HDL-Boosting Drugs Fail to Deliver but Higher Levels Remain Goal

CLEVELAND, Aug. 20 -- The efforts to raise HDLs to reduce atherosclerosis is still a worthy objective despite a series of disappointments with new drugs, said clinicians here.

While efforts continue to develop effective and safe HDL-boosting agents, physicians should turn to lifestyle measures, niacin, statins, and carefully monitored use of fibrates, recommended Mehdi H. Shishehbor, D.O., M.P.H., of the Cleveland Clinic, and colleagues, in the Aug. 15 issue of the Journal of the American Medical Association.

The review of efforts to raise HDLs was based on 31 randomized controlled trials and also included meta-analyses, basic science or preclinical studies, observational studies, and position statements and guidelines.

"HDL is very difficult to raise," commented Steven Nissen, M.D., also of the Cleveland Clinic. "We do have some drugs to raise HDL but they're not very powerful."

The researchers noted that statins have proven no more effective than lifestyle measures, such as exercise and tobacco cessation, with about a 5% to 10% increase in HDL all that could be expected.

"Due to their modest effect on HDL-C levels, statins generally are not adequate as monotherapy for increasing HDL-C," the researchers said.

Fibrates, such as fenofibrate (TriCor and Lofibra) and gemfibrozil (Lopid), have likewise been shown to increase HDL-C levels 10% to 20% and even reduce coronary events. But, combining these agents with statins risks muscle toxicity, including rhabdomyolysis.

Therefore, "the precise role of fibrate treatment remains uncertain but likely includes some patients at high risk of coronary artery disease, low levels of HDL-C, and increased levels of serum triglycerides," Dr. Shishehbor and colleagues said.

The most effective existing medication has been niacin, which has been shown to raise HDL 20% to 30% and to improve outcomes as well, they said. A major limitation, though, has been the characteristic flushing and itching side effects, Dr. Nissen noted.

The big hope for a blockbuster, targeted HDL-raising drug had been torcetrapib, an investigational cholesteryl ester transfer protein (CETP) agent, commented Edward A. Fisher, M.D., Ph.D., M.P.H., of New York University Medical Center in New York and an American Heart Association spokesperson.

The drug did everything hoped for with HDL levels. But, development of torcetrapib was halted in December 2006 when the ILLUMINATE trial showed a 61% increase in all-cause mortality and other cardiovascular events for torcetrapib plus atorvastatin (Lipitor).

Other trials presented in part by Dr. Nissen at the 2007 American College of Cardiology meeting also showed the drug held no benefit for atherosclerosis and actually some increase in intima-medial thickness. (See: ACC: Torcetrapib Studies Offer More Questions About HDL Booster)

Another agent to reach phase III trials, the acyl-cholesterol acyltransferase inhibitor pactimibe, was likewise found at best ineffective and in some cases it even promoted coronary artery disease progression. Development on pactimibe stopped last year, the researchers said.

Nevertheless, "the negative results with these compounds do not refute the concept of increasing HDL-C levels, targeting HDL function, or both to treat atherosclerosis," the Cleveland Clinic researchers cautioned.

Rather, it points out that "it does seem to matter a lot how you raise HDL not just how much you raise it," Dr. Nissen said. "What kind of HDL you're producing seems to be very important."

Other HDL-raising agents in the pipeline continue to move forward, including other CETP inhibitors and the investigational agent MK-0254, which is based on niacin but without the characteristic flushing and itching.

In the meantime, the primary HDL-raising strategy should be aggressive overall lifestyle modification, including exercise, diet, weight loss, and smoking cessation, the researchers concluded.

Niacin and statin therapy may be effective and fibrate therapy also merits consideration alone "or in closely supervised combination with statin therapy in patients at high risk for coronary heart disease," they added.

But, HDL-raising strategies remain appropriate only for patients with low HDL levels as reflected in Adult Treatment Panel III guidelines, Dr. Fisher said.

"As much as I love HDL, I agree with these authors that we need more studies," Dr. Fisher concluded. "Whether you're a fan or a foe or sitting on the fence frankly there's just not enough information to make a firm conclusion."

Dr. Nissen said he received research grants and done consulting for many pharmaceutical companies but said all honoraria or fees are donated directly to charity and he claims neither income nor tax deductions. Dr. Fisher disclosed that he is on the advisory board in the lipid management area for Merck, Pfizer, AstraZeneca, and Takeda.