ARE STATINS NECESSARY?

[This article was submitted for publication in my column Art of Healing in Oct 2013, but was rejected]

IS STATIN THERAPY TO REDUCE CHOLESTEROL NECESSARY?

In the previous article, I reported some studies which showed that the prevailing understanding about cholesterol and health needs to be re-assessed. In particular, while the link between high cholesterol and heart disease in men is established, high cholesterol may be protective against other causes of death such that high cholesterol does not correlate with higher overall deaths. Secondly, high cholesterol is in fact beneficial for women and therefore doctors should not prescribe anything to lower their cholesterol level (except perhaps a few exceptional cases).

Today I shall discuss some studies on statins which confirm the above conclusions.

STATINS DO NOT BENEFIT IN PRIMARY PREVENTION - STATIN THERAPY TO LOWER CHOLESTEROL LOWERS HEART DEATHS BUT INCREASES OTHER CAUSES OF DEATH

With the realization that some of the scientific studies were biased towards justifying the use of cholesterol-lowering drugs, researchers re-studied the data for the use of statins in patients who never had angina, heart attack or stroke (ie. statins were used as primary prevention) after excluding the doubtful and obviously biased studies (eg. the JUPITER trial, see below). They discovered that statins indeed reduced cholesterol levels and heart attacks, but did not reduce the overall death rates. Observational studies had already shown that lower cholesterol did not equate to lower overall deaths. Also, the heart benefits of statins were completely negated by the side-effects. Their conclusion – “Statins do not have a net health benefit in primary prevention populations and thus when used in that setting do not represent good use of scarce healthcare resources” (see Do Statins Have a Role in Primary Prevention? An Update. Therapeutics Letter, March-April 2010).

That statins only lower deaths from heart disease but not overall death rates is a very important fact that cannot be ignored. It means the net benefit is zero, because of increased deaths from other causes as a result of statin therapy. The doctors were impressed by the reduced cardiac deaths to justify prescribing statins, when in fact the evidence says that statins increase other causes of death, otherwise the death rates will not remain the same. It is a grave mistake to ignore this fact.

STATINS SHOULD NOT BE USED IN WOMEN & ELDERLY MEN FOR PRIMARY PREVENTION

In 2007 researchers at Harvard Medical School discovered that the treatment guidelines issued by the US National Cholesterol Education Program (NCEP) did not follow the available evidence. They discovered that according to the evidence, statins should not be given for primary prevention to women of any age, and to men above 69 years old (see Abramson J, et al. Are Lipid-lowering Guidelines Evidence-based? The Lancet 2007, 369:168-169).

Since 2001, the NCEP had advised all men and women with high cholesterol to take statins as primary prevention, in addition to diet and lifestyle modification despite these studies that show there is no benefit whatsoever for women to go on statins. Some of the studies were done on men, and generalized to women. Some of the studies were done on both sexes, but the results were lumped together. Most studies that evaluated the men and women separately found that women don’t need statins at all.

I had referred to the Norwegian HUNT 2 Study (J Eval Clin Prac 2012 Feb) which followed 52,087 Norwegians aged 20-74 who were free of cardiovascular disease (CVD) for 10 years, then assessed the relationship of total cholesterol with total mortality, CVD mortality, and heart disease mortality. It concluded that the cholesterol-risk profiles for men and women were totally different. Women in fact benefited from having higher cholesterol levels!

OVERALL BENEFIT OF STATINS IS LOW

The same Harvard study also showed that even for the younger men in whom there was some net benefit from statin therapy, the benefit was very small: 67 people have to take statin drugs for 5 years for 1 person to avoid getting a “cardiovascular event” (eg. angina, heart attack). Even the biased JUPITER trial (statin for primary prevention, see below) showed that 95 people need to take the statin for 2 years (extrapolated to 25 people for 5 years) to prevent 1 cardiovascular event. In other words, the statin drug reduced the absolute risk for heart attacks, stroke or death by only 0.2-0.6% in one year. How cost-effective is that? And what about the side-effects?

VERY LOW CHOLESTEROL IS DANGEROUS

The normal total cholesterol (Total-C) level is generally taken to be up to 5.2 mmol/L (with some variations between guidelines issued by expert committees). Many studies have shown that Total-C of about 4.0-5.0 gives the lowest mortality. Levels below 4.0 and above 5.2 correlate with higher mortality rates. See graph of MRFIT study below (N Engl Jnl Med 1989 Apr 6;320(14):904-10). This study showed that high cholesterol does correlate with higher overall deaths.

 

      [Note: 200mg/dL = 5.2 mmol/L]

However, many physicians and cardiologists advise their patients who are at very high risk of heart attacks to reduce the LDL-C level to below 1.8, which means the Total-C can be 3 or even lower if the HDL-C is also low. This can only be achieved with statins. Even if the very low cholesterol level reduces cardiac deaths, the studies show it increases other causes of death such that there is no net benefit.

A study showed that Total-C levels below 4 also tend to cause cognitive impairment, aggressiveness and suicidal tendencies. This underscores the importance of cholesterol for overall health, and reminds us that less is not always better (see Neurologia 9 Oct 2012). In October 2012, the US FDA conceded that statins can cause memory loss and cognitive decline, and required this warning to be included in the drug safety information.

INSUFFICIENT EVIDENCE TO SUPPORT MAXIMAL LOWERING OF LDL-CHOLESTEROL

The Cholesterol Treatment Trialists (CTT) is a UK-based collaboration of doctors and researchers who are largely responsible for promoting “evidence-based” aggressive cholesterol-lowering treatment using intensive statin therapy which has been adopted by doctors worldwide. It is the UK equivalent of the US NCEP (see above). Recently, researchers in Canada re-examined the studies used by CTT to justify their stance and discovered flaws in some of the studies used by CTT. After correcting for these flaws, they found that doubling the dose of atorvastatin (one of the most popular statins used) from 40mg to 80mg to achieve target levels improved outcomes only by 2% (ie. less angina, heart attacks), while increasing significantly the side-effects of fatigue, muscle pain, liver damage and kidney damage (the doubling of financial cost to the patient was not even considered, as rarely is consumer cost a factor in all these drug studies). They concluded that definitive evidence supporting maximal lowering of LDL-cholesterol or maximal dosing of statins is still lacking (see Sinderman A, et al. Is Lower and Lower Better and Better? A Re-evaluation of the Evidence from the Cholesterol Treatment Trialists’ Collaboration Meta-analysis for Low-density Lipoprotein Cholesterol. J Clin Lipidol 2012; 6(4):303-9).

Incidentally, in November 2012 the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) reduced the recommended maximum dose of statins from 80mg to 40mg because of safety concerns.

STATINS BENEFIT MEN ONLY IN VERY HIGH RISK PRIMARY PREVENTION

The most convincing study that supports the use of statins is ASCOT-LLA (Lancet 2003 Apr 5;361(9364):1149-58). The study was on 19,342 very high risk patients aged 40-79 years with hypertension plus at least three other cardiovascular risk factors. The study ended early for ethical reasons because the statin drug proved convincingly beneficial against the placebo and it was unethical to continue. The drug reduced cardiac deaths.  But somehow everyone seems to ignore the glaring fact that the results showed the risk of dying was higher for women who took statins than those who took placebo! This is another clear evidence that women should not be prescribed statins as primary prevention, even in high risk cases (see chart below).

While this study did not separate the older men (60-69 years) from the elderly men (70 years and above), note that other studies showed that the benefits of statins were confined only to men 69 years and below (see Harvard study above).

 

 Effect of atorvastatin vs. placebo on risk of death from heart disease in very high-risk subjects. Note that for women, the placebo was better than the drug!

BIASED STUDIES HAVE CORRUPTED EVIDENCE-BASED MEDICINE

A meta-analysis has great significance because it combines the results of several or many studies. However, most doctors, after being convinced by the experts brought in by the drug companies, are unlikely to be aware of some contrary aspect of the “evidence-based” data, as studies and conclusions negating the prevailing claims in support of the drugs are never highlighted to the doctors. The studies with “favourable results” are trumpeted to the doctors by the drug promoters, but reviews which negate the earlier findings are never brought to our attention. Those who have interest in the subject have to discover this through their own research.

A case in point is the JUPITER trial (reported in 2008 in NEJM 359 (21):2195-207) which showed that people with normal cholesterol and no heart disease, but were at higher risk of heart disease (as determined by elevated hsCRP levels) benefited from statin therapy (rosuvastatin was the drug used) by having less heart attacks and strokes. The trial was funded by the drug manufacturer, and their sales boomed after the results were published. Doctors were feted to “continuing medical education” talks and seminars to update them on this new finding. Soon many doctors started prescribing statins to patients even with normal cholesterol levels (as primary prevention).

But look what happened 2 years later. An independent research group reviewed the trial’s data and published this conclusion in the Archives of Internal Medicine (2010): “The trial was flawed. It was discontinued (according to pre-specified rules) after fewer than 2 years of follow-up, with no differences between the 2 groups on the most objective criteria….The results of the trial do not support the use of statin treatment for primary prevention of cardiovascular diseases and raise troubling questions concerning the role of commercial sponsors.”

Again we see the role of the drug company influencing the outcome of what is supposed to be an unbiased, objective scientific study.

How many doctors are aware of this damning refutation of the original claims made from the flawed trial conclusions? Since the drug companies do not publicize later findings which refute their claims, most doctors don’t know and continue to prescribe statins as primary prevention, costing the patients unnecessary expenses and side-effects, but benefiting themselves and the drug companies. Until now, most Malaysian doctors still prescribe statins for high cholesterol as primary prevention.

The CTT also based their conclusions on meta-analysis of many studies, but some of their conclusions are questionable when re-examined by other researchers. At least the CTT is honest in admitting that most of the studies were funded by the drug companies, and that its work was “observed” by representatives of these drug companies. Now I ask, how objective and independent can such researchers be?

SO IS STATIN THERAPY TO REDUCE HIGH CHOLESTEROL NECESSARY?

For now, there is enough evidence to state that women (even those at high risk with multiple risk factors) do NOT benefit from statin therapy to lower cholesterol, which may in fact cause more harm than good.

There is insufficient evidence to prescribe statins for elderly men (70 and above) with no history of heart disease or stroke (as primary prevention). 

For men below 70, primary prevention with statins reduces deaths from heart disease but increases other causes of death. For those with low risk, the evidence does not seem to justify statin therapy. The patients must be adequately informed of the potential risks and side-effects if statins are to be prescribed.

For very high-risk men below 70 with hypercholesterolemia and multiple risk factors for heart disease, primary prevention with statin therapy definitely reduces the risk of dying from heart disease to justify its use, but may increase the risk of dying from other causes such that the net effect is that there is no reduction in overall risk of dying. 

If you are one of them, you can choose what to die of - If you don’t want to die of heart disease, take statins, but your risk of dying from other causes increases, and your overall chance of dying (from heart and other causes) is unchanged by taking statins! But before you die (from whatever cause) you may suffer from memory loss, dementia, muscle cramps, and other side-effects.

While the benefit of statins for men with known heart disease (secondary prevention) is more convincing,  there is insufficient evidence that those who have heart disease will benefit overall from aggressive therapy to lower cholesterol to extremely low levels because of the side-effects on the brain and the increase in other causes of death. In such cases, the treatment must be individualized, and the patient should be informed of all the potential adverse effects. 


With the above scenario, we should consider reducing cholesterol (in men) by non-statin methods. These measures may include improving the metabolism by optimizing hormones and doing sufficient exercise, and herbal/nutritional therapies (eg. bergamot extract, oat beta-glucan, phytosterols, etc.). Hopefully more studies will be done on these safer alternatives so that they can be more "evidence-based" and more widely adopted.

DR AMIR FARID ISAHAK