Journal of Clinical Lipidology (2014) 8, S1–S4 Executive Summary NLA Task Force on Statin Safety - 2014 update Terry A. Jacobson, MD, FNLA, Chair, The NLA Task Force on Statin Safety - 2014 Update* Department of Medicine, Office of Health Promotion and Disease Prevention, Emory University, 49 Jesse Hill Jr Drive SE, Atlanta, GA 30303, USA KEYWORDS: Statins; Statin drug; Statin muscle; Statin intolerance; Statin brain; Statin liver; Statin diabetes Statins are the most widely prescribed class of medications classified into these risk categories. Although shocking, in the United States and their benefits for lowering low- these numbers do not even account for the hundreds of mil- density lipoprotein cholesterol (LDL-C) and reducing the lions of patients who qualify for statins because they risk for coronary heart disease (CHD) are well docu- already have ASCVD, diabetes mellitus, or extremely mented.1 Statins have been the cornerstone of pharmaco- high LDL-C levels. Therefore, the potential risks and ben- therapy for the management of high blood cholesterol efits of statin use are a major US and worldwide public levels virtually since their development. The American health concern. Heart Association /American College of Cardiology 2013 In 2006, the National Lipid Association (NLA) guidelines recently expanded the number of individuals convened a Statin Safety Assessment Task Force of experts eligible for statin therapy by recommending it for those who published their findings on specific questions related to with: (1) clinical atherosclerotic cardiovascular disease the muscle, liver, renal, and neurologic effects of statins.5 (ASCVD), (2) LDL-C $190 mg/dL, (3) type 2 diabetes In the period since the report from that Task Force, the and age between 40 and 75 years with LDL-C 70 to body of evidence for the benefits and potential risks of 189 mg/dL, and (4) an estimated 10-year risk of ASCVD statin use has expanded.6–8 Prompted by examination of $7.5% and age 40 to 75 years.2,3 Considering only those those data, in 2012, the US Food and Drug Administration who qualify according to their estimated 10-year risk of (FDA) made new labeling rules that included (1) removal ASCVD, it has been reported that of the 101 million people of the routine periodic monitoring of liver enzymes in pa- in the United States age 40 to 79 years who do not have car- tients taking statins, recommending instead that liver diovascular disease, 33 million have an estimated 10-year enzyme tests be performed before statin therapy, and as risk of ASCVD $7.5%, and another 13 million have a clinically indicated thereafter; (2) adding information about risk between 5% and 7.4%.4 Using crude global estimates, the potential for generally nonserious and reversible cogni- 920 million people worldwide would be expected to be tive side effects and reports of increased blood sugar and * Corresponding author. Submitted March 6, 2014. Accepted for publication March 6, 2014. E-mail address: [email protected] 1933-2874/$ - see front matter Ó 2014 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2014.03.003 S2 Journal of Clinical Lipidology, Vol 8, No 3S, June 2014 Evidence grading: Strength of recommendation* Grade Strength of recommendation A Strong recommendation There is high certainty based on the evidence that the net benefit** is substantial B Moderate recommendation There is moderate certainty based on the evidence that the net benefit is moderate to substantial, or there is high certainty that the net benefit is moderate C Weak recommendation There is at least moderate certainty based on the evidence that there is a small net benefit D Recommend against There is at least moderate certainty based on the evidence that it has no net benefit or that the risks/harms outweigh benefits E Expert opinion There is insufficient evidence or evidence is unclear or conflicting, but this is what the expert panel recommends N No recommendation for or against There is insufficient evidence or evidence is unclear or conflicting *The system was adapted as a hybrid of the National Heart Lung and Blood Institutes (NHLBI) rating system (NHLBI cardiovascular-based method- ology) used in the new American Heart Association/American College of Cardiology cholesterol guidelines (Stone, 2013) and adapted from the original GRADE system of evidence rating (Guyatt, 2008). **Net benefit is defined as benefits minus risks/harms of the service/intervention. glycated hemoglobin associated with statin use; and (3) $12 months without evidence of muscle injury, and adding expansion of the contraindications and dose limitations new contraindications and dose limitations for simvastatin for lovastatin use.9 This followed an FDA-mandated label- with certain medicines.10 ing change in 2011 limiting the use of 80 mg simvastatin to These labeling changes have raised numerous questions only those patients who have been taking this dose for among clinicians regarding the benefits vs risks of statin Evidence grading: Quality of evidence Type of evidence Quality rating* Well-designed, well executed RCTs that adequately represent populations to which the results are applied High and directly assess effects on health outcomes Well-conducted meta-analyses of such studies Highly certain about the estimate of effect; further research is unlikely to change our confidence in the estimate of effect RCTs with minor limitations affecting confidence in, or applicability of, the results Moderate Well-designed, well-executed nonrandomized controlled studies and well-designed, well-executed observational studies Well-conducted meta-analyses of such studies Moderately certain about the estimate of effect; further research may have an impact on our confidence in the estimate of effect and may change the estimate RCTs with major limitations Low Nonrandomized controlled studies and observational studies with major limitations affecting confidence in, or applicability of, the results Uncontrolled clinical observations without an appropriate comparison group (eg, case series, case reports) Physiological studies in humans Meta-analyses of such studies Low certainty about the estimate of effect; further research is likely to have an impact on our confidence in the estimate of effect and is likely to change the estimate. RCT, randomized controlled trial. This was the system used in the new American Heart Association/American College of Cardiology cholesterol guidelines3, which were published in the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report from the Panel members appointed to the Eighth Joint Na- tional Committee.21 Table reprinted with permission.21 *The evidence quality rating system used in this guideline was developed by the National Heart, Lung, and Blood Institute’s (NHLBI’s) Evidence-Based Methodology Lead (with input from NHLBI staff, external methodology team, and guideline panels and work groups) for use by all the NHLBI cardiovas- cular disease guideline panels and work groups during this project. As a result, it includes the evidence quality rating for many types of studies, including studies that were not used in this guideline. Additional details regarding the evidence quality rating system are available in the online Supplement. Jacobson Update on Statin Safety 2014 S3 use and have led to the desire by the leadership of the NLA compared with the general clinical population, which tends to convene a new Statin Safety Task Force to update the to have more comorbidity and frailty. Examples of 2006 review and provide expert panel opinion regarding the exclusions from recent statin RCTs are: pregnancy, reduced issues, which were reviewed in that report, as well as others renal or hepatic function, on drugs known to affect statin raised in the interim. In October 2013, a group of experts in metabolism (ie, cytochrome 3A4 inhibitors, cyclosporine, the fields of clinical lipidology, diabetes, neurology, fibrates, immunosuppressants), advanced age .75 years, hepatology, and myology participated in an NLA Statin uncontrolled diabetes mellitus, congestive heart failure, Safety Task Force meeting to discuss the available evidence dementia, cancer, substance abuse, history of noncompli- regarding statin safety. The moderators of the Task Force ance, and active rheumatologic or musculoskeletal condi- were Dr Terry A. Jacobson (Chair, Emory University, tions. Thus, patients who are more susceptible to adverse Atlanta, GA), Dr Harold Bays (Louisville Metabolic and events may be underrepresented in RCTs. Atherosclerosis Research Center, Louisville, KY), Dr Vera In assessing safety or harm of any therapy, going beyond Bittner (University of Alabama, Birmingham, AL), Dr John RCTs is thus very important. Evidence needs to be gathered R. Guyton (Duke University, Durham, NC), Dr Kevin C. from a broad range of sources, including observational and Maki (Midwest Center for Metabolic & Cardiovascular clinical epidemiologic studies, FDA adverse event report- Research, Chicago, IL), Dr Robert S. Rosenson (Icahn ing systems, meta-analysis of clinical trials, analysis of School of Medicine at Mount Sinai, NY, NY), and Dr Peter large health care databases (Veterans Administration, Kai- P. Toth (CGH Medical Center, Sterling, IL). After the full ser, Medicare, other claims databases), and case reports. In panel met, subpanels developed individual papers on the assessing harm or safety, the quality of study reports needs topics of statin use and (1) cognition, (2) glucose homeo- to be made explicit