Statin Drugs

 

My LDL cholesterol is 111.  My doctor offers a statin drug because the Cholesterol Assessment and Treatment guidelines say that LDL-cholesterol should be treated aggressively in diabetics, even though they acknowledge that AModification of blood pressure and lipids in people with diabetes, however, does not reduce CHD risk.@ (p. II -15).  My cholesterol is 165, my triglycerides are 63, my ratios are good, my pulse barely gets off the peg on the treadmill ... but I should be on a statin drug? 

 

I have questions: what=s the possible benefit?  And, what=s the risk?

 

Statins Work by Lowering C-Reactive Protein, Not By Lowering Cholesterol

The answer to the first question is that statins reduce C-reactive protein, a marker for inflammation which is an Aemerging risk factor@ for CHD.  Two studies in the New England Journal of Medicine suggest the benefit of statins must come from this effect:

 

APatients who have low CRP levels after statin therapy have better clinical outcomes than those with higher CRP levels, regardless of the resultant level of LDL cholesterol. Strategies to lower cardiovascular risk with statins should include monitoring CRP as well as cholesterol.@ (Ridker PM et al, NEJM 2005 352(1):20‑28)

 

AFor patients with coronary artery disease, the reduced rate of progression of atherosclerosis associated with intensive statin treatment, as compared with moderate statin treatment, is significantly related to greater reductions in the levels of both atherogenic lipoproteins and CRP.@ (Nissen SE, NEJM 2005 352(1):29‑38)

 

So in the studies showing a protective effect, such effect kicks in long before the cholesterol and LDL-cholesterol levels change; and those in whom LDL-cholesterol is not a risk factor also benefit.  It’s plain that statin drugs protective effect cannot stem from their effect on cholesterol or LDL-cholesterol, and must therefore come from lowered C-reactive protein.  But my C-reactive protein level is already below the limits of measurement, so statins are unlikely to help me! 

 

And the magnitude of the possible benefit?  Somewhere between 0.12% and 3.5% less absolute risk of death, depending on which of 5 statin drug trials you put your faith in.  This is usually quoted as 21% to 41% less relative risk of death, which sounds so much more encouraging but is actually profoundly misleading. 

 

Lies, damned lies and statistics

Benjamin Disraeli

 

It works like this.  In the Scandinavian Simvastatin Survival Study, there were about 2,222 CHD patients with high cholesterol in each of the experimental and control groups.  In the experimental group there were 111 deaths, compared with 189 deaths in the control group, which is 5% and 8.5% respectively, and the difference between these figures can be said to be 41% (the relative risk) or 3.5% (the absolute risk).

 

lex non curat de minimis

the law doesn=t care about trifles

 

This is a trifling improvement.  Consider that initially healthy women in the Nurses Health Study who took vitamin E 200IU for two years had 41% less relative risk of coronary disease (and 13% less relative risk of all cause mortality than those with low intakes), which is directly comparable with the statin drug figure.  (Stampfer MJ et al, Vitamin E consumption and the risk of coronary disease in women. NEJM 1993 328:1444-9). 

 

And what=s the risk of side effects?  In Statin Drugs ‑ A Critical Review of the Risk/Benefit Clinical Research, Dr Joel Kauffman writes:

 

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. [Newman CB et al, Safety of Atorvastatin Derived from Analysis of 44 Completed Trials in 9,416 Patients.  Am J Cardiol  2003;92:670‑6.] The PROSPER trial on pravastatin showed no change in the all‑cause death rate, and increased cancer and stroke rates. (Kauffman, JM, DrugIntel.com, 12/9/03)

 

The meta-analysis Dr Kauffman refers to is by a doctor who works for Pfizer Global Pharmaceuticals, and it=s wildly entertaining that the study’s abstract claims only 3 or 4% suffered side-effects, yet in a Table in the body of the paper we find the incidence of one or more side‑effect was 67% among statin-treated patients, compared to 45% in the Placebo group:

 

TABLE 3. All Completed Studies Data Grouping: Overview of Safety, Comparing Atorvastatin With Other Statins and Placebo

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Newman CB (of Pfizer) et al, Am J Cardiol 2003, 92(6):670-6

 

Usually, the incidence of side-effects in the placebo group (45%) is subtracted from the incidence in the drug group (67%) to arrive at the incidence of side effects of the drug (22%).  But the investigator arbitrarily reclassified so many side-effects as Anot treatment-related@  so that the incidence of side-effects magically became 3% for atorvastatin, and 4% for other statin drugs.  The true rate of the side-effects of statins may approach 22% per year.

 

What are the side-effects of statin drugs?  Baycol (cerivastatin) was pulled from the market in August, 2001, because of 31 deaths from rhabdomyolisis, which is kidney failure cause by massive release of myoglobin from damaged muscles.  However, individual doctors have reported the incidence of myalgia (muscle pain), cardiomyopathy (a failing, enlarged heart), liver dysfunction and memory problems in up to 30% of those who take statins.  The side-effects are likely caused by the drug inhibiting HMG coenzyme A, which inhibits both cholesterol synthesis and coenzyme Q10 production.  Less of this enzyme, which is required for energy production within cells, probably causes the myalgia and cardiomyopathy.  A 22% incidence of side-effects in the first year is consistent with prescribing doctors observations, and is profoundly disquieting because these side-effects will likely increase with length of treatment.

 

So, let us reflect.  In the West of Scotland primary prevention trial, in which men with high cholesterol were given Pravastatin, the conclusion was that:

 

treating 1000 middle-aged men with hypercholesterolemia and no evidence of a previous myocardial infarction with pravastatin for five years will result in 14 fewer coronary angiograms, 8 fewer revascularization procedures, 20 fewer nonfatal myocardial infarctions, 7 fewer deaths from cardiovascular causes, and 2 fewer deaths from other causes than would be expected in the absence of treatment. (the WOSCOPS primary prevention trial)

 

 

This speaks of 51 fewer bad outcomes over five years of treatment of 1000 men, an absolute risk reduction of 5.1%, or 1% per year which was reported as a 31% reduction in relative risk.  This introduces a new and fascinating number, the Number Needed to Treat, which supposedly helps make the discussion of risk more understandable.  In this case, the number is 1/0.01, or 100 people.  This means if I and 100 fellow citizens take this stuff for a year, one of our lives will be saved!

 

In the 5-year Cholesterol and Recurrent Events secondary prevention trial, “The frequency of … [a fatal coronary event or a nonfatal myocardial infarction] was 10.2 percent in the Pravastatin group and 13.2 percent in the placebo group, an absolute difference of 3 percentage points and a 24 percent reduction in risk” (CARE trial) so that the Number Needed to Treat is 1/0.06, or 154 people.

 

The world is flat

 

If 154 people must be treated to save one life, it is the drug manufacturer who enjoys the house percentage!  A Table of Numbers Needed to Treat for various drugs indicates how woefully ineffective statins actually are.  In treating arthritis with glucosamine, for example, the number needed to treat is only 5, meaning one in five people experience benefit in 3 to 8 weeks, which is pretty good odds.  The magic number for treatment with nutrition is only 1.3 people!  If I take the statin for the rest of my life, twenty years, say, my risk of death is only reduced by 13%, but my risk of side effects becomes 20 times 22%, or 440%, a statistical certainty!  By now I’m thinking that cholesterol treatment by statin drugs belongs in the book Extraordinary Popular Delusions and the Madness of Crowds (Three Rivers Press, 1995):

 

Why do otherwise intelligent individuals form seething masses of idiocy when they engage in collective action? Why do financially sensible people jump lemming-like into hare-brained speculative frenzies – only to jump broker-like out of windows when their fantasies dissolve? We may think that the Great Crash of 1929, junk bonds of the '80s, and over-valued high-tech stocks of the '90s are peculiarly 20th century aberrations, but Mackay's classic – first published in 1841 – shows that the madness and confusion of crowds knows no limits, and has no temporal bounds. These are extraordinarily illuminating, and, unfortunately, entertaining tales of chicanery, greed and naivete. (from a review at Amazon.com)