Low HDL Cholesterol Levels
http://www.100md.com
《新英格兰医药杂志》
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations.
A 41-year-old man with dyslipidemia, hypertension, and a history of myocardial infarction four years previously comes to establish care. He is physically inactive and consumes a diet high in saturated fat. He does not smoke. Medications include a statin, a beta-blocker, an angiotensin-converting – enzyme inhibitor, and aspirin. His blood pressure is 110/80 mm Hg, and his body-mass index (the weight in kilograms divided by the square of the height in meters) is 32. The fasting glucose level is 96 mg per deciliter (5.33 mmol per liter). The total cholesterol level is 155 mg per deciliter (4.01 mmol per liter), the low-density lipoprotein (LDL) cholesterol level 72 mg per deciliter (1.86 mmol per liter), the high-density lipoprotein (HDL) cholesterol level 28 mg per deciliter (0.72 mmol per liter), and the triglyceride level 277 mg per deciliter (3.13 mmol per liter). What strategies can increase his HDL cholesterol level?
The Clinical Problem
Persons with low HDL cholesterol levels (less than 40 mg per deciliter in men and less than 50 mg per deciliter in women) are at increased risk of coronary heart disease,1 restenosis after angioplasty,2 and death from cardiovascular causes, especially if such persons are male3 or have diabetes.4 Often, persons with low HDL cholesterol levels also have other cardiovascular risk factors, such as diabetes, hypertension, or both, which further increase risk.
Epidemiologic studies and studies in animals suggest that raising the levels of HDL cholesterol may retard the development of atherosclerosis. In humans, each increase in baseline HDL cholesterol of 1 mg per deciliter (0.03 mmol per liter) is associated with a 6 percent decrease in the risk of death from coronary disease or of myocardial infarction.5 Studies in animals have shown that overexpression of the apolipoprotein A-I gene (the major apolipoprotein in HDL cholesterol) prevents the development or progression of atherosclerosis.6,7
HDL cholesterol transports excess cholesterol from peripheral tissues to the liver for excretion, a process known as reverse cholesterol transport (Figure 1). In addition, HDL cholesterol inhibits the oxidation of LDL cholesterol and the expression of cellular adhesion molecules and monocyte recruitment, and it may reduce the risk of thrombosis by inhibiting platelet activation and aggregation.8
Figure 1. Reverse Cholesterol Transport.
In reverse cholesterol transport,7 lipid-poor pre- HDL cholesterol, rich in apolipoprotein A-I (A-I), is synthesized by the liver or intestinal mucosa and released into the circulation. There it promotes the transfer of excess cellular-free cholesterol (FC) from macrophages to A-I by interacting with the ATP-binding cassette transporter A1 (ABCA1) in arterial-wall macrophages. Plasma lecithin–cholesterol acyltransferase (LCAT) converts free cholesterol in pre- HDL cholesterol to cholesteryl ester (CE), resulting in maturation of pre- HDL cholesterol to mature HDL cholesterol. HDL cholesterol is transported to the liver by a direct or indirect pathway.
In the direct pathway, selective uptake of cholesteryl ester by hepatocytes occurs with the scavenger receptor, class B, type 1 (SR-B1). In the indirect pathway, HDL cholesterol cholesteryl ester is exchanged for triglycerides (TG) in apolipoprotein-B–rich particles (B), LDL cholesterol, and very-low-density lipoprotein (VLDL) cholesterol through cholesteryl-ester–transfer protein (CETP), with uptake of cholesteryl ester by the liver through the LDL receptor (LDLR). Cholesterol that is returned to the liver is secreted as bile acids and cholesterol. Acquired triglycerides in the modified HDL cholesterol particle are subjected to hydrolysis by hepatic lipase (HL), thereby regenerating small HDL cholesterol particles and pre- HDL cholesterol for participation in reverse cholesterol transport.
Strategies and Evidence
Lifestyle Modifications
Exercise
Regular aerobic exercise increases the HDL cholesterol level by 3 to 9 percent in healthy, sedentary persons.9 This increase is related to the frequency and intensity of physical activity, with greater increases in HDL cholesterol occurring with frequent, low-intensity exercise (e.g., five 30-minute sessions per week vs. three 60-minute sessions).9 However, there is little evidence that walking significantly increases HDL cholesterol levels.10 HDL cholesterol levels may increase with as little as eight weeks of regular exercise, although changes may not be evident for two years.9 Exercise may increase HDL cholesterol levels by stimulating the production of pre- HDL cholesterol and reverse cholesterol transport.11
Regular exercise yields greater increases in HDL cholesterol in men with low HDL cholesterol levels, elevated triglyceride levels, and abdominal obesity than in those with isolated low HDL cholesterol levels.12 Weight loss may be crucial for an increase in HDL cholesterol to occur. In one randomized, controlled trial, persons who walked or jogged 10 miles per week but did not lose weight did not have different HDL cholesterol levels from those of controls.13 Nevertheless, it is reasonable to recommend a program of regular, brisk aerobic exercise for 30 minutes on most days of the week.
Smoking Cessation
Cigarette smoking is associated with reduced HDL cholesterol,14 lecithin – cholesterol acyltransferase activity,15 and cholesteryl-ester – transfer protein (CETP) activity.16 After smoking cessation, HDL cholesterol increases (by a mean of 4 mg per deciliter ), more so in women than in men and in persons with elevated baseline HDL cholesterol levels (>47 mg per deciliter ).17 A comprehensive approach to smoking cessation (involving pharmacotherapy, nicotine replacement, and counseling) should be recommended.18
Weight Control
Obesity is associated with reduced HDL cholesterol levels and elevated serum triglyceride levels.19 A negative correlation exists between HDL cholesterol and body-mass index.20 A meta-analysis examining the effect of weight loss on HDL cholesterol levels demonstrated that the levels increased by 0.35 mg per deciliter (0.009 mmol per liter) per kilogram of weight reduction in subjects who achieved a stabilized, reduced weight (P0.01) but decreased by 0.27 mg per deciliter (0.006 mmol per liter) in subjects during active weight loss (P0.05).21 In subjects who maintained a stable weight for six weeks after weight loss, HDL cholesterol levels, lipoprotein lipase levels, and lecithin – cholesterol acyltransferase activity increased; these increases may contribute to enhanced cholesterol esterification and reverse cholesterol transport.22 A reasonable weight-loss goal for overweight or obese patients is 1 lb (0.45 kg) per week, with a target body-mass index of less than 25.
Alcohol Intake
Moderate alcohol consumption raises HDL cholesterol levels.14 A meta-analysis indicated that the consumption of 30 g (1 fluid oz) of alcohol per day increases HDL cholesterol levels by a mean of 4 mg per deciliter, irrespective of the kind of alcohol consumed.23 Persons who consume one to three drinks daily have higher HDL cholesterol levels and a lower risk of myocardial infarction than do those who drink less, even after adjustment for other likely confounding factors.24 Thus, mild-to-moderate alcohol consumption (no more than one to two drinks per day) appears to be reasonable for many persons with low HDL cholesterol levels. However, the potential risks associated with this recommendation may outweigh the benefits in persons with hepatic dysfunction or the potential for addiction. Alcohol consumption may elevate HDL cholesterol levels by increasing cellular cholesterol efflux and plasma cholesterol esterification.25
Dietary Fat Intake
Plasma LDL cholesterol and HDL cholesterol levels decline with reductions in the intake of dietary fat. In a study comparing calorically balanced diets (i.e., intake is equal to expenditure) that differed in fat content,26 subjects who consumed a low-fat diet (19 percent of total calories were from fat) had lower HDL cholesterol and apolipoprotein A-I levels than did subjects who were fed a high-fat diet (50 percent of total calories were from fat) (54 mg per deciliter vs. 63 mg per deciliter and 118 mg per deciliter vs. 127 mg per deciliter , respectively; P<0.005). The concomitant decrease in LDL cholesterol that occurs with a diet low in saturated fat may override the effects associated with the decline in HDL cholesterol.27 Native Alaskan populations that eat a diet rich in n–3 polyunsaturated fatty acids have high HDL cholesterol levels.28 Although a diet high in monounsaturated fats does not elicit a significant change in HDL cholesterol levels,29 the dietary glycemic load (which represents the equivalent elevating effect on blood-glucose levels of 1 g of pure glucose or white bread) is negatively correlated with HDL cholesterol levels.30 Thus, a diet rich in n–3 polyunsaturated fatty acids — sources include oils (olive, canola, soy, flaxseed), nuts (almonds, peanuts, walnuts, pecans), cold-water fish (salmon, mackerel), and shellfish — with limited carbohydrates that contribute a high glycemic load (such as those found in ready-to-eat cereals, potatoes, white bread, and snack foods) can be recommended to increase serum HDL cholesterol levels.
Lifestyle and Modifying Factors
Improvement in HDL cholesterol levels associated with exercise, alcohol consumption, and weight loss is greatest in persons with the highest baseline HDL cholesterol levels (60 mg per deciliter or more); those with low baseline levels have less improvement.31 Interactions between genes and the environment may influence the magnitude of improvement in HDL cholesterol levels associated with lifestyle modifications. Specifically, improvement with exercise may depend on individual CETP and endothelial lipase genotypes.32,33 However, genetic tests for these factors are not currently used in routine practice, and lifestyle changes as described above should be recommended routinely, both to raise HDL cholesterol levels and to lower LDL cholesterol levels and improve other cardiovascular risk factors.
Medication
Several classes of medications increase HDL cholesterol levels; these include niacin and fibrates, in particular, and, to a lesser degree, statins. These medications also lower triglycerides and LDL cholesterol levels. Without trials designed to isolate the effects of drugs on changes in HDL cholesterol levels and on coronary outcomes, it is difficult to determine how much of the drugs' benefit in reducing the rates of coronary heart disease are due to changes in HDL cholesterol levels. At present, there is no clear consensus regarding when to use medications for the purpose of raising HDL cholesterol levels, although drugs are most often considered for patients with established coronary disease or for those at high risk.
Niacin
Niacin (nicotinic acid or vitamin B3) is the most effective medication to raise HDL cholesterol levels, causing increases of 20 to 35 percent.34 The Coronary Drug Project35 demonstrated a significant reduction in the incidence of death and myocardial infarction after five years of niacin treatment among men with a history of myocardial infarction. Niacin inhibits hepatic uptake of apolipoprotein A-I and increases plasma pre- HDL cholesterol levels.36 Niacin therapy is associated with improved endothelial function and nitric oxide synthase activity.37
The side effects of niacin therapy include cutaneous flushing, dyspepsia, and elevation of plasma glucose and uric acid levels. Flushing, which is largely mediated by prostaglandins, may be minimized with the use of an extended-release formulation of niacin (not the same as sustained-release niacin); with the concurrent consumption of a low-fat snack at bedtime, 30 minutes after ingestion of an aspirin; and with a regimen that begins with a low dose (e.g., 500 mg each night) and increases gradually (Table 1).
Table 1. Lipid-Lowering Medications and Effects on HDL Cholesterol Levels.
Fibrates
Fibrate therapy results in an increase in HDL cholesterol levels of 10 to 25 percent by activating peroxisome-proliferator–activated receptor (PPAR), which stimulates expression of the hepatic apolipoprotein A-I gene.43 The Helsinki Heart Study38 and the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial39 demonstrated increases in HDL cholesterol (10 percent and 6 percent, respectively) and a large reduction in triglyceride levels in asymptomatic men and those with primary dyslipidemia or coronary heart disease, respectively, who had been randomly assigned to receive gemfibrozil (1200 mg daily), as compared with subjects who received placebo. Gemfibrozil significantly reduced the risks of coronary events (34 percent) and the combined outcome of coronary death, nonfatal myocardial infarction, and stroke (24 percent). Subsequent analysis of the Veterans Affairs trial indicated that only the increase in HDL cholesterol levels, not the change in LDL cholesterol or triglyceride levels, significantly predicted a reduced risk of coronary events.44 A large clinical trial involving the use of fenofibrate is in progress.
Statins
In addition to lowering LDL cholesterol levels, statins raise HDL cholesterol levels by 2 to 15 percent by increasing apolipoprotein A-I synthesis.45 Different agents vary in efficacy (Table 1).46 In a randomized trial comparing the effects of simvastatin and atorvastatin (maximum dose, 80 mg and 40 mg, respectively, titrated to LDL cholesterol levels) among patients with elevated LDL cholesterol levels, there was a moderately greater increase with simvastatin in HDL cholesterol levels (9 percent vs. 7 percent, P<0.001) and apolipoprotein A-I levels (6 percent vs. 3 percent, P<0.001); clinical outcomes were not assessed.47
Several trials have documented reduced risks of major coronary events associated with the use of a statin, as compared with placebo,40 but it is not clear whether the rise in HDL cholesterol levels is an independent predictor of the reduced risk of coronary events with the use of these agents.
Combination Therapy
In some patients with low HDL cholesterol levels, various lipid-modifying medications may be useful in combination. The HDL Atherosclerosis Treatment Study (HATS)41 demonstrated that a combination of low-dose simvastatin (10 to 20 mg per day) and high-dose niacin (2 to 4 mg per day) significantly increased HDL cholesterol levels (26 percent), as compared with placebo, in patients with HDL cholesterol levels of 40 mg per deciliter or less, LDL cholesterol levels of 145 mg per deciliter (3.75 mmol per liter) or less, and triglyceride levels of less than 400 mg per deciliter (4.52 mmol per liter). In the simvastatin–niacin treatment group, coronary stenoses, as documented on angiography, moderately regressed over three years (0.4 percent, P<0.001 vs. placebo; 3.9 percent increase).
The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 study,42 which involved subjects who had established coronary disease, HDL cholesterol levels of less than 45 mg per deciliter (1.16 mmol per liter), and LDL cholesterol levels of less than 130 mg per deciliter (3.36 mmol per liter), showed that the addition of extended-release niacin (1000 mg daily) to existing statin therapy increased mean HDL cholesterol levels by 21 percent (from a mean of 39 to 47 mg per deciliter ; P<0.001 vs. the change in the placebo group). Medial thickness of the carotid intima significantly increased in the placebo group (mean change, 0.044 mm; P<0.001) but not in the placebo group (mean change, 0.014 mm; P=0.23); however, a comparison of changes in intimal thickness over time did not show a significant difference between the two groups (P=0.08).
Areas of Uncertainty
Randomized, controlled trials are needed to demonstrate that drugs specifically aimed at raising HDL cholesterol levels will reduce cardiovascular events as well as to provide guidance for the use of medications and for treatment goals among patients with varying levels of coronary risk.
Several therapies to increase HDL cholesterol levels are being studied. Partial inhibitors of CETP activity increase HDL cholesterol levels and reverse cholesterol transport, whereas complete inhibition of CETP activity results in cholesterol-laden, dysfunctional HDL cholesterol particles, with reduced cholesterol-efflux capability.48 In a single-blind, placebo-controlled study of adults with low HDL cholesterol levels (mean, 32 mg per deciliter ), treatment with the partial CETP inhibitor torcetrapib resulted in a 46 percent increase in HDL cholesterol levels. Torcetrapib is currently being studied in a phase 3 trial involving the use of intravascular ultrasonography and medial thickness of the carotid intima to monitor plaque size.49 The macrophage ATP-binding cassette transporter A 1 (ABCA1) facilitates the transfer of cholesterol to apolipoprotein A-I. PPAR may raise HDL cholesterol levels by enhancing ABCA1 transcription. Thiazolidinediones (approved for the treatment of diabetes but not for lipid management) and a new class of agents known as glitazars (which are under review by the Food and Drug Administration) activate PPAR; their role in the management of low levels of HDL cholesterol is uncertain.50
Bioengineered molecules, such as recombinant apolipoprotein A-I Milano, which mimic the properties of nascent HDL cholesterol, cause regression of plaques in animal models. In a placebo-controlled study of 47 subjects, five weekly infusions of apolipoprotein A-I Milano produced modest regression of coronary atherosclerosis, as measured with the use of intravascular ultrasonography.51 Data from a study of mice treated with D4F, an apolipoprotein A-I-mimetic peptide, suggest that a beneficial effect may depend on the stage of atherosclerosis; a benefit was observed in vein grafts (which rapidly develop atheromatous lesions) but not in established native aortic disease.52
Guidelines from Professional Associations
The National Cholesterol Education Program emphasizes that initial treatment should be directed toward achieving a target LDL cholesterol level (and non-HDL cholesterol if the triglyceride level is more than 200 mg per deciliter ) before considering niacin or fibrates in persons with low HDL cholesterol levels (www.nhlbi.nih.gov/guidelines/cholesterol/atglance.htm).53 The National Cholesterol Education Program does not specifically recommend that HDL cholesterol be a primary or secondary target. The Expert Group on HDL recommends considering the addition of a fibrate or niacin for persons whose HDL cholesterol level is less than 40 mg per deciliter and who have diabetes mellitus or the metabolic syndrome (defined as the presence of three or more of the following: central obesity ; a fasting triglyceride level of 150 mg per deciliter or more; an HDL cholesterol level of less than 40 mg per deciliter in men or less than 50 mg per deciliter in women; blood pressure of 130/85 mm Hg or higher; and a fasting glucose level of more than 110 mg per deciliter ).54 The American Diabetes Association recommends that adults with diabetes should first aim for an LDL cholesterol level of less than 100 mg per deciliter (2.59 mmol per liter); secondary targets should include an HDL cholesterol level of more than 40 mg per deciliter and a triglyceride level of less than 150 mg per deciliter (3.88 mmol per liter). Caution is recommended with regard to the use of high-dose niacin in patients with diabetes, because this may increase glucose levels (www.diabetes.org).55
Summary and Recommendations
A low level of HDL cholesterol is an independent risk factor for future cardiovascular events. A comprehensive approach to achieving optimal HDL cholesterol levels (40 mg per deciliter or more in men and 50 mg per deciliter or more in women) should include lifestyle modifications, followed by the consideration of pharmacotherapy in high-risk patients. The patient in the vignette has established coronary heart disease and a low level of HDL cholesterol. His plasma LDL cholesterol level is appropriate given that he is taking a statin, but his triglyceride level is elevated, and he is obese.
Lifestyle changes should be recommended as the first approach to raise HDL cholesterol levels, which would lead to other cardiovascular benefits. We would initially recommend a program of regular aerobic exercise (a gradual increase to 30 minutes of brisk aerobic activity five days per week), weight loss (1 lb per week, with a target body-mass index of less than 25), and the substitution of sources of polyunsaturated fats such as oils (olive, canola, soy, flaxseed), nuts (almonds, peanuts, walnuts, pecans), cold-water fish (salmon, mackerel), and shellfish for saturated fats and simple carbohydrates. Persons who smoke should be advised to quit. Moderate alcohol intake is reasonable for patients who so choose and for whom there are no contraindications.
Whether to add medication to lifestyle changes to raise HDL cholesterol levels will depend on the degree of cardiovascular risk. Although data are currently lacking to prove that elevating HDL cholesterol levels with drugs reduces the incidence of cardiovascular events, medication to raise these levels should be considered, once the target LDL cholesterol level has been achieved, in persons who have established atherosclerotic disease (such as the patient described in the vignette) or major risk factors such as diabetes and in whom HDL cholesterol levels remain low despite lifestyle modifications. If the triglyceride level remains above 250 mg per deciliter (2.82 mmol per liter), it would be reasonable to prescribe a fibrate in addition to reinforcing lifestyle recommendations. The use of a fibrate should lower the triglyceride level and can be expected to increase HDL cholesterol by 10 to 25 percent. Niacin is an effective alternative, although it should be used with caution in patients with diabetes.
Dr. Blumenthal reports having received speaker's fees or consulting fees from Pfizer, Merck, AstraZeneca, and Kos.
We are indebted to Dr. Navin K. Kapur for his thoughtful suggestions on the manuscript.
Source Information
From the Johns Hopkins Hospital, Baltimore.
Address reprint requests to Dr. Blumenthal at Johns Hopkins Hospital, Blalock 524C, Johns Hopkins Ciccarone Preventive Cardiology Center, 600 N. Wolfe St., Baltimore, MD 21287, or at rblument@jhmi.edu
References
Miller NE, Thelle DS, Forde OH, Mjos OD. The Tromso heart-study: high-density lipoprotein and coronary heart-disease: a prospective case-control study. Lancet 1977;1:965-968.
Shah PK, Amin J. Low high density lipoprotein level is associated with increased restenosis rate after coronary angioplasty. Circulation 1992;85:1279-1285.
Wilson PW, Abbott RD, Castelli WP. High density lipoprotein cholesterol and mortality: the Framingham Heart Study. Arteriosclerosis 1988;8:737-741.
Goldbourt U, Yaari S, Medalie JH. Isolated low HDL cholesterol as a risk factor for coronary heart disease mortality: a 21-year follow-up of 8000 men. Arterioscler Thromb Vasc Biol 1997;17:107-113.
Gordon DJ, Knoke J, Probstfield JL, Superko R, Tyroler HA. High-density lipoprotein cholesterol and coronary heart disease in hypercholesterolemic men: the Lipid Research Clinics Coronary Primary Prevention Trial. Circulation 1986;74:1217-1225.
Benoit P, Emmanuel F, Caillaud JM, et al. Somatic gene transfer of human ApoA-I inhibits atherosclerosis progression in mouse models. Circulation 1999;99:105-110.
Brewer HB Jr. High-density lipoproteins: a new potential therapeutic target for the prevention of cardiovascular disease. Arterioscler Thromb Vasc Biol 2004;24:387-391.
Shah PK, Kaul S, Nilsson J, Cercek B. Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins: an idea whose time for testing is coming. Circulation 2001;104:2376-2383.
King AC, Haskell WL, Young DR, Oka RK, Stefanick ML. Long-term effects of varying intensities and formats of physical activity on participation rates, fitness, and lipoproteins in men and women aged 50 to 65 years. Circulation 1995;91:2596-2604.
Kelley GA, Kelley KS, Tran ZV. Walking, lipids and lipoproteins: a meta-analysis of randomized controlled trials. Prev Med 2004;38:651-661.
Gupta AK, Ross EA, Myers JN, Kashyap ML. Increased reverse cholesterol transport in athletes. Metabolism 1993;42:684-690.
Couillard C, Despres JP, Lamarche B, et al. Effects of endurance training on plasma HDL cholesterol levels depend on levels of triglycerides: evidence from men of the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study. Arterioscler Thromb Vasc Biol 2001;21:1226-1232.
Stefanick ML, Mackey S, Sheehan M, Ellsworth N, Haskell WL, Wood PD. Effects of diet and exercise in men and postmenopausal women with low levels of HDL cholesterol and high levels of LDL cholesterol. N Engl J Med 1998;339:12-20.
Ellison RC, Zhang Y, Qureshi MM, Knox S, Arnett DK. Lifestyle determinants of high-density lipoprotein cholesterol: the National Heart, Lung, and Blood Institute Family Heart Study. Am Heart J 2004;147:529-535.
Imamura H, Teshima K, Miyamoto N, Shirota T. Cigarette smoking, high-density lipoprotein cholesterol subfractions, and lecithin: cholesterol acyltransferase in young women. Metabolism 2002;51:1313-1316.
Mero N, Van Tol A, Scheek LM, et al. Decreased postprandial high density lipoprotein cholesterol and apolipoproteins A-I and E in normolipidemic smoking men: relations with lipid transfer proteins and LCAT activities. J Lipid Res 1998;39:1493-1502.
Maeda K, Noguchi Y, Fukui T. The effects of cessation from cigarette smoking on the lipid and lipoprotein profiles: a meta-analysis. Prev Med 2003;37:283-290.
Rigotti NA. Treatment of tobacco use and dependence. N Engl J Med 2002;346:506-512.
Denke MA, Sempos CT, Grundy SM. Excess body weight: an underrecognized contributor to high blood cholesterol levels in white American men. Arch Intern Med 1993;153:1093-1103.
Wakabayashi I. Relationship of body mass index with blood pressure and serum cholesterol concentrations at different ages. Aging Clin Exp Res 2004;16:461-466.
Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr 1992;56:320-328.
Weisweiler P. Plasma lipoproteins and lipase and lecithin:cholesterol acyltransferase activities in obese subjects before and after weight reduction. J Clin Endocrinol Metab 1987;65:969-973.
Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ. Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ 1999;319:1523-1528.
Gaziano JM, Buring JE, Breslow JL, et al. Moderate alcohol intake, increased levels of high-density lipoprotein and its subfractions, and decreased risk of myocardial infarction. N Engl J Med 1993;329:1829-1834.
van der Gaag MS, van Tol A, Vermunt SH, Scheek LM, Schaafsma G, Hendriks HFJ. Alcohol consumption stimulates early steps in reverse cholesterol transport. J Lipid Res 2001;42:2077-2083.
Meksawan K, Pendergast DR, Leddy JJ, Mason M, Horvath PJ, Awad AB. Effect of low and high fat diets on nutrient intakes and selected cardiovascular risk factors in sedentary men and women. J Am Coll Nutr 2004;23:131-140.
Berglund L, Oliver EH, Fontanez N, et al. HDL-subpopulation patterns in response to reductions in dietary total and saturated fat intakes in healthy subjects. Am J Clin Nutr 1999;70:992-1000.
Gerasimova E, Perova N, Ozerova I, et al. The effect of dietary n-3 polyunsaturated fatty acids on HDL cholesterol in Chukot residents vs Muscovites. Lipids 1991;26:261-265.
Pelkman CL, Fishell VK, Maddox DH, Pearson TA, Mauger DT, Kris-Etherton PM. Effects of moderate-fat (from monounsaturated fat) and low-fat weight-loss diets on the serum lipid profile in overweight and obese men and women. Am J Clin Nutr 2004;79:204-212.
Slyper A, Jurva J, Pleuss J, Hoffmann R, Gutterman D. Influence of glycemic load on HDL cholesterol in youth. Am J Clin Nutr 2005;81:376-379.
Williams PT. The relationships of vigorous exercise, alcohol, and adiposity to low and high high-density lipoprotein-cholesterol levels. Metabolism 2004;53:700-709.
Wilund KR, Ferrell RE, Phares DA, Goldberg AP, Hagberg JM. Changes in high-density lipoprotein-cholesterol subfractions with exercise training may be dependent on cholesteryl ester transfer protein (CETP) genotype. Metabolism 2002;51:774-778.
Halverstadt A, Phares DA, Ferrell RE, Wilund KR, Goldberg AP, Hagberg JM. High-density lipoprotein-cholesterol, its subfractions, and responses to exercise training are dependent on endothelial lipase genotype. Metabolism 2003;52:1505-1511.
Alderman JD, Pasternak RC, Sacks FM, Smith HS, Monrad ES, Grossman W. Effect of a modified, well-tolerated niacin regimen on serum total cholesterol, high density lipoprotein cholesterol and the cholesterol to high density lipoprotein ratio. Am J Cardiol 1989;64:725-729.
Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245-1255.
Piepho RW. The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol. Am J Cardiol 2000;86:35L-40L.
Kuvin JT, Ramet ME, Patel AR, Pandian NG, Mendelsohn ME, Karas RH. A novel mechanism for the beneficial vascular effects of high-density lipoprotein cholesterol: enhanced vasorelaxation and increased endothelial nitric oxide synthase expression. Am Heart J 2002;144:165-172.
Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia -- safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237-1245.
Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410-418.
Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-1622.
Brown BG, Zhao X-Q, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-1592.
Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004;110:3512-3517.
Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998;98:2088-2093.
Robins SJ, Collins D, Wittes JT, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 2001;285:1585-1591.
Schaefer JR, Schweer H, Ikewaki K, et al. Metabolic basis of high density lipoproteins and apolipoprotein A-I increase by HMG-CoA reductase inhibition in healthy subjects and a patient with coronary artery disease. Atherosclerosis 1999;144:177-184.
Blumenthal RS. Statins: effective antiatherosclerotic therapy. Am Heart J 2000;139:577-583.
Kastelein JJP, Isaacsohn JL, Ose L, et al. Comparison of effects of simvastatin versus atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I levels. Am J Cardiol 2000;86:221-223.
Ikewaki K, Nishiwaki M, Sakamoto T, et al. Increased catabolic rate of low density lipoproteins in humans with cholesteryl ester transfer protein deficiency. J Clin Invest 1995;96:1573-1581.
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;350:1505-1515.
Saad MF, Greco S, Osei K, et al. Ragaglitazar improves glycemic control and lipid profile in type 2 diabetic subjects: a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm. Diabetes Care 2004;27:1324-1329.
Nissen SE, Tsunoda T, Tuzcu EM, et al. Effects of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized. controlled trial. JAMA 2003;290:2292-2300.
Li X, Chyu K-Y, Neto JRF, et al. Differential effects of apolipoprotein A-I-mimetic peptide on evolving and established atherosclerosis in apolipoprotein E-null mice. Circulation 2004;110:1701-1705.
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.
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;43:717-724.
Haffner SM. Management of dyslipidemia in adults with diabetes. Diabetes Care 2003;26:Suppl 1:S83-S86.(M. Dominique Ashen, Ph.D.)
A 41-year-old man with dyslipidemia, hypertension, and a history of myocardial infarction four years previously comes to establish care. He is physically inactive and consumes a diet high in saturated fat. He does not smoke. Medications include a statin, a beta-blocker, an angiotensin-converting – enzyme inhibitor, and aspirin. His blood pressure is 110/80 mm Hg, and his body-mass index (the weight in kilograms divided by the square of the height in meters) is 32. The fasting glucose level is 96 mg per deciliter (5.33 mmol per liter). The total cholesterol level is 155 mg per deciliter (4.01 mmol per liter), the low-density lipoprotein (LDL) cholesterol level 72 mg per deciliter (1.86 mmol per liter), the high-density lipoprotein (HDL) cholesterol level 28 mg per deciliter (0.72 mmol per liter), and the triglyceride level 277 mg per deciliter (3.13 mmol per liter). What strategies can increase his HDL cholesterol level?
The Clinical Problem
Persons with low HDL cholesterol levels (less than 40 mg per deciliter in men and less than 50 mg per deciliter in women) are at increased risk of coronary heart disease,1 restenosis after angioplasty,2 and death from cardiovascular causes, especially if such persons are male3 or have diabetes.4 Often, persons with low HDL cholesterol levels also have other cardiovascular risk factors, such as diabetes, hypertension, or both, which further increase risk.
Epidemiologic studies and studies in animals suggest that raising the levels of HDL cholesterol may retard the development of atherosclerosis. In humans, each increase in baseline HDL cholesterol of 1 mg per deciliter (0.03 mmol per liter) is associated with a 6 percent decrease in the risk of death from coronary disease or of myocardial infarction.5 Studies in animals have shown that overexpression of the apolipoprotein A-I gene (the major apolipoprotein in HDL cholesterol) prevents the development or progression of atherosclerosis.6,7
HDL cholesterol transports excess cholesterol from peripheral tissues to the liver for excretion, a process known as reverse cholesterol transport (Figure 1). In addition, HDL cholesterol inhibits the oxidation of LDL cholesterol and the expression of cellular adhesion molecules and monocyte recruitment, and it may reduce the risk of thrombosis by inhibiting platelet activation and aggregation.8
Figure 1. Reverse Cholesterol Transport.
In reverse cholesterol transport,7 lipid-poor pre- HDL cholesterol, rich in apolipoprotein A-I (A-I), is synthesized by the liver or intestinal mucosa and released into the circulation. There it promotes the transfer of excess cellular-free cholesterol (FC) from macrophages to A-I by interacting with the ATP-binding cassette transporter A1 (ABCA1) in arterial-wall macrophages. Plasma lecithin–cholesterol acyltransferase (LCAT) converts free cholesterol in pre- HDL cholesterol to cholesteryl ester (CE), resulting in maturation of pre- HDL cholesterol to mature HDL cholesterol. HDL cholesterol is transported to the liver by a direct or indirect pathway.
In the direct pathway, selective uptake of cholesteryl ester by hepatocytes occurs with the scavenger receptor, class B, type 1 (SR-B1). In the indirect pathway, HDL cholesterol cholesteryl ester is exchanged for triglycerides (TG) in apolipoprotein-B–rich particles (B), LDL cholesterol, and very-low-density lipoprotein (VLDL) cholesterol through cholesteryl-ester–transfer protein (CETP), with uptake of cholesteryl ester by the liver through the LDL receptor (LDLR). Cholesterol that is returned to the liver is secreted as bile acids and cholesterol. Acquired triglycerides in the modified HDL cholesterol particle are subjected to hydrolysis by hepatic lipase (HL), thereby regenerating small HDL cholesterol particles and pre- HDL cholesterol for participation in reverse cholesterol transport.
Strategies and Evidence
Lifestyle Modifications
Exercise
Regular aerobic exercise increases the HDL cholesterol level by 3 to 9 percent in healthy, sedentary persons.9 This increase is related to the frequency and intensity of physical activity, with greater increases in HDL cholesterol occurring with frequent, low-intensity exercise (e.g., five 30-minute sessions per week vs. three 60-minute sessions).9 However, there is little evidence that walking significantly increases HDL cholesterol levels.10 HDL cholesterol levels may increase with as little as eight weeks of regular exercise, although changes may not be evident for two years.9 Exercise may increase HDL cholesterol levels by stimulating the production of pre- HDL cholesterol and reverse cholesterol transport.11
Regular exercise yields greater increases in HDL cholesterol in men with low HDL cholesterol levels, elevated triglyceride levels, and abdominal obesity than in those with isolated low HDL cholesterol levels.12 Weight loss may be crucial for an increase in HDL cholesterol to occur. In one randomized, controlled trial, persons who walked or jogged 10 miles per week but did not lose weight did not have different HDL cholesterol levels from those of controls.13 Nevertheless, it is reasonable to recommend a program of regular, brisk aerobic exercise for 30 minutes on most days of the week.
Smoking Cessation
Cigarette smoking is associated with reduced HDL cholesterol,14 lecithin – cholesterol acyltransferase activity,15 and cholesteryl-ester – transfer protein (CETP) activity.16 After smoking cessation, HDL cholesterol increases (by a mean of 4 mg per deciliter ), more so in women than in men and in persons with elevated baseline HDL cholesterol levels (>47 mg per deciliter ).17 A comprehensive approach to smoking cessation (involving pharmacotherapy, nicotine replacement, and counseling) should be recommended.18
Weight Control
Obesity is associated with reduced HDL cholesterol levels and elevated serum triglyceride levels.19 A negative correlation exists between HDL cholesterol and body-mass index.20 A meta-analysis examining the effect of weight loss on HDL cholesterol levels demonstrated that the levels increased by 0.35 mg per deciliter (0.009 mmol per liter) per kilogram of weight reduction in subjects who achieved a stabilized, reduced weight (P0.01) but decreased by 0.27 mg per deciliter (0.006 mmol per liter) in subjects during active weight loss (P0.05).21 In subjects who maintained a stable weight for six weeks after weight loss, HDL cholesterol levels, lipoprotein lipase levels, and lecithin – cholesterol acyltransferase activity increased; these increases may contribute to enhanced cholesterol esterification and reverse cholesterol transport.22 A reasonable weight-loss goal for overweight or obese patients is 1 lb (0.45 kg) per week, with a target body-mass index of less than 25.
Alcohol Intake
Moderate alcohol consumption raises HDL cholesterol levels.14 A meta-analysis indicated that the consumption of 30 g (1 fluid oz) of alcohol per day increases HDL cholesterol levels by a mean of 4 mg per deciliter, irrespective of the kind of alcohol consumed.23 Persons who consume one to three drinks daily have higher HDL cholesterol levels and a lower risk of myocardial infarction than do those who drink less, even after adjustment for other likely confounding factors.24 Thus, mild-to-moderate alcohol consumption (no more than one to two drinks per day) appears to be reasonable for many persons with low HDL cholesterol levels. However, the potential risks associated with this recommendation may outweigh the benefits in persons with hepatic dysfunction or the potential for addiction. Alcohol consumption may elevate HDL cholesterol levels by increasing cellular cholesterol efflux and plasma cholesterol esterification.25
Dietary Fat Intake
Plasma LDL cholesterol and HDL cholesterol levels decline with reductions in the intake of dietary fat. In a study comparing calorically balanced diets (i.e., intake is equal to expenditure) that differed in fat content,26 subjects who consumed a low-fat diet (19 percent of total calories were from fat) had lower HDL cholesterol and apolipoprotein A-I levels than did subjects who were fed a high-fat diet (50 percent of total calories were from fat) (54 mg per deciliter vs. 63 mg per deciliter and 118 mg per deciliter vs. 127 mg per deciliter , respectively; P<0.005). The concomitant decrease in LDL cholesterol that occurs with a diet low in saturated fat may override the effects associated with the decline in HDL cholesterol.27 Native Alaskan populations that eat a diet rich in n–3 polyunsaturated fatty acids have high HDL cholesterol levels.28 Although a diet high in monounsaturated fats does not elicit a significant change in HDL cholesterol levels,29 the dietary glycemic load (which represents the equivalent elevating effect on blood-glucose levels of 1 g of pure glucose or white bread) is negatively correlated with HDL cholesterol levels.30 Thus, a diet rich in n–3 polyunsaturated fatty acids — sources include oils (olive, canola, soy, flaxseed), nuts (almonds, peanuts, walnuts, pecans), cold-water fish (salmon, mackerel), and shellfish — with limited carbohydrates that contribute a high glycemic load (such as those found in ready-to-eat cereals, potatoes, white bread, and snack foods) can be recommended to increase serum HDL cholesterol levels.
Lifestyle and Modifying Factors
Improvement in HDL cholesterol levels associated with exercise, alcohol consumption, and weight loss is greatest in persons with the highest baseline HDL cholesterol levels (60 mg per deciliter or more); those with low baseline levels have less improvement.31 Interactions between genes and the environment may influence the magnitude of improvement in HDL cholesterol levels associated with lifestyle modifications. Specifically, improvement with exercise may depend on individual CETP and endothelial lipase genotypes.32,33 However, genetic tests for these factors are not currently used in routine practice, and lifestyle changes as described above should be recommended routinely, both to raise HDL cholesterol levels and to lower LDL cholesterol levels and improve other cardiovascular risk factors.
Medication
Several classes of medications increase HDL cholesterol levels; these include niacin and fibrates, in particular, and, to a lesser degree, statins. These medications also lower triglycerides and LDL cholesterol levels. Without trials designed to isolate the effects of drugs on changes in HDL cholesterol levels and on coronary outcomes, it is difficult to determine how much of the drugs' benefit in reducing the rates of coronary heart disease are due to changes in HDL cholesterol levels. At present, there is no clear consensus regarding when to use medications for the purpose of raising HDL cholesterol levels, although drugs are most often considered for patients with established coronary disease or for those at high risk.
Niacin
Niacin (nicotinic acid or vitamin B3) is the most effective medication to raise HDL cholesterol levels, causing increases of 20 to 35 percent.34 The Coronary Drug Project35 demonstrated a significant reduction in the incidence of death and myocardial infarction after five years of niacin treatment among men with a history of myocardial infarction. Niacin inhibits hepatic uptake of apolipoprotein A-I and increases plasma pre- HDL cholesterol levels.36 Niacin therapy is associated with improved endothelial function and nitric oxide synthase activity.37
The side effects of niacin therapy include cutaneous flushing, dyspepsia, and elevation of plasma glucose and uric acid levels. Flushing, which is largely mediated by prostaglandins, may be minimized with the use of an extended-release formulation of niacin (not the same as sustained-release niacin); with the concurrent consumption of a low-fat snack at bedtime, 30 minutes after ingestion of an aspirin; and with a regimen that begins with a low dose (e.g., 500 mg each night) and increases gradually (Table 1).
Table 1. Lipid-Lowering Medications and Effects on HDL Cholesterol Levels.
Fibrates
Fibrate therapy results in an increase in HDL cholesterol levels of 10 to 25 percent by activating peroxisome-proliferator–activated receptor (PPAR), which stimulates expression of the hepatic apolipoprotein A-I gene.43 The Helsinki Heart Study38 and the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial39 demonstrated increases in HDL cholesterol (10 percent and 6 percent, respectively) and a large reduction in triglyceride levels in asymptomatic men and those with primary dyslipidemia or coronary heart disease, respectively, who had been randomly assigned to receive gemfibrozil (1200 mg daily), as compared with subjects who received placebo. Gemfibrozil significantly reduced the risks of coronary events (34 percent) and the combined outcome of coronary death, nonfatal myocardial infarction, and stroke (24 percent). Subsequent analysis of the Veterans Affairs trial indicated that only the increase in HDL cholesterol levels, not the change in LDL cholesterol or triglyceride levels, significantly predicted a reduced risk of coronary events.44 A large clinical trial involving the use of fenofibrate is in progress.
Statins
In addition to lowering LDL cholesterol levels, statins raise HDL cholesterol levels by 2 to 15 percent by increasing apolipoprotein A-I synthesis.45 Different agents vary in efficacy (Table 1).46 In a randomized trial comparing the effects of simvastatin and atorvastatin (maximum dose, 80 mg and 40 mg, respectively, titrated to LDL cholesterol levels) among patients with elevated LDL cholesterol levels, there was a moderately greater increase with simvastatin in HDL cholesterol levels (9 percent vs. 7 percent, P<0.001) and apolipoprotein A-I levels (6 percent vs. 3 percent, P<0.001); clinical outcomes were not assessed.47
Several trials have documented reduced risks of major coronary events associated with the use of a statin, as compared with placebo,40 but it is not clear whether the rise in HDL cholesterol levels is an independent predictor of the reduced risk of coronary events with the use of these agents.
Combination Therapy
In some patients with low HDL cholesterol levels, various lipid-modifying medications may be useful in combination. The HDL Atherosclerosis Treatment Study (HATS)41 demonstrated that a combination of low-dose simvastatin (10 to 20 mg per day) and high-dose niacin (2 to 4 mg per day) significantly increased HDL cholesterol levels (26 percent), as compared with placebo, in patients with HDL cholesterol levels of 40 mg per deciliter or less, LDL cholesterol levels of 145 mg per deciliter (3.75 mmol per liter) or less, and triglyceride levels of less than 400 mg per deciliter (4.52 mmol per liter). In the simvastatin–niacin treatment group, coronary stenoses, as documented on angiography, moderately regressed over three years (0.4 percent, P<0.001 vs. placebo; 3.9 percent increase).
The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 study,42 which involved subjects who had established coronary disease, HDL cholesterol levels of less than 45 mg per deciliter (1.16 mmol per liter), and LDL cholesterol levels of less than 130 mg per deciliter (3.36 mmol per liter), showed that the addition of extended-release niacin (1000 mg daily) to existing statin therapy increased mean HDL cholesterol levels by 21 percent (from a mean of 39 to 47 mg per deciliter ; P<0.001 vs. the change in the placebo group). Medial thickness of the carotid intima significantly increased in the placebo group (mean change, 0.044 mm; P<0.001) but not in the placebo group (mean change, 0.014 mm; P=0.23); however, a comparison of changes in intimal thickness over time did not show a significant difference between the two groups (P=0.08).
Areas of Uncertainty
Randomized, controlled trials are needed to demonstrate that drugs specifically aimed at raising HDL cholesterol levels will reduce cardiovascular events as well as to provide guidance for the use of medications and for treatment goals among patients with varying levels of coronary risk.
Several therapies to increase HDL cholesterol levels are being studied. Partial inhibitors of CETP activity increase HDL cholesterol levels and reverse cholesterol transport, whereas complete inhibition of CETP activity results in cholesterol-laden, dysfunctional HDL cholesterol particles, with reduced cholesterol-efflux capability.48 In a single-blind, placebo-controlled study of adults with low HDL cholesterol levels (mean, 32 mg per deciliter ), treatment with the partial CETP inhibitor torcetrapib resulted in a 46 percent increase in HDL cholesterol levels. Torcetrapib is currently being studied in a phase 3 trial involving the use of intravascular ultrasonography and medial thickness of the carotid intima to monitor plaque size.49 The macrophage ATP-binding cassette transporter A 1 (ABCA1) facilitates the transfer of cholesterol to apolipoprotein A-I. PPAR may raise HDL cholesterol levels by enhancing ABCA1 transcription. Thiazolidinediones (approved for the treatment of diabetes but not for lipid management) and a new class of agents known as glitazars (which are under review by the Food and Drug Administration) activate PPAR; their role in the management of low levels of HDL cholesterol is uncertain.50
Bioengineered molecules, such as recombinant apolipoprotein A-I Milano, which mimic the properties of nascent HDL cholesterol, cause regression of plaques in animal models. In a placebo-controlled study of 47 subjects, five weekly infusions of apolipoprotein A-I Milano produced modest regression of coronary atherosclerosis, as measured with the use of intravascular ultrasonography.51 Data from a study of mice treated with D4F, an apolipoprotein A-I-mimetic peptide, suggest that a beneficial effect may depend on the stage of atherosclerosis; a benefit was observed in vein grafts (which rapidly develop atheromatous lesions) but not in established native aortic disease.52
Guidelines from Professional Associations
The National Cholesterol Education Program emphasizes that initial treatment should be directed toward achieving a target LDL cholesterol level (and non-HDL cholesterol if the triglyceride level is more than 200 mg per deciliter ) before considering niacin or fibrates in persons with low HDL cholesterol levels (www.nhlbi.nih.gov/guidelines/cholesterol/atglance.htm).53 The National Cholesterol Education Program does not specifically recommend that HDL cholesterol be a primary or secondary target. The Expert Group on HDL recommends considering the addition of a fibrate or niacin for persons whose HDL cholesterol level is less than 40 mg per deciliter and who have diabetes mellitus or the metabolic syndrome (defined as the presence of three or more of the following: central obesity ; a fasting triglyceride level of 150 mg per deciliter or more; an HDL cholesterol level of less than 40 mg per deciliter in men or less than 50 mg per deciliter in women; blood pressure of 130/85 mm Hg or higher; and a fasting glucose level of more than 110 mg per deciliter ).54 The American Diabetes Association recommends that adults with diabetes should first aim for an LDL cholesterol level of less than 100 mg per deciliter (2.59 mmol per liter); secondary targets should include an HDL cholesterol level of more than 40 mg per deciliter and a triglyceride level of less than 150 mg per deciliter (3.88 mmol per liter). Caution is recommended with regard to the use of high-dose niacin in patients with diabetes, because this may increase glucose levels (www.diabetes.org).55
Summary and Recommendations
A low level of HDL cholesterol is an independent risk factor for future cardiovascular events. A comprehensive approach to achieving optimal HDL cholesterol levels (40 mg per deciliter or more in men and 50 mg per deciliter or more in women) should include lifestyle modifications, followed by the consideration of pharmacotherapy in high-risk patients. The patient in the vignette has established coronary heart disease and a low level of HDL cholesterol. His plasma LDL cholesterol level is appropriate given that he is taking a statin, but his triglyceride level is elevated, and he is obese.
Lifestyle changes should be recommended as the first approach to raise HDL cholesterol levels, which would lead to other cardiovascular benefits. We would initially recommend a program of regular aerobic exercise (a gradual increase to 30 minutes of brisk aerobic activity five days per week), weight loss (1 lb per week, with a target body-mass index of less than 25), and the substitution of sources of polyunsaturated fats such as oils (olive, canola, soy, flaxseed), nuts (almonds, peanuts, walnuts, pecans), cold-water fish (salmon, mackerel), and shellfish for saturated fats and simple carbohydrates. Persons who smoke should be advised to quit. Moderate alcohol intake is reasonable for patients who so choose and for whom there are no contraindications.
Whether to add medication to lifestyle changes to raise HDL cholesterol levels will depend on the degree of cardiovascular risk. Although data are currently lacking to prove that elevating HDL cholesterol levels with drugs reduces the incidence of cardiovascular events, medication to raise these levels should be considered, once the target LDL cholesterol level has been achieved, in persons who have established atherosclerotic disease (such as the patient described in the vignette) or major risk factors such as diabetes and in whom HDL cholesterol levels remain low despite lifestyle modifications. If the triglyceride level remains above 250 mg per deciliter (2.82 mmol per liter), it would be reasonable to prescribe a fibrate in addition to reinforcing lifestyle recommendations. The use of a fibrate should lower the triglyceride level and can be expected to increase HDL cholesterol by 10 to 25 percent. Niacin is an effective alternative, although it should be used with caution in patients with diabetes.
Dr. Blumenthal reports having received speaker's fees or consulting fees from Pfizer, Merck, AstraZeneca, and Kos.
We are indebted to Dr. Navin K. Kapur for his thoughtful suggestions on the manuscript.
Source Information
From the Johns Hopkins Hospital, Baltimore.
Address reprint requests to Dr. Blumenthal at Johns Hopkins Hospital, Blalock 524C, Johns Hopkins Ciccarone Preventive Cardiology Center, 600 N. Wolfe St., Baltimore, MD 21287, or at rblument@jhmi.edu
References
Miller NE, Thelle DS, Forde OH, Mjos OD. The Tromso heart-study: high-density lipoprotein and coronary heart-disease: a prospective case-control study. Lancet 1977;1:965-968.
Shah PK, Amin J. Low high density lipoprotein level is associated with increased restenosis rate after coronary angioplasty. Circulation 1992;85:1279-1285.
Wilson PW, Abbott RD, Castelli WP. High density lipoprotein cholesterol and mortality: the Framingham Heart Study. Arteriosclerosis 1988;8:737-741.
Goldbourt U, Yaari S, Medalie JH. Isolated low HDL cholesterol as a risk factor for coronary heart disease mortality: a 21-year follow-up of 8000 men. Arterioscler Thromb Vasc Biol 1997;17:107-113.
Gordon DJ, Knoke J, Probstfield JL, Superko R, Tyroler HA. High-density lipoprotein cholesterol and coronary heart disease in hypercholesterolemic men: the Lipid Research Clinics Coronary Primary Prevention Trial. Circulation 1986;74:1217-1225.
Benoit P, Emmanuel F, Caillaud JM, et al. Somatic gene transfer of human ApoA-I inhibits atherosclerosis progression in mouse models. Circulation 1999;99:105-110.
Brewer HB Jr. High-density lipoproteins: a new potential therapeutic target for the prevention of cardiovascular disease. Arterioscler Thromb Vasc Biol 2004;24:387-391.
Shah PK, Kaul S, Nilsson J, Cercek B. Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins: an idea whose time for testing is coming. Circulation 2001;104:2376-2383.
King AC, Haskell WL, Young DR, Oka RK, Stefanick ML. Long-term effects of varying intensities and formats of physical activity on participation rates, fitness, and lipoproteins in men and women aged 50 to 65 years. Circulation 1995;91:2596-2604.
Kelley GA, Kelley KS, Tran ZV. Walking, lipids and lipoproteins: a meta-analysis of randomized controlled trials. Prev Med 2004;38:651-661.
Gupta AK, Ross EA, Myers JN, Kashyap ML. Increased reverse cholesterol transport in athletes. Metabolism 1993;42:684-690.
Couillard C, Despres JP, Lamarche B, et al. Effects of endurance training on plasma HDL cholesterol levels depend on levels of triglycerides: evidence from men of the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study. Arterioscler Thromb Vasc Biol 2001;21:1226-1232.
Stefanick ML, Mackey S, Sheehan M, Ellsworth N, Haskell WL, Wood PD. Effects of diet and exercise in men and postmenopausal women with low levels of HDL cholesterol and high levels of LDL cholesterol. N Engl J Med 1998;339:12-20.
Ellison RC, Zhang Y, Qureshi MM, Knox S, Arnett DK. Lifestyle determinants of high-density lipoprotein cholesterol: the National Heart, Lung, and Blood Institute Family Heart Study. Am Heart J 2004;147:529-535.
Imamura H, Teshima K, Miyamoto N, Shirota T. Cigarette smoking, high-density lipoprotein cholesterol subfractions, and lecithin: cholesterol acyltransferase in young women. Metabolism 2002;51:1313-1316.
Mero N, Van Tol A, Scheek LM, et al. Decreased postprandial high density lipoprotein cholesterol and apolipoproteins A-I and E in normolipidemic smoking men: relations with lipid transfer proteins and LCAT activities. J Lipid Res 1998;39:1493-1502.
Maeda K, Noguchi Y, Fukui T. The effects of cessation from cigarette smoking on the lipid and lipoprotein profiles: a meta-analysis. Prev Med 2003;37:283-290.
Rigotti NA. Treatment of tobacco use and dependence. N Engl J Med 2002;346:506-512.
Denke MA, Sempos CT, Grundy SM. Excess body weight: an underrecognized contributor to high blood cholesterol levels in white American men. Arch Intern Med 1993;153:1093-1103.
Wakabayashi I. Relationship of body mass index with blood pressure and serum cholesterol concentrations at different ages. Aging Clin Exp Res 2004;16:461-466.
Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr 1992;56:320-328.
Weisweiler P. Plasma lipoproteins and lipase and lecithin:cholesterol acyltransferase activities in obese subjects before and after weight reduction. J Clin Endocrinol Metab 1987;65:969-973.
Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ. Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ 1999;319:1523-1528.
Gaziano JM, Buring JE, Breslow JL, et al. Moderate alcohol intake, increased levels of high-density lipoprotein and its subfractions, and decreased risk of myocardial infarction. N Engl J Med 1993;329:1829-1834.
van der Gaag MS, van Tol A, Vermunt SH, Scheek LM, Schaafsma G, Hendriks HFJ. Alcohol consumption stimulates early steps in reverse cholesterol transport. J Lipid Res 2001;42:2077-2083.
Meksawan K, Pendergast DR, Leddy JJ, Mason M, Horvath PJ, Awad AB. Effect of low and high fat diets on nutrient intakes and selected cardiovascular risk factors in sedentary men and women. J Am Coll Nutr 2004;23:131-140.
Berglund L, Oliver EH, Fontanez N, et al. HDL-subpopulation patterns in response to reductions in dietary total and saturated fat intakes in healthy subjects. Am J Clin Nutr 1999;70:992-1000.
Gerasimova E, Perova N, Ozerova I, et al. The effect of dietary n-3 polyunsaturated fatty acids on HDL cholesterol in Chukot residents vs Muscovites. Lipids 1991;26:261-265.
Pelkman CL, Fishell VK, Maddox DH, Pearson TA, Mauger DT, Kris-Etherton PM. Effects of moderate-fat (from monounsaturated fat) and low-fat weight-loss diets on the serum lipid profile in overweight and obese men and women. Am J Clin Nutr 2004;79:204-212.
Slyper A, Jurva J, Pleuss J, Hoffmann R, Gutterman D. Influence of glycemic load on HDL cholesterol in youth. Am J Clin Nutr 2005;81:376-379.
Williams PT. The relationships of vigorous exercise, alcohol, and adiposity to low and high high-density lipoprotein-cholesterol levels. Metabolism 2004;53:700-709.
Wilund KR, Ferrell RE, Phares DA, Goldberg AP, Hagberg JM. Changes in high-density lipoprotein-cholesterol subfractions with exercise training may be dependent on cholesteryl ester transfer protein (CETP) genotype. Metabolism 2002;51:774-778.
Halverstadt A, Phares DA, Ferrell RE, Wilund KR, Goldberg AP, Hagberg JM. High-density lipoprotein-cholesterol, its subfractions, and responses to exercise training are dependent on endothelial lipase genotype. Metabolism 2003;52:1505-1511.
Alderman JD, Pasternak RC, Sacks FM, Smith HS, Monrad ES, Grossman W. Effect of a modified, well-tolerated niacin regimen on serum total cholesterol, high density lipoprotein cholesterol and the cholesterol to high density lipoprotein ratio. Am J Cardiol 1989;64:725-729.
Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245-1255.
Piepho RW. The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol. Am J Cardiol 2000;86:35L-40L.
Kuvin JT, Ramet ME, Patel AR, Pandian NG, Mendelsohn ME, Karas RH. A novel mechanism for the beneficial vascular effects of high-density lipoprotein cholesterol: enhanced vasorelaxation and increased endothelial nitric oxide synthase expression. Am Heart J 2002;144:165-172.
Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia -- safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237-1245.
Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410-418.
Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-1622.
Brown BG, Zhao X-Q, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-1592.
Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004;110:3512-3517.
Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998;98:2088-2093.
Robins SJ, Collins D, Wittes JT, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 2001;285:1585-1591.
Schaefer JR, Schweer H, Ikewaki K, et al. Metabolic basis of high density lipoproteins and apolipoprotein A-I increase by HMG-CoA reductase inhibition in healthy subjects and a patient with coronary artery disease. Atherosclerosis 1999;144:177-184.
Blumenthal RS. Statins: effective antiatherosclerotic therapy. Am Heart J 2000;139:577-583.
Kastelein JJP, Isaacsohn JL, Ose L, et al. Comparison of effects of simvastatin versus atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I levels. Am J Cardiol 2000;86:221-223.
Ikewaki K, Nishiwaki M, Sakamoto T, et al. Increased catabolic rate of low density lipoproteins in humans with cholesteryl ester transfer protein deficiency. J Clin Invest 1995;96:1573-1581.
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;350:1505-1515.
Saad MF, Greco S, Osei K, et al. Ragaglitazar improves glycemic control and lipid profile in type 2 diabetic subjects: a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm. Diabetes Care 2004;27:1324-1329.
Nissen SE, Tsunoda T, Tuzcu EM, et al. Effects of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized. controlled trial. JAMA 2003;290:2292-2300.
Li X, Chyu K-Y, Neto JRF, et al. Differential effects of apolipoprotein A-I-mimetic peptide on evolving and established atherosclerosis in apolipoprotein E-null mice. Circulation 2004;110:1701-1705.
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.
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;43:717-724.
Haffner SM. Management of dyslipidemia in adults with diabetes. Diabetes Care 2003;26:Suppl 1:S83-S86.(M. Dominique Ashen, Ph.D.)