MALAYSIA - There are few drugs in the history of medicine that have saved as many lives and prevented so many heart attacks in its short life span of 25 years as the "statins", a class of drugs including lovastatin, simvastatin, atorvastatin and rosuvastatin.
Lovastatin was the first in its class and only appeared in 1987.
Yet if one were to surf the internet, one would discover thousands, if not hundreds of thousands of reports and blogs (some written by doctors) condemning the statins.
I personally know a professor of biochemistry who claims that trials showing the benefits of statins have been cooked up by drug companies to sell their products.
Can these opposing views be reconciled?
I will start at the "very beginning" - a mere 40 years ago. Today, any school-going kid will be able to tell you that cholesterol will clog up the arteries of the heart, eventually causing a heart attack. But not 40 years ago.
In the 1970s and 1980s, a huge debate was raging among medical professionals over the "Lipid Hypothesis", the link between cholesterol and heart disease, and whether lowering cholesterol levels would prevent heart disease.
I put it to my students this way: "If men (or women) with green hair were prone to heart disease, would shaving off their green hair prevent it?"
The trial which put an end to the debate was the 4S trial or Scandinavian Simvastatin Survival Study, published in 1994. Over 4,000 patients known to have heart disease were enrolled. Half of them were put on simvastatin and half on placebo. Over five years, there was a 30 per cent relative reduction in deaths in the group treated with simvastatin. Just 30 patients needed to be treated to prevent one death, or to put it another way - the treatment of 100 patients for six years would prevent four deaths and seven non-fatal heart attacks. This would be classified as a SECONDARY PREVENTION study since the subjects already had heart disease; and the aim of treatment was to prevent a second heart attack or death.
Years later, I met up with one of the original 4S investigators and he had this interesting story to share. Very soon after the trial began, it became evident that patients NOT on simvastatin were dying off more quickly. There was a discussion on whether the trial should be immediately terminated as it seemed unethical to continue withholding simvastatin from the control group.
But the chief investigator said, "We'll continue the trial. If we stop now and the p value (significance value) is only 0.05 nobody will believe us." So the trial continued, and when it was terminated, the p value was 0.00001.
(Note: the lower the p value the more significant the results are. A p value of 0.00001 is highly significant! Nowadays, the power to continue or stop a trial would not rest with the chief investigator, but with an independent panel.)
After the 4S trial result was released, there was no more debate on the role of statins in SECONDARY PREVENTION; ie giving statins to subjects who had not only a raised cholesterol level but also established heart disease. The Lipid Hypothesis had become fact.
The debate then shifted to PRIMARY PREVENTION. If a high cholesterol level led to heart attacks, why not treat early to lower it and prevent heart disease?
The first such big trial was the WOSCOPS trial (West of Scotland Coronary Prevention Study), published in 1996. It confirmed the efficacy of primary prevention, but THREE times more subjects had to be treated over five years to prevent heart attacks or death compared to the 4S trial. This seems logical since the subjects were at lower risk compared to those in the 4S trial.
Hence, when reading about the role of statins, it is of CRUCIAL importance to differentiate between PRIMARY PREVENTION and SECONDARY PREVENTION.
All the controversy centres around PRIMARY PREVENTION and whether the RISKS of a statin (side-effects) justify its usage in subjects who have a raised cholesterol level but no heart disease yet.
The Cochrane Collaboration, a highly rated independent medical think tank, published a review in January 2013 entitled Statins for the primary prevention of cardiovascular disease.
The authors' conclusions were "reductions in all-cause mortality, major vascular events and revascularisations were found with no excess of adverse events among people without evidence of CVD treated with statins".
But this is unlikely to quell the online debate, so let us review the positive and negative effects of the statins beyond its cholesterol-lowering property.
The most common complaint of patients on statins is "muscle" pain, ranging from a mild discomfort to severe pain (it is difficult to determine the actual source of the pain in mild cases).
In the most severe cases, the muscles can actually break down (rhabdomyolysis). This is extremely rare.
Next is inflammation of the muscles. Patients experience moderate to severe muscle pains, and the inflammation can be confirmed by checking for the presence of an enzyme called creatine phosphokinase or CPK for short.
I see one case every year or two, so it is still uncommon.
By far the most common complaint is a generalised discomfort. It is highly subjective as the CPK is not raised in these cases. In other words, there may be no link at all with statin usage. All of us suffer discomfort and muscle aches at one time or another due to a variety of causes!
Last month, a report on Statin Discontinuation appeared in the Annals of Internal Medicine (Huabing Zhang et al, April 2013).
A substantial number of patients who stopped their statins because of side effects were persuaded to restart the statin again.
After 12 months, 92.2 per cent of them were still on the statin with no side effects this time round. The authors suggested that their original symptoms were probably UNRELATED to statin usage.
Raised liver enzymes
In some patients, the statins seem to interact with their liver, causing the liver enzymes to be elevated.
The standard teaching is to withdraw treatment or reduce the dosage of the statin if the enzymes are elevated three times above the normal range.
In my experience, very few patients need to have their statins withdrawn for this reason.
It is also important to note that in the Malaysian setting, the commonest cause of raised liver enzymes is probably fatty liver. In some cases, treatment with a statin may actually reduce the enzyme levels.
The statins seem to have pleiotropic effects or "value-added benefits" beyond cholesterol lowering. For example they exert a powerful anti-inflammatory effect.
The cholesterol plaque within the coronary blood vessel is often inflamed and liable to rupture. Statins reduce the inflammation and convert an UNSTABLE plaque which may rupture any moment, to a STABLE plaque.
This will reduce the risk of a heart attack.
SEPTICAEMIA (blood poisoning) and other serious infections can be life-threatening There are now many observational studies on patients with these infections who incidentally happened to be taking statins to lower their cholesterol levels, compared to those not on a statin.
Those on a statin had a lower chance of dying compared to those who were not on a statin.
It has been postulated that reduced tissue/organ inflammation might contribute to the better survival.
Patients with AUTO-IMMUNE DISEASE like SLE (systemic lupus erythematosus) also have intense inflammation of their tissues and certain organs. Those who happen to be on a statin survive longer.
In one report, it was suggested that all patients with auto-immune disease should be put on a statin for this reason.
A recent report based on the entire Danish medical database (Statin Use and Reduced Cancer-Related Mortality, Sune F. Nielsen et al, New England Journal of Medicine, 2012) identified almost 300,000 patients who had cancer. Those who happened to be on a statin had improved survival compared to those not on a statin.
They hypothesised that cancer cells need a lot of cholesterol to multiply and spread, and by lowering cholesterol levels, they were in fact "starving" the cancer cells. The accompanying editorial cautioned that more studies need to be conducted in other populations.
Statins seem to push subjects who are prone to diabetes (prediabetes) into overt diabetes.
The incidence ranges from 9-20 per cent. But in these same studies, even those who became diabetic derived substantial benefits from the statins.
In an editorial (Statins: Is It Really Time to Reassess Benefits and Risks? New England Journal of Medicine, 2012), Allison Goldfine had this to say: "On average, treatment of 255 patients with statins for four years resulted in one additional case of diabetes, but it must be considered in the context of the simultaneous prevention of 5.4 vascular events (heart attacks and strokes) among those 255 patients."
Research continues into other areas where specific statins also appear to have a favourable effect, including dementia, lung cancer, cataracts, osteoporosis and prostate cancer. Statins may be a true wonder drug if all these value-added benefits turn out to be correct.
Do I have to fast to check my cholesterol levels?
Traditionally, patients have been asked to fast for at least eight hours before they have their lipid levels checked.
In a study of over 200,000 subjects in Canada (Fasting Time and Lipid Levels in a Community-Based Population, Davinder Sidhu et al, Arch Internal Medicine 2012) the authors found that the lipid levels on average did not change much even if checked after food.
The total and HDL cholesterol levels increased by 2 per cent; the LDL cholesterol by 10 per cent and triglyceride by 20 per cent. So for logistical reasons (convenience), your blood may even be taken after food and the results interpreted accordingly.
Love them or hate them, the statins are here to stay. Besides their main function of lowering cholesterol, preventing heart attacks and strokes and thereby saving lives, the statins appear to have many value-added benefits. These are probably related to their anti-inflammatory properties.
The deluge of articles on the internet is confusing to many readers.
My advice is to critically identify them as either primary or secondary prevention reports (sometimes the authors themselves are confused!) and to give credence to properly conducted randomised placebo controlled trials.
This article is contributed by The Star Health & Ageing Panel, which comprises a group of panellists who are not just opinion leaders in their respective fields of medical expertise, but have wide experience in medical health education for the public. The members of the panel include: Datuk Prof Dr Tan Hui Meng, consultant urologist; Dr Yap Piang Kian, consultant endocrinologist; Datuk Dr Azhari Rosman, consultant cardiologist; A/Prof Dr Philip Poi, consultant geriatrician; Dr Hew Fen Lee, consultant endocrinologist; Prof Dr Low Wah Yun, psychologist; Datuk Dr Nor Ashikin Mokhtar, consultant obstetrician and gynaecologist; Dr Lee Moon Keen, consultant neurologist; Dr Ting Hoon Chin, consultant dermatologist; Prof Khoo Ee Ming, primary care physician; Dr Ng Soo Chin, consultant haematologist. For more information, e-mail firstname.lastname@example.org. The Star Health & Ageing Advisory Panel provides this information for educational and communication purposes only and it should not be construed as personal medical advice. Information published in this article is not intended to replace, supplant or augment a consultation with a health professional regarding the reader's own medical care. The Star Health & Ageing Advisory Panel disclaims any and all liability for injury or other damages that could result from use of the information obtained from this article.