Despite Pfizer's high-profile drug failure, boosting HDL still a key heart-disease strategy

Despite the recent failure of torcetrapib -- Pfizer's once-touted but now-torpedoed heart-disease drug -- the strategy of attacking heart disease by boosting HDL cholesterol, along with lowering LDL, remains crucial to reducing the toll from America's No. 1 killer, say heart-disease experts."There's a tremendous amount of promise to HDL-raising drugs. This is really the decade of HDL," says Frederick Samaha, MD, chief of cardiology at the Philadelphia VA Medical Center and associate professor of medicine at University of Pennsylvania.Whether or not inhibiting CETP (cholesteryl ester transfer protein) -- the mechanism by which torcetrapib worked -- is a doomed strategy for increasing HDL levels, several other drugs in development use different mechanisms to boost levels of the "good cholesterol." Meanwhile, heart-disease experts emphasize the therapies that physicians can use now to increase HDL levels in patients at risk of heart disease or heart attack."It's very important for primary care physicians to understand that the failure of torcetrapib doesn't take away from the overall strategy of increasing HDL," says Richard Karas, MD, director of preventive cardiology at Tufts-New England Medical Center. "We have drugs that raise HDL, and physicians aren't using them enough."Current guidelines emphasize LDLCurrent guidelines on cholesterol management, from the National Cholesterol Education Program, say relatively little about HDL, focusing instead on lowering LDL and triglycerides. The guidelines define low HDL as < 40 mg/dL, but they don't set a target for raising HDL, saying "the evidence is insufficient to specify a goal of therapy" and "available drugs do not robustly raise HDL."For patients with low HDL, the guidelines recommend first lowering LDL levels, through statins and lifestyle changes. They recommend HDL-boosting drugs for high-risk patients whose chief risk is low HDL, particularly when combined with high triglyceride levels. Unfortunately, many patients with target-level LDL still have heart attacks (see study). "We've tried the LDL therapies and clearly they benefit patients, but there's still more we need to do," Samaha says. Encouraging evidence on HDLMounting evidence, meanwhile, is demonstrating the benefits of HDL for protecting against heart disease and heart attack, suggesting that increasing HDL is as important as lowering LDL. Several studies () have shown that treatment with niacin-based therapies or fibrates -- the two available types of HDL-boosting drugs -- significantly reduced patients' risk of heart attack and death. Overall, research suggests that every 1 percent increase in HDL reduces patients' risk of heart disease by 2 percent. While these studies have drawn considerable interest in HDL-boosting therapies, large-scale trials have not yet proven the benefits of HDL-raising drugs. The torcetrapib trials, in fact, were the first Phase 3 trials to address this question. Torcetrapib had generated such enthusiasm because it boosted HDL so significantly -- nearly 50 percent. By comparison, statins raise HDL by 5-10 percent, niacin by 20-35 percent, and fibrates by 5-15 percent.CETP inhibitors and other strategiesGiven the high expectations for torcetrapib, Pfizer's decision to terminate its clinical trials -- due to a larger-than-expected number of heart attacks and deaths among those taking the drug -- was a huge disappointment. It's not yet clear exactly why torcetrapib caused these bad outcomes or whether all CETP inhibitors are doomed to failure. At least three drug companies are developing other CETP inhibitors, though those drugs reportedly don't increase blood pressure -- an effect of torcetrapib which some say might have led to the adverse events. Even if development of those drugs continues, however, recruiting patients for their clinical trials could be difficult.Aside from CETP inhibitors like torcetrapib, a handful of other promising, early-stage HDL-boosting therapies are in development:

• Apo A-1 mimetic peptides are a synthetic version of a type of genetically mutated HDL particle, known as apo A-1 Milano, which prevents the accumulation of plaque in the arteries even at low HDL levels.
• LXR agonists enhance the process of reverse cholesterol transport by affecting the expression of the ABCA1 gene.
• Novel PPAR agonists also act on the ABCA1 gene and on the synthesis of apo A-1 (the protein on HDL most important in reverse cholesterol transport). Existing HDL therapiesIn the meantime, there's plenty that primary-care physicians can do now to boost HDL in appropriate patients. Heart-disease experts recommend using HDL-raising drugs in patients with an HDL of 40 or less, and taking a more aggressive approach for those whose HDL is 35 or less. Medication offers particular benefits for low-HDL individuals who have already lowered their LDL and triglycerides, and those with additional risk factors -- such as a prior heart attack or a family history of heart disease."My perspective is that HDL therapies are certainly underused," says Greg Brown, MD, a professor of medicine at University of Washington and an expert on lipids and heart disease. "If you add raising HDL along with lowering LDL, you get much more benefit. Many physicians aren't aware of that." There are two types of existing HDL-raising therapies:
• Niacin increases HDL levels 25-35 percent. While over-the-counter supplements are available, physicians generally prescribe Niaspan, an extended-release formulation typically taken with a statin. Modest-sized trials have shown significant benefit from niacin plus a statin, and a Phase 3 trial called AIM HIGH is comparing this combination with a statin alone in 3,300 patients.Some patients find niacin difficult to take because of itching and flushing side effects in the upper body. While some data indicate that 20-25 percent of patients taking niacin discontinue it for this reason, Brown has found that counseling patients about the therapy's benefits, and reassuring them that flushing is not harmful and usually diminishes over time, can raise patients' compliance to more than 90 percent. At least two drugmakers are testing niacin-based therapies designed to minimize the side effects.
• Fibrates (fenofibrate [Tricor] and gemfibrozil [Lopid] ) are mainly prescribed to lower triglycerides -- yielding reductions of 20-40 percent -- but they also increase HDL by 5-15 percent. Fibrates have demonstrated benefit in several trials, and a current trial, ACCORD, is testing fenofibrate in 5,900 patients. Fibrates are most appropriate for patients with high triglycerides, and those with low HDL who can't tolerate niacin. Side effects include gastrointestinal complaints and a small risk of myopathy when combined with statins. Lifestyle changesLifestyle changes can also help raise HDL and cut overall cardiovascular risk. HDL-boosting changes include dietary modifications (replacing saturated fats with monounsaturated fats; and eating foods containing omega-3 fatty acids, niacin and soy); weight loss; regular aerobic exercise; moderate alcohol consumption (1-2 drinks a day, several days a week); and quitting smoking.These changes confer broad health benefits, cause no side effects -- and don't get the attention they deserve, say heart-disease experts."We put too much emphasis on drugs and not enough on diet and exercise. Those are still the mainstays for improving HDL," says Roger Blumenthal, MD, director of the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease. "A good doctor is not just a good clinician, but also a good coach," he adds.RELATED LINKSNews ArticlesNew HDL mimetic shows promise (Heartwire, March 26, 2007)Drugs for 'Good' Cholesterol Fail Tests (Washington Post, March 26, 2007)Garlic Gets Lipid Comeuppance (MedPage Today news, Feb. 26, 2007)Mortality in Phase III Trial Pulls Plug on HDL-Booster (MedPage Today news, Dec. 4, 2006)Pfizer Stops All Torcetrapib Clinical Trials in Interest of Patient Safety (FDA press release, Dec. 3, 2006)Published ResearchThird Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (JAMA, May 16, 2001)High density lipoprotein as a protective factor against coronary heart disease: The Framingham study (American Journal of Medicine, May 1977)Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: Implications for treatment (Circulation, Jan. 1, 1992)The independent correlation between high-density lipoprotein cholesterol and subsequent major adverse coronary events (American Heart Journal, March 2006)Fifteen-year mortality in Coronary Drug Project patients: long-term benefit with niacin (Journal of the American College of Cardiology, December 1986)Reduction in Stroke With Gemfibrozil in Men With Coronary Heart Disease and Low HDL Cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT) (Circulation, June 12, 2001) Gemfibrozil for the Secondary Prevention of Coronary Heart Disease in Men with Low Levels of High-Density Lipoprotein Cholesterol (New England Journal of Medicine, Aug. 5, 1999)

Have comments or questions on this article? Please e-mail the author, Sara Selis, at sselis@cmp.com.