PCSK9 Inhibitors for Statin Intolerance

Opinion EDITORIAL PCSK9 Inhibitors for Statin Intolerance? David D. Waters, MD; Priscilla Y. Hsue, MD; Sripal Bangalore, MD, MHA Statin intolerance is a common problem most clinicians en- counter when treating patients taking these drugs. Balancing the symptoms of muscle aches in a patient in need of choles- terol-lowering medication with the clinical trial–proven ben- efits of statins for reducing cardiovascular events in a broad spectrum of patients can be a difficult clinical challenge. Muscle-related adverse effects from statins are highly mu- table. Considerable evidence suggests that nonpharmaco- logic mechanisms account for most muscle-related statin in- tolerance. The prevalence of statin-associated muscle symptoms ranges from 7% to 29% in registries and observa- tional studies. 1 The incidence of muscle symptoms is similar among statin-treated and placebo-treated patients across 26 long-term trials involving 170 000 patients. 2 In a large retro- spective cohort study, 6579 of 11 124 patients who discontin- ued a statin due to adverse effects were rechallenged, with 92% success in restoring therapy, although not necessarily with the same statin or dose. 3 In an international survey, the inci- dence of intolerable statin-related adverse effects ranged from 2% in Japan, Spain, Italy, and Sweden to 10% to 12% in Canada, the United Kingdom, and the United States. 4 These substan- tial differences are likely to be modulated by cultural factors and patient perception. Nevertheless, statins are capable of causing severe Related article muscle damage, very rarely leading to rhabdomyolysis, with this adverse effect most com- mon with simvastatin. In 2011, the US Food and Drug Admin- istration recommended that the 80-mg dose of simvastatin should only be used in patients who had been taking this medi- cation for a year without adverse effects. 5 Although the un- derlying mechanism of statin-induced myopathy remains un- clear, risk factors include older age, impaired renal or hepatic function, surgery, human immunodeficiency virus infection, genetic susceptibility, and high levels of physical activity. 6 Stat- ins may rarely cause an autoimmune myopathy that persists after the drug is discontinued, with muscle weakness, myo- cyte necrosis, autoantibodies against the HMG-CoA reduc- tase enzyme, and a need for immunosuppressive therapy. 7 Guidelines provide common-sense recommendations for the management of statin intolerance. 1,6,8 In some patients the appearance of muscle aches turns the risk-benefit ratio unfa- vorable, so that stopping the statin and turning to diet and ex- ercise is reasonable. Restarting a different statin at a lower dose after symptoms abate is a widely recommended strategy. Al- most all patients will eventually find a tolerable statin and dose, even if it is just a low dose taken once or twice per week. In general, any statin is better than no statin when indicated, and most low-density lipoprotein cholesterol (LDL-C) lowering is obtained with the first 5 to 10 mg of statin. 9 Nonstatin therapies are available to lower LDL-C levels. Ezetimibe is not approved to prevent cardiovascular events, and data from the only outcomes trial with this drug indicate that the number needed to treat per year to prevent a cardio- vascular event is 350. 10 Bile acid sequestrants are poorly tol- erated at high doses because of gastrointestinal adverse ef- fects, but these agents lower LDL-C levels synergistically with statins and can play a useful role at low doses. The newest class of drugs, protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, has been shown to markedly lower LDL-C levels. Two of these monoclonal antibodies, evolocumab and ali- rocumab, were approved by the Food and Drug Administra- tion in 2015 for use in addition to maximally tolerated statin therapy in adults with familial hypercholesterolemia or ath- erosclerotic cardiovascular disease who require additional low- ering of LDL-C levels. In this issue of JAMA, Nissen and colleagues 11 report the results of the GAUSS-3 trial, which used a rigorous protocol to investigate the use of the PCSK9 inhibitor evolocumab among patients with statin intolerance related to muscle-related ad- verse effects. The results are illuminating, but many unan- swered questions remain. In phase A of the trial, 491 patients with well-docu- mented muscle-related adverse effects to 2 or more statins were randomized to receive either atorvastatin (20 mg daily) or pla- cebo for 10 weeks, followed by a 2-week washout, followed by crossover to the alternate treatment for 10 weeks. Intolerable muscle-related symptoms developed in 209 patients (42.6%) while taking atorvastatin but not placebo, 130 (26.5%) while taking placebo but not atorvastatin, 48 (17.3%) while taking both treatments, and 85 (17.3%) while taking neither treat- ment. In phase B, 218 patients who had exhibited muscle- related adverse effects while taking atorvastatin but not while taking placebo, or who had experienced a 10-fold increase in creatine kinase level after statin administration, were random- ized to receive ezetimibe (10 mg daily) (n = 73 patients) or evo- locumab (420 mg monthly) (n = 145 patients). At 24 weeks, LDL-C levels were reduced by 16.7% (from 221.9 mg/dL at base- line to 181.5 mg/dL at 24 weeks) in the ezetimibe group and by 52.8% (from 218.8 mg/dL at baseline to 104.1 mg/dL at 24 weeks) in the evolocumab group (P < .001). This result is not surprising; indeed, similar results have been reported with evo- locumab or alirocumab in statin-intolerant patients in 3 pre- vious trials, although in this trial Nissen et al followed a pre- cise protocol that identified patients who were truly statin intolerant. 12-14 jama.com jamanetwork/2016/jama/04_03_2016/jed160026pap (Reprinted) JAMA Published online April 3, 2016 PAGE: right 1 SESS: 24 E1 OUTPUT: Mar 23 15:12 2016