The insidious impact of under-diagnosed proximal weakness induced by statins

ABSTRACT

Introduction: This Perspective reassesses the consensus opinion that statin-associated muscle symptoms (SAMS) occur in <1% of users and associated myopathic proximal muscle weakness is even more rare.

Areas covered: Of the over 180,000 participants in clinical trials and large registries of statin users, only a few studies have included a standard manual muscle test (MMT), dynamometry or a focused questionnaire to assess for proximal weakness and related disability in daily and recreational activities. Formal strength testing suggests, however, that weakness can be demonstrated in at least 10% of users.

Expert opinion: Reporting inaccuracies about SAMS, confirmation bias among experts and physicians, absence of a standard questionnaire regarding the potential consequences of weakness on physical capacity, and the failure to routinely perform an objective assessment of strength may have led to under-diagnosis of statin-induced myopathy. A brief MMT before cholesterol-lowering agents are started and at follow-up visits, a 12-week withdrawal of the statin in the presence of new paresis without an alternative cause, and the exam finding that strength recovers off the statin are necessary to assess the incidence of drug-induced proximal weakness and inform alternative therapeutic strategies.

KEYWORDS:

• Statin myopathy
• myalgia
• myalgia
• proximal muscle weakness
• toxic myopathy
• muscle fatigue
• falls
• gait disorder

Article highlights

• Based on large randomized clinical trials, expert panels generally conclude that statin-associated muscle symptoms (SAMS), including the proximal weakness of a myopathy, occur in <1% of users.

• This consensus belief is shaken a bit by the higher incidence of SAMS and statin intolerance, from 20% to 50%, found in large observational studies and the 10–20% greater incidence over placebo in some randomized trials. It is especially made moot by the failure of trials to provide standardized, detailed questionnaires about SAMS that enable patients to better articulate their symptoms and by the universal failure of physicians to perform a routine manual muscle test (MMT) on at least the neck flexors and proximal leg muscles.

• A variety of genetic, metabolic, mitochondrial, organelle, and cholesterol pathway alterations may predispose or cause the spectrum of myalgia, proximal weakness with or without myalgia, and myositis. Such mechanisms may be far easier to identify in subjects with objective weakness rather than vague SAMS complaints, but no such studies exist.

• When an MMT reveals the weakness, improvement based on the MMT takes at least 8–12 weeks following discontinuation of a statin. Myalgia often resolves within 4 weeks, so weakness may persist.

• Alternative strategies, including switching from a statin to newer drugs that lower LDL-C, should be considered in patients who develop proximal weakness with impaired mobility or balance, a decline in daily physical or recreational activities, exercise intolerance or an increased risk for falls.

• ∙ By pairing an MMT with direct questions about SAMS-associated declines in proximal muscle-supported functional activities, physicians protect against confirmation bias about SAMS that may be nurtured by published trials and reviews, as well as have an opportunity to show their caring side to patients to improve compliance.

• Individual physicians and future clinical trials of lipid-lowering treatments may discern the real incidence of potentially debilitating proximal weakness by incorporating an MMT (Table 1) on a routine basis.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.