FormalPara Key Points

This is the first analysis to address the experience of physicians themselves affected by adverse effects (AEs) of statin medications, encompassing muscle, neuropathic, cognitive, and behavioral AEs.

The impact of statin AEs in physicians can be profound, professionally and personally, in some cases requiring major professional modification or early retirement.

Poor awareness of statin problems by medical providers, and low receptiveness to reports of such problems, can extend even to patients when they themselves are physicians.

Introduction

Statins (HMG-CoA reductase inhibitors) are among the best-selling prescription drugs and have been viewed as having a favorable safety profile, but like all drugs, they bear potential side effects. While adverse effects (AEs) are reported to be rare in clinical trials, they are less uncommon in clinical experience [1, 2]. It has been observed that physicians often dismiss the possibility of statin-related etiology when patients present with side effects linked to statin use [3], and that patients with statin AEs commonly perceive that their physicians do not appreciate the quality-of-life impact of their AE [4].

Physicians, current and retired, are among those who take statins. There are two reasons for our interest in statin AEs in physicians. First, consideration of AE impact has focused primarily on direct health ramifications and has not investigated professional consequences to the individual. Properly contextualizing the impact of statin AEs requires attention to this additional dimension. Second, patients with statin AEs have communicated instances in which their physician became more receptive to the possibility of statin AEs when the physicians themselves or their personal family or professional contacts developed statin AEs. We were interested in the issue of whether experiencing a statin AE altered physicians’ own attitudes regarding statin AEs reported by others.

We present seven cases of statin AEs in physicians.

Method

The Statin Effects Study is a patient-targeted statin AE reporting effort approved by the University of California, San Diego Human Research Protections Program (HRPP). Materials were reviewed to identify individuals who had communicated with the study group and noted that they were physicians. Fourteen physicians who had reported statin AEs were identified. Ten qualifying individuals provided informed consent and completed a self- or interviewer-administered HRPP-approved survey, which elicited information on subject characteristics including risk factors for statin AEs [5], statin usage, adverse effect features, professional impact, adherence to Naranjo criteria, and the subject’s experience within the medical community. Using the Naranjo Adverse Drug Reaction (ADR) probability scale, cases were coded as meeting criteria for doubtful, possible, probable or definite presumptive statin AE causality. Three cases lacked a trial off statins, followed by improvement, limiting the causality determination to at most “possible”; these cases were therefore excluded, providing seven cases that are presented.

For brevity, two cases are highlighted in the text, with five additional cases detailed in a table. For purposes of exposition, cases have been assigned arbitrary, alphabetically-ordered, letter labels (unconnected to subject names).

Results

Dr. A, a radiologist in his 50s, stated that he developed marked cognitive problems and also neuropathy shortly after increasing his atorvastatin dose from 40 to 80 mg/day. Effects were new, marked, sustained, and interfered with his work, leading to difficulty understanding case presentations, to radiology reading errors (including right/left errors on readings), and to placement of orders for the wrong patients. These consequences to his professional accuracy led him to fear medicolegal repercussions. He did not share his cognitive concerns with his own physician, leery of risks and ramifications from such disclosure. However, he did share the neuropathy symptoms. His physician, whom Dr. A noted bore a “Top Doctor” designation, stated that no further assessment was warranted for neuropathy symptoms except in diabetics. No suggestion was made by his doctor of a possible statin role, or suggestion for a trial of statin discontinuation, until a medical student commented on the association of neuropathy to statin use. Discontinuation of statins, after 3 years of sustained symptoms, led to rapid and striking improvement in cognitive function. By a week after discontinuation, Dr. A noted dramatic cognitive recovery, which he perceived to be approximately complete. He observed more gradual recovery of neuropathy symptoms, which he characterized as having improved by an estimated 95% at 8 months (improvement having apparently plateaued at that level).

Dr. B is an internist in his 40s who reported that, 6 weeks after commencing statins, he developed rapidly progressing muscle symptoms comprising fatigue, pain, weakness and shortness of breath. Numerous specialist referrals occurred and tests were conducted, and concerns regarding possible amyotrophic lateral sclerosis (ALS) were expressed. Ultimately a muscle biopsy showed mitochondrial myopathy that was attributed in the biopsy pathology report to statin use (compatible literature is available [5–7]). Statin discontinuation was undertaken after only ~2 months of statin use, and although what had been a rapid progression of symptoms fully arrested, according to the patient, recovery was limited and remains partial, 13 years later. Professional impact of his statin-related problems was marked: he discontinued inpatient care, call, and curtailed his hours, patient volume, and pay, also refitting his offices with higher desks and chairs to enable him to slide off chairs to rise.

Medical specialty, age at symptom onset, sex, statin, dose, risk factors, adverse effect, and Naranjo Causality score for these two and five additional physician cases are presented in Table 1. Information on the five additional affected physicians, with further cognitive, muscle, neuropathic, and adding behavioral AEs, are provided in Table 2 with brief details on the AEs, interaction with physician, referrals/tests/diagnoses, effect on attitude as a physician, as well as professional impact (where relevant).

Table 1 Synopsis of physician cases
Full size table
Table 2 Further information on the five additional cases
Full size table

These cases illustrate key points. AEs of statins include muscle [4], cognitive [8], neuropathy [9], and behavioral symptoms [10] (among others) and physicians and retired physicians are not exempt from risk. AE cases reported here have evidence for at least probable statin causality [11]. Career implications of statin problems can arise from cognitive and muscle problems, as in the two cases above, as well as from behavioral AEs of statins (Case C in Table 2). Each have potential for impact to physicians’ career, and some AEs, perhaps particularly cognitive and behavioral AEs, have potential for ramifications to patients. (We did not elicit, and participants did not volunteer, instances—if any—in which such ramifications were realized.) Physicians seen by individuals affected by statin AEs (including physicians seen by physicians reporting such AEs) were commonly unfamiliar with these statin AEs, and for five of the cases, some of the physicians consulted were initially dismissive [3].

Many participants experienced professional impact. In neither cases of Dr. A nor Dr. B did the physicians caring for the statin-affected physician-patients have an understanding of the potential causal role of statins initially. Dr. A was informed of the possible connection of statins to neuropathy not by his physician, but by a medical student working with his physician, who was aware of the reported association. Dr. B’s statin experience occasioned the positive development of increased awareness of statin adverse effects—and vigilance for them—both in himself (though still affected, he has retained a primary care practice) and among other physicians in his community. Finally, both physicians saw arrest of progression, and symptom improvement after discontinuing the statin, however neither returned fully to their previous health states [7, 12]. (Dr. A states that he retains some residual neuropathy, though it has markedly abated.) We emphasize that for each of the reported symptoms, recovery profiles (in time course and completeness) vary across affected individuals; the swift reported recovery of cognitive function reported by Dr. A is on the rapid end of the recovery-time course spectrum.

Discussion

To our knowledge, this is the first report to address statin AEs in physicians and to evaluate how experiencing a statin AE affected physicians professionally, how knowledgeable and receptive these physicians find other professionals to be in professional encounters, and whether and how experiencing statin-associated problems influenced their own (and if known, other physicians’) attitudes towards statin AEs. These cases underscore that commonly reported statin AEs—here encompassing muscle [4], cognitive [8], fatigue [13], neuropathic [9], and behavioral [10]—also afflict high functioning professionals such as physicians, in whom these symptoms can have profound professional implications, contributing in some to early retirement (Table 2) or persistent disability. These cases reprise a number of observations from other settings. Symptom onset can be delayed [4, 8]. Older age is a risk factor for statin AEs [5, 14, 15], and people continue to age while taking statins—moreover, physiological aging may be accelerated by the processes that underlie statin AEs [5]. Higher dose increases risk (Drs. A, C, D) [5]. For those who remain on statins after the first symptom arises, emergence of symptoms spanning several categories is not uncommon, likely reflecting common pathophysiological foundations [5]. Rarely, symptoms may initially worsen with discontinuation. (We note this is consistent with evidence that antioxidant effects can arise (and reverse) quickly, prior to lipid effects [16]; while some prooxidant effects, linked for instance to recovery of lipid transport of antioxidants, may take longer to reverse. This may, in some, engender an initial worsening of statin-induced prooxidant-antioxidant balance, on statin discontinuation.) Resolution of AEs can be incomplete (whether by patient report or objective testing) [6, 7] and residual disability may be profound [4, 17]. Statin AEs, including muscle wasting, weakness, and exercise intolerance as well as neuropathy perhaps in particular [18] (but also cognitive dysfunction) may fail to fully resolve clinically [19, 20] and pathologically [7]. (Indeed, there may be failure of full resolution pathologically even when there is apparent clinical resolution [19].) Persistent muscle problems can reflect mitochondrial myopathy [5–7]. Regarding cases in Table 2: Behavioral symptoms may be recognized by others rather than the individual in whom they occur (Dr. C) [21, 22]. Athletes may be at special risk for statin muscle problems (Dr. E) [23, 24]. Physicians seeing those who experience statin AEs may be dismissive of symptoms or of a possible statin connection—even, we find here, when reported by physicians-as-patients [3].

In addition to reprising previous findings regarding the symptoms themselves, these cases offer new insights into impact. Professional impact in these cases varied depending on the nature and severity of the AEs—and the proximity to planned retirement—from no professional effect to early retirement to significant curtailment of hours and income, professional review, and fears about patient consequences and medicolegal action. Costs for evaluations and referrals may be high. Some physicians, on whom patients (including other physicians) rely for compassion and care, may fail to take statin-related problems seriously and may fail to follow-up on possible statin associations of symptoms, while other physicians are receptive, and responsive, to experiences and concerns of their patients. Patients may not reveal cognitive symptoms to their physicians fearing repercussions of disclosure. This may lead to delays in addressing the cause, which can increase prospects for repercussions to the patients whom the physician serves. Physicians reported that their experience altered their attitudes toward statins, reflecting awareness of potential for symptoms, but also increased appreciation of the impact such symptoms can have. Each of the AEs described here has been documented in the literature in association with statins; discussion of potential mechanisms of these statin AEs can be viewed in other sources [5–7].

As in other case series and AE surveillance approaches, there is no defined base population or control group, so relative rates and risk-ratios cannot be calculated. However, rates and risk-ratios are not the goal. Since the purpose is to characterize and understand these AEs and their potential impact, only subjects who have experienced an AE are relevant. Like all studies with volunteer subjects, there is self-selection, which may affect generalizability; however AE reports are in any case about illustrating potential effects, not normative ones. Subjects with mild symptoms may not feel motivated to share their experiences; those with extremely severe symptoms may be unable to do so. Regarding the most severe problems, there is the additional limitation that statin AEs can seldom qualify as meeting presumptive criteria for probable or definite AE causality if there was no improvement after drug discontinuation. Thus, people who continue on statins with symptoms or those in whom a progressive or irreversible problem may have been triggered are excluded from consideration. Self-reported data may be influenced by recall and reporting bias, but this shortcoming affects all questionnaire studies. Most importantly, even if the findings reported here apply only to a subset, they remain important for that subset. Prior studies have shown that patient AE self-reporting can be a reliable, valuable tool [25, 26]. Additionally, Naranjo presumptive causality criteria provide an independent form of causality estimate, and the seven cases presented met literature-based criteria for definite or probable AE causality. Physicians’ experience of statin AEs is among a suite of factors that could influence approaches to statin prescribing; whether or how these experiences influenced prescribing, in practitioners who prescribed statins, was not assessed.

Conclusion

This case series, with its focus on physicians, underscores the quality-of-life and professional impact that can attend statin AEs, and reinforces the understanding that consequences can be persistent. Greater awareness of these problems, and greater compassion when patients present with these conditions may be merited. Lessons drawn from these physicians-as-patients have relevance to other professions. (For instance, delay in addressing the cause of cognitive compromise may have repercussions for those served by the professional, not only for doctors but for pilots, drivers, lawyers, nuclear facility workers, drug/chemical/vehicle production personnel, and many other professionals.) Care should be taken in management decisions in relation to statin use to limit unnecessary occurrence of AEs, and to recognize and mitigate the impact of such AEs when they occur.