Statin adverse effects
How well have they been studied?
The statin class of drugs are widely prescribed to reduce blood cholesterol levels, according to the hypothesis that this will reduce the risk of heart disease and benefit the individual taking the statin. However, like most drugs, it is inevitable that statins will have unanticipated effects in certain individuals. While some of these effects might be beneficial (e.g. statins can be mildly anti-inflammatory), statins can also have unintended adverse consequences. What is surprising is that the adverse effects (AEs) of statins have received only superficial study — the benefits have received far more attention than the harms.
AEs from randomised controlled trials (RCTs)
While RCTs are considered the gold-standard for demonstrating the effectiveness of a drug such as a statin, they are at a disadvantage for detecting AEs because that is not their primary objective. Ten reasons why statin-related AEs may be underreported by RCTs:
1) Most statin trials have been funded by the drug company manufacturing the statin, creating a conflict of interest favouring benefit over harm;
2) The participants in a RCT have self-selected themselves (conditional on meeting the inclusion criteria) and are not necessarily representative of the more general target population for the drug. They are, for example, usually healthier;
3) The practice of eliminating people taking multiple medications (polypharmacy), the elderly or those with comorbidities (especially ones that may be exacerbated by the statin, such as liver, kidney or muscle disease) — thereby eliminating patients most at risk of AEs before the trial gets underway;
4) Some trials test statin compliance prior to inclusion in the study, further eliminating people who may not be compliant because of an AE;
5) Allowing for a ~10% dropout rate (that is, recruiting 10% more people than needed) to allow for people who withdraw during the trial, likely because of an AE. In earlier RCTs these people were not reported as having been part of the trial;
6) The definitions and scope of AEs are inconsistent;
7) The methodology and frequency of testing for AEs is rarely described in publications;
8) Not all AEs may be measured (e.g. cognitive decline) or, AEs may be based on patient self-reporting or physician discretionary reports;
9) AEs may be measured, but only selectively reported in publications;
10) RCTs run for only a relatively short period of time (a few years) compared to the exposure of people prescribed statins in general (which could be for decades). Thus RCTs cannot detect slowly-developing AEs that initially may not have clinical signs.
These points do not mean that RCTs cannot tell us something about AEs, even if they underestimate them. However, the results from RCTs are used for drug approval, which means that a drug may be approved before longer-term AEs become apparent.
In recognition of this problem, the US Food and Drug Administration (FDA) maintains a database, the Adverse Event Reporting System (AERS), and members of the public (or their physicians) can upload AEs that they have encountered at any time. This system has many limitations of its own, for example: the existence of the AERS is not common knowledge, and only a minority of AEs are likely to be uploaded; the AERS does not apply quality control over uploaded data, or check data for veracity, and; external factors (such as publicity or marketing) might influence reporting. However, the database can identify AEs that may warrant more detailed investigation.
The real-world experience
About half to three-quarters of people prescribed a statin for primary prevention discontinue by the end of the first year. The numbers are less, but not dramatically so, for people with chronic heart disease or a recent acute bout of heart disease. The most common complaints are those that affect quality of life, sometimes only subtly, such as muscle aches, weakness, fatigue (at the level of muscle or brain), or non-specific cognitive impairments such as ’fuzziness’ or ‘confusion’.
However, more insidious are the silent AEs that only manifest with time, such as new-onset type 2 diabetes, cataracts, liver and kidney damage and cognitive decline. All of these have been associated with statins to some degree. Statin advocates would say that these AEs are rare, and point to short-term RCTs to support that. However, AEs are likely more prevalent than realised and are important for the individuals experiencing them. Even at low-incidence, they can be significant. For example, the rate of new-onset diabetes is estimated at ~2%, whereas the benefit of statins for heart disease rarely exceeds ~1%, creating net harm. The FDA issued a warning for diabetes in 2012.
These AEs may be sufficient to explain why, on average, there is no reduction in all-cause mortality in people taking a statin.
Various surveys have indicated the importance that individuals place on AEs when making a decision to initiate, or continue to take, a statin. For example, in people considering a statin for primary prevention, the willingness to take medication is relatively insensitive to benefit but highly sensitive to AEs. This is true even for mild AEs that may still impact on quality of life (e.g. fatigue). Common mild AEs therefore take on an importance in the decision-making process. Nevertheless, physician and patient surveys show that discussion in a clinical setting is heavily biased towards benefits over AEs. Clinicians may discount AEs experienced by a patient or not ascribe the AE to the statin, or ascribe it to normal ageing (e.g. cognitive decline, cataracts). Conversations about AEs usually have to be initiated by the patient.
While the risks are manifest if there are indicative symptoms, the benefit of a statin is unknown for any given individual. So long as they remain alive, no-one taking a statin can know if the statin has helped them avoid a heart attack, however mild — the benefits are entirely statistical. Think of it this way: let’s assume we had a theoretical drug that genuinely reduced the incidence of a fatal heart attack by 5% (i.e. not a statin) and had no associated AEs. We could frame this by saying that out of 100 possible futures you might experience, 5 of them involve you living longer than you would have otherwise, and 95 of them don’t — but we cannot say which of those possible futures will be yours.
Over 75 years of age and healthy?
Current US cardiovascular guidelines for primary prevention in people over 75 years of age do not recommend statin therapy. The Pfizer data sheet for Lipitor (atorvastatin) recommends caution in people over 70.
AEs in older people are particularly troubling and may be more serious than in younger individuals. For example: muscle AEs may contribute to physical deconditioning, wasting and frailty; accelerated cognitive decline may contribute to reduced functional status and risk of falls, and; cataracts may impact visual-motor coordination and add to the risk of falls. Nevertheless, 2012 data from the US indicates that about half of the population over 75 years of age were being prescribed a statin.
Statins are designed to be intercepted by the liver, where they act to reduce cholesterol synthesis in the liver. Ultimately, statins are metabolised by liver enzymes and their breakdown products discharged through the bile duct to the small intestine and eliminated in faeces. Different statins have different liver selectivity, and individuals may have differing levels of liver enzymes or may be taking other medication (or even foods like grapefruit) that interfere with these enzymes. Thus, there is always potential for some level of statin to transit through the liver and enter the circulation. Circulating statins have the potential to affect multiple biological systems.
Some AEs and their possible mechanisms
This is the chief complaint from statin users. The main mechanisms thought to underly muscle symptoms are to do with energy availability and free radical damage. The cholesterol synthesis pathway (that is inhibited by statins) also produces a coenzyme abbreviated Q10. This is sometimes called ubiquinone — from ‘ubiquitous’ meaning everywhere — indicating its systemic importance. By reducing cholesterol synthesis, statins also reduce the levels of Q10. Q10 is important for energy production and free radical defence. The energy-producing organelles (mitochondria) in cells can become less efficient, more damaged by free radicals and reduced in number. It’s not a leap to imagine that the consequences for muscle cells could be fatigue and weakness.
In a study analysing the AERS database, it was concluded that the rate of muscle-related AEs for rosuvastatin were the highest across statins. Atorvastatin and simvastatin showed intermediate risks, while pravastatin and lovastatin had the lowest risk rates. Relative risk of muscle-related AEs, therefore, approximately tracked with statin potency. Other studies have indicated that muscle AEs also scale with dosage.
In rare instances (0.3–13.5 cases per 1,000,000 statin prescriptions, according to the FDA), muscle AEs can be life-threatening. Rhabdomyolysis is a serious condition in which muscle cells break down and release muscle proteins into the circulation. One of these proteins, myoglobin, can precipitate in the kidneys as they attempt to filter it out, causing acute renal failure.
There is evidence that long-term exposure to statins can increase the risk of polyneuropathy — multiple nerve damage, including nerves that innervate muscle.
Again, Q10 is implicated in this process. However, as well, cholesterol is an essential component of all human cell membranes, including nerve cells. By reducing cholesterol availability, statins have the potential to induce structural alterations in nerves that could be damaging. While these factors can act across multiple systems, damage to nerve fibres innervating muscle could induce neuromuscular dysfunction and add to muscle weakness. Damage to sensory fibres may underlie muscle pain.
Statins have the potential to cross from the circulation via. the blood-brain barrier (BBB) and thereby enter the brain. In 2012, The FDA added “memory loss and confusion” to statin labels. It was noted that these symptoms reversed with cessation of the drug.
Statins are particularly problematic for the brain because cholesterol is fundamental to virtually all aspects of brain function. About 20% of total body cholesterol is contained in the brain even though the brain accounts for only 2% of bodyweight — the brain cannot function without it.
Cholesterol from the circulation does not cross the BBB, hence cholesterol synthesis within the brain is essential to supply demand for this biomolecule. By crossing the BBB and interfering with this process, statins have the disturbing potential to interfere with brain function.
Statins probably cross the BBB by passive diffusion. It is generally thought that this depends on whether the statin is more fat-soluble than water-soluble. The more fat-soluble statins include simvastatin (highest solubility), fluvastatin, atorvastatin and lovastatin. The more water-soluble statins are rosuvastatin and pravastatin. However, there is also evidence that it is more complex than this, and that other properties of statins, besides their fat-solubility, matter. A conservative approach would be to assume that all statins cross the BBB to some degree. As well, because this is diffusion-driven, a higher statin dosage would be expected to increase diffusion into the brain. Statin potency will also be a factor (e.g. rosuvastatin may cross the BBB poorly, but have a disproportionate effect because of its potency).
Cataract surgery rates in the US have more than doubled in the last two decades, a statistic that cannot be fully explained by an ageing demographic. Cholesterol is particularly important for the human crystalline lens because it requires high cholesterol for proper membrane formation and to maintain its transparency. The risk of cataract formation returns to normal within ~1 year after stopping statin treatment. One of the first drugs targeting the cholesterol synthesis pathway, developed in the 1960s, was withdrawn from the market because of an increased incidence of cataracts.
Type 2 diabetes is a known risk factor for heart disease, and most diabetics would be on statins. As well, statins are widely prescribed for people with elevated cholesterol but without heart disease or diabetes. Exacerbating or inducing diabetes in either group is a significan AE.
Statins can interfere with insulin-mediated uptake of glucose by liver cells, thereby resulting in more glucose in the circulation and an increase in glycated haemoglobin (HbA1c) in the blood, both of which are precursors for diabetes. Furthermore, cholesterol is important for the functioning of membrane proteins associated with glucose transport into the cell (through lipid rafts). Additionally, while statins block the cholesterol synthesis pathway early on, they do not do so right at the start of the pathway, leading to an accumulation of a biochemical (acetyl CoA) upstream of the statin-block. This is diverted to the fatty acid synthesis pathway, thereby causing an accumulation of free fatty acids. The liver has a number of options at this point, one of which is to convert the fatty acids to glucose (called gluconeogenesis) and release it into the circulation. There are also other proposed mechanisms of action, including effects on the pancreas.
I have probably gone into too much detail here, but the point is that we have a complex biology, and there are many unforeseen ways that it can be upset when we poke it in the eye with a statin.
This topic remains controversial and I have provided a curated perspective. The study of AEs has been given scant attention by medical authorities, and seems out of step with patients’ experience. Uncertainty as to the risk of acute and chronic AEs remains.
Meanwhile, exercise and diet are more powerful than any statin.
Disclaimer: I am not a medical doctor. Nothing herein is, nor should be taken to be, medical advice.