By Dr. Duane Graveline, M.D., M.P.H.
Study after study has shown the benefit of statin drugs in reducing the risk of heart attack and stroke. Almost buried in this barrage of positive results, however, is the growing research evidence that this reduction of cardiovascular disease morbidity and mortality from statin use has occurred independently of cholesterol effect.
Statins, originally felt to work solely as an inhibitor of cholesterol biosynthesis, now appear to work independently of cholesterol reduction. Adding to cholesterol's innocence is its vital role in the body - mediator of synaptic transmissions, precursor of vital hormones and the most abundant biochemical in our brains.
Despite this evidence of a new non-cholesterol factor in cardiovascular disease risk, the nutritional and pharmaceutical world remains steadfastly focused on cholesterol as the villain. Statins appear to work by another mechanism, some researchers now say. They relieve inflammation in the endothelial lining of blood vessels - this reduces sclerotic change.
The good I see from the large numbers of excellent studies having to do with this anti-inflammatory role of statin drugs is that the attention of clinicians is now beginning to be focused on the true cause of arteriosclerosis and atherosclerosis and the realization will soon dawn that cholesterol is conspicuously absent in the "usual suspects" line-up.
Since the development of statin drugs, the end-point for judging effectiveness has been the cholesterol response. If cholesterol seemed reluctant to be lowered, a higher dosage of statin was the almost automatic response.
The focus on cholesterol as the culprit has led to higher and higher statin dosages over the years as target levels for serum cholesterol have been progressively lowered. Today it is almost standard that the starting dose be at least 20 to 40 mg, of Lipitor® or Zocor® (or its equivalent in the other statins).
With the incidence of statin-associated myopathy by some estimates at 12-15% (Ref. 1) and millions of patients the world over now on the statin class of drugs, statin myopathy is now running at epidemic levels. With most doctors remaining steadfastly focused on cholesterol causation, they prefer their patients to remain on statins if at all possible. Additionally, it is generally understood that statin myopathy is dose related.
In today's world it is common to allow CPK (creatine phosphokinase - muscle enzyme levels) to be 10 times the upper limit of normal before taking precautions. I strongly disagree with this, and would not have allowed this when I was in practice, but the guidance is coming from the drug companies with FDA approval.
In view of the established fact that some of the most serious myopathy cases in terms of future long-term disability are associated with entirely normal CPK's, I would have used the presence of pain and weakness to take action immediately - with or without a positive CPK test result.
However, there are certain circumstances where a doctor might feel compelled to continue with statins despite the muscle pain and weakness and that is in the case of high risk where in the doctor's judgment a lot may be riding on their use.
This is not just some cholesterol elevation problem. This is one with a patient's past history of heart attack or stroke or some other extenuating circumstance.
Nor do I agree with the common ploy of changing to another statin for generally speaking they are all alike. They are all inhibitors of a single reductase step in the synthesis of cholesterol and side effects from one statin are very likely to occur in the alternative as well.
Since cholesterol response no longer seems to be a valid end-point in determining statin dose, the entire strategy for dosing these drugs has been called into question and this has resulted in a number of studies where doctors are exploring the use of statins at doses far below their usual dosing levels.
In a study by Degreef and Opdam (2) statin intolerance was defined as not being able to tolerate a statin due to myalgia-myopathy, myositis, or elevation of serum liver enzyme levels.
35 patients were treated with Zocor with an initial dose of 2.5mg every other day. The dose was titrated upwards if possible. The Zocor dose reached in this study ranged from 0.825 to 8.75mg/day with a mean dose of 4mg/day. Amazingly enough, even with this small amount of statin, their cholesterol decreased by an average of 26 percent.
In another study by Malalka (3), thirty five patients without statin intolerance were given Lipitor 10mg every other day producing an average cholesterol reduction of 27 percent.
This result is almost identical to the Degreef study, supporting the generally held belief that Lipitor and Zocor are very similar in potency. The average statin dose in Degreef's study was 4mg daily compared to 5mg in Malaka's study.
Gargarla (4) reported on the use of Crestor® 5mg twice weekly in 40 patients, giving an average reduction of cholesterol of 26 percent. Mol reported in The Lancet in 1986 that the use of 2.5mg of synvinolin, an early statin, reduced blood cholesterol by 17.7 percent (5). In none of these studies was the effect of the statin on cardiovascular disease documented.
It can now be said with reasonable confidence that the stronger statins, dosed at the levels of 2 to 5mg daily result in substantial cholesterol reduction. But since there is now widespread disbelief in the cholesterol causation hypothesis and a welcome return to butter, eggs and whole milk in the diet, the question remains - will statin dosing at this level provide benefit to those with cardiovascular disease?
Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor
1) Markus Mohaupt and others. Association between statin-associated myopathy and skeletal muscle damage.
CMAJ 181 (1-2). E11-E18 7 July, 2009
2) Degreef LE and Opdam FL. The tolerability and efficacy of low-dose simvastatin in statin-intolerant patients. Eur J Intern Med 21(4):293-6 Nov 2010
3) Matalka MS, Ravnan MC, Deedwania PC. Is alternate daily dose of atorvastatineffective in treating patients with hyperlipidemia? The Alternate Day Versus Daily Dosing of Atorvastatin Study (ADDAS). Am Heart J 2002;144(4):674-7.
4) Gadarla M, Kearns AK, Thompson PD. Efficacy of rosuvastatin (5 mg and 10 mg)twice a week in patients intolerant to daily statins. Am J Cardiol 2008;101(12): 1747-8.
5) Mol MJ, Erkelens DW, Leuven JA, Schouten JA, Stalenhoef AF. Effects of synvinolin (MK-733) on plasma lipids in familial hypercholesterolaemia. Lancet 1986;2(8513):936-9.
Updated October 2011