Are The Numerous Adverse Risks of Taking Statins Worth It?
by James Odell, OMD, ND, LAc
Part 1 Understanding and Managing Cholesterol Bioregulation (in the BRMI May E-Journal) discussed the bioregulatory importance of cholesterol and specific factors that can corrupt this molecule, leading to its potential participation in cardiovascular disease risk. This article will focus more specifically on statins and the ongoing controversy around their usage.
Managing Cholesterol Bioregulation
During the last 20 years, the industry has mounted an incredible promotional campaign, enlisting scientists, advertising agencies, the media, and the medical profession that has turned statins into one of the bestselling pharmaceuticals of all time. Today, over sixteen million Americans take Lipitor® (atorvastatin calcium), the most popular statin, and drug company officials claim that 36 million Americans are candidates for statin drug therapy. However, what the industry does not want to report is the growing list of side effects that manifest after the commencement of statin therapy.
Understanding How Statins Work and Their Metabolism
Statins are a class of drugs that inhibit the enzyme HMG-CoA reductase. The biochemical process begins with acetyl-CoA, a two-carbon molecule sometimes referred to as the “building block of life.” Three acetyl-CoA molecules combine to form six-carbon hydroxymethyl glutaric acid (HMG). HMG then converts to mevalonate and this step from HMG to mevalonate requires the enzyme, HMG-CoA reductase. Statins inhibit this enzyme and are thus called HMG-CoA reductase inhibitors. Inhibiting this enzyme has consequences downstream that can lead to side effects.
Statins have become the mainstay of chemical therapy for elevated LDL cholesterol and are among the most profitable medicines generated by the pharmaceutical industry. The first statin that was produced was lovastatin by Merck. Since then, numerous other statins have come to market. Statins that are currently marketed include atorvastatin (Lipitor®), fluvastatin (Lescol®), lovastatin (Mevacor® or Altoprev™), pitavastatin (Livalo® or Zypitamag®), pravastatin (Pravachol®), rosuvastatin (Crestor® or Ezallor Sprinkle®), and simvastatin (Zocor® or Flolipid®).
Statins as a family differ in their metabolism, and this can determine the character, effectiveness, and severity of side effects. Statins, lovastatin, and simvastatin are administered as pro-drugs that must be activated within the body.1 Human cytochrome P450 (CYP) enzymes play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. Most statin metabolism occurs primarily through CYP3A4 for simvastatin, lovastatin, and atorvastatin, whereas fluvastatin is metabolized mainly through CYP2C92, 3 and Rosuvastatin also is slowly metabolized through CYP2C19.
This is important because some individuals have defects in certain cytochrome pathways that inhibit the metabolism of drugs through that enzymatic path. For example, CYP3A4 is often considered the most important drug-metabolizing enzyme, given its relatively high expression in the liver and intestine. Certainly, CYP3A4 is among the most abundant CYP enzymes in the liver composing approximately 15–20% of hepatic CYP content. CYP2C9 accounts for approximately 20% of total hepatic CYP content and metabolizes approximately 15% of clinically used drugs. Thus, genetic impairments of either of these pathways (single nucleotide polymorphism or SNP) will reduce the metabolic activity for the associated drug substrates. With current genomic testing, it can now be determined if there are SNPs in any of the cytochrome enzyme pathways that would impair drug metabolism.
The statins also differ in their order of lipophilicity which refers to the ability of a chemical compound to dissolve in fats, oils, and lipids. Thus, this leads to the observation that some statins cross the blood-brain barrier, while others do not. Lovastatin and (to some extent) simvastatin are lipophilic, which allows them to cross the blood-brain barrier, while pravastatin and atorvastatin are hydrophilic and do not cross the blood-brain barrier. This becomes more important when considering their potentially toxic impact on the brain and CNS, particularly in relation to Alzheimer’s disease and other CNS degenerative diseases. Simvastatin and lovastatin are administered in an inactive lactone form that is converted to an active form in the body. In contrast, atorvastatin, fluvastatin, pravastatin, rosuvastatin, and pitavastatin are administered in active acid form.4
Hydrophilic statins require carrier-mediated uptake into the liver, whereas lipophilic statins can passively diffuse through the cell membrane, which decreases their hepato selectivity as they are also able to diffuse into other tissues. Lipophilic statins are generally cleared via oxidative biotransformation, whereas hydrophilic statins are excreted unchanged.5, 6, 7
Biochemical Mechanisms of Side Effects
Statin drugs not only inhibit the production of cholesterol but a whole family of intermediary substances, many if not all of which have important if not critical biochemical functions. Both inhibiting all-important cholesterol synthesis and its intermediaries are in part the reason why statins cause side effects. Cholesterol is one of three end products in the mevalonate chain. The two others are ubiquinone and dolichol. Ubiquinone or coenzyme Q10, is a critical cellular nutrient biosynthesized in mitochondria. It plays a role in ATP production in the cells and functions as an electron carrier to cytochrome oxidase, our main respiratory enzyme. Coenzyme Q10 (both in its oxidized ubiquinone and reduced ubiquinol forms) and ‘heme-A’ are essential components of the electron transport chain and are synthesized from prenyl-intermediates in the cholesterol pathway. Statins inhibit coenzyme Q10 and ‘heme-A’ biosynthesis and thereby impair ATP generation.
The heart requires high levels of coenzyme Q10, and it is critical to nerve conduction and muscle integrity. The bioenergetic effect of coenzyme Q10 is believed to be of fundamental importance in its clinical application, particularly as it relates to cells with exceedingly high metabolic demands such as cardiac myocytes (cells of the myocardium). Coenzyme Q10 is also vital to the formation of elastin and collagen.
Squalene, the immediate precursor to cholesterol, is in turn the biochemical precursor to a whole family of steroid hormones. Research indicates that squalene inhibits blood vessel formation in tumors, raising the possibility that it may have anti-cancer effects.
Biochemical Pathways Inhibited by Statins
Dolichols also play a role of immense regulatory importance. In the cells, dolichols direct various proteins ensuring that the cells respond correctly to genetically programmed instructions. The phosphorylated form, dolichyl phosphate, is required for the biosynthesis of biologically important N-linked glycoproteins. Dolichols are essential for glycoprotein and glycolipid biosynthesis, and their suppression by statins would produce modified glycoproteins. This, for example, could result in an un-glycosylated insulin receptor, thus adversely affecting insulin status. In short, the inhibition of dolichols by statins can result in numerous side effects.
Thus, because statin drugs inhibit the mevalonate metabolism, they can cause a multitude of downstream chaos on the cellular level. Particularly, the side effects of coenzyme Q10 deficiency include muscle wasting leading to weakness and severe back pain, heart failure of the myocardium, neuropathy, and inflammation of the tendons and ligaments, often leading to rupture. Other statin-mediated side effects include cataracts, gastrointestinal effects, urogenital health effects, gynecomastia, and reproductive effects, most of which have been purported to be a result of reduced production of intermediate and end products of the mevalonate pathway.
The major reason for the discontinuation of statin therapy is statin-associated muscle symptoms (SAMSs). which are the most well-documented side effects of statins.8 SAMSs are by far the most prevalent and important adverse event, with up to 72% of all statin adverse events being muscle related.9 These can manifest as myalgia, myopathy, myositis with elevated CK (creatinine kinase), or at its most severe, rhabdomyolysis, with some people reporting severe joint and abdominal pain.10 Other skeletal-related side effects include tendinopathies and tendon disorders, as well as arthralgias.
SAMS usually presents a symmetrical (bilateral) condition that affects the large proximal muscles, particularly the lower extremities. Symptoms can occur at rest or shortly after exercise and usually occur within 1 month of initiation of therapy or after an increase in dosage.11, 12
The test for muscle wasting or rhabdomyolysis is elevated levels of a chemical called creatine kinase (CK). But many people experience pain and fatigue even though they have normal CK levels. Thus, there is a lack of universal definitions of statin toxicity, particularly concerning SAMS. This means laboratory biomarkers identifying either risk of developing adverse events or confirming their presence have not been clearly identified.
Peripheral neuropathy is characterized by weakness, tingling, and pain in the hands and feet, as well as difficulty walking. Long-term statins therapy, mainly with atorvastatin and simvastatin, is linked with the development of peripheral neuropathy.13, 14 Researchers who studied 500,000 residents of Denmark, about nine percent of that country’s population, found that people who took statins were more likely to develop polyneuropathy.15 The damage is often irreversible.16 People who take large doses for a long time may be left with permanent nerve damage, even after they stop taking the drug.17 Physicians and pharmacists should be aware of this potential toxicity and monitor patients appropriately.
Now we have reached the true heart of the matter. Probably the most concerning adverse reaction with HMG-CoA reductase inhibitors (statins) is the myotoxicity effect on the myocardium as well as their potential to create atherosclerosis in the coronary arteries. Statins inhibit the production of mevalonate, a precursor of both cholesterol and coenzyme Q10, a compound crucial for mitochondrial function and the provision of energy for cellular processes. The myocardium cannot function properly when deprived of coenzyme Q10, and this can weaken cardiac output and result in potential myocardial damage (degeneration of the myocytes).
Equally concerning, mounting evidence now points to statins as a potential causative factor in coronary artery calcification. This occurs through the depletion of coenzyme Q10 and ‘heme-A’, (impairing ATP generation), and inhibiting critical selenium enzymes, necessary for protecting the heart vessels from plaque. 18, 19, 20, 21, 22, 23, 24 Statins inhibit the synthesis of vitamin K2, the cofactor for matrix Gla-protein activation, which in turn protects arteries from calcification.25, 26, 27
Statins inhibit the biosynthesis of selenium-containing proteins, one of which is glutathione peroxidase serving to suppress peroxidative/oxidative stress.28, 29 An impairment of selenoprotein biosynthesis may be a factor in congestive heart failure, reminiscent of the dilated cardiomyopathies seen with selenium deficiency. Thus, the epidemic of heart failure and atherosclerosis that plagues the modern world may paradoxically be aggravated by the pervasive use of statin drugs.
Statin research on the myocardium is still in its infancy and lacks extensive research to prove long-term safety. From research thus far, it is counterintuitive that patients are placed on statins to prevent cardiovascular disease when in fact they can potentially weaken the myocardium and cause biochemical chaos that may result in plaquing of the coronary arteries. Yet, doctors continue to prescribe statins to lower cholesterol levels in their patients in ever greater amounts. Many patients have existing heart failure and low cholesterol levels but are still prescribed statin drugs. Physicians must be certain that no harm comes to patients by creating a widespread deficiency of a nutrient critically important for normal heart function.
To date, most studies of statins and cognition have been observational, with few randomized controlled trials. Randomized trials, case reports, observational studies, and post-marketing surveillance have all reported data regarding cognitive impairment in people using statins.30, 31 Symptoms of confusion, forgetfulness, and memory loss have been reported within a few days after therapy, while other reports described symptom onset years after commencing statin use.
Observations indicate that statins seem to cause a range of cognitive problems, especially in elderly patients. This concern was enough for the FDA to issue a warning cautioning that statins may cause cognitive impairment in certain individuals. Of course, aging populations face an increase in disease burden due to chronic neurodegenerative conditions, among which dementia is a major contributor.
Numerous factors play into this age-related cognitive decline. A deficiency of cholesterol from inhibition of HMG-CoA reductase may certainly be a part of that cause. Cholesterol is critical to brain architecture and function of the brain and CNS. Brain cholesterol is involved in synapse development, synapse formation, dendrite differentiation, axonal elongation, and long-term potentiation.32, 33 Although the human brain only accounts for about 2% of total body weight, it contains as much as 25% of cholesterol and cholesterol derivatives. Cholesterol is essential for the formation and function of the brain's membranes, synapses, myelin, and lipid rafts. If the brain does not have enough cholesterol, these structures cannot form or function properly.
Thus, it is not surprising that statins can result in cognitive impairment. Randomized trials that were designed to assess the cognitive effects of statins have shown a worsening in cognitive function.
There have been reports involving global transient amnesia, or complete memory loss for a brief or lengthy period. Sufferers report incidents involving complete loss of memory, such as arriving at a store and not remembering why they are there, unable to remember their name or the names of their loved ones and being unable to find their way home. These episodes occur suddenly and disappear just as suddenly. One case was described by former astronaut Duane Graveline in his book Lipitor: Thief of Memory.
Because of the potentially grim nature of cognitive dysfunction patient reports regarding cognition should be taken seriously and appropriately evaluated.
Renal (Kidney) Toxicity
Controversy still exists about the effects of statins on renal function. Except for hydrophilic statins (pravastatin and rosuvastatin), other statins are metabolized by the liver and minimally cleared by the kidney. However, mild to moderate proteinuria is sometimes seen with statin treatment. Proteinuria is a marker for the diagnosis and prognosis of kidney disease. It is still not determined what long-term statin use has on renal function. Those individuals with impaired renal function are usually advised to avoid statins.34
Androgen (Testosterone, DHEA) Depletion
Statins are also associated with reductions in androgens (testosterone and DHEA) as they inhibit the production of the substrate (pregnenolone) required for their production. An early meta-analysis highlighted the testosterone-lowering effect of statins in both men and women.35, 36 This may lower libido and affect the ability to achieve an orgasm.37 Libido is related to serum testosterone levels: lower testosterone levels decrease male libido.38, 39
Testosterone in males is produced mainly in the Leydig cells, where cholesterol is the main substrate. The Leydig cells can absorb cholesterol from the blood via the LDL receptor but are also capable of de novo cholesterol synthesis.40 In biochemistry de novo synthesis (from Latin 'from the new') refers to the synthesis of complex molecules from simple molecules such as sugars or amino acids, as opposed to recycling after partial degradation.
Statins may interfere with the synthesis of testosterone in three ways. First, by decreasing plasma LDL-cholesterol, HMGCoA-reductase inhibitors lower the total amount of cholesterol offered to the Leydig cell. Statins are rather liver selective but are found in small quantities in the testes, where they can inhibit the de novo synthesis of cholesterol out of acetate by HMGCoA-reductase. Lastly, certain statins directly suppress testosterone synthesis by inhibiting the 17-ketosteroid-oxidoreductase catalyzed conversion from dehydroepiandrosterone and dehydroandrostenedione to androstenediol and testosterone, respectively. This inhibition lowers testosterone.41, 42, 43
Fetal exposure to statins may also result in adverse effects, and this is particularly relevant when considering patients with familial hypercholesterolemia who require lipid-lowering therapy from an early age. A recent cohort analysis of pregnant women found that statin exposure during the first trimester was associated with an increased risk of fetal ventricular septal defect, and there was a higher incidence of congenital cardiac abnormalities in pregnancies exposed to statin therapy.44, 45 It has been shown that there is an association between first-trimester statin exposure during pregnancy and fetal ventricular septal defect.46
Certainly, more information about the long-term effects of in-utero exposure to statins and the effect on other neonatal outcomes are needed before statin use during pregnancy can be considered safe.
Cancer And Immunity
The mevalonate pathway downstream products play critical roles in the different steps of the immune response, including immune cell activation, migration, cytokine production, immune metabolism, and immune cell survival. Thus, inhibiting this important metabolic pathway can have a detrimental effect on overall immune function. Manufacturers of statin drugs have long recognized the fact that statins depress the immune system, an effect that can lead to cancer and infectious disease. Because these drugs can suppress immunity they are often recommended as an immune suppressor for transplant patients.47, 48, 49
Early studies in animal models raised concerns that statins may have carcinogenic properties. A review of findings on rodent carcinogenicity of lipid-lowering drugs reported that all statins available in 1994, initiate or promote cancer in rodents at concentrations equivalent to those commonly prescribed in humans.50
It has been also shown that disruptions of these processes in cancer cells by statins in some cases may result in control of tumor initiation, growth, and metastasis, which has been shown to inhibit cancer cell growth.51, 52, 53, 54 It has also been suggested that the possible tumor suppressive activity of statins was linked to downregulating or inhibiting matrix metalloproteinases (MMPs).55 MMPs degrade extracellular matrix components involved in processes such as tumor growth, invasion, and metastasis.
Certainly, there is still not enough evidence to advocate statins as an anticancer therapy. Thus, statins cannot be recommended for the prevention of any site-specific cancer or the improvement of cancer among patients with already diagnosed cancers until further trials have been performed. Some people have adverse reactions to statins shortly after taking them and their potential carcinogenicity in the long term is still questionable and debatable. The reason why we have not seen a definitive correlation between statins and cancer in human studies is that cancer takes a long time to develop and most statin studies on carcinogenesis have been short-term.
Coenzyme Q10 Supplementation
Coenzyme Q10 is an endogenous lipid-soluble antioxidant found naturally throughout the body, with the highest levels in the heart, liver, kidney, and pancreas. One of its primary functions is to improve mitochondrial respiration by creating adenosine triphosphate (ATP), which is involved in cellular energy transfer. It also serves as an antioxidant and protects cells against oxidative damage. High oxidative stress and chronic inflammation can contribute to the pathogenesis of coronary artery disease (CAD). Deficiencies of coenzyme Q10 can result in several neurologic and myopathic syndromes. Statins interfere with the production of mevalonic acid, which is a precursor in the synthesis of coenzyme Q10. The statin medications routinely result in lower coenzyme Q10 levels in the serum and muscle tissue adversely affecting cellular energy. Such coenzyme Q10 deficiency is one mechanism that causes statin-induced myopathies and neurological impairments.
Thus, many physicians and health care providers recommend that those individuals taking statins be supplemented with coenzyme Q10. Some studies have shown that coenzyme Q10 to alleviate statin-induced myalgia and neuropathy.56, 57, 58
However, in one study CoQ 10 supplementation improved endothelial dysfunction in
statin-treated type 2 diabetic patients, possibly by altering local vascular oxidative
stress, 59 while others have not. 60, 61
Essentially coenzyme Q10 supplementation at 300 mg daily significantly enhances antioxidant enzyme activity, restores lost coenzyme Q10 levels, and lowers inflammation in patients on statins therapy.62
Coenzyme Q10 supplements come in two forms: ubiquinone and ubiquinol. There seems to be an ongoing marketing controversy over which form is better. The truth is both forms work well to restore intercellular coenzyme Q10. Many manufacturers now market the ubiquinol form, telling consumers it is the superior form of coenzyme Q10 because it is better absorbed than other forms of Coenzyme Q10. However, one notable thing about ubiquinone is its history. There have been thousands of clinical trials conducted with ubiquinone, but very few with ubiquinol. Ubiquinone is also less expensive than ubiquinol. Some individuals report that they take both forms and reap the benefits of both.
Most doctors are convinced and seek to convince their patients that the benefits of statin drugs far outweigh the side effects. They can cite several pharmaceutical-paid studies in which statin use has lowered the number of coronary deaths compared to controls. The adverse effects that worry patients and their physicians most frequently are those related to muscular symptoms. Many physicians are unaware of all the far-reaching adverse consequences that statins can cause. Adverse effects appear to be related to the type and doses of statins used, the duration of treatment, as well as the physical condition of the individual. Importantly, patients must be informed of all statin’s adverse effects, including the ability to cause coronary heart disease and heart failure, the onset of diabetes mellitus, carcinogenicity, teratogenicity and fetal harm, and central and peripheral nervous disorders besides the well-known rhabdomyolysis and liver toxicity. Most of these adverse effects of statins become apparent some months after the commencement of the drug.
Aside from potential side effects, statin drugs are very expensive. A course of statins for a year cost between $900 and $1400. They constitute the most widely sold pharmaceutical drug, accounting for 6.5 percent of the market share and 12.5 billion dollars in revenue for the industry. Of course, insurance companies may pay most of that cost, but consumers always ultimately pay higher insurance premiums.
Numerous other dietary and lifestyle strategies that can improve one’s cardiovascular health are equally effective as statins without the risk and without cutting off the body’s vital supply of cholesterol.
Consider the following:
Taking antioxidants prevents cholesterol from oxidizing – Vitamin C, E, and coenzyme Q10.
Avoid trans-fats, known to contribute to inflammation.
Avoid excess sugar and especially refined sugars like fructose, and artificial sweeteners such as aspartame; these are known to stimulate clumping of the blood platelets.
Taking cod liver oil, or algae oil is an excellent dietary source of anti-inflammatory vitamin A, vitamin D, EPA, and DHA
Taking evening primrose, borage, or black currant oil, as a source of GLA which the body uses to make anti-inflammatory prostaglandins.
Eating foods high in copper - copper deficiency is associated with clot formation and inflammation in the arteries.
Avoid reduced-fat milk and powdered milk products (such as powdered whey); they contain oxidized cholesterol, shown to cause irritation of the artery wall.
Eating sulfur rich foods (garlic, onions, cruciferous vegetables). When a diet is sufficient in sulfur and there is adequate circulating cholesterol, sunlight catalyzes the blood cells, platelets, and cells in the skin to form cholesterol sulfate. Cholesterol sulfate is water-soluble, so it can travel freely in the blood without needing to be packaged up inside an LDL particle. This amazing negatively charged molecule leads to decreased aggregation of red blood cells thus preventing clots, improves the gradient between arterial and venous flow, and is used in the building and repair of all cells.
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25. Schlieper G, Westenfeld R, Kruger T, et al. Circulating nonphosphorylated carboxylated matrix gla-protein predicts survival in ESRD. J Am Soc Nephrol 2011;22(2): 387-95.
26. Nielsen SF, Nordestgaard BG, Bojesen SE, et al. Statin use and reduced cancer-related mortality. N Engl J Med 2012;367(19): 1792-802. This large-scale, cohort study of Danes, compares statin users and statin non-users. This is a good example of the risk of simply reading the abstract without examining the presented data; the possibility of statins causing cardiovascular diseases is obvious in the data presented.
27. Silver MA, Langsjoen PH, Szabo S, et al. Effect of atorvastatin on left ventricular diastolic function and ability of coenzyme Q10 to reverse that dysfunction. Am J Cardiol2004;94(10):1306-10. This study demonstrates that statins commonly produce diastolic dysfunction, a precursor to heart failure, in previously healthy subjects.
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34. Mach, François, Kausik K. Ray, Olov Wiklund, Alberto Corsini, Alberico L. Catapano, Eric Bruckert, Guy De Backer et al. "Adverse effects of statin therapy: perception vs. the evidence–focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract." European heart journal 39, no. 27 (2018): 2526-2539.
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42. Libido is related to serum testosterone levels and lower testosterone levels decrease both male and female libido.
43. De Graaf, L., A. H. P. M. Brouwers, and W. L. Diemont. "Is decreased libido associated with the use of HMG‐CoA‐reductase inhibitors?." British journal of clinical pharmacology 58, no. 3 (2004): 326-328.
44. Lee, Ming-Sum, Avetis Hekimian, Tanya Doctorian, and Lewei Duan. "Statin exposure during first trimester of pregnancy is associated with fetal ventricular septal defect." International journal of cardiology 269 (2018): 111-113.
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