Statin intolerance: more questions than answers

Abstract

The dramatic effectiveness of statins in improving the course of atherosclerotic cardiovascular disease tends to overshadow questions of statin intolerance. Thus after more than 25 years of clinical statin use, intolerance remains a poorly understood, frustrating issue for patients and providers. It has been extraordinarily difficult to define statin intolerance and its implications for clinical practice. Here, we briefly summarize current knowledge and raise questions that need to be addressed.

Keywords::

• adverse effects
• aging
• atherosclerosis
• LDL-lowering
• myalgia
• myopathy
• risk reduction
• statins

Statins are safe, at least over 5 years of treatment. In the first decade of statin use, myopathy emerged as the only substantial safety concern with statins, and the incidence of severe myopathy in randomized trials is about 0.01% [1].

Tolerability of statin treatment, though related to safety, presents a different kind and much more perplexing dilemma for clinical practice. Intolerance to statins encompasses a spectrum of complaints including myalgia, back pain, generalized fatigue, memory lapses and other symptoms. As early as 1991, a clinic in New Zealand reported that 5 of their first 110 patients prescribed simvastatin stopped within 6 months due to perceived side effects, and overall 15 patients, most of whom continued treatment, described muscle aches [2]. In 1995, a leading lipidologist expressed an opinion that about 5% of people taking lovastatin developed some kind of myopathy ‘with or without elevation of muscle enzyme levels’ [3]. In 2002, Phillips et al. described biopsy-proven myopathy accompanied by weakness in statin-treated patients without elevations of serum creatine kinase (CK) [4]. Lovastatin has been shown to potentiate post-exercise CK elevation, and clinical experience has suggested interaction between statins and exercise in muscle adverse effects [5,6]. Mikus et al. reported recently that statin-treated subjects did not benefit from the training effect of a 12-week exercise program. In a randomized, placebo-controlled trial among 41 subjects, those treated with simvastatin showed significant failure to increase peak oxygen consumption and, in muscle biopsy specimens, a significant lack of increase in an enzyme marker of mitochondrial content [7].

The most extensive survey of statin-associated muscle symptoms was the PRIMO study (Prediction of Muscular Risk in Observational Conditions) [8]. The investigators found that 10.5% of 7924 patients receiving high-dose statins (fluvastatin 80 mg or atorvastatin, pravastatin or simvastatin ≥40 mg daily) experienced troubling muscular symptoms at a median of 1 month following statin initiation or dose increase. Significant clinical predictors of muscle pain included prior history of muscle pain with lipid-lowering therapy, history of CK elevations, hypothyroidism and personal or family history of muscle pain.

On the other hand, randomized clinical trials suggest a far lower frequency of muscle adverse effects actually attributable to statins. In the Heart Protection Study (HPS), comparing simvastatin 40 mg versus placebo, about 6% of participants reported unexplained muscle symptoms at any given visit. But the fraction of subjects ever reporting such symptoms was exactly the same at 33% in both simvastatin- and placebo-allocated groups. HPS included a run-in phase with 4 weeks of placebo followed by 4–6 weeks of simvastatin treatment, during which 36% of potential subjects were dropped from the study. Nevertheless, only 1% had adverse symptoms from simvastatin as the reason for stopping [9].

If randomized trials suggest 1–3% frequency of statin muscle reactions versus roughly 10% in observational real world data, does that mean that 7 to 9 out of 10 patients are mistaken in attributing symptoms to the drug? Many lipidologists, including the authors, think that the clinical trial data seriously underestimate the true incidence of statin intolerance. One of us (JRG) is reminded of a patient who suffered through cholestyramine therapy for 5 years in a randomized trial [10], then stopped and never took it again despite his progressive coronary disease. Unfortunately, no randomized, double-blind, placebo-controlled trial has appeared specifically testing the relationship of muscle symptoms to statin use in subjects who previously complained of statin-associated muscle reactions.

There are cogent reasons why more attention needs to be given to statin intolerance. Foremost is the issue of trust between patients and providers. Too many patients’ complaints have been dismissed by well-intentioned clinicians.

Questions related to lifelong drug treatment may not be addressed adequately by the use of secondary data from 5-year clinical trials. Are there some patients in whom myopathy is cumulative and perhaps even permanent? Is there any interaction between statins and the natural decline of strength with aging? The recent data of Mikus et al. may be pertinent [7]. What are optimal doses for lifelong statin treatment? Should we favor the 80 mg dose of atorvastatin, mainly because it is the dose featured in several large randomized trials? Among three reports of 5-year randomized trials using 80 mg atorvastatin daily, none showed a trend toward overall mortality benefit [11]. Would atorvastatin 40 mg daily give 90% of the clinical benefit, as it gives 90% of the LDL-C lowering effect of atorvastatin 80 mg daily, and yet avoid half of the adverse effects? The pathophysiologic rationale for the higher dose largely depends on the clinician’s acceptance of net benefit from pleiotropic effects of statins, a dubious viewpoint [12]. Nontarget effects of drugs a priori are more likely to confer harm than benefit. The clearest pleiotropic effects of statins are muscle reactions. All of this is not to detract from the enormous clinical benefit of statins, but only to say that we need to understand their adverse effects better. The authors continue to use atorvastatin 80 mg daily in many patients.

The diabetogenic effect and occasional memory problems associated with statins are less likely to cause treatment discontinuation compared with myopathy. Although an increase in new-onset diabetes has been observed in subjects with one or more risk factors for diabetes, the cardiovascular benefits from statin use exceed the risk for development of diabetes [13]. Memory problems leading to statin discontinuation were identified among only 0.06% of statin users in a large cohort study [14].

A practical clinical approach divides the causation of statin intolerance into three categories: The first is drug disposition. Too high a fraction of statin escapes uptake and metabolism in the liver and reaches peripheral tissues including muscle. This applies to drug–drug interactions and also to genetic influences on statin hepatic uptake such as the SLCO1B1*5 mutation. This mutation, present in approximately 15% of alleles (28% of patients), may impair uptake of simvastatin and atorvastatin more than it does uptake of rosuvastatin [15]. The second category for statin intolerance is genetically enhanced sensitivity of the target pathway (i.e., β-hydroxy-β-methylglutaryl coenzyme A reductase) to statins. In addition to isolated individual cases, this appears true for East Asians compared with other ethnic groups, and the response is to use lower doses. Third, muscle may be subject to stressors independent of statins from genetic, immune, lifestyle or metabolic conditions leading to additive adverse effects. The most common are vigorous exercise and hypothyroidism.

Having considered these effects, our usual response is to make at least a fourfold reduction in the effective statin dose. Switching to a different statin with equivalent LDL-lowering efficacy rarely works, because muscle reactions are largely due to class effect. A holiday of statin withdrawal for 2 weeks or more can be considered if muscle symptoms have been severe, followed by the lower dose. The strategy of dose reduction takes advantage of the fact that LDL-lowering responds to the logarithm of statin dose, while adverse effects appear to be more or less proportionate to dose. Nondaily statin dosing and tablet splitting are strategies that often decrease LDL-C more than full doses of nonstatin drugs [16,17]. We commonly try 5 mg atorvastatin taken 2 or 3 days a week and decide if it is sufficient based on the individual patient’s LDL-C result. We do not routinely advise coenzyme Q-10 or vitamin D supplementation. The occurrence of myopathy in deficiency states of these nutritional factors provides a partial rationale for supplementation, but randomized clinical trials showing clear and consistent benefit in the usual patient are lacking.

Statin intolerant patients may require combination therapy using 2 nonstatin drugs or a nonstatin together with a statin taken at very low dose. In our experience, niacin and bile acid sequestrants generally do not bother muscles, but muscle reactions may occur uncommonly with ezetimibe or fibrates in patients intolerant to statins. The nonstatin combination of niacin with a fibrate reduced clinical cardiovascular events in two randomized trials, and bile acid sequestrants have also been associated with clinical outcome benefit [10,18,19]. Two forms of nutritional supplements, plant sterol/stanol esters and viscous fibers such as psyllium, can effectively lower LDL, and their combination in the context of a vegan diet gives LDL lowering comparable with nonstatin monotherapy [20]. In the near future, new drugs may become available for lowering LDL without affecting skeletal muscle, particularly monoclonal antibodies or other agents that bind PCSK9 (proprotein convertase subtilisin kexin Type 9) [21]. Until that time, multiple strategies are available to allow high-risk statin intolerant patients to achieve reasonable lowering of LDL-C without limitation of daily activities including exercise.

Financial & competing interests disclosure

JR Guyton has received research funding from Merck, Regeneron, Sanofi-Aventis, Genzyme/ISIS, Amgen, Amarin and GlaxoSmithKline. He has received speaker’s honoraria from Merck and consulting fees from Merck, Regeneron and Kowa. WC Lakey has received research funding from Janssen, Amarin, Regeneron and Sanofi-Aventis. The authors have no other 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 apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.