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

December 20, 2006

Despite Pfizer's high-profile drug failure, boosting HDL still a key heart-disease strategy. Several drugs in development use various mechanisms to raise levels of "good cholesterol." Meanwhile, physicians can do plenty right now to raise patients' HDL levels.

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 (see Related Links) 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:

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