Targeting HDL

Raising HDL is as important as lowering LDL for reducing cardiovascular risk. By Dr Ajay Kumar Gupta.

Recent epidemiological studies have found an inverse relationship between HDL levels and coronary artery disease (CAD) risk. An increase in HDL of 0.03mmol/l produces a significant decrease in cardiovascular disease (CVD) mortality.

The Framingham study showed that low HDL is an independent risk factor for CAD and premature atherosclerosis, regardless of the level of LDL, total cholesterol and triglycerides. According to the study's 35 years of data, low HDL is as much a risk factor for CAD as high LDL.

More than a quarter of adults may have low HDL levels. They are associated with conditions such as type-2 diabetes and metabolic syndrome.

Protective mechanism
The primary atheroprotective mechanism of HDL is transport of excess cholesterol from peripheries to the liver for excretion by a mechanism called reverse cholesterol transport. HDL also inhibits LDL oxidation and platelet activation and aggregation, reducing the risk of thrombosis.

There is significant clinical evidence relating to HDL (see box below). The data show clear benefits for treating patients with low HDL in the presence of CAD, diabetes or the metabolic syndrome. The evidence on patients with low HDL but normal LDL and triglyceride levels is not so clear. These patients should only be treated if they have other CVD risk factors.

Lifestyle change
First-line management is through lifestyle modification. Regular aerobic exercise increases HDL cholesterol by 3-9 per cent in sedentary patients. Weight loss and smoking cessation also increase serum HDL, as does moderate alcohol consumption.

Traditional low-fat diets reduce both LDL and HDL. However, diets that restrict intake of foods with a high glycaemic load, such as processed cereals, potatoes and white bread, and that substitute saturated fats with omega-3 polyunsaturated fatty acids such as olive oil, increase HDL.

Consider pharmacotherapy for patients who fail to respond to lifestyle measures (see box). Statins should be first-line therapy, especially in patients with elevated LDL. They reduce CVD morbidity and mortality and can increase HDL by approximately 6-14 per cent. Simvastatin and rosuvastatin increase HDL more than other statins. In general, statins are safe, but serious adverse effects such as myopathy or hepatotoxicity, may occur. Fibrates benefit patients with raised triglycerides and low HDL, especially if LDL is below 3.3mmol/l. This profile is seen in patients with diabetes or metabolic syndrome. Trials have shown that fibrates can reduce coronary events, especially in patients with low HDL at baseline.

Fibrates often need to be used in combination with statins. However, combination therapy can increase the risk of myopathy. Individual fibrates may differ in their effect on statin safety. The statin-fenofibrate combination appears to be safest.

Niacin, also known as nicotinamide, can raise HDL by up to 35 per cent. It may also reduce triglyceride and LDL levels.

Studies on niacin-statin combination therapy showed improvements in lipid profile, a decrease in coronary events and reduction in the rate of progression of atherosclerosis.

Flushing can occur in patients on niacin therapy, but this can be reduced by gradually increasing the dosage, using an extended-release preparation, having a low-fat snack with the bedtime dose, and taking aspirin 30 minutes beforehand.

Niacin may increase serum glucose and uric acid levels. Recent studies have shown that it can safely be given to most diabetic patients, with glucose monitoring and adjustment of diabetes medication.

On the horizon
New therapies to raise HDL are being developed, including apo A-1 Milano, HDL mimetics and rimonabant. The role of thiazolidinediones and glitazars in the management of low HDL is also being tested. Partial cholesteryl ester transfer protein (CETP) inhibitors look promising, although a recent trial was stopped because of increasing toxicity.

UK guidelines recommend that treatment should primarily target LDL, but also now stress the importance of HDL. One expert group recommends considering treatment of low HDL in patients with CHD, diabetes or metabolic syndrome.

The American Diabetes Association recommends lowering LDL (<2.6mmol/l) as the primary target, and increasing HDL (>1.03mmol/l) and reducing triglycerides as the secondary target in patients with type-2 diabetes.

Dr Gupta is a GP at St Mary's Hospital, London, and clinical research fellow at the International Centre for Circulatory Health, National Heart and Lung Institute, London.

This article was originally published in MIMS Cardiovascular. To subscribe see

HDL research - main findings

Helsinki Heart Study: gemfibrozil v placebo

  • 11 per cent increase in HDL.
  • 35 per cent decrease in triglyceride.
  • 11 per cent decrease in LDL.
  • 34 per cent reduction in new CHD.

HDL atherosclerosis treatment study: simvastatin plus niacin

  • 24 per cent increase in HDL.
  • 42 per cent decrease in LDL.
  • Angiographic-proven regression of stenosis.
  • 90 per cent relative CVD risk reduction.

Veterans Administration HDL Intervention Trial: gemfibrozil v placebo

  • 6 per cent increase in HDL.
  • 24 per cent decrease in triglyceride.
  • 22 per cent reduction in MI and coronary death.

Bezafibrate Infarction Prevention Study: bezafibrate v placebo

  • 41 per cent risk reduction in patients with triglycerides >2.3mmol/l and HDL <1.1mmol/l.

Fenofibrate Intervention and Event Lowering in Diabetics: fenofibrate

  • 1 per cent increase in HDL.
  • 6 per cent decrease in LDL.

Drug Therapy: benefits and risks

  • 5-15 per cent HDL increase.
  • Reduce major coronary events, CAD deaths and total mortality.
  • Reduced progression of atherosclerosis.
  • Risk of myopathy, increased liver enzymes, GI effects, rash, stroke, influenza-like syndrome.


  • 10-20 per cent HDL increase.
  • Reduced major coronary events and rate of progression of atherosclerosis.
  • Risk of dyspepsia, myopathy, headache, dizziness, pruritus, raised liver aminotransferase.


  • 15-35 per cent HDL increase.
  • Reduced major coronary events and possibly total mortality.
  • Flushing, hepatotoxicity, hyperuricaemia, upper GI distress, hyperglycaemia, hypersensitivity reactions.



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