Doctors Push Fibrate Cholesterol Drugs Despite Scant Evidence of Effectiveness

March 23, 2011— -- U.S. prescriptions for cholesterol-lowering medications predating statins have increased steadily despite uncertain benefit, researchers reported Tuesday. The findings suggest that aggressive marketing has trumped scientific evidence, prominent cardiologists and diabetes experts said.

These drugs, called fibrates, modestly reduce blood levels of artery-clogging bad cholesterol, raise good cholesterol and are most effective at lowering levels of other damaging blood fats called triglycerides, although the overall picture from clinical trials remains confusing.

Fibrates include gemfibrozil (Lopid), which got the regulatory nod in 1981; fenofibrate (TriCor, Triglide), approved in 2007, and the closely related drug fenofibric acid (TriLipix, Fibricor), which entered the U.S. pharmaceutical marketplace in December 2008. In 2009, fenofibrate and fenofibric acid together accounted for almost 74 percent of the U.S. market share of fibrates, the researchers said. While fenofibric acid isn't available in Canada, bezafibrate (Bezalip) is available in Canada but not in the United States.

The increase in fibrate prescriptions, driven by a 200 percent jump in the use of fenofibrate, has outpaced the growth of statins, according to an analysis of U.S. and Canadian fibrate use appearing in the current issue of JAMA. But, to keep things in perspective: statins, which are among the most commonly prescribed medications, remain blockbuster drugs that dominate lipid-lowering treatment, with fibrates accounting for just 9.4 percent of the U.S. lipid-lowering market in 2009.

The study authors found that U.S. prescriptions for fibrates grew from 336 per 100,000 people in January 2002, to 730 per 100,000 people in December 2009. That's a 117.1 percent hike. At the same time, Canadian prescriptions for fibrates held nearly steady, at 402 per 100,000 in early 2002 and 474 per 100,000 in late 2009.

"The use of fibrates in America is very troubling," said Dr. Steven E. Nissen, chairman of cardiovascular medicine at the Cleveland Clinic Foundation. Noting that fibrates are among medications advertised directly to consumers, he said: "This is a classical example of marketing triumphing over science." He described the increasing use of fibrates as an expensive failure to educate doctors and regulators.

In the past five years, two major studies found fenofibrate failed to reduce heart disease risks among diabetic men and women. Last year, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which involved 10,000 patients with diabetes, found that those who took both simvastatin and fenofibrate suffered about as many heart attacks, strokes and deaths as diabetic patients treated with simvastatin alone. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, which involved nearly 10,000 patients and has reported results since 2005, found that fenofibrate failed to decrease cardiovascular deaths more than a placebo.

U.S. Patients Stick to Brand-Name Fibrates, While Canadians Take Generics

Study authors noted that generic fibrates were widely prescribed in Canada, where they've been available for years, but that brand-name formulations continue to dominate U.S. prescribing, where they are "associated with a great economic burden for U.S. consumers and third-party payors," wrote Cynthia A. Jackevicius, an associate professor of pharmacy practice at Western University of Health Sciences in Pomona, Calif., and colleagues from the United States and Canada.

Dr. James H. Stein, director of preventive cardiology at the University of Wisconsin-Madison School of Medicine and Public Health, said most people don't realize the influence of marketing on health care. He said that negative studies about fibrates have been "spun to focus on the possible benefits" and cautioned that fenofibrate is associated with significant side effects, including "increased creatinine, which might indicate kidney dysfunction; gallstones, and more serious complications like pancreatitis, blood clots, and pulmonary embolism."

Dr. Cam Patterson, cardiology chief and physician-in-chief of the Center for Heart and Vascular Care at the University of North Carolina, Chapel Hill, said fibrates hold "a lot of promise, but so far that promise is unfulfilled." He, too, expressed concern about the ramifications of "recommending costly medications that don't confer real benefits to our patients. We've been burned before."

To date, "statins are the only cholesterol-lowering drugs that have been shown conclusively to save lives. Fibrates may be an option as add-on therapy, but there is no compelling case to use them as first-line therapy" for patients with elevated cholesterol. He said the substantial increase in fibrate use demonstrated "unfortunate tribal behavior by physicians that is no doubt driven by the big pharma marketing machinery."

Several doctors offered a more tempered view of fibrates. Dr. Christopher Cannon, a specialist in cardiovascular disease prevention at Brigham and Women's Hospital in Boston, said the drugs may not be effective in heart disease prevention, but have a role in reducing high triglycerides, which has become a bigger health concern "as the population has gotten obese."

Dr. Merle Myerson, an expert on lipid management who runs the Cardiovascular Disease Prevention Program at New York's St. Luke's-Roosevelt Hospital, cited circumstances where fibrate use is prudent, such as among patients who "cannot tolerate or do not want to take a statin," and suggested that one contributor to increased fibrate use might be that more doctors are aggressively treating high triglycerides among their obese patients.

Fibrate Defenders See Use for Patients Who Are Obese, Have High Triglycerides

Dr. Joel Zonszein, a professor of clinical medicine at Albert Einstein College of Medicine in the Bronx, found fault with the study. First, he said doctors need "more and better studies" of fibrate use in patients with severe lipid abnormalities, particularly men and women who suffer from metabolic syndrome, a condition that includes high blood pressure, high cholesterol, obesity and resistance to insulin, which predispose them to heart attack, stroke and diabetes. Zonszein said the ACCORD and FIELD trials never addressed the effectiveness of fibrates in these patients, for whom early, aggressive treatment is important. As a result, he said the latest JAMA study provides a "non-accurate and erroneous message to the medical community."

Dr. Henry Ginsberg, an endocrinologist and director of the Irving Institute for Clinical and Translational Research at Columbia University Medical Center, who has been a consultant for Abbott, the pharmaceutical company that markets Tricor and Trilipix, said that as the lead investigator for the ACCORD Lipid trial, he believes the study was negative and agrees "that our results indicate that physicians should not give fenofibrate to every diabetic already receiving a statin: we did not find that adding fenofibrate to a statin provided any benefit over statin alone."

However, Ginsberg said that for a subgroup of diabetics whose cholesterol is well-controlled by statins, but whose triglycerides remain elevated, ACCORD provided what he called "good evidence" that they could benefit by adding fenofibrate. "I say fenofibrate and not gemfibrozil because fenofibrate does not interact with statins and the chance of severe muscle complications is almost non-existent," he said.