No Clinical Benefit to Raising HDL With Existing Therapies, Meta-Analysis Shows

July 23, 2014

LONDON, UK – A meta-analysis investigating the clinical benefit of fibrates, niacin, and cholesteryl ester transfer protein (CETP) inhibitors casts yet more doubt on the tenuous hypothesis that raising HDL-cholesterol levels with these drugs translates into a reduction in CV events[1].

In the era of widespread statin use, where LDL-cholesterol levels are pushed lower and lower, investigators say that the clinical trials investigating fibrates, niacin, and CETP inhibitors do not support raising HDL cholesterol pharmacologically to reduce clinical outcomes.

"In patients not taking a statin, fibrates and niacin appear to reduce myocardial infarction by 20% to 30%, which is certainly worthwhile," investigator Dr Matthew Shun-Shin (Imperial College, London, UK) told heartwire . "However, almost all patients in whom we are intervening on lipids are on statins. Such patients appear not to have a reduction in events from niacin. It is unclear whether such patients benefit from adding fibrates because the number of events is still too small to answer with precision, but, even if there is, it might be mediated by LDL lowering rather than HDL raising."

The meta-analysis, published July 18, 2014 in the BMJ, includes the AIM-HIGH and HPS2-THRIVE studies, two recently published large trials showing no benefit of niacin therapy in patients well treated with statins. In HPS2-THRIVE, for example, the baseline LDL- and HDL-cholesterol levels were 63 and 44 mg/dL, respectively.

The analysis also includes studies investigating the once-promising CETP inhibitors. These drugs, including torcetrapib and dalcetrapib , significantly raised HDL-cholesterol levels—anywhere between 30% to 72% from baseline—that did not translate into a meaningful clinical benefit. In fact, torcetrapib was abandoned when it was shown to increase the risk of death and CV events. Two other agents are currently being tested—evacetrapib (Lilly) and anacetrapib (Merck)—but CV outcomes data are not yet available.

"As patients and clinicians we are very fortunate to have so many large clinical trials of therapy aimed at raising HDL," senior investigator Dr Darrel Francis (Imperial College, London, UK) told heartwire. "We must not be disappointed that patients already taking statins seem not to benefit from adding these therapies. It is much better to know this clearly than be ignorant. We should all salute the patients who volunteered for these trials and the researchers who ensured they were conducted well and reported clearly. Those trials are not failures but among clinical science's greatest successes."

Large Meta-Analysis of the Major HDL-Raising Studies

The meta-analysis included 39 trials and 117 411 patients. For the end points of all-cause or coronary heart disease mortality, neither niacin, fibrates, nor the CETP inhibitor class had any impact. In addition, none of the drugs reduced the risk of stroke.

In studies investigating the HDL-raising therapies before the statin era, treatment with niacin was associated with a significant 31% reduction in nonfatal MI among patients not treated with statins. A 22% reduction in nonfatal MI was also observed with fibrates in patients not taking statins. However, among patients taking statins, neither niacin nor fibrates had an impact on the end point of nonfatal MI.

To heartwire, Shun-Shin and Francis said they conducted the meta-analysis after marveling at the number of sponsored satellite sessions at major cardiology meetings. These sessions were often entitled the "emerging role of HDL" in CVD prevention and promoted niacin, fibrates, and more commonly these days, CETP inhibitors. For all the interest and study of these therapies, they had yet to see the HDL-raising drugs show a meaningful clinical benefit.

"Once you have statins that are cheap enough and free enough from side effects to be given to large numbers of people, then you would need a very good reason to add in another drug, one that might have side effects and doesn't seem to prevent events," Francis said.

In HPS2-THRIVE, for example, treatment with niacin was associated with significant toxicity, including increased risks of gastrointestinal and musculoskeletal events, infection, and skin-related and bleeding adverse events. Niacin also increased the risk of diabetes and impaired glucose control among those with diabetes at baseline. Despite these negative clinical trials, Francis said that many drugs, including niacin, always find a way to survive.

"Cardiovascular therapies never seem to get unanimously agreed upon as ineffective," said Francis. "They instead shift into what I call 'tick-box purgatory.' " Proponents of the therapy, he said, will argue that the trials were too small, too short, tested the wrong patients, used the wrong drug or dose, treated patients with inappropriate background therapy, or measured the wrong end point. He believes that HDL-raising therapies have entered into such a purgatory, with the many treatments still having their share of defenders.

Still, Francis is not completely pessimistic about the future, including the future of evacetrapib and anacetrapib, the two CETP inhibitors still being studied. His interest, however, has little to do with the reason the drugs are being investigated—that being their HDL-raising abilities—and more to do with the fact that the drugs have an additional benefit of also lowering LDL cholesterol.

"The HDL-raising concept does not seem to be beneficial in any of the statin-era trials, but it doesn't mean that any therapy that raises HDL will never work," he said. "For all we know, the LDL reduction might be doing the trick. So I am a bit pessimistic about the focus on HDL. I think if we're going to look at things, we might as well look at LDL cholesterol. That's where we've seen the most success."

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