THE EFFECT OF HDL LEVELS ON CARDIOVASCULAR DISEASE
Overview
High-density lipoprotein (HDL), also known as good cholesterol, is a strong and independent risk factor for coronary artery disease (CAD). Persons with high HDL levels are relatively protected from atherosclerosis, and those with low HDL levels exhibit increased cardiovascular morbidity and mortality. Raising the level of HDL cholesterol leads to reduction in heart disease risk by an order of magnitude higher than that achievable by lowering the levels of low-density lipoprotein (LDL), known as bad cholesterol. For example, lowering the LDL level by 1 mg/dL reduces CAD risk by 1%, but raising the HDL level by 1 mg/dL results in a risk reduction of 2% in men and 3% in women. Thus, to decrease the risk of CAD, modifying HDL levels is as effective as, if not more effective than, modifying LDL levels.
In 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 [ATP] III), a low HDL level for both men and women is defined as an HDL level <40 mg/dL, while a high HDL level is defined as an HDL level of ≥60 mg/dL. HDL level is also one of the five components that define metabolic syndrome, and a level <40 mg/dL for men or <50 mg/dL for women is considered the cut-off point. Currently, the NCEP does not specifically recommend that HDL be a primary target of intervention. However, in patients with metabolic syndrome and those with low HDL levels, the HDL level is an appropriate secondary target of intervention that may be modified by medications that raise HDL levels. Finally, in high-risk patients, such as those who have diabetes, those who have established atherosclerotic disease, and those of south Asian origin, treating isolated low HDL cholesterol levels may be reasonable.
THE PHYSIOLOGIC ROLE OF HDL
HDL drives the reverse cholesterol transport. Excess cholesterol is picked up from the peripheral tissues by binding to the ATP-binding cassette transporter 1 (ABCA1) receptors in arterial wall macrophages, and it is released in the liver for elimination through one of two pathways. In the direct pathway, the hepatocytes take up excess cholesterol ester directly from HDL using the scavenger receptor B1 (SR-B1). In the indirect pathway, an enzyme known as cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol ester to very low-density lipoprotein (VLDL) or LDL particles with subsequent uptake into the liver via the LDL receptor.
HDL has 3 major subtypes: pre-beta (or nascent) HDL, HDL2, and HDL3. As HDL cholesterol is transported from the periphery, it progresses through these subtypes. The pre-beta, or nascent, HDL particle contains very little cholesterol but does contain the major cardioprotective HDL apolipoprotein apoA-I. In the circulating nascent HDL, apoA-I acts as a scavenger and binds cholesterol. As cholesterol binds, it is converted to cholesteryl ester, filling out the nascent HDL so that it changes to a spheroidal particle, HDL3. Eventually, after picking up and transforming more cholesterol to cholesteryl ester, the HDL3 changes in size and density to form the largest HDL particle, HDL2. HDL2 particles can release this cholesterol directly into the liver via the SR-B1, or it can be transferred to the apoB-containing lipoproteins such as VLDL or LDL via CETP for uptake into hepatocytes by the LDL receptor. The latter mechanism, involving the indirect pathway, has been a focus of recent attention because medications that would inhibit CETP are undergoing clinical trial evaluation. Cholesterol that is returned to the liver by either pathway is then secreted into the bile for elimination.
BENEFITS OF RAISING HDL LEVELS
HDL appears to exert its protective effect via a number of mechanisms. In addition to cholesterol trapping and excretion through reverse cholesterol transport, these mechanisms include prevention of endothelial dysfunction through the anti-inflammatory, antioxidant, and antithrombotic properties of HDL. According to ATP III, animal research has shown that in genetically modified animals, high levels of HDL appear to protect against atherogenesis; in vitro, HDL promotes efflux of cholesterol from foam cells in atherosclerotic lesions. The structure and function of HDL particles play a greater role than overall blood level in predicting the risk. Some patients with CAD actually have pro-inflammatory HDL, which is less able to promote cholesterol efflux and could occasionally be paradoxically atherogenic.
TREATMENT OF LOW HDL CHOLESTEROL
A strategy of raising HDL levels to protect against atherosclerotic
disease is intriguing. Based on current guidelines, the primary target
in preventing coronary heart disease (CHD) is lowering LDL levels, and
first-line therapy is with the HMG-CoA reductase inhibitors (statins).
Raising low HDL levels is considered a secondary but important target
for reducing CAD risk. Raising HDL levels appears to offer a number of
benefits, including reductions in morbidity and mortality. Even a
relatively small improvement in HDL levels can prove beneficial.
In the Veterans Affairs
HDL Intervention Trial (VA-HIT), the HDL level increase was very small.
On average, the HDL merely increased
from 31 mg/dL to 33 mg/dL, but that increase resulted in a significant
22-24% reduction in cardiovascular events. Thus, even a small increase
in HDL seemed to have a significant positive impact.
THERAPEUTIC LIFESTYLE CHANGES (TLC)
Physical exercise
Regular exercise can increase HDL levels by about 3-9%, and the greatest effect appears to be with frequent short bursts of relatively high-intensity exercise. Moderate alcohol intake, smoking cessation, and weight loss have also been shown to increase HDL levels. According to the ATP III, therapeutic lifestyle modification is recommended as first-line therapy for raising HDL levels. This includes increased physical activity (about 30 min of brisk walking daily), a reduced-energy diet (about 500-1000 cal/d reduction), and substitution of unsaturated fats for carbohydrates.
Dietary strategies
The 2005 Dietary Guidelines for Americans describe a healthy diet as one that (a) emphasizes fruits, vegetables, whole grains, and fat-free or low-fat milk; (b) includes lean meats, poultry, fish, beans, eggs, and nuts; and (c) has lower amounts of saturated fats, trans fats, cholesterol, salt (sodium), and added sugars. People tend to eat the same amount (bulk) of food regardless of the number of calories. No matter what type of food is available, people fill their plates with the same amount of food. If, then, the foods are energy-dense, they contain more calories, and people consume more calories. However, foods that are energy-light, such as fruits and vegetables, contain a lot of water, air, or fiber. Eating the same bulk of energy-light foods makes people feel full without the caloric load.
The growing incidence of teenage obesity needs to be curtailed with utmost priority. While school vending machines are profitable ventures, they dispense extra calories and contribute to the development of obesity, hypercholesterolemia, diabetes, and hypertension early in life. Children who drink 3 or more sodas per day have a 60% higher risk of becoming overweight compared with children who do not drink soda. These vending machines should be stocked with water and low-fat milk, as recommended by California’s Healthy School Lunch Resolution.
The 5+15 rule can help people select appropriate foods (ie, foods
with no more than 5 g of fat and 15 g of sugar per serving). Tropical
oils, such as palm and coconut oils, are high in saturated fat and are
found in nondairy coffee creamers, whipped toppings, baked goods,
cookies, and chocolate candies. These oils should be avoided, as should
the trans-fatty acids found in foods that are chemically modified by
hydrogenation.
Monounsaturated fats
found in olive and canola oils and polyunsaturated fatty acid (PUFA)
found in vegetable oils such as safflower oil and corn oil should be
increased to provide omega-6 (linoleic acid), a fatty acid that is
essential to growth and development, and omega-3 (linolenic acid), which
is also essential for growth and development and is found in salmon,
bluefish, mackerel, tuna, herring, and sardines. Intake of soluble
fiber, found in oats, legumes, apples, pears, plums, carrots, okra, and
barley, should also be increased.
PHARMACOLOGIC APPROACHES: Niacin, fibrates, and statins
Multiple studies have shown that niacin, fibrates, and statins can decrease the risk of cardiovascular disease and atherosclerosis progression by affecting multiple lipid parameters. Overall, fibrates reduce the risk for major coronary events by 25%, whereas currently available data for niacin suggest a risk reduction of approximately 27%. Statins have modest
effects on HDL levels, increasing concentrations by 5-10%, providing a secondary benefit to this therapy beyond the reduction of LDL levels.
COMBINATION THERAPY
ADVOCATE study
In the ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation (ADVOCATE), 315 patients with high LDL levels (≥160 mg/dL without CAD or ≥130 mg/dL with CAD) and low HDL levels (<45 mg/dL in men, <50 mg/dL in women) were randomized to 16 weeks of a combination of niacin and lovastatin versus standard doses of atorvastatin or simvastatin. At all dose combinations, the combination of niacin and lovastatin increased HDL levels significantly more than did statin alone (p <0.001). In addition, a significant decrease in LDL levels was observed (42% vs 34%, p <0.001), and significant improvements were observed in the levels of triglycerides, lipoprotein(a), apoA-I, and apoB.
HATS study
A combination of niacin and statin was evaluated in the HDL-Atherosclerosis Treatment Study (HATS), in which LDL levels fell by 42% (p <0.001) and HDL levels increased by 26% (p <0.001). The stenosis regression was significantly enhanced with the combination therapy on angiographic analysis, and the combination of niacin and statin resulted in a 60-90% reduction in the incidence of major coronary events.
ARBITER 2 study
The ARterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2) trial was a double-blind, placebo-controlled trial of an extended-release niacin plus statin therapy. HDL levels rose by 21% (p = 0.002) and triglyceride levels decreased significantly (p = 0.009) compared to placebo. The primary endpoint of ARBITER 2 was change in common carotid intimal-medial thickness (IMT). Carotid IMT progression was 68% lower in the niacin group. The end result was a 50% reduction in the composite cardiovascular endpoint.
EMERGING TREATMENT STRATEGIES
Several novel approaches to increasing HDL levels are currently being investigated, including the following:
- Torcetrapib, a partial CETP inhibitor, may increase HDL levels by as much as 46%.
- The glitazones, which are dual agonists of peroxisome proliferator-activated receptor (PPAR)-alpha (like fibrates) and PPAR-gamma (like thiazolidinediones), act by lowering free fatty acid (FFA) and triglyceride levels and raising HDL levels. Rosiglitazone appears to cause a shift in the size of LDL particles from small to large.
- Recombinant apoA-I Milano mimics the activity of nascent HDL and has shown promise in early trials of patients with acute coronary syndromes.
CETP inhibition therapy
CETP mediates the exchange of cholesteryl ester for triglycerides between HDL and VLDL-LDL and may be proatherogenic if the VLDL-LDL cholesteryl ester is taken up by arterial macrophages. Blocking CETP prevents the transfer of cholesterol from HDL2 to the apoB-containing lipoproteins; therefore, the HDL concentration in terms of cholesterol rises.
CETP inhibitor trials
Two pharmacologic inhibitors of CETP have recently undergone phase 3 clinical trials: torcetrapib (Pfizer) and JTT-705 (Japan Tobacco, Tokyo, Japan, and Hoffmann-La Roche, Basel, Switzerland). These inhibitors differ in chemical structure. With torcetrapib, CETP activity is only inhibited by about 50-60% to address the fact that patients with complete CETP deficiency, mostly found in Japan, exhibit a paradoxically increased risk of CAD. The effect of torcetrapib is dose-dependent; for example, increasing the twice-daily dose from 10-120 mg is associated with almost 90% CETP inhibition and a greater rise in HDL levels. LDL levels are also reduced by torcetrapib by as much as 40%. During the 12-week study, subjects experienced a small increase in blood pressure. This increase may not be a side effect of CETP inhibition; it may be an independent effect that resolves rapidly on drug discontinuation.
ILLUMINATE study
Torcetrapib is being studied in a large phase 3 global trial called the Investigation of Lipid Level management to Understand its iMpact IN ATherosclerotic Events (ILLUMINATE). Judging from all the data that are now available from the lipoprotein studies, torcetrapib as monotherapy appears to be an effective agent for CAD risk reduction. Furthermore, patients with metabolic syndrome and diabetes may significantly benefit by raising HDL levels alone or in combination with statins.
ApoA-I Milano complexes
ApoA-I Milano, an apolipoprotein A-I variant identified in a rural Italian population, is associated with cardioprotection due to its super-HDL properties. These Italians have very low levels of HDL and yet have low prevalence of atherosclerotic disease because most of their HDL is apoA-I Milano. Recently, a recombinant form of apoA-I Milano–phospholipid complex called ETC-216 (Esperion Therapeutics, now part of Pfizer) was found effective in reducing coronary atheroma volume as measured by intravascular ultrasound (IVUS). This study showed that the atherosclerosis in the coronary vessel wall could be modified in a much shorter time than anticipated, ie, within 5-6 weeks.
Novartis is developing a new apoA-I mimetic peptide, D-4F, which is targeted not to raise HDL levels but to change proinflammatory HDL to anti-inflammatory HDL in high-risk patients.
CONCLUSION
The role of HDL as an atheroprotective agent is well established, and currently emerging data support interventions for raising HDL levels. Thus, despite the primary emphasis by ATP III on LDL levels, a tremendous amount of potential risk reduction exists in targeting therapy beyond LDL levels, since 70% of cardiovascular events occur despite statin therapy. One way to target these events is by looking more broadly at dyslipidemia. HDL has a number of beneficial effects in addition to LDL metabolism. Its anti-inflammatory effects may be an important component of its antiatherosclerotic role. Currently, no pharmacologic therapies to raise HDL levels are approved for use. Therefore, low HDL levels should be treated with lifestyle and dietary changes; appropriate weight loss alone can increase HDL levels by 5-10%. Other strategies include incorporating relevant aspects of the Mediterranean diet to increase intake of monounsaturated fats and decrease intake of high glycemic carbohydrates. Exercise can also help raise HDL levels by 5-20%. Above and beyond statin therapy, combination regimens using niacin should be considered. Finally, medications that specifically raise HDL levels, such as CETP inhibitors and apoA-I Milano complexes, are emerging as the potential new addition to dyslipidemia therapy that would benefit patients with low HDL cholesterol levels in the future.
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