Is Lower Really Better for Cholesterol?

Study Casts Doubt, Shows High-Dose Drug May Cause Muscle Problems

By Peggy Peck
WebMD Medical News
Reviewed By Michael Smith, MD
on Tuesday, September 14, 2004

Sept. 14, 2004 -- In a study of people with heart disease, results show that high doses of the popular cholesterol-lowering drug Zocor may not prevent heart disease deaths and heart attacks -- and may cause muscle damage. But experts say that the new adage of "lower is better" still holds true when it comes to cholesterol.

The study results were presented last month at the European Society of Cardiology Congress 2004 and appear in the new issue of The Journal of the American Medical Association.

High doses of Zocor were associated with increased rates of muscle damage. Nonetheless, study researcher Michael Blazing, MD, said at a news conference at the meeting that doctors should still consider starting treatment at a higher dose and to be more aggressive when prescribing Zocor and other cholesterol-lowering drugs in its class, known as statins. Blazing is with Duke University Medical Center in Durham, N.C.

Asked to clarify that statement, Blazing told WebMD that he and his study colleagues recommend a 40 mg dose, rather than an 80 mg dose of Zocor.

Blazing added that studies of other statins -- notably recent studies of high-dose Lipitor -- suggest that the high-dose statins are both safe and effective.

His study looked at nearly 4,500 patients who had severe chest pain or a heart attack. The researchers were trying to determine if there was any benefit to starting Zocor right away. Half the patients received early aggressive treatment -- 40 mg of Zocor for a month (started within an average of three to four days) followed by 80 mg Zocor -- or conservative treatment with four months of placebo followed by 20 mg of Zocor.

The study did show that early aggressive Zocor treatment appeared to slightly decrease the risk of heart disease death, heart attack, and stroke. However, the study findings were not strong enough to be considered significant. All patients also received other traditional heart disease treatments, including aspirin.

In those treated with placebo first, LDL "bad" cholesterol levels increased by 11% during the initial placebo phase. LDL then decreased 31% from baseline after four months of 20 mg Zocor. However, in those that took Zocor for the entire study, LDL cholesterol decreased by 39% over the first four months. LDL then decreased an additional 6% following the increase to 80 mg of Zocor.

Christopher P. Cannon, MD, associate professor at Harvard Medical School, tells WebMD that "the real message of this study is that it confirms the 'lower is better' message" when it comes to cholesterol.

Cannon, who did not participate in the current study, was principle researcher of a previous study that showed high-dose Lipitor was associated with an approximately 50% reduction in LDL "bad" cholesterol, reducing LDL down to approximately 62 mg/dL. Moreover, aggressive Lipitor treatment reduced the risk of death, heart attack, severe chest pain, or stroke by 16%.

Cannon's findings were closely followed by a change in cholesterol guidelines for patients at highest risk of dying from heart attacks and strokes. The National Cholesterol Education Program (NCEP) reduced target LDL levels from 100 mg/dL to 70 mg/dL for those at the very highest risk of heart disease. This includes people who already have heart disease in addition to diabetes, poorly controlled high blood pressure, or metabolic risk factors including obesity, high triglycerides, and low HDL "good" cholesterol. Smokers with heart disease also fall into this category.

The lead researcher of the current study, James de Lemos, MD, tells WebMD he does not doubt that the high-dose Zocor regimen is beneficial. Nonetheless, de Lemos says his study does support new guidelines that contend lower is better. He is assistant professor at the University of Texas Southwestern Medical Center in Dallas.

Asked if doctors will be reluctant to prescribe high doses of Zocor because of the reported safety concerns, both Cannon and de Lemos declined to speculate.

But not everyone is so reluctant. In a JAMA editorial that accompanies the study, Steven Nissen, MD, of The Cleveland Clinic in Ohio, points out that high-dose Lipitor packs a double punch. Studies indicate that it not only reduces LDL "bad" cholesterol, but also sharply decreases blood levels of an inflammatory marker called C-reactive protein (CRP). Research has shown that signs of inflammation, such as a high CRP, are associated with an increased risk of heart disease.

Patients in the current study treated with high-dose Zocor did not have similar declines in CRP. In the previous study, high-dose Lipitor decreased CRP by 38%, while high-dose Zocor reduced CRP by just 17% in the current study. More research is needed to determine if these differing CRP results stand true.

Zocor and Muscle Damage

As for the increased risk of muscle damage, Nissen, who was lead researcher for another favorable high-dose Lipitor study, writes that the increased risk of muscle damage applies only to a specific dose of a single drug and should not tarnish this remarkable class of drugs. It must also be emphasized that Zocor in doses up to 40 mg per day has shown excellent safety and effectiveness in a series of clinical trials, he adds. For now, though, he says, the 80 mg daily dose of Zocor should be used with caution, particularly because other effective drugs are available.

But David Faxon, MD, professor of medicine at the University of Chicago and former president of the American Heart Association, tells WebMD that the safety concerns of the high-dose Zocor are not surprising. "I think muscle pain with statin therapy is more common then the studies indicate." Moreover, Faxon, who was not involved in the study, agrees that the take-home message from the current study "does support our 'lower is better' message."

In June 2004, the FDA advised doctors to be careful about how they prescribe the statin Crestor. This was in response to reports of serious toxicity in some patients taking the drug. The FDA and the drug's manufacturer say Crestor is safe when given to the right patients at the right dose. Patients should promptly call their doctor if they have signs of muscle damage: muscle pain or weakness, feeling weak or sick, fever, dark urine, nausea, or vomiting.

SOURCES: ESC Congress 2004. de Lemos, J. The Journal of the American Medical Association, early online edition. Michael Blazing, MD, Duke University Medical Center, Durham, N.C. Christopher P. Cannon, MD, associate professor, Harvard Medical School. David Faxon, MD, professor of medicine, University of Chicago; former president, American Heart Association. FDA.

http://my.webmd.com/content/Article/94/102648.htm

The study is on-line:
http://jama.ama-assn.org/cgi/content/full/292/11/1307
with an editorial:
http://jama.ama-assn.org/cgi/content/full/292/11/1365

So, their own study says they really didn't do any good, and they may cause muscle damage, but they want doctors to go right ahead and perscribe those high dosages of statin drugs ... the greed of the pharmafia never ceases to amaze me ...

They're at least able to identify metabolic risk factors, but insist on treating these things one by one with a slew of different drugs for each disorder instead of the underlying metabolic problem. This is not responsible medicine.

Huh? Isn't "the message of the study" is that Stains lower LDL?

How does any of this translate into "lower is better" ????

I agree. I don't think it does.

The 'high-dose' regimen lowered LDL by much more. But it did NOT prevent any more heart attacks.

Lower did NOT come out better.

I think this is turning into religion, not science.

The storyline should have been:
"Another study shows statins don't work."