Table 2.

Further information on the five additional cases

Dr. C Irritability Muscle pain Fatigue	(1) Following initiation of statins, Dr. C developed fatigue and muscle pain. New development of irritability/short temper toward coworkers, though not noted by Dr. C., was noted by coworkers, leading to professional action/referral. Statin discontinuation led to resolution of fatigue/muscle symptoms (judged by Dr. C) and irritability (judged by coworkers)
	(2) At Dr. C’s suggestion of a possible statin link, Dr. C’s physician acknowledged that he had heard of side effects with rosuvastatin at the 40 mg dose. At Dr. C’s request, the psychiatrist to whom his employer referred Dr. C communicated with physician investigators familiar with behavioral changes as a manifestation of statin AEs, who advised that the behavioral manifestations could represent a statin AE, with likelihood of a statin foundation augmented by concurrent development of fatigue and muscle symptoms. On this basis the statin was discontinued
	(3) Dr. C’s employer referred him for psychiatric evaluation because of behavioral problems at work
	(4) Dr. C. previously held statins in favorable opinion, he now says, “I have no interest in going back on statins.” He reports awareness that statins can lead to behavioral changes, and deems more education on statin AEs is needed
	(5) Professional review, psychiatric evaluation
Dr. D Mitochondriopathy Myopathy Fatigue Exercise intolerance	(1) Dr. D. experienced a clear decline in exercise tolerance that progressed over a 4 year period on statins, with development and progression of myalgias ultimately rated 8–9/10 in severity, and extreme lethargy. Discontinuation of statins led to gradual improvement in muscle pain: 3.5 years after statin discontinuation, he reports 75% improvement in myalgias, however, there has been no discernible improvement in exercise intolerance
	(2) Dr. D’s non-physician sister proposed the statin connection after she herself suffered intolerance. Dr. D’s physicians were generally dismissive of a statin connection. Dr. D describes a “pervasive skepticism” at the idea, with physicians “rolling their eyes” at the suggestion, even when he presented them with literature supporting the relationship
	(3) Referrals were made to cardiology, rheumatology, and neurology. Testing encompassed blood tests, MRI brain and spine, multiple cardiac catheterizations, EMG/NCS, and ultimately a muscle biopsy with mitochondrial testing. The NCS identified conduction problems of unclear etiology. The biopsy report read “reproducible abnormalities were found most prominently in complexes II-III (succinate cytochrome C reductase) and complex IV (cytochrome C oxidase) with reductions to 12 and 18% of their respective normal means. This patient is considered to have statin-induced myopathy”
	(4) Dr. D. described his own prior attitude toward statins as “elementary and naïve, that they were bad in some people, but that there would be clear manifestations and happen quickly within weeks. I thought a normal CK would essentially rule it out, that the symptoms were largely reversible.” He now emphasizes that the side effects “can be very disabling, can happen in substantially delayed fashion, the CK can be normal”
	(5) Disability from statin AEs contributed to retirement
Dr. E Muscle weakness Muscle pain	(1) Dr. E tolerated simvastatin for 13 years, however after a 2 year trial off, he resumed simvastatin with niacin. He retired early to pursue athletic adventures, but a month after recommencing statin and niacin, developed new exercise intolerance, rapid muscle fatigue, and loss of muscle strength. He discontinued the statin a month later. Two years later, although notable improvement has occurred, there remains a significant residuum
	(2) Dr. E’s experience with the healthcare system was unfavorable. He felt his doctors were unsympathetic, and that his symptoms “did not register much concern” from them
	(3) Neurological evaluation with NCS/EMG showed atypical proximal muscle unit abnormalities, slowed nerve conduction, and fasciculations. Brain and spinal MRI were negative. He also saw a urologist for low testosterone (simvastatin has been shown to reduce testosterone [27, 28]), but a 4 month trial of testosterone replacement did not confer benefit
	(4) Dr. E’s perspective following this experience is that “statins should not be prescribed to those who are athletically inclined.” He observes that they have “a very real propensity to adversely impact the mitochondria on a permanent basis”
	(5) N/A, already retired
Dr. F Muscle weakness Muscle pain	(1) Dr. F developed muscle pain and weakness (to the point where he could no longer drive) with each of a succession of lipid lowering medications (most statins), with improvement when these were discontinued. However, an extensive cardiac history caused trials off statins to be short-lived. For instance, atorvastatin was stopped in 2000 when his weakness became severe, and improvement in walking was noted 2 months later, but rosuvastatin was prescribed due to elevated cholesterol levels, resulting in a rapid return of weakness
	(2) Dr. F’s interaction with the medical system was relatively positive. Although his cardiologist initially dismissed the possible connection of statins to his weakness, when the cardiologist’s own family member developed similar statin AEs, he began to investigate the relationship
	(3) Dr. F. was referred to neurology and endocrinology, had blood tests, NCS/EMG, and muscle biopsy. He received successive diagnoses of arthritis, diabetic neuropathy, depression, and normal aging. His muscle biopsy showed changes consistent with mitochondrial myopathy on histology (based on ragged red fibers and Cox staining), without confirmatory evidence on electron microscopy
	(4) Prior to his own experience, Dr. F. had no strong opinions about statins. He felt they were mostly safe and certainly indicated for people with cardiovascular disease. Now, whenever he and his wife (also a physician) notice gait abnormalities in their friends and even strangers, they inquire whether or not they are on statins
	(5) N/A, already in the process of retiring
Dr. G Cognitive problems	(1) Shortly after statin initiation, Dr. G developed confusion, disorientation, and short-term memory loss. She asked repetitive questions and had a short attention span. Statins were discontinued, followed by marked improvement in cognitive function. A month after discontinuation, she recalled running into one of her former colleagues in the grocery store and being able to immediately recognize the person (a clear improvement over her prior state). This acquaintance exclaimed that she looked much better than 8 months previously, when they had last interacted
	(2) Dr. G’s physician dismissed the potential statin connection. Her son stated, “He replied in a condescending tone of disbelief that I ‘read too much’”
	(3) Dr. G. was referred to a neurologist, and treated with donepezil for a year under the assumption the cognitive problems may be Alzheimer’s. Other diagnoses that had been considered included depression and pseudo-dementia
	(4) Not known
	(5) Disability from statin AEs contributed to retirement

(1) Statin AE synopsis; (2): Interaction with Physician; (3): Referrals/Tests/Diagnoses; (4): Effect on Attitude as a Physician; (5): Professional Impact

AE adverse effect, CK creatine kinase, EMG electromyography, NCS nerve conduction study, MRI magnetic resonance imaging