"How Low Should Cholesterol Lowering Go?"

     While New Studies Encourage the Aggressive Use of Statins, Patients Continue to Balk. Why? Is Lipitor Really Better Than Pravachol -- and for Whom?

     Recently, the New York Times published an article on the new trend toward using cholesterol-lowering drugs even more aggressively. This trend has gained momentum following the publication of studies suggesting that aggressive therapy can halt plaque buildup in arteries. The most influential study, comparing the statins Lipitor and Pravachol, made front-page news last month.

Separating Medical Science from Sharp Marketing

     The Lipitor-Pravachol study was reported as groundbreaking, but it was also a calculated marketing device that the media fell for big time. Comparing the maximum 80-mg dose of Lipitor to moderate-dose 40-mg Pravachol was a mismatch from the start. The lead author, Dr. Stephen Nissen of the respected Cleveland Clinic, stated that Pfizer, the maker of Lipitor and underwriter of the study, "could have lost big time." Hardly. Milligram for milligram, Lipitor is four times stronger than Pravachol, so comparing 80 mg of Lipitor to 40 milligram of Pravachol was no contest at all, but a commonly seen strategy of comparing a strong drug to a weaker competitor.
     Yet, while it wasn't unexpected that high-dose Lipitor reduced the bad LDL-cholesterol more than moderate-dose Pravachol, the study did provide one promising finding: that Lipitor seemed to halt the progression of plaque accumulation in the wall of a coronary artery. Does this mean that high-dose Lipitor can stop atherosclerosis? Maybe -- but many questions remain.
     Only one coronary artery was studied. Were the findings representative of all coronary arteries? This hasn't been proven. The study results were reported as averages, but what were the results in individual patients? How many people actually showed halting of plaque growth and how many didn't? We don't know because the results were presented by Dr. Nissen at the annual scientific meeting of the American Heart Association in early November. The study itself hasn't been published, so it isn't available for closer public scrutiny.
     How objective was Dr. Nissen? While claiming to pride himself on independence from conflict of interests, it was his new ultrasound technology that was used in this study. How accurate is this technology? We don't know. Furthermore, the study was funded by Pfizer, and many of Dr. Nissen's statements made him sound more like a Pfizer spokesman than an objective scientist.
     I would like to ask: Why was a weaker dose of Pravachol involved at all? If they wanted to study the effects of aggressive vs. moderate lipid lowering, they could have studied 80 mg of Lipitor vs. 10 or 20 mg of Lipitor. But there's no potential public relations windfall in doing that.

Lowering Cholesterol: High-Risk vs. Low-Risk Patients

     The findings that a high-dose statin could halt atherosclerosis within a coronary artery wall is indeed promising, but it is preliminary. Even if Lipitor halts the growth of plaque, will this translate into less heart disease and fewer heart attacks and coronary deaths? This was the question asked by many experts, as the Wall Street Journal reported: "Heart experts cautioned that the results aren't strong enough to make recommendations to change medical practice." One expert told me, "We've long known that Lipitor is more powerful at lowering cholesterol than Pravachol. That doesn't mean everyone needs more power." Dr. Raymond Gibbons of the Mayo Clinic told the Wall Street Journal that this study of people with serious heart disease might not apply to the far larger numbers of people with lower risks.
     The guidelines for lowering cholesterol are very different for high-risk vs. low-risk patients. High-risk patients, including cardiac patients, warrant vigorous treatment. In contrast, studies have repeatedly shown that in low-risk patients, aggressive therapy conveys few extra benefits but does increase side effects and costs. The fact is, for people with mild-to-moderate cholesterol elevations and few risk factors, the greatest benefit is seen with the initial 15%-20% reduction of LDL cholesterol. This latter group represents the vast majority of people with elevated cholesterol, and for them many doctors find that milder statins such as Pravachol, Mevacor, and Lescol, work just fine. And generic Mevacor, lovastatin, is now available and much cheaper at some discount pharmacies.
     And even for people with heart disease, aggressive therapy isn't always successful. Just because a person needs aggressive therapy doesn't mean his/her body can tolerate aggressive therapy. So an individualized approach is mandatory.
     Moreover, even as experts now debate whether to lower the recommended LDL levels for cardiac patients from 100 to 80 mg/dl, we still aren't clear whether statins work solely by lowering cholesterol or by reducing the levels of C-reactive protein, a marker of inflammation. In the Lipitor-Pravachol study, Lipitor reduced C-reactive protein by 36%, while Pravachol reduced it by 5%. Maybe that's why the Lipitor worked better. If so, the debate on LDL levels may be focusing on the wrong parameter.

Facing vs. Denying Statin Side Effects

     The Lipitor-Pravachol study is encouraging, but it is only one study. Medical history is littered with promising studies that were refuted when studied independently. The inescapable conclusion is that we need confirmatory studies performed by independent, objective investigators before rushing to put everyone on maximum doses of powerful statins.
     There's another reason, too. Remember Baycol? It didn't cause many problems at lower doses, but when the manufacturer began pushing the maximum dose, people died and the drug was withdrawn. Higher doses of any statin bring higher risks. Experts may claim that these drugs are imminently safe, but millions of patients aren't so sure, and their concerns are warranted. There's a lot of evidence that statins aren't as benign as experts suggest.
     In a new article Wednesday, the New York Times addressed this issue, stating: "The heart institute, along with the American Heart Association and the American College of Cardiology, wrote a paper on statins' risks noting that the worst side effect, severe muscle disease that can be fatal if the drugs are not stopped, afflicts less than one patient in a million. Other problems - muscle breakdown in one patient in a thousand and elevated liver enzyme in about 1 percent, may require that a person take a lower dose of the drug, change to a statin made by another company or stop taking the drug temporarily." This may be true, but isn't the whole truth. Unmentioned is the fact that substantial numbers of patients get muscle aches, joint pains, weakness, fatigue, abdominal discomfort, or memory or mood problems with statins. Just about every other person I've met who's taken statins has experienced substantial muscle pains, including several doctors.
     I am very concerned about the talk about higher and stronger statin doses. No doubt, many people need and benefit from high-dose statins. But just because aggressive therapy works doesn't mean everyone can tolerate aggressive therapy. The main reason that people quit treatment is from side effects -- all of which are dose-related: the higher the dose, the more frequent and more severe the side effects. I already hear of many people having problems with 10, 20, and 40 mg of Lipitor and equivalent doses of other statins. What will happen if doctors push the doses even higher?
     Yet, the unrelenting message from some experts and drug advertising is that more is better. I get concerned when I see increasing calls for stronger and stronger statins that isn't balanced by a clear definition of who actually requires such strong therapy and or by the fact that 80 mg of Lipitor isn't necessarily the ideal dose for everyone. Already, too many doctors are so enamored with statins that they are starting patients with mild-to-moderate cholesterol elevations and few cardiac risk factors at strong doses fitting only for people with major heart disease.

Successful Treatment Means Addressing Patients' Concerns about Statins

     So we have a dilemma: statins may work very well indeed, but I fear that the trend toward stronger and stronger doses will not only drive even more people from treatment, but may produce a backlash. Perhaps it already has. When people refuse statins, it reveals distrust in doctors, drug companies, and the entire healthcare system. But maybe there's a valid reason for this distrust. I receive case after case of people with typical statin side effects that their doctors have refused to acknowledge. Until the medical profession is willing to acknowledge patients' concerns and problems with statins, patients aren't going to trust what they're being told or the unrelenting hype for more and stronger statins.
     And until we develop a better model for using statins safely, nothing is going to change. As I've been saying for many years in my books and medical journal articles, we need to adopt a precision-prescribing, safety-first, patient-friendly model with statins. This model should mirror the start-low go-slow approach used with drugs for high blood pressure. By starting low and increasing each person's dose to the exact amount of statin he/she needs, patients can be assured that the risks of statin side effects are minimized. Doctors may be enamored with statins, but it is the patients who are taking the drugs, paying the cost, and getting the side effects. Their concerns deserve to the addressed. And by using a model doctors already understand, doctors will know how to prescribe statins properly rather than the widespread underdosing and overdosing seen today.

References
Kolata, G. The cholesterol challenge: Just how low can you go? New York Times, Dec. 2, 2003:nytimes.com.
Kolata, G. Study of Two Cholesterol Drugs Finds One Halts Heart Disease. New York Times, Nov. 13, 2003:www.nytimes.com.
Winslow, R. Study signals how low to go on cholesterol. Wall Street Journal, Nov. 13, 2003:D1.
Haney, D. Cut cholesterol more aggressively, study suggests. San Diego Union-Tribune, Nov. 13, 2003:A1.
Fager, G, Wiklund, O. Cholesterol reduction and clinical benefit. Are there limits to our expectations? Arteriosclerosis, Thrombosis, and Vascular Biology, 1997;17(12):3527-33.
Lewis, SJ, Moye, LA, Sacks, FM, et al. Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial. Annals of Internal Medicine 1998;129(9):681-9.
West of Scotland Coronary Prevention Study: identification of high-risk groups and comparison with other cardiovascular intervention trials. Lancet 1996;348(9038):1339-42.
Corvol, J, Bouzamondo, A, Sirol, M, et al. Differential effects of lipid-lowering therapies on stroke prevention. Archives of Internal Medicine 2003;163:669-676.
Cohen, JS. Over Dose. Tarcher/Putnam, New York: October 2001.
Cohen, JS. Do Standard Doses of Frequently Prescribed Drugs Cause Preventable Adverse Effects in Women? JAMWA (The Journal of the American Medical Women's Association) 2002;57:105-110.
Cohen, JS. Dose Discrepancies between the Physicians' Desk Reference and the Medical Literature, and Their Possible Role in the High Incidence of Dose-Related Adverse Drug Events. Archives of Internal Medicine 2001:161:957-64.
Cohen, JS. Adverse Drug Reactions: Effective Low-Dose Therapies for Older Patients. Geriatrics 2000;55(2):54-64.Copyright 2003, Jay S. Cohen, M.D.

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