Last year I wrote a couple of articles about statin therapy, so maybe you think I should give it a rest. However, I think it is such a hugely important issue, and I have this strong feeling that the truth really has not emerged yet. There are two reasons for the issue resurfacing on my blog now. Firstly, two recent scientific papers touching on the effects of statins on cognitive function, glucose tolerance, skeletal muscle function and coenzyme Q10 really had me thinking a lot about how much we still don”t know about the long-term use of statins. Secondly, last month I happened to read a fantastic book about “the other side” of statin therapy written by an American cardiologist. A well written, thought-provoking, easy to read book that everyone interested in modern-day health care should read, not least doctors. I’ll get back to the book later.

Statins are used by about 25 percent (1) of Americans 45 years and older. Between six and seven million people in the UK (2) take statin drugs every day. But what are they used for? What disease or disorder in our society motivates drug therapy for such a large proportion of the population? In short, statins are prescribed by doctors to help protect healthy but high-risk people from heart disease and to prevent heart attacks and strokes in people who have already been diagnosed with cardiovascular disease.

One has to wonder what gives medical professionals the right to prescribe therapy to such a huge number of people? Firstly, prove of efficacy must be substantial and there is really no room for any doubt. You would expect such therapy to significantly lessen the burden of disease and to prolong life. Secondly, it has to be absolutely proven that such treatment does not cause harm. If we trust regulatory authorities, we will have to assume this is true for statin drugs.

Statins were approved to lower cholesterol in the United States in 1987. Lovastatin (Mevacor) was the first statin approved by the FDA. At that time there was evidence that this drug lowered LDL-cholesterol (3) but it had not been proven that doing so would reduce the risk of heart disease or improve survival. During the next 20 years a number of large clinical trials adressed the clinical efficacy of statin therapy in healthy people with increased risk of heart disease (primary prevention) and in patients with documented cardiovascular disease (secondary prevention).

Approximately 65 thousand patients were included in the primary prevention trials (4), 65 percent were men and 35 percent were women. Taken together, all-cause mortality rate was 11.4 per one thousand person years among people on placebo and 10.7 per one thousand patient years on people on statins. This difference is not statistically significant. Furthermore, there was no relationship between the amount of reduction of LDL-cholesterol and all-cause mortality. So, shockingly some might say, the evidence that statin drugs prolong life among healthy people with increased risk of cardiovascular disease is nonexistent.

Several studies have addressed the efficacy of statin drugs compared with placebo among patients with documented cardiovascular disease. The three largest trials, 4S (Scandinavian Simvastatin Survival Study), LIPID (Long-Term Intervention with Pravastatin in Ischemic heart Disease study) and HPS (Heart Protection Study) showed that all-cause mortality was significantly lower among patients receiving statin therapy compared with placebo. The absolute reduction in all-cause mortality was 4 percent, 3.1 percent and 1.8 precent in the three trials respectively.

So, if we focus on all cause mortality, the conclusion is twofold. Firstly, statin therapy is effective and saves lives among patients with documented cardiovascular disease such as prior heart attack or stroke. Some might say the effect is small, but it is consistent and cannot be ignored. Therefore, not giving statins to patients with documented atherosclerotic cardiovascular disease is bad clinical practice and goes against evidence based medicine. Many will say it is malpractice. Secondly, however, it has not been proven that statin drugs reduce mortality among healthy people with increased risk of heart disease,except for individuals with diabetes (5) and those with the relatively rare disorder of familial hypercholesterolemia (6).

Thus, it is absolutely clear that we are treating a substantial proportion of the adult population with statin drugs, despite the fact that treatment has not been proven to reduce the risk of death. However, treatment is commonly motivated by study results showing that treatment will reduce the risk of cardiovascular events such as heart attacks and stroke.

Among relatively low risk individuals, it has been estimated that for every 1 mmol/L reduction in LDL-cholesterol there is an absolute reduction in major vascular events of about 11 per 1000 over 5 years. What does this really mean? Let’s say that I am a low risk patient and my LDL-cholesterol is 143 mg/dl ( 3.7 mmol/L ). My doctor prescribes a statin and I decide that I will take it every day for the next five years. My LDL-C goes down to 104 mg/dl (2.7 mmol/L) while I’m taking the drug. This treatment is going to make it one percent less likely for me to have a coronary event or a stroke during those five years, compared to if I do not take the drug. Not very impressive indeed. One has to wonder whether this proposed benefit outweighs the risk of treatment. If there is doubt, we should not treat. Primum non nocere; first do no harm.

The other side of statin therapy?

The clinical studies comparing statins with placebo indicate that statins are remarkably safe drugs with few side effects, muscle ache being the most common. However, it is well-known that side effects ar less common among patients participating in clinical trials compared to “real life” patients. In most clinical trials involving statins, less than one percent of subjects are reported to develop muscle pain or myopathy. In clinical practice, however, far more will experience myopathy. The much lower rate reported in clinical trials may be because eligibility criteria usually exclude patients with significant potential for drug interactions or concurrent health problems, whereas healthcare providers obviously cannot exclude such patients in clinical practice. Some studies have suggested that a quarter or even up to a third of patients who take statins will sooner or later develop a clinically significant myopathy. Cases of rhabdomyolysis have been reported. This happens when muscle fibers die and release a protein called myoglobin into the blood stream. High blood levels of this protein can lead to kidney failure. Although this is a rare disorder, it can be fatal.

In october last year a study addressing the possible negative effects of statin therapy on cognitive function was published in the American Journal of Geriatric Pharmacotherapy. Statin therapy was withdrawn in eighteen older subjects with Alzheimer’s disease. After six weeks the patients were put back on statin therapy. MMSE (mini mental state examination) was used to assess cognitive function. This is a standardized mental status examination reflecting memory and simple thought processes. In short, cognitive function improved when the patients were taken off statins and worsened again when statin therapy was restarted. The authors conclude that statins may adversely affect cognitive function in patients with dementia. This is a small study and the results will have to be confirmed by more research. However, it is not the first study to show negative effects of statins on cognitive function. The next most common adverse effect reported by people taking statins, next to the muscle side effects, involve cognitive impairment. These are interference with inability to think, concentrate, remember and solve mental problems. It has been suggested that this may have to to with the lowering effects of statins on CoQ10 levels. CoQ10 is important for mitochondrial function and mitochondrial density is high in brain tissue.

An interesting study by Danish researchers was published in the very recent first issue of the 2013 Journal of the American College of Cardiology. The study addresses the effects of statin therapy on glucose metabolism, muscle function and CoQ10. Twenty male subjects were recruited for the study. Ten were on treatment with the statin drug simvastatin due to high blood cholesterol and ten were healthy control subjects. The groups were matched for age, weight, body mass index, fat percent (total and abdominal) and maximal oxygen uptake. Fasting glucose and insulin measurements were done and a standard glucose tolerance test was performed. Muscle biopsies were taken for analyses of mitochondrial respiratory capacity of muscle cells. Insulin levels were similar in the groups under the glucose tolerance test, but glucose concentrations were higher in subjects on simvastatin, indicating impaired insulin sensitivity compared with the healthy controls. Q10 protein content in muscle was reduced in patients on simvastatin compared with controls. There were signs of impaired mitochondrial respiratory capacity in patients on simvastatin compared to controls.

According to the authors of the study, impaired glucose tolerance found in simvastatin treated patients is in agreement with earlier findings of impaired insulin sensitivity with statin treatment, although a deleterious effect on glucose tolerance by simvastatin has not been reported before. Remember that last year, regulatory authorities warned against an increased risk of diabetes with statin therapy.

The Danish scientists suggest that there may be a relationship between the decrease in Q10 protein content and reduced mitochondrial respiratory capacity among patients on long-term treatment with simvastatin. Possibly, muscle pain, impaired exercise tolerance and fatigue seen among some patients on statins may be traced to these mechanisms.

Statins inhibit an enzyme called HMG-CoA reductase which is involved early in the pathway leading to cholesterol synthesis. Statins therfore also affect other products of this pathway, including production of CoQ10. Statins have been shown to reduce blood levels of CoQ10. CoQ10 is important for cellular function and the generation of cellular energy by so-called mitochondria which are cellular organs that play a key role for many cells in the body. Nerve cells, heart muscle cells and skeletal muscle cells are rich in mitochondria. Several diseases are caused by abnormal mitochondrial function. There is some evidence that statin myopathy may, at least partly be related to low levels of Q10. However, it has not been proven yet that statin induced myopathy may be successfully treated with Q10.

The truth about statins

Doctor Barbara H. Roberts has written a book called “The Truth About Statins” that was released in April last year. Dr. Roberts is a cardiologist, associate clinical professor at the Alpert Medical School of Brown University as well as director of the Women’s Cardiac Center at the Miriam Hospital in Rhode Island. In her book Dr. Roberts discusses the benefits and health risks of statin therapy in a very professional way. She discusses the role of cholesterol in the body and explains the role of cardiovascular risk factors. She explains the “cholesterol hypothesis” and the evidence supporting it. She cites clinical trials and explains in laymen terms how they are interpreted, underlining for example the difference between absolute and relative risk reduction. She thoroughly goes through the Yin and Yang of statin therapy. She also mentions the possibility that LDL-cholesterol may be less important as a risk factor among women than men, and that data showing that statins reduce risk appears less convincing for women. Her discussion is objective, evidence based, and she does not jump to any conclusions. Although she has a point to make, her writing is careful and unbiased. She finally presents a possible healthy lifestyle alternative to statin therapy, based on the Mediterranean diet concept. This is an honestly written book. Unlike so many medical authors today, Dr. Roberts does not to my knowledge have any product line designed to enrich her bank account.

I recommend everyone interested in cardiovascular disease and modern-day health care to read Dr Roberts’s book. It is a strong reminder of our real lack of knowledge of the long-term effects of drugs that are being prescribed to millions of people worldwide.