Statins: Apocalypse or Pleiotropic Nirvana?
A 65 year old male with previous 2 vessel coronary artery bypass surgery at age 50 and severely elevated LDL-C at 219 mg/dL (see:The Repeat Offender (The Heart Attack Survivor)) with a strong family history of premature coronary artery disease (brother died of a heart attack in his mid 40’s and his father had his first heart attack in his 50’s and died of another in his 70s) is referred to the cardiology clinic.
He declines statin therapy due to beliefs in the “inflammation theory of atherosclerosis” through his own readings and research. He further explains that since he works in the nutraceutical industry, he fears his boss would look down upon him if he found out he was taking a statin.
After much counseling, he agrees to try a statin. At the follow up visit 2 months later, however, he admits he never started it; favoring diet and lifestyle measures which he proudly reports dropped his LDL-C by 30 points to 189 mg/dL. The cardiologist congratulates him on the positive change, but informs him that it isn’t enough to significantly alter the course of the disease. He again agrees to reconsider the statin.
His cardiologist submits genetic testing through Ambry Genetics, which confirms suspicion for heterozygous familial hypercholesterolemia (see: Hiding in Plain Sight - Familial Hypercholesterolemia) and the statin myopathy gene. He cancels his follow up visit and this time returns 6 months later and reports that he failed the statin due to fatigue and myalgias. He is prescribed evolocumab (Repatha), a PCSK9 monoclonal antibody inhibitor.
It’s the beginning of the year and with insurance coverage changes, another 6 weeks goes by and the expensive branded drug is finally approved. By this time, he is enjoying a much anticipated extended vacation in Hawaii and sends a message asking for the prescription to be sent to a local pharmacy.
4 weeks later he suffers sudden cardiac arrest while surfing. After 75 minutes of CPR by surrounding surfers, weeks in the ICU, intubated, on continuous dialysis, with discussions of withdrawing care, he makes a miraculous full recovery and returns to see his cardiologist in clinic.
Flying Under the Radar
Why do these cases go undertreated?
This case above illustrates several layers of complexity, making this phenotype a particularly dangerous, underappreciated, undertreated and forgotten patient.
It’s not as simple as “take your medicine.” Or, “trust us, we’re doctors.” These issues are nuanced and require individualized discussion and education on both sides of the patient-clinician relationship.
While there may be obstacles in treating this phenotype, failure is not an option. Not today. Not with the tools we currently have available.
Statins are highly effective, safe, inexpensive and widely available medications. However, they may not be enough. Statins, apart from the LDL-C lowering effects (which represents an historical medical revolution), don’t necessarily offer additional “magical” qualities.
Don’t let statin intolerance prevent you from tackling and overcoming atherosclerotic disease. We have more than one tool now for eradicating heart disease.
A checklist of targeted recommendations based on published guidelines
- Visit the ACC Statin Intolerance App - American College of Cardiology to further assess for typical characteristics of statin intolerance and expert guidance and management
- Consider more common alternative causes for myopathy
- DOMS (Delayed Onset Muscle Soreness) following a workout
- Degenerative Joint Disease
- Degenerative Arthritis
- Hypothyroidism
- Vitamin D deficiency
- Reduce dose of current statin to ¼ of previous dose
- Switch to another statin
- Try a combination approach with lower dose of statin with ezetimibe
- Hack: ezetimibe typically reduces LDL-C only 10-15% when used as sole therapy, but when coupled with any statin, will produce 20-25% reduction in LDL-C
- So, ezetimibe, when used with any modest intensity statin or dosing is equivalent to high intensity statin (> 50% LDL-C reduction)
- Consult with a lipid specialist
If considering taking a statin:
Going into detail on the evidence behind the recommendations and history of treatment for this phenotype.
Undertreated
Patients with statin intolerance are invariably undertreated for their cardiometabolic risk. There are a number of reasons for this. As illustrated above, there are inevitable delays in achieving adequate treatment. The higher their baseline risk, the more aggressive the treatment needs to be to achieve the more rigorous therapeutic targets for optimal management. Coupled with typical delays in healthcare access, unforeseeable appointment cancellations, the need for repeat laboratory testing and insurance prior authorizations to include the requirements to try and fail multiple statin regimens and combinations (not an unreasonable request, but a delay nonetheless) it’s not hard to fathom months, if not years going by before a patient finally achieves therapeutic goals. The majority never do. And that’s AFTER the clinician gets buy-in from the patient.
How Common is Statin Intolerance?
In randomized clinical trials (RCT), 1:1000 blinded patients stop their statin due to adverse effects, mostly myalgias. In clinical practice (prevention clinic), about 15% of patients report adverse effects. The truth lies somewhere in between. There are biases present everywhere. This topic is no different. RCT participants suffer from a participation bias. They tend to tolerate things.
Clinical trials using patients as their own control (double crossover), demonstrate that the vast majority (90%) of cases of statin intolerance are attributable to the nocebo effect, meaning that they attribute an unfavorable side effect to a placebo. But that leaves 10% experiencing true myalgias. In the case above, the patient tested positive for the simvastatin statin myopathy gene, which may increase the likelihood of true statin myopathy and intolerance. It is well documented that patients with FH tend to have a higher rate of statin myopathy. They also tend to have a blunted response to statins (or any LDL lowering therapy which works by upregulating LDLR).
The Forgotten Patient
When patients become labeled as “statin intolerant,” they often fail to achieve optimal lipid levels despite the availability of alternative techniques and highly effective and safe non-statin therapies. The reasons for this are multifactorial. Clinicians often lack the tools to distinguish true statin intolerance from other more common complaints. Even with such tools, they often lack the time (and sometimes interest) to spend with patients on this particular issue. Patients on the other hand, are exposed to a plethora of misinformation - whether it’s from Aunt Sally, their neighbor Joe or the growing number of “self-proclaimed” non-medical experts promoting misinformation on social media to enhance their followership (See: The Straw That Breaks the Camel's BacK - LMHR (Lean Mass Hyper Responder). This, coupled with the growing struggles with access to specialists leads suboptimal treatment of an already identified high risk population of patients.
This is particularly frustrating when, as described elsewhere, we’ve already cleared two big hurdles in 1) Identifying a high risk patient and 2) getting that patient access to a clinician capable of treating such cardiometabolic risk, only to be tripped up by a poorly understood but exaggerated entity, sending patients running away from the therapy that may save their lives.
Whether its frustration, apathy or the lack of access or time this aspect of cardiometabolic risk becomes listed in the chart as “statin intolerance” as if to say “well, we tried and it didn’t work, so stop addressing it” and the patient is left behind. This unfortunately becomes a major source of “residual risk.”
Risk of Dementia
There has been no signal of dementia with regards to statins. Aggressive lowering of LDL-C has not demonstrated any increased risk for dementia, cognitive dysfunction or hemorrhagic stroke. See this Scientific statement from the American Heart Association: Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke: A Scientific Statement From the American Heart Association | Arteriosclerosis, Thrombosis, and Vascular Biology
Risk of Liver Damage
The following statements can be obtained from: An assessment by the Statin Liver Safety Task Force: 2014 update - Journal of Clinical Lipidology
- Statins are associated with elevated liver enzymes
- Statin-associated elevations in liver enzymes are not indicative of liver damage or dysfunction
- Statins do not increase the risk of liver failure
- Routine liver enzyme checks are not recommended for monitoring patients taking statins
- Statins are safe with nonalcoholic fatty liver disease (NAFLD)
- Chronic liver diseases to include compensated cirrhosis are not contraindications for statins
Statins should be stopped when liver enzymes are greater than 3 times the upper limit of normal, to allow for appropriate diagnostic workup and rule out all potential causes.