Cholesterol and cancer: do cholesterol-lowering drugs lead to tumors? - includes related article on American College of Physician's cholesterol screening proposal

Science News, March 2, 1996 by Kathleen Fackelmann

Do cholesterol-lowering drugs lead to tumors?

Millions of people in the United States take cholesterol-lowering drugs to reduce their risk of heart attack. They know that a high concentration of this waxy substance in the bloodstream increases their risk of developing clogged arteries.

Now, a controversial scientific report highlights evidence that such drugs cause cancer in rats and mice. The finding raises the question of whether cholesterol-lowering drugs pose a risk of cancer to humans.

During the past 10 years, prescriptions for cholesterol-lowering medication have increased 10-fold, according to Thomas B. Newman and Stephen B. Hulley of the University of California, San Francisco. They expect those sales will continue to soar because o f aggressive marketing by drug companies.

Are such drugs safe, especially when taken by people for 30 years in order to reduce their risk of heart disease? In view of the animal studies, Newman and Hulley think caution is in order. They present their view in the Jan. 3 Journal of the American Med ical Association (JAMA).

"We, along with everyone else, are strong advocates of the appropriate use of cholesterol-lowering drugs," Hulley says. Yet the researchers contend that the cancer-causing potential of the drugs outweighs the advantages for many people.

Not surprisingly, the duo has drawn criticism from a bevy of medical experts.

James I. Cleeman, director of the National Cholesterol Education Program of the National Heart, Lung, and Blood Institute in Bethesda, Md., calls the Newman-Hulley report "much ado about nothing." He goes on to say that "there is just no evidence of a can cer risk in humans."

William S. Dalton, a cancer specialist at the University of Arizona in Tucson, agrees that it's very difficult to draw conclusions from rodent studies. "The bottom line is, Do you tell people with heart disease who you know are at higher risk of heart att acks to stop a known effective drug? My answer is no."

This isn't the first time that cholesterol-lowering drugs have drawn fire.

Journalist Thomas J. Moore attacked them as unnecessary and sometimes dangerous in a provocative article in the September 1989 Atlantic Monthly. He detailed what he called the myths surrounding the link between cholesterol and heart disease.

Newman, a pediatrician, got started down this research track somewhat reluctantly. A few years ago, he noticed something odd while looking up information on lovastatin (Mevacor), a popular cholesterol-lowering drug, in the Physicians' Desk Reference (PDR) , a directory of federally approved prescription drugs.

"The last time I had looked, it said that lovastatin caused liver cancer in mice at 312 times the human dose," Newman says. Two years later, it said three to four times-"that's a big difference."

Newman thought other physicians should take note of that modification. He sent a letter to the New England Journal of Medicine. It was rejected. He sent a letter to JAMA. It was rejected. And so went things with a handful of other prestigious medical jour nals.

Eventually, Newman teamed up with epidemiologist Hulley, and together they began a project that culminated in the JAMA article. Newman and Hulley began by taking a close look at the information from animal studies that the Food and Drug Administration r equires as part of its drug approval process. After a drug wins the agency's approval, the PDR summarizes those data. The scientists homed in on two classes of cholesterol-lowering drugs, the fibric acid derivatives and the statins.

"The product information for [cholesterol-lowering] drugs indicates that all the fibric acid derivatives and statins caused cancer in rodents," they say.

"In most cases, the rodent exposure at which carcinogenicity was observed was of the same order of magnitude as that observed with the maximum dose recommended for humans."

By comparing the 1992 and 1994 editions of the PDR, the researchers discovered the reason for the discrepancy in cancer risk that had piqued Newman's interest. In 1992, drug companies presented cancer risk in terms of milligrams of drug per kilogram of bo dy weight.

In 1994, however, the companies presented the information in terms of the drug concentration produced in the bloodstream by a given dose.

Comparing concentrations of drugs in the blood produces a more accurate view of cancer risk, according to Elizabeth Barbehenn, a pharmacologist at FDA's Division of Metabolism and Endocrine Drug Products. In 1993, the agency started requiring certain comp anies to report such drug concentration data.

That change in policy led to the discrepancy in cancer risk for lovastatin.

Another cholesterol-lowering drug, gemfibrozil (Lopid), showed a similar difference when measured in the two ways. The 1992 PDR says this drug causes liver cancer in rats at 10 times the human dose. The 1994 version says cancer can occur at 1.3 times the human dose.

For comparison, Newman and Hulley looked at PDR data on drugs used to combat high blood pressure. These drugs, like the cholesterol-lowering medications, are prescribed to large numbers of healthy people, most of whom take them for many years in order to reduce the risk of stroke and heart attack. The researchers wondered if such drugs also pose a cancer risk. Most appeared to be a safer bet, however-causing no tumors when given to rodents, the authors report.