Studies Cast Doubt on the Benefits of Raising HDL (‘Good’) Cholesterol

In the August 2013 issue of Worst Pills, Best Pills News, Public Citizen’s Health Research Group wrote about two studies showing that the cholesterol drug niacin (NIACOR, NIASPAN) was ineffective in preventing heart attacks and other cardiovascular events in patients with heart disease who were already taking cholesterol-lowering statin medications.[1] This was despite the fact that niacin consistently raised blood levels of high-density lipoprotein (HDL), often called “good” cholesterol, in both studies.

Since the publishing of that article, a review of the medical literature has been published showing that niacin and two other types of drugs used to raise HDL cholesterol do not ultimately improve patients’ cardiovascular health. Taken together, these three studies have raised serious questions about the long-held practice of “chasing” higher HDL cholesterol levels through — often dangerous and expensive — medications.

The HDL-raising theory

There are several types of cholesterol found in blood. The type most associated with the development and worsening of cardiovascular disease is low-density lipoprotein (LDL), or “bad,” cholesterol. Studies have consistently found that lowering LDL cholesterol through diet, exercise and drugs such as most statins prevents heart attacks, strokes and death in patients with cardiovascular disease.[2],[3]

The significance of HDL always has been more uncertain. Past studies had suggested that high HDL levels predicted better cardiovascular health.[4] But it never was known for certain whether the high HDL levels or other factors led to those better outcomes. The conventional wisdom was that if HDL was responsible, raising the blood levels of this so-called good cholesterol would result in improved cardiovascular health.

Studies cast doubt on theory

In the August 2013 article in Worst Pills, Best Pills News, we reported that two studies, the AIM-HIGH trial[5] and the HPS2-THRIVE trial,[6] had demonstrated no benefit in taking niacin to prevent heart attacks and strokes in subjects who had cardiovascular disease and were already on statin drugs.[7]

In July 2014, the HPS2-THRIVE trial’s full results were published in the New England Journal of Medicine (NEJM; only preliminary results had been available at the time of our August 2013 article).[8] The researchers gave more than 25,000 subjects with a history of cardiovascular disease either niacin or a placebo, with all subjects also receiving a statin medication. Subjects were treated for an average of four years. As expected, niacin significantly raised blood levels of HDL cholesterol, in addition to lowering LDL cholesterol.

The results of this trial echoed the results of the earlier AIM-HIGH trial. But despite these improvements in cholesterol levels, niacin did not prevent deaths or cardiovascular events, such as heart attack or stroke, compared with statin therapy alone. It did, however, increase the risk of a number of side effects, including worsening diabetes and new diabetes diagnoses,[9] infections, bleeding, muscle damage and pain, gout, peptic ulcer and other gastrointestinal problems, and skin rashes and ulcers.[10]

Other nonstatin cholesterol drugs have not fared any better. In July 2014, a large review of 39 clinical trials was published in the British Medical Journal. The trials investigated the benefits and risks of niacin and medications known as fibrates, which are used to raise HDL levels.[11] The review found that neither niacin nor fibrates prevented death, heart attacks or strokes when given with statins. Although niacin and fibrates did seem to reduce nonfatal heart attacks when used alone, the introduction of statins in other trials eliminated any benefit of the two drugs. These nonstatin drugs also caused serious side effects.

Our impressions

Taken together, these studies strongly suggest that the introduction of statins in recent decades has rendered nonstatin cholesterol-lowering drugs unnecessary for patients with cardiovascular disease. In response to the publication of the HPS2-THRIVE results, several physicians wrote to the NEJM arguing that subjects in this trial had higher HDL (and lower LDL) levels than the typical patient before the trial began and were therefore less likely to derive additional benefit from niacin.[12] However, the earlier AIM-HIGH trial included only subjects with lower HDL levels and still did not show any added benefit.[13]

While it is possible that some future drug or other intervention to raise HDL levels might well result in better health outcomes or longer lives for patients with cardiovascular disease, as of today, physicians and patients have no basis for chasing ever-higher levels of HDL. It is also possible, and perhaps more likely, that those with naturally occurring high HDL levels may also have other traits that are responsible for the observed reduction in cardiovascular risk.

In patients with cardiovascular disease who are on statins, nonstatin cholesterol medications pose serious dangers and have no role in treatment. The drugs are beneficial only in the treatment of patients who, for medical reasons, cannot take statins.

What You Can Do

We do not recommend that you take a drug solely to raise your HDL cholesterol levels. If you have cardiovascular disease — including coronary artery disease, peripheral vascular disease, or a history of stroke — you should take a statin to lower your LDL cholesterol. If you are one of the few patients with cardiovascular disease who cannot take a statin due to side effects or for medical reasons, you can consider niacin, cholestyramine (CHOLESTYRAMINE LIGHT, PREVALITE) or fish oil (EPANOVA, LOVAZA, OMTRYG, VASCEPA) after discussing the risks of the medications with your doctor.

We recommend that you not use any of the drugs known as fibrates. These include fenofibrate (ANTARA [MICRONIZED], FENOGLIDE, LIPOFEN, TRICOR, TRIGLIDE, TRILIPIX), fenofibric acid (FIBRICOR) and gemfibrozil (LOPID).

References

[1] Niacin ineffective in treating cardiovascular disease. Worst Pills, Best Pills News. August 2013. /newsletters/view/861. Accessed February 26, 2015.

[2] National Institutes of Health. 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. http://www.nhlbi.nih.gov/files/docs/resources/heart/atp3full.pdf. Accessed March 17, 2015.

[3] Naci H, Brugts JJ, Fleurence R, et al. Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: A network meta-analysis of placebo-controlled and active-comparator trials. Eur J Prev Cardiol. 2013;20(4):641-657.

[4] Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302(18):1993-2000.

[5] Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes.

[6] Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events.

[7] Niacin ineffective in treating cardiovascular disease. Worst Pills, Best Pills News. August 2013. /newsletters/view/861. Accessed February 26, 2015.

[8] HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203-212.

[9] Ibid.

[10] Ibid.

[11] Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: Meta-analysis of randomised controlled trials including 117,411 patients. BMJ. 2014;349:g4379.

[12] [Multiple Letters to the Editor]. Niacin for reduction of cardiovascular risk. N Engl J Med. 2014;371(20):1940-1944.

[13] AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255-2267.