Author + information
- Steven E. Nissen, MD∗ ()
- ↵∗Address for correspondence:
Dr. Steven E. Nissen, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F-15, Cleveland, Ohio 44195-0001.
Few controversies in contemporary cardiovascular medicine provoke the extreme reactions and intense disagreement as the concept of muscle-related statin intolerance. On one side of the controversy are several prominent academic clinical trialists who emphatically assert that intolerance to statins is a rare and mostly psychosomatic disorder (1). On the other side are many equally thoughtful lipidologists and practicing physicians who claim that as many as 20% of statin-treated patients are unable to tolerate evidence-based doses of statins due to muscle-related adverse effects (2). The controversy has been amplified by the elusive nature of the disorder. Afflicted patients rarely exhibit abnormal levels of muscle biomarkers, such as creatine kinase, but describe intolerable muscle pain or weakness when prescribed a statin, often at initial starting doses, and report relief of these symptoms when statin therapy is interrupted.
Much of the controversy originates from different perceptions about the evidence for and against the existence of this syndrome. The skeptics cite large randomized trials of statins that have not demonstrated a significant rate of drug discontinuation due to muscle-related symptoms. The believers, however, point out that many of these trials used an active run-in period and, subsequently, only randomized patients who tolerated effective doses of the study drug. For the practicing physician, these academic arguments are largely irrelevant. Faced with a patient with a high low-density lipoprotein-cholesterol (LDL-C) and increased risk for a recurrent cardiovascular event, prescribers must cope with a fundamental dilemma. Some patients will adamantly refuse to attempt another therapeutic trial of a statin despite being informed of the high risk of a morbid or mortal event.
For the skeptics who doubt the existence of muscle-related statin intolerance, it is important to keep an open mind. We recently conducted a randomized clinical trial (GAUSS-3 [Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin Intolerant Subjects-3]) that sought to distinguish between patients with true statin intolerance and those suffering from the nocebo effect (3). The results provided support for both skeptics and believers, but clearly confirmed the existence of true statin intolerance in some patients. In the trial, approximately 500 patients with a history of muscle symptoms while taking when treated with multiple statins, entered a double-blind phase during which one-half of the enrollees received placebo for 10 weeks and the other half received atorvastatin, 20 mg, with subsequent cross-over to the alternate treatment group. During this phase, 26.5% of patients experienced muscle symptoms on placebo but not on atorvastatin, whereas 42.6% of patients had symptoms on atorvastatin but not on placebo. Subsequently, patients with muscle-related symptoms only on atorvastatin were randomized to ezetimibe or the PCSK9 inhibitor evolocumab. More than 90% of these patients were able to tolerate alternative therapies without muscle symptoms.
Contributing to the controversy and confusion is the uncertainty of regulatory authorities on how to address this issue. The U.S. Food and Drug Administration (FDA) has not granted any alternative lipid-lowering therapy a label claim for efficacy in statin-intolerant patients. The cautious approach by regulators is understandable. Because statins are the only LDL-lowering therapy approved to reduce morbidity and mortality in patients with coronary disease, the FDA has expressed concern that awarding any claims to alternative agents could direct patients away from potentially life-saving drugs toward non-statin therapies without established outcome benefits, including ezetimibe, which is commonly used in statin-intolerant patients Although ezetimibe showed some evidence of a reduction in morbidity (although not mortality) in the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) trial, an FDA advisory panel declined to support any clinical outcomes claims.
The study by Serban et al. (4) in this issue of the Journal provides important insights into the ongoing controversy about statin intolerance. The authors used a clever and thoughtful approach to identify statin-intolerant patients and assessed the impact of this diagnosis on clinical outcome. Few prior data have addressed the clinical consequences of statin intolerance, although most reasonable observers would expect that nonadherence to evidence-based preventive measures would have a serious negative impact. In the current study, patients meeting the authors’ definitions of statin intolerance compared with Medicare beneficiaries with high levels of adherence were approximately 50% more likely to have a coronary event (myocardial infarction or coronary revascularization procedure). Given the high prevalence of statin intolerance in clinical practice, these findings have major public health consequences.
The lack of association between statin intolerance and all-cause mortality is not surprising and does not weaken the findings. The median duration of treatment was only approximately 2 years. A large meta-analysis of statin trials showed only modest effects on all-cause mortality after a median of 5 years of treatment, a hazard ratio (HR) of 0.90 (95% confidence interval [CI]: 0.97 to 0.93) (5). The same meta-analysis showed a larger effect on cardiovascular mortality (HR: 0.80; 95% CI: 0.74 to 0.87). Because noncardiovascular death is not favorably influenced by cholesterol reduction, nonadherence had a predictably lower effect on all-cause mortality.
The current study has both strengths and weaknesses. Ascertainment of statin intolerance was inferred, not documented, and included events such as switching among 3 or more statins within a year or down-titration of a statin with addition of ezetimibe. This definition may underestimate the incidence of statin intolerance. Some patients with a strong history of statin intolerance would not be captured by the definitions used in the study. Physicians, particularly at lipid clinics, see referral patients with a history of statin-associated muscle symptoms who simply refuse to take any statin regimen, who would not be identified using this algorithm. Over-ascertainment also remains a possibility. Physicians may alter therapy (“switching”) for inadequate clinical response rather than intolerance. Despite these limitations, the definitions used in this study represent a useful and practical approach to research which should be further investigated and validated by other investigators by studying populations in whom a clinical history of statin intolerance is well documented.
Like all observational studies, the potential for residual confounding is an ever-present cause for concern. Patients who complain about statin-related symptoms may be less adherent to a broad range of treatments, not just lipid-lowering therapy. Other unmeasured characteristics may distinguish patients likely to complain about statin-associated symptoms. The strengths of the study are self-evident. The authors studied a large population of ethnically diverse Medicare beneficiaries and included many subjects with important comorbidities such as diabetes, heart failure, and kidney disease. However, the study of Medicare beneficiaries is also a potential limitation. In previous studies of statin intolerance, the average age of the patients was considerably younger than the average age of Medicare beneficiaries.
The study has important implications for the pharmaceutical industry and regulators. For industry, the development of non-statin LDL-lowering therapies with a low likelihood of provoking muscle symptoms should be a high priority. Some promising efforts are currently underway. Bempedoic acid is an LDL-lowering drug treatment that works by inhibition of adenosine triphosphate-citrate lyase (ACL), an enzyme upstream of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway (6). Like statins, bempedoic acid decreases liver cholesterol synthesis, which results in increased hepatic LDL receptor activity and clearance of LDL from the blood. However, unlike statins, bempedoic acid is inactive in skeletal muscle, which should result in a low probability of producing muscle symptoms. Phase 3 lipid-lowering studies for consideration of FDA approval are underway. We are also conducting a large randomized clinical outcome trial in patients with elevated LDL-C levels who are unable to tolerate evidence-based statin doses.
The findings of the current study clearly show that there are serious morbid consequences to the elusive disorder of statin intolerance and support an aggressive management strategy for clinicians treating these anguished and challenging patients. We must make every possible effort to administer evidence-based doses of statins to patients with appropriate clinical indications for treatment. Additional efforts to study the phenomenon of statin intolerance are critically important and must include development of alternative therapies for treating the substantial cardiovascular morbidity associated with this disorder.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Nissen has received clinical trial funding through his institution from AbbVie, AstraZeneca, Amgen, Cerenis, Eli Lilly, Esperion, Pfizer, and The Medicines Company. Dr. Nissen does not accept personal reimbursement for relationships with industry.
- 2017 American College of Cardiology Foundation
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