterol goal of <100 mg/dl for patients with coronary heart disease (CHD) risk equivalent, and a goal of <130 mg/dl for patients at high risk for cardiovascular events (CV) events (our patients with multiple-risk factors with a 10-year CHD risk <20%) (1).

What is often under emphasized in the management of these patients is the HDL cholesterol. Low levels of high-density lipoprotein (HDL) cholesterol are common in patients at high risk for coronary heart disease (CHD), including patients who are obese and those with the ever increasing metabolic syndrome. There are estimates that low HDL cholesterol levels (< 40 mg/dL) are found in almost 40% of men and 15% of women ages 20 years and older. Many of these patients also have elevated LDL cholesterol levels (1).

How often do we experience this scenario with one of our patient’s? “Doc, how did I develop heart blockages? I eat right, and my cholesterol has always been less than 200”. In the Framingham Heart Study, those patients who had a 1% increase in HDL cholesterol had a subsequent 2% reduction in the risk of development of CHD (2). Other studies have supported this specifically the Physicians Health Study (3) in which patients with low HDL cholesterol had increased risk of CHD, and the Israeli Heart Disease study in which patients with low total cholesterol and high HDL cholesterol levels had the lowest levels of morbidity and mortality (4).

The NCEP ATP III guidelines revised the guideline and definition of low HDL cholesterol to < than 35 mg/dL. It had previously been < than 40 mg/dL. So, how do we as health care providers go about getting our patients to meet these guidelines? Therapeutic lifestyle modification (TLM) is traditionally the 1st line of therapy recommended. A reduction of dietary intake of cholesterol and total calories is often advised, albeit with usually limited success. Additional components of (TLM) include increasing physical activity, smoking cessation, overall body fat loss, and moderate alcohol intake. (1). Guidelines for dietary modifications now strongly support the increased intake of omega-3 fatty acids via fish consumption or supplementation with fish oils. A daily Intake of 4 g/d of marine omega-3 fatty acids was associated with an up to 3% increase of HDL, a modest 10% decrease in LDL and up to 30% reduction in serum triglycerides (5). Unfortunately, these TLM are not often enough to reach our target goals for our patients who are at obvious increased risk for a CVD event.

There are multiple drugs for use in getting our patients to goal. They are briefly summarized below and are put into table form in Figure 1.

Pharmacologic intervention

Statin therapy is used as a common approach to managing CHD. Statins are used in CHD to target the reduction of elevated LDL and to improve the lipid level profile. Statins have other non-LDL lipid effects, including decreasing triglyceride levels and raising HDL cholesterol. Other therapies with significant non-LDL lowering effects such as fibrates and niacin, which lower triglyceride levels and raise HDL cholesterol, have also been shown to reduce CVD events (1) despite less potent effects on lowering LDL cholesterol levels. The NCEP ATP III guidelines outline that in a high risk patient with a low HDL cholesterol, consideration should be given to combination therapy with a fibrate or nicotinic acid in addition to an LDL–lowering drug (1).

• Statin therapy – Statin therapy remains the first choice in management of patients with CV disease. A wide range of pleiotropic effects have been reported for the statins including vasodilation, antithrombosis, antioxidant, antiproliferative, and anti-inflammatory effects; and plaque stabilization (6). Results from large statin end point trials, including the WOSCOPS (7) and AFCAPS (8) trials have demonstrated that patients with high LDL cholesterol and low HDL benefit significantly from statin therapy. ATP III guideline recommendations indicate that a total cholesterol to HDL cholesterol ratio goal of <4.0 should be targeted in high risk patients.

• Niacin Therapy – Niacin, or nicotinic acid, is a soluble B vitamin that has favorable effects on all major lipid subractions but historically has limited use because of its adverse side effect profile. Niacin was one of the first lipid altering agents to demonstrate a reduction in CHD events in the Coronary Drug Project (9). At present niacin is the most effective HDL cholesterol raising therapy available. Niacin has been shown to lower LDL cholesterol by up to 20%, triglycerides by 20 to 40% and raise HDL cholesterol by 15 to 30% (9). The adverse effect profile includes the potential for liver toxicity. Other common and well known adverse effects include rash, flushing, GI problems, hyperglycemia, and gout.

• Statin/Niacin combination therapy- Often, we may be getting our patients to LDL goal, but are still left with patients at high CV risk with low HDL levels. Adding niacin to a statin is a common strategy to reduce the overall CV risk and inhibit the development of further atherosclerosis. This was borne out in data (9), which demonstrated that the addition of extended release Niacin to statin therapy showed a 21% increase in HDL cholesterol and a reduction in the progression of atherosclerosis via measurement of change in carotid intima-media thickness, compared with statin therapy alone in patients with known Coronary Heart Disease and low HDL levels.

• Statin/Fibrate combination therapy – This is considered a good therapeutic option in those patients whom lipid goals are not achieved with statin monotherapy. The statin/fibrate combination strategy is effective in reducing LDL cholesterol and triglyceride levels and increasing HDL cholesterol levels. There are only 2 approved agents available in the United States (gemfibrozil and fenofibrate). The patient with hypertryglyceridemia and low HDL cholesterol levels is the prime candidate for this management strategy.

FIGURE 1

Class
HDL-C increase
Adverse Effects
Contraindications
Clincal Trial
Results
Statins
5-15%
Myopathy,
Increased LFT’s
Absolute: active or chronic liver disease
Reduced major CHD events, stroke, mortality
Fibrates
10-20%
Dyspepsia, gallstones
Myopathy, unexplained
Non-CHD deaths
Absolute: severe hepatic, or renal disease
Reduced major CHD events
Niacin
15-35%
Flushing, hepatoxicity
Gout, GI distress
Absolute: chronic liver disease
Relative: Diabetes
Reduced major CHD events and possible total mortality

Adapted from Toth (10 ) Am J Cardiology

There is ample evidenced based medicine to support aggressively treating our patients who have CHD risk and a low HDL. There are number of strategies that can be implemented to increase HDL cholesterol levels to lower CV risk reduction. Increasing HDL levels in our patient population must be done on multiple levels. Dietary and therapeutic lifestyle modifications (TLM) are just the starting point. The use of statins, statin combination therapy, and future investigational therapies will be needed to maximize our patients CV disease and residual risk.

Written by Joel R. Garcia, MD
Orlando Heart Center

Partner of Dr. Mark Steiner, Cardiologist in Orlando

References

• 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). Final Report. Circulation. 2002; 106:3143-3421

• Castelli WP. Cholesterol and lipids in the risk of coronary artery disease-The
Framingham Heart Study. Can J Cardiol. 1988;4(suppl A):5A-10A.

• Stampfer MJ, Sacks FM, Salvin S, et al. A prospective study of cholesterol,
apolipoproteins, and the risks of myocardial infarction. N Engl J Med. 1991;
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• Goldbourt U, Yaari JS, Medalie JH. Isolated low HDL cholesterol as a risk factor
for coronary heart disease mortality: a 21-year follow up of 8,000 men.
Arterioscler Thromb Vasc Biol. 1997:17:107-113.

• Harris WS. N-3 Fatty acids and serum lipoproteins human studies. Am J Clin
Nutr. 1997;65(5 suppl):1645S-1654S

• Birjmouhun RS, Hutten BA, Kastalein JJP, et al. Efficacy and safety of high
density lipoprotein cholesterol-increasing compounds: A meta analysis of
randomized controlled trials. J Am Coll Cardiol. 2005; 45:185-197

• Sheperd JJ, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with
pravastatin in men with hypercholesteremia. West of Scotland Coronary
Prevention Study Group. N Engl J Med. 1995; 333:1301-1307

• Downs JR, Clearkeindl M, Weis S, et al. Primary Prevention of acute coronary
events with lovastatin in men and women with average cholesterol levels: result of
AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.
JAMA. 1998;279:1615-1622

• Grundy SM, Cleeman JI, Metz CN, et al. Implications of recent trials for the
national cholesterol education program adult treatment panel III guidelines.
Circulation. 2004:100:227-239

• Toth PP. High-density lipoprotein as a therapeutic target: clinical evidence and
treatment strategies. Am J Cardiol 2005;96(9A):50K-58K

Written by Dr. Mark Steiner, Cardiologist in Orlando