Statins
|
|
In 1976, the Japanese biochemist Akira Endo isolated a novel substance from the fungus Penicillium citrinum, one that displayed a remarkable ability to inhibit cholesterol synthesis by cells (1). The substance, which he called compactin, was the first of the statins, a class of drugs that now stands in the midst of considerable controversy within the realm of medicine.
Since the 1990s, medical doctors have been prescribing statins copiously to their patients. This is best demonstrated by the rise of the drug atorvastatin, which during 1996 to 2012 became the best-selling pharmaceutical of all time (2). Today, statins are among the most widely prescribed drugs in existence, a behaviour that is endorsed by most cardiologists around the world (3).
Yet despite their meteoric rise and seal of approval from the medical mainstream, many members of the public are wary of these drugs. They prefer to turn to other health sources such as the alternative medicine proponent Dr Joseph Mercola, who openly argues against taking statins (4). Despite hordes of cardiologists recommending statins, many people reject this advice; they would rather go with Dr Mercola.
|
Alternative medicine proponent, Dr Mercola, is anti-statin. |
Many medical doctors remain genuinely perplexed by this trend - why would anyone disregard the advice of numerous prestigious cardiologists and turn to other less reputable alternatives? The answer is quite simple, but before we address it, let's take a balanced look at statins, at how they work and their effects on human health.
How Statins Work
Mechanistically, statins work on two levels. First, they inhibit cell cholesterol formation. Second, they exert pleiotropic effects (multiple additional effects unrelated to the inhibition of cholesterol formation). It is necessary to understand both of these processes if we are to know how statins work.
Cholesterol is a lipid (fat) molecule synthesized by all animal cells. In addition to being a vital component of cell membranes, cholesterol is essential for the synthesis of steroid hormones, bile acids, and vitamin D. Statins inhibit the enzyme HMG-CoA reductase, the rate-limiting step in cell cholesterol formation (3). Since HMG-CoA reductase is the rate-limiting step, statins have broad and potent effects on the cholesterol profile - but there's a lot more to statins than that.
|
Cell cholesterol formation is a multi-step pathway; the step involving HMG-CoA reductase (top of diagram) is but one of many. |
Thus, statins do a lot more than just lower cholesterol formation within the cell - by inhibiting isoprenoid synthesis, they also exert numerous pleiotropic effects which have a diversity of consequences throughout the body.
Statin Effects On Health
Now that we know how statins work in a basic sense, we are in a better position to gauge their effects on health. Statins are currently recommended for people with cardiovascular disease, a class of disease involving hardening and narrowing of the arteries that results in heart attacks and ischemic strokes. In these people (with a history of heart attacks or strokes), the aim of a statin is secondary prevention (preventing further heart attacks and strokes). However, statins are also recommended for people who may be at risk of cardiovascular disease, which includes people with high LDL cholesterol (the so-called "bad" cholesterol). In these people (with no history of heart attacks or strokes), the aim of a statin is primary prevention (preventing heart attacks or strokes at all). Since these two types of prevention are fundamentally different, we need to look at the statin evidence for them separately.
Currently, there is decent evidence that statins are useful for secondary prevention of cardiovascular disease. Many large randomized controlled studies support this assertion (6-8), although the gains have probably been historically over-stated, as shown by a 2015 systematic review showing that the median increase in life expectancy for patients taking statins every day for several years in the secondary prevention of cardiovascular disease was a mere four days (9). Despite these unimpressive gains, statins still stand on reasonable ground in the secondary prevention of cardiovascular disease. Yet how do they do so? Is it through their ability to lower cholesterol levels, or is it through their pleiotropic effects?
Despite the lingering notion among most medical doctors that cholesterol is evil, it is becoming apparent that the ability of statins to inhibit cholesterol formation is unrelated to their usefulness in the secondary prevention of cardiovascular disease. Currently, there are a whopping 44 randomized controlled studies of drug or diet interventions showing that simply lowering a person's LDL cholesterol confers no benefit on mortality, including the very recent, well-designed ACCELERATE study which used the non-statin drug evacetrapib to achieve an impressive 37% reduction in LDL cholesterol in high-risk patients with cardiovascular disease yet reported no benefit on mortality, a result which has dumbfounded many experts (10), as well as the very recent FOURIER study which used the non-statin drug evolocumab to achieve an insane 60% reduction in LDL cholesterol in patients with cardiovascular disease yet reported no benefit on mortality (11). In fact, several recent (and massive) studies have shown that all lowering cholesterol through non-statin drugs or diet interventions does is increase harmful events, including an increased rate of accidental deaths and suicide (12,13). To be frank, the idea that "high cholesterol is bad" is now an archaic notion, with many large studies demonstrating that a person's LDL cholesterol level has very little, if anything to do with their risk of having a heart attack or ischemic stroke (14-16). Thus, any usefulness of statins in the secondary prevention of cardiovascular disease is more likely related to their pleiotropic effects, not their ability to inhibit cholesterol formation.
The notion that high total or LDL cholesterol are "bad" is a sorely out-dated one.
If statins confer small but sure gains in the secondary prevention of cardiovascular disease, what about their effects in primary prevention, in people who have never had a heart attack or stroke yet may have high cholesterol levels? Since we have just shown that reducing cholesterol levels alone does not improve health outcomes and therefore the usefulness of statins likely results from their pleiotropic effects, you probably already know the answer to this question.
Currently, there is very weak evidence that statins are useful for primary prevention of cardiovascular disease. Several older studies showed that statins provide a very weak benefit on mortality (17). However, more recent studies show no benefit on mortality at all, such as the very recent ALLHAT-LLT study which showed that giving statins to adults aged 65 years and older, with high cholesterol and blood pressure, conferred no benefit on mortality, although there was a non-significant direction towards increased all-cause mortality in adults aged 75 years and older (18). Why might there be a trend towards increased mortality in people taking statins?
Like any drug, statins have adverse effects, a fact that is often swept under the rug by prescribing medical doctors. In fact, patients state that physicians often dismiss the possibility that any unexplained symptoms they are experiencing might be related to their statin (19). The potential adverse effects in people taking statins include the following:
(1) Overall, 10-25% of people on a statin experience statin-associated muscle symptoms, ranging from mild myalgia or cramps to life-threatening rhabdomyolysis or necrotizing myositis (20).
(2) A well-documented increased risk of type 2 diabetes (21,22).
(3) An increased risk of a variety of cognitive changes, ranging from mild memory loss to frank dementia (20).
(4) Increased risk of liver toxicity, ranging from mild elevation of liver-related enzymes in the blood to liver failure (23,24).
(5) Increased risk of kidney toxicity, ranging from reduced kidney function to kidney failure (20).
(6) Increased risk of tendon rupture; there are literally hundreds of reported cases of this (20).
(7) A well-documented increased risk of intracerebral hemorrhage (25,26).
(8) An increased risk of depression (20).
Does this mean that a person taking a statin will definitely experience any of these? No. However, there is a good chance that at least one or two of these adverse effects will occur in a person on a statin, given enough time.
The effects of statins on health can be summed up as follows:
(1) First, there is decent evidence that statins are useful for secondary prevention (in people with a history of heart attacks or ischemic strokes) of further cardiovascular disease, however this effect is often over-stated, and it is unrelated to the statin ability to lower cholesterol levels, rather it is likely related to pleiotropic effects.
(2) Second, there is very weak evidence that statins are useful for the primary prevention (in people deemed to be "at risk" of heart attacks or strokes) of future cardiovascular disease.
(3) Third, statins have an impressive list of potential adverse effects, and chances are good that a person on a statin will experience at least one or two of them.
Should you be on a statin? Make an informed choice based on the information presented above. If you have proven cardiovascular disease (have suffered from a heart attack or stroke), a statin is reasonable, but watch for adverse effects. If you have risk factors but no known cardiovascular disease, a statin will probably not confer much of a benefit on mortality, and you still have to watch out for adverse effects.
A Lack Of Trust
It may come as a surprise to know that the randomized controlled studies presented above have one major thing in common - the ones that claim statins are highly effective in reducing heart attacks and strokes, with a low adverse effect profile, were published prior to 2005, and nearly all of them were sponsored directly by a pharmaceutical company, or had authors directly compensated by a pharmaceutical company, whereas the ones questioning the effects of statins were published very recently, many of them not sponsored by a pharmaceutical company in any way.
Thus we come to the heart of the matter, the reason that many people disregard the advice of numerous prestigious cardiologists and turn to other less reputable alternatives such as Dr Mercola. The reason is simple. It is that many people do not trust the advice of their doctors any more. Why might this be? The answer is two-fold.
First, most practicing medical doctors learned in medical school that drugs were the best way to treat disease. We were all taught that drugs can thin the blood, lower blood pressure, reduce cholesterol - and they can. However, given the epic rise of the number one killer of our time, the metabolic syndrome (obesity, type 2 diabetes, high blood pressure etc), it is crystal clear that the drugs have failed, in a grand sense. Let's call a spade a spade - there are more people with metabolic syndrome than ever now. We now live in an era of metabolic disease, which requires metabolic therapies, such as dietary intervention (fasting, whole food diets, low-carbohydrate diets and so forth). The right diet reverses obesity. The right diet can cure type 2 diabetes. The right diet lowers blood pressure. The Lyon Diet Heart Study showed that the right diet (a Mediterranean-style diet) in people with known cardiovascular disease can reduce cardiovascular events to a more impressive extent than any statin, minus the adverse effects (28). Many doctors don't know this; they were never taught this. A fair number of people have a sneaking suspicion that this is the case - well, they're probably right.
Public enemy number one - the metabolic syndrome.
Second, and of greater concern, is the glaring fact that many prestigious medical doctors receive financial support from pharmaceutical companies as so eloquently described by the Canadian nephrologist and fasting specialist Dr Jason Fung (29). The more prestigious or academic the doctor, the more they are "on the take" - for example, of the 22 members of the Canadian Cardiovascular Society, 20 have received money from the pharmaceutical industry (29). Some prestigious cardiologists write papers stating that people who stop their statins will suffer "deadly consequences" (30), yet it would be relevant to know whether they received $80,000 US dollars from pharmaceutical companies last year (29). It's a terrible shame that the most expert of medical doctors are also the most compromised. These prestigious doctors, the ones educating medical students, general practitioners, and other physicians, the ones that ought to be safe-guarding the public, appear to have sold out on themselves.
The more prestigious the medical doctor, the more he or she tends to be on the take from Big Pharma.
Finally, we have arrived full-circle, realizing that while statins may stand in the midst of controversy within the realm of medicine, the controversy is not really about statins - like any drug, they have their uses, over-stated as they are; it makes no sense to be simplistically pro-statin or anti-statin. The real controversy, the thing that really bothers people, is that (1) many medical doctors today are not aware that we live in an era of metabolic diseases, that no drug can cure, and (2) many prestigious medical doctors are on the take from the pharmaceutical industry; they've sold themselves out.
It's not statins people hate; the statin debate is merely a flagship for the nescience and financial compromise that exist to variable degrees within the medical profession today. Is it really too much to ask our academic medical doctors to inform themselves on the power of dietary intervention in the greatest diseases of our time?
To stop taking money from Big Pharma?
Solace.
References
(1) Endo A. 2010. A historical perspective on the discovery of statins. Proc Jpn Acad Ser B Phys Biol Sci. 86(5), 484–493.
(2) Nordmann, Briel. 2012. Statins: pleiotropic, but less than previously thought. Eur Heart J 33(13), 1551-1552.
(3) McFarland et al. 2014. Molecular mechanisms underlying the effects of statins in the central nervous system. Int J Mol Sci. 10;15(11), 20607-20637.
(4) https://articles.mercola.com/sites/articles/archive/2016/02/10/5-reasons-why-you-should-not-take-statins.aspx.
(5) Wang et al. 2008. Pleiotropic effects of statin therapy: molecular mechanisms and clinical results. Trends Mol Med. 14(1), 37-44.
(6) Scandinavian Simvastatin Survival Study Group. 1994. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1389.
(7) Cholesterol and Recurrent Events Trial investigators. 1996. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. New Engl J Med 335, 1001–1009.
(8) The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. 1998. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 339, 1349–1357.
(9) Kristensen et al. 2014. The effect of statins on average survival in randomised trials, an analysis of end point postponement. BMJ Open. http://bmjopen.bmj.com/content/5/9/e007118.
(10) DuBroff. 2017. Cholesterol paradox: a correlate does not a surrogate make. Evid Based Med 22(1), 15–19.
(11) The FOURIER Steering Committee and Investigators. 2017. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. New Engl J Med 376, 1713-1722.
(12) Muldoon et al. 1990. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ 301(6747), 309-314.
(13) Lindberg et al. 1992. Low serum cholesterol concentration and short term mortality from injuries in men and women. BMJ 305(6848), 277-279.
(14) Sachdeva et al. 2009. Lipid levels in patients with coronary artery disease: an analysis of 136,905 hospitalizations in Get With The Guidelines. Am Heart J 157(1), 111-117.
(15) Akerblom et al. 2008. Relation of plasma lipids to all-cause mortality in Caucasian, African-American and Hispanic elders. Age Ageing 37(2), 207-213
(16) Schupf et al. 2005. Relationship between plasma lipids and all-cause mortality in nondemented elderly. J Am Geriatr Soc 53(2), 219-226.
(17) Shepherd et al. 1995. Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia. N Engl J Med 333, 1301-1308.
(18) Han et al. 2017. Effect of Statin Treatment vs Usual Care on Primary Cardiovascular Prevention Among Older Adults: The ALLHAT-LLT Randomized Clinical Trial. JAMA Intern Med 177(7), 955-965.
(19) Golomb et al. 2007. Physician response to patient reports of adverse drug effects: implications for patient-targeted adverse effect surveillance. Drug Saf 30, 669– 675
(20) Thompson et al. 2016. Statin-Associated Side Effects. J Am Coll Cardiol 67(20), 2395-2410.
(21) Sattar et al. 2010. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 375, 735-742.
(22) Culver et al. 2012. Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch Intern Med 172, 144-152.
(23) Silva et al. 2007. Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy. Clin Ther 29, 253–260.
(24) Dale et al. 2006. Does More Aggressive Statin Therapy Increase Muscle and Liver Risk? 55th Annual Scientific Sessions of the American College of Cardiology, Atlanta, GA, Mar 11-14.
(25) Collins et al. 2004. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 363(9411), 757-767.
(26) Amarenco et al. 2006. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 355(6), 549-559.
(27) Rabaeus et al. 2017. Recent Flaws in Evidence-Based Medicine: Statin Effects in Primary Prevention and Consequences of Suspending the Treatment. JCBMR 3(1), 1-10.
(28) de Lorgeril et al. 1994. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 343(8911), 1454-1459.
(29) https://idmprogram.com/corruption-academic-medicine/.
(30) http://annals.org/aim/article-abstract/2645554/statin-denial-internet-driven-cult-deadly-consequences.
