Low HDL-C is a criterion for the diagnosis of the metabolic syndrome. As any diabetologist will agree, a low HDL with raised triglycerides is the most common lipid abnormality in diabetics.( Papadakis JA, Milionis HJ, Press M et al. Treating dyslipidaemia in non-insulin-dependent diabetes mellitus-a special reference to statins. J Diabetes Comp 2001;15:211-26).

The implications of HDL levels on cardiovascular risk is widely known, but physicians are often not proactive about treating low levels. This is partly attributable to the preoccupation  with LDL lowering, and the ease of statin prescription.   Lack of availability of a full lipid profile also makes prescriptions for HDL raising drugs minimal. Many physicians do not realise that statins have only a minimal effect on raising HDL levels and do not bother with further lipid assessments once total cholesterol is within target. In fact, 40% of patients with CHD without a definite indication for lipid-lowering therapy have low levels of HDL-C (Rubins HB, Robins SJ, Collins D et al. Distribution of lipids in 8,500 men with coronary artery disease. Department of Veterans Affairs HDL Intervention Trial Study Group. Am J Cardiol 1995;75:1196-201). The recently recognised  problems with combining fibrates and statins has probably contributed to this neglect. Another scenario often happens when HDL cholesterol calculations are not made available due to high triglycerides. The fact that HDL level starts to fall when triglycerides exceed a magic number of 1.7 mmol/L is rarely heeded. An inclination to treat triglycerides is low among physicians who feel that an association with cardiovascular risk has not been proved yet!

The National Cholesterol Education Program Adult Treatment Panel  (NCEP ) ATP III guidelines in 2001 redefined low HDL-C as <1.0 mmol/L (<40 mmol/dL)  (as opposed to the previous 0.9 mmol/L (<35 mg/dL).  This lowering of threshold puts an additional 14 million Americans in the LOW HDL category.

Reference:

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.

Hence the page dedicated to HDL cholesterol and its importance in cardiovascular risk.

HDL: mechanism of cardioprotective effect:

HDL facilitates reverse cholesterol transport to the liver from peripheral tissues, and thus probably prevents vascular atherosclerotic lesions from developing. HDL may also have antioxidant effects, as well as inhibit adhesion molecule expression and platelet activation.

Recent studies have shown that peroxisome proliferator-activated receptor a (PPAR-a) and PPAR-g both facilitate gene transcription of products that increase cholesterol efflux from the macrophages resulting in less atherosclerosis. Drugs targeting these receptors (fibrates and Glitazones respectively) can clearly exert positive effects on HDL.

More recently interest has been engendered by the recognition of the role of cholesteryl ester transfer protein (CETP) in HDL metabolism. CETP transfers cholesteryl esters (CE) from HDL to the apo B–containing lipoproteins, very low density lipoprotein (VLDL) and LDL. CETP inhibitors are in clinical trials.  

Manipulation of transgenic mice to overproduce ApoA1, the major protein in HDL reduced the onset and progression of atherosclerosis. So are we going to increase ApoA1 gene transcription, or are we going to infuse apoA1?  Probably much easier to increase HDL production!

HDL and cardiovascular risk:

•The Framingham study epidemiological analysis has revealed that the incidence of MI was increased 2 fold in men and six fold in women with HDL <1.3

•CVS events were four fold in men with HDL <0.9 mmol/L. A 1% increase in HDL is associated with a 2-4% reduction in CHD

Lopid  Coronary Angiography Trial (LOCAT) for 1 year using Gemfibrozil in men with previous CABG.

Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT): 92 males with previous MI were treated with Bezafibrate  for 5 years.

Lipoprotein and Coronary Atherosclerosis Study (LCAS): 339 patients treated with Fluvastatin for 2.5 years demonstrated improved survival and lower progression of atherosclerotic lesions, especially so in the group with low HDL levels(<0.9 mmol/L) [p<0.002]

Before we think about starting efforts to raise HDL, what evidence do we have to show that increasing HDL improves cardiovascular risk?

 In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), Gemfibrozil reduced cardiovascular events by 22% compared with placebo in patients with low HDL-C and coronary disease. In the study, HDL-C levels were increased modestly by about 6% (statistically significant) , and the triglyceride levels were decreased by 31%.  There was no change in LDL-C.

Reference: Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. 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.

For every 0.025 mmol/L rise in HDL, the risk of CHD decreases 2% in men and 3% in women. (Framingham study)

Low HDL-C levels are commonly found in patients who smoke, who are sedentary or obese, who are insulin resistant or diabetic, who have high triglycerides, or who have chronic inflammatory disorders.  Does it mean that it is not HDL but mere presence of these other factors, or their accompaniments that contribute to the excess cardiovascular risk. Apparently not so: Low HDL-C is an independent predictor of CHD risk even when LDL-C is low as shown in the Framingham Heart Study

Ref: (Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977;62:707-714.)

In the Caerphilly and Speedwell cohort study high TG, high total cholesterol and low HDL-C levels were independent predictors of CHD and the combination of these lipid abnormalities increased the overall risk of coronary events

Ref: (Yarnell JW, Patterson CC, Sweetman PM et al. Do total and high density lipoprotein cholesterol and triglycerides act independently in the prediction of ischemic heart disease?: ten-year follow-up of Caerphilly and Speedwell cohorts. Arterioscler Thromb Vasc Biol 2001;21:1340-45)

Life style and HDL:

Life style modifications as weight loss, exercise, stopping smoking and  the occasional socialising drink remain excellent therapeutic options to raise HDL- where possible! For every 3 kg (7 lb) of weight loss, HDL-C levels increase 0.03 mmol/L (1 mg/dL). The others need to be considered for fibrates, nicotinic acid, other modalities or combinations of these.In the Münster Heart Study [PROCAM], i mean HDL-C levels were reduced by 6.4% in male smokers and by 6.7% in female smokers versus nonsmokers.  In ex-smokers, HDL-C levels increased by 5.7 mg/dL by day 30 and by an additional 6.8 mg/dL by day 60, reaching 63.9 mg/dL.  In contrast, HDL-C levels in re-smokers returned to pre-cessation values (50.7 mg/dL) by day 60 (P < 0.05)

How much improvement of HDL can I expect from exercising, doctor?

2,906 healthy, nonsmoking, middle-aged men (mean age: 43 years) participated in a study.  (Kokkinos PF, Holland JC, Narayan P, et al. Miles run per week and high-density lipoprotein cholesterol levels in healthy, middle-aged men. Arch Intern Med. 1995;155:415–420)  Mean HDL-C was found to increase by 0.308 mg/dL with each 1-mile increase in running distance.  Significantly higher HDL-C levels were observed in the groups that ran 7 or more miles per week compared with the non-runners (P < 0.001). 

Low fat diets!

22 subjects on very-low-fat diets had lower HDL-C levels without significantly lower LDL-C levels.  This Australian study is one of the few studies  to confirm the epidemiologic observation that dietary fat increases HDL-C concentrations. (Morgan SA, Sinclair AJ, O’Dea K. Effect on serum lipids of addition of safflower oil or olive oil to very-low-fat diets rich in lean beef. J Am Diet Assoc. 1993;93:644–648). In the Lifestyle Heart Trial, angiographic benefit was observed with a very-low-fat (vegetarian) diet plus smoking cessation, exercise, weight loss, and stress-management training (meditation). (Ornish D, Brown SE, Scherwitz LW, et al. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial).   82% of the 28 study subjects showed a trend toward atherosclerosis regression, whereas stenosis increased in 20 usual-care control subjects.

But Epidemiologic data indicate that populations that consume low-fat diets have lower rates of coronary heart disease (CHD) as well as lower low- and high-density lipoprotein cholesterol (LDL-C and HDL-C) levels compared with populations that consume high-fat diets. This is confusing!

 So which bit of the dietary fat is beneficial?   In the Lyon Diet Heart Study, changes in fat composition (not quantity) led to a significant reduction in CHD events.  The experimental group in this study consumed significantly less lipids, saturated fat, cholesterol, and linoleic acid but more oleic and alpha-linoleic acids.( de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linoleic acid-rich diet in secondary prevention of coronary heart disease. Lancet.1994;343:1454–1459.)

So how much alcohol is good for me, doctor?

Alcohol intake increases HDL-C concentrations. consumption of half a bottle of white wine (39 g alcohol) per day for 6 weeks significantly (P < 0.01) increased mean HDL-C levels from 41 to 48 mg/dl in12 healthy, non smoking, normolipidemic subjects (nine women and three men) [Thornton J, Symes C, Heaton K. Moderate alcohol intake reduces bile cholesterol and raises HDL cholesterol. Lancet. 1983;ii:819–822].  Total plasma cholesterol (Total-C), total triglyceride (Total-TG), or low-density lipoprotein cholesterol (LDL-C) concentrations did not change.   This degree of alcohol intake translates into 11,466 additional calories:i.e. 3 lbs of additional weight  over 6 weeks, or approximately 27 lbs per year! 

Even lower amounts of alcohol in moderation has been shown to be effective at raising HDL. (McConnell MV et al. Effects of a single, daily alcoholic beverage on lipid haemostatic markers of cardiovascular risk. Am J Cardiol. 1997;80:1226–1228.)

Statins and HDL:

In the West of Scotland Coronary Prevention Study (WOSCOPS), Cholesterol and Recurrent Events (CARE) and the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID), Pravastatin treatment was associated with beneficial effects upon levels of HDL-C comparable to those achieved in VA-HIT. In the Scandinavian Simvastatin Survival Study (4S), Simvastatin treatment produced a 22% reduction in CHD risk.

High doses of statins may decrease HDL. So is it safe, or does it help,  to prescribe a statin in low HDL?

Yes,  as analysis in the four studies below show:

The benefit of Simvastatin therapy was relatively similar across the quartiles of baseline HDL in the 4S.

Reference: Scandinavian Simvastatin Survival Study Group. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S). Lancet 1995;345:1274-1275.

Pravastatin showed similar benefit across all HDL ranges  in the LIPID and CARE studies. 

Reference: Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with Pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-1357.

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), recruited patients in part based on low HDL-C,  In this study, patients with  lowest HDL-C tertile at baseline, <34 mg/dL, had the greatest relative risk reduction with lovastatin , while the tertile with the highest HDL-C, greater than 40 mg/dL, had the lowest relative risk reduction.  This confirms that statins are effective in reducing cardiovascular risk even in patients with low HDL-C.

(Reference: Downs JR, et al.  for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615-1622. )

The Simvastatin Combined Hyperlipidemia Study examined the efficacy and safety of Simvastatin dosed at 40 mg/d and 80 mg/d compared with placebo in patients with mixed hyperlipidemia. Simvastatin provided significant improvements in LDL-C, triglyceride, and HDL-C, with greater improvements obtained at the higher dosage.  At high dosages, statin therapy can substantially decrease triglyceride and increase HDL-C, particularly in patients with elevated triglyceride and low HDL-C.(Hunninghake DB et al. Large, dose dependent effects of simvastatin 40 and 80 mg/day in combined hyperlipidemia [abstract]. J Am Coll Cardiol 1999;33:244A.)

 Does that mean all statins produce HDL rises at varying doses?

Apparently not!

•A 12-week, open-label, randomized, parallel-group, multicenter study on •842 patients, ages 21-70 • (four groups of Simvastatin 40 mg, Simvastatin 80 mg, Atorvastatin 20 mg, Atorvastatin 40 mg)  found that a corresponding dosages, LDL-C and triglyceride reductions were similar with Simvastatin and Atorvastatin.  However, Simvastatin provided greater increases in HDL-C and the HDL-associated Apolipoprotein (apo) A-I than did Atorvastatin, and higher-dose Atorvastatin provided smaller increases in both parameters than did lower-dose Atorvastatin. (Crouse JR III et al. Simvastatin and Atorvastatin have different effects on HDL cholesterol and Apolipoprotein A-I [abstract]. J Am Coll Cardiol 1999;33:244A)

A direct comparison of the lipid-modifying effects of Atorvastatin, Pravastatin, lovastatin, Fluvastatin and Simvastatin was performed in the CURVES study (Jones P, Kafonek K, Laurora I et al. for the CURVES Investigators. Comparative dose efficacy study of Atorvastatin versus Simvastatin, Pravastatin, lovastatin and Fluvastatin in patients with hypercholesterolemia. Am J Cardiol 1998;81:582-7). Atorvastatin produced significantly greater reductions in LDL-C and total cholesterol levels than the other statins at equivalent doses but had a low potential for increasing HDL-C. Increasing doses of Atorvastatin were associated with progressively smaller increases in HDL-C levels and a dose of 80 mg was associated with a mean decrease of 0.1% from baseline HDL-C level. It is important in this context to mention that this was noted in only 10 patients.  Fluvastatin 40 mg lowered HDL-C levels by 3%.

 So how much improvement can one expect with different drugs

♠ Hunninghake DB, Chitra RR, Simonson SG et al. Treatment of hypertriglyceridemic patients with rosuvastatin. Diabetes 2001;50:2(Suppl):143

How much lipid modulation can be achieved by combination therapy? 

Pravastatin 40 mg/day + Gemfibrozil 1200 mg/day

 LDL-C  reduction by 37%
HDL-C rise by 17%
TG reduction by 42%

 (Wiklund O, et al.. Pravastatin and Gemfibrozil alone and in combination for the treatment of hypercholesterolemia. Am J Med 1993;94:13-20.)

 Simvastatin 10 mg/day + nicotinic acid titrated up to 1.5 g/day1

LDL-C reduction by 29%
HDL-C rise by 31%
TG reduction by 31%

 (Stein EA, et al,  Efficacy and tolerability of low-dose Simvastatin and niacin, alone and in combination, in patients with combined hyperlipidemia: a prospective trial. J Cardiovasc Pharmacol Therapeut 1996;1:107-116. )

Lovastatin   +  Niaspan (extended release niacin)

 LDL-C reduction by 47%
HDL-C rise by 30%  

(Kashyap ML, Evans R, Simmons PD et al. New combination niacin/statin formulation shows pronounced effects on major lipoproteins and is well tolerated. J Am Coll Cardiol 2000;35(Suppl A):326)

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    This page was last updated on: 07/03/2007

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