Statin Drugs: A Critical Review of the Risk/Benefit Clinical Research

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Statin Drugs:

A Critical Review of the Risk/Benefit Clinical Research

Statin Drugs - A Critical Review of the Risk/Benefit Clinical Research

www.drugintel.com/drugs/statins/statins_critical_review.htm

Joel M. Kauffman, Ph.D.

Professor of Chemistry Emeritus USP Philadelphia, PA, USA

9 Dec 2003

Abbreviations:

CVD - Coronary Heart Disease; FH - Familial Hypercholesteremia; HDL -

High Density Lipoprotein; HPS -Heart Protection Study; LDL - Low

Density Lipoprotein; NO - Nitric Oxide; RR - Relative Risk; TC - Total

Cholesterol

The statin drugs are essentially the

HMG-CoA reductase inhibitors: atorvastatin (Lipitor™), cerivastatin

(Baycol™, withdrawn 8/01), fluvastatin (Lescol™), lovastatin

(Mevacor™), pravastatin (Pravachol™), simvastatin (Zocor™),

pitavastatin and rosuvastatin (Crestor™), which were introduced to

lower total cholesterol (TC) levels, and especially LDL-cholesterol

(LDL) levels, ostensibly to prevent coronary heart disease (CVD).

Many

well-funded sources attempt to justify the wide use of the statin drugs

to lower TC and LDL by citing references in support of the claims that

high levels of TC and LDL have been correlated with cardiovascular

disease. Such claims are unfounded, since high TC and LDL are

well-correlated with age, which is a risk factor.[1,2] With age

removed, there is almost no correlation, and certainly none that allows

a worthwhile prediction of risk for a given individual. The rare

familial hypercholesterolemia (FH), in which TC > 400 mg/dL, is

usually represented as more deadly than it really is, when the sales of

statin drugs are at stake. Moreover, the removal of those with FH from

the high TC and LDL groups in epidemiological studies also removes any

predictive ability.[1]

The supposed benefits of the

statins, beyond a large, but meaningless lowering of TC and LDL, long

recognized as a worthless surrogate endpoint,[3] are usually given as

lowered relative risks (RR) of mostly non-fatal heart attacks without

the slightest indication of the low magnitude of the more meaningful

reduction of absolute risk or of all-cause death rates. This

misrepresentation has been noted.[1,4] So the usual tout of pravastatin

in the WOSCOPS trial, based on a 22% drop in all-cause mortality, was

given without the information that this was only a 0.9% drop absolute

in the 5-year trial period, or 0.18% per year. The higher all-cause

death rates in 2 of the big trials of lovastatin were ignored, as was

the higher breast cancer rate (RR = 1500%) in the CARE trial with

pravastatin.[1] Furthermore, it is also known that studies of drugs

sponsored by their maker are often biased or selected, so even the 0.9%

was probably exaggerated.[5-7]

Besides cancer, the

other side effects of statins listed were incomplete, and should have

included constipation, myalgia, myopathy, polyneuropathy, liver and

kidney damage, congestive heart failure and amnesia. Side-effects are

usually said to affect 2-6% of patients. In fact, a recent

meta-analysis noted side-effects in 20% of patients above the placebo

rate (65% vs. 45%), and no change whatever in the all-cause death rate

for atorvastatin. [8] The PROSPER trial on pravastatin showed no change

in the all-cause death rate, and increased cancer and stroke rates. 9

Statins are commonly used at a dose to lower TC to <160 mg/dL, a

level noted in the report of a NHLBI conference to be associated with

higher cancer rates.[10]

Statins decrease the body's

production of the essential coenzyme Q-10 and dolichol, among other

things. Low Q-10 levels are strongly associated with congestive heart

failure.[10a]

There is some recognition that statins

operate to lower non-fatal heart attack rates by mechanisms other than

cholesterol lowering, but none that their desirable effect on

thromboxane A2 is less than men can obtain with buffered aspirin,[11]

or that the desirable effect of raising nitric oxide (NO) levels is

less than one can obtain with the supplement L-arginine with no

side-effects. These effects of statins are independent of initial or

final TC or LDL levels,[12] and thus there is no way to determine who

"should be treated" with statins, or what the dose should be.

Since

the use of statins for primary prevention of CVD has been shown to

increase all-cause mortality by 1% over a 10-year period,13 and has

very little to no effect in secondary prevention of death,[9,11,14,15]

it would seem that there is no cost-benefit in primary prevention, and

very little for secondary prevention.

The most

favorable trial with seemingly impeccable reporting and minimal

financial conflict of interest was the Heart Protection Study (HPS), on

simvastatin for 5 years, in which secondary prevention in men (86% of

patients) of any unwanted vascular event gave a RR = 0.76 (5.5%

absolute, 1.1% per year), and an all-cause death rate drop of 0.38% per

year.16 Since this performance is inferior to that of either Bufferin™

in men [11] or omega-3 fatty acid supplements,[17] both of which have

lesser side-effects, and are far less expensive, the logic of

prescribing simvastatin seems faulty.

In another

example, total cardiovascular events and procedures were 2% absolute

lower with atorvastatin than with placebo after 3.5 years, giving RR =

0.79. This is a poorer performance than that of Bufferin™ for which RR

= 0.31 for non-fatal MI in men during 7 years.[11] With omega-3 fatty

acid supplements during 3.5 years, total cardiovascular events had RR =

0.80, and for all fatal events in this period RR = 0.7917 vs. about 1.0

for atorvastatin.[8]

Atorvastatin and simvastatin are the statin drugs most likely to cause memory loss.[18]

In

the ASCOT-LLA trial19 on hypertensive subjects with average or lower

TC, there was no change in the all-cause death rate vs. placebo after

3.5 years; however there was a higher incidence of the arbitrarily

defined primary endpoint of non-fatal MI plus fatal CVD among the 19%

women in the trial, similar to the effect of aspirin in women.[20]

Careful

examination of the literature on statin drugs reveals false premises,

minimal to no benefits, serious side-effects leading to very low

adherence rates,[8,21] and safer, low-cost alternatives for prevention

of CVD deaths.

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Wagstaff LR, Mitton MW, McLendon Arvik B, Doraiswamy PM.

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of the Literature. Pharmacotherapy 2003;23(7):871-880.

 

19. Sever PS, Dahlof B, Poulter NR et al. Prevention of coronary and

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average or lower-than-average cholesterol concentrations, inthe

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Elderly Patients With and Without Acute Coronary Syndromes. J Am Med

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