Meta-analysis supports raising high-density lipoprotein (HDL) cholesterol

HDL Forum Editor Professor Philip Barter highlights findings from a meta-analysis of interventions for raising high-density lipoprotein (HDL) cholesterol by IM Singh and researchers, published in the Journal of the American Medical Association.

Publication: Singh IM, Shishehbor MH, Ansell BJ. High-density lipoprotein as a therapeutic target. A systematic review. JAMA 2007;298:786-98.

This meta-analysis showed that adding nicotinic acid (niacin) to a statin is the most effective pharmacological approach in patients at increased cardiovascular risk and with low HDL cholesterol. Aggressive lifestyle intervention (exercise, diet, weight loss and stopping smoking) are also shown to be appropriate strategies for raising HDL cholesterol.

The authors searched published literature between 1965 and May 2007, presentations given at major cardiovascular meetings, ongoing trials at ClinicalTrials.gov and current guidelines using the key words HDL-C and apolipoprotein A-I, and subheadings reverse cholesterol transport, CVD prevention and control, drug therapy and therapy. In total, 754 studies were identified, of which 537 were randomized controlled trials that met the inclusion criteria for the analysis. The authors then prioritized their search to 31 randomised controlled clinical trials of interventions for raising HDL cholesterol levels with clinical or surrogate outcome measures.

On review of these studies, the authors highlighted the value of lifestyle interventions to raise HDL cholesterol levels (table).

Intervention Increase in HDL cholesterol
Aerobic exercise5-10%
Stopping smoking 5-10%
Weight loss 0.35 mg/dL per kg of weight lost
Diet (omega-3 fatty acids or monosaturated fatty acids) Up to 5%
Alcohol 5-15%

The authors recommended the following lifestyle interventions to increase HDL cholesterol levels optimally:

  • 5 x 30 minute sessions of brisk aerobic exercise (> 2 hours) per week
  • Stopping smoking
  • Achieving a body mass index < 25 kg/m2 (< 24 kg/m2 in people of Asian descent) Moderate alcohol use, i.e. 1-2 drinks per day in men and 1 per day in women. The researchers did not, however, recommend that nondrinkers should start drinking to protect their hearts
  • Replacing dietary saturated fatty acids with monosaturated and polysaturated fatty acid sources such as plant oils (olive, canola, soy, mustard or flaxseed), nuts (almonds, peanuts, walnuts, pecans) or fish (salmon, tuna, mackerel or marine oils).

Pharmacotherapy for raising HDL-C levels
These can be broadly categorised into two types.

1. Agents that increase or modify levels of the components of HDL (i.e., HDL cholesterol, apolipoprotein A-I and phospholipids)
These include nicotinic acid (niacin), nicotinic acid-based formulations, statins, cholesteryl ester transfer protein inhibitors and apolipoprotein A-I (apoA-I) directed therapies (such as recombinant phospholipids/apoA-I complexes and apoA-I mimetic peptides).

The authors highlighted nicotinic acid as the most effective agent for raising HDL cholesterol currently available, with increases of 20-30%.

2. Agents that regulate reverse cholesterol transport and efflux of cholesterol from macrophages. These include peroxisome proliferator-activated receptor (PPAR) agonists, such as fibrates (PPARα agonists).

The authors summarized the effects of these interventions on HDL cholesterol levels (table)

Agent classIncrease in HDL cholesterol
Nicotinic acid (niacin)20-30%
Fibrates10-20%
Statins5-10%

However, the researchers emphasized that not all strategies that raise HDL are beneficial. Effects on the quality of HDL, which may influence the ability of HDL to be atheroprotective, are as important as effects on raising HDL cholesterol levels.

HDL particles vary in their physico-chemical characteristics, structure, intravascular metabolism and biological activity. Among the spectrum of circulating HDL particles, small, dense lipid-poor HDL (HDL3) have potent cholesterol efflux capacity, protect LDL against oxidative stress, and attenuate inflammation. Changes in HDL metabolism, such as that due to moderate to marked hypertriglyceridaemia characteristic of type 2 diabetes or the metabolic syndrome, result in the production of functionally defective HDL with reduced ability to facilitate cellular cholesterol efflux, as well as protect LDL against oxidative modification.

Ongoing clinical trials that target specific pathways in HDL metabolism may help to expand the therapeutic options. In the meantime, the researchers conclude that aggressive overall lifestyle intervention is of benefit, and that niacin or a fibrate, in addition to a statin may merit consideration in patients at high risk for cardiovascular disease.