Zee
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.
All rights reserved. Readers have permission to copy and disseminate all or part of these articles
if it is clearly identified as the work of: Jay S. Cohen, M.D., the MedicationSense E-Newsletter,
www.MedicationSense.com. You may not use this work for commercial purposes.
If you find this article informative, please tell your friends, family members, colleagues, and
doctors about www.MedicationSense.com and the free MedicationSense E-Newsletter.
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.
All rights reserved. Readers have permission to copy and disseminate all or part of these articles
if it is clearly identified as the work of: Jay S. Cohen, M.D., the MedicationSense E-Newsletter,
www.MedicationSense.com. You may not use this work for commercial purposes.
If you find this article informative, please tell your friends, family members, colleagues, and
doctors about www.MedicationSense.com and the free MedicationSense E-Newsletter.
