New drug fizzles at raising HDL
Tried-and-true strategies are still excellent ways to boost good cholesterol.
When pharmaceutical giant Pfizer pulled the plug on torcetrapib, its experimental HDL-raising drug, media reports made it sound like we were losing our last, best ally in the battle against heart disease. The decision was unquestionably a huge setback for Pfizer, which had sunk $800 million into developing torcetrapib. And it was a big bump in the road for researchers hoping that high-density lipoprotein (HDL, the so-called good cholesterol) would be the next big thing in cholesterol-targeted drug therapy. But it shouldn’t be taken as a sign that raising HDL is a bad or dangerous strategy for preventing heart disease and stroke — just that torcetrapib isn’t the way to do it.
The torcetrapib story starts in the late 1970s with the discovery of cholesteryl ester transfer protein (CETP), a protein that circulates in the bloodstream attached to HDL particles. Its job is to shuttle cholesterol and other fats between different types of cholesterol-carrying lipoprotein particles.
Although cholesterol is a four-letter word when it comes to heart disease, it is essential for good health. The body uses it to build cell membranes, bile acids for digestion, vitamin D, and hormones such as estrogen and testosterone. As is the case for any vital nutrient, the body has systems that give it great flexibility in handling cholesterol during feast, famine, and everything in between. CETP is part of such a system. But for most Americans, who are overloaded with cholesterol, CETP’s action is counterproductive. It pulls cholesterol out of protective HDL, which sponges up excess cholesterol from artery walls and ferries it to the liver for disposal, and puts it into harmful LDL, which is responsible for creating artery-clogging plaque.
The discovery of CETP raised an interesting question: Could blocking or disabling this molecule increase the amount or activity of HDL and thus reduce plaque? Statins have taken us about as far as we can go with lowering harmful LDL. Boosting helpful HDL represents another tantalizing target for slowing or preventing heart disease. Every 1% increase in HDL translates into a 2%-3% decrease in heart disease risk. Existing drugs raise HDL by 35% at best. Kicking it up a notch or two should theoretically save lives. It would also be worth billions of dollars to the drug company that gets there first.
Classifying HDL
Low: below 40 mg/dL
Average: 40-60 mg/dL
High: above 60 mg/dL
Warning signs
Early studies of CETP in humans were hard to decipher. People with mutations that led to low levels of CETP had higher than average HDL. When their HDL was really high, above 80 milligrams per deciliter of blood (mg/dL), they seemed to be protected against heart disease. When it only got moderately high, though, some studies showed an increase in heart disease, while others showed a decrease.
Despite the contradictions, the search was on for drugs that could inhibit CETP. A Japanese company developed one, called JTT-705, that raised HDL by 34% and lowered LDL by 7%; it is still being investigated. Pfizer scientists developed a different CETP inhibitor, called torcetrapib, in 1992. An early test of the drug’s safety showed that it boosted HDL a whopping 106%.
That was enough for Pfizer to start the kind of large-scale clinical trial the FDA needs for approving a new heart disease drug. Dubbed ILLUMINATE, the trial included 15,000 people at high risk of heart disease. Half took torcetrapib plus Lipitor (Pfizer’s blockbuster cholesterol-lowering statin), and the other half took an identical pill containing Lipitor alone. The trial was supposed to last until 2009.
An early look at the data raised some concerns about torcetrapib. It appeared to elevate blood pressure, a bad sign for a medicine designed to prevent heart trouble. The death knell came about halfway through the trial, when independent overseers found that 82 volunteers taking torcetrapib and Lipitor had died, compared to 51 taking Lipitor alone. They determined that the difference wasn’t due to chance, and that the situation wasn’t likely to reverse itself. Pfizer stopped the trial and all further work on torcetrapib.
Meanwhile, Cleveland Clinic researchers were doing a parallel study in which they threaded tiny ultrasound cameras through the coronary arteries of 1,200 volunteers taking torcetrapib plus Lipitor or Lipitor alone. Their findings, which they present at the American College of Cardiology meeting in New Orleans in March 2007, may offer some clues as to how or why torcetrapib increases the risk of heart disease even as it raises protective HDL.
It could be that this particular drug does something else that’s harmful in addition to boosting blood pressure. It is also possible that blocking CETP in any way may have unintended consequences. We won’t know for sure until results are in from ongoing trials of other CETP inhibitors.
Hurrah for HDL
The demise of torcetrapib shouldn’t tarnish HDL’s reputation as part of the body’s natural protection against heart disease. In numerous large studies, people with naturally high HDL have less heart disease than those with low HDL. And evidence from earlier clinical trials shows that raising HDL lowers the risk of heart attack or premature death from cardiovascular disease.
There are several things you can do right now to boost your HDL (see “Raising HDL today”). These strategies work, though none offers a huge increase in HDL. Lifestyle changes are the place to start, since they don’t have negative side effects. For people with low HDL, doctors sometimes prescribe niacin (generic, Niaspan) or a fibrate such as fenofibrate (generic, Tricor, Lofibra, others), gemfibrozil (generic, Lopid), or clofibrate (generic, Atromid). Both of these drug types have been used for years. Statins can also modestly boost HDL.
Raising HDL today
There’s no need to wait for the development of new HDL-raising drugs. You can boost yours now with several tried-and-true methods.
Exercise. Moderate to vigorous exercise can boost HDL by 3%-9%.
Smoking cessation. On average, HDL rises by about 4 mg/dL after stopping smoking.
Trans fats. Eating trans fats increases LDL (bad) cholesterol and decreases HDL. Avoiding them and switching to unsaturated fats improves HDL.
Weight control. In clinical trials, HDL increased 1.6 mg/dL for every 10 pounds lost.
Alcohol. One alcoholic drink a day, regardless of the beverage, boosts HDL by about 4 mg/dL.
Medicines. Niacin, fibrates, and statins all increase HDL. Of these, niacin is the most powerful, with increases of 20% to 35%.
Sooner or later a new HDL-raising drug will come along. No matter how well it seems to work, heed the lesson from torcetrapib, drug-coated stents, and other new drugs and devices: Don’t be an “early adopter.” Instead, wait until the hazards are as well known as the benefits.
