Statins are the pharmaceutical cornerstone of primary and secondary prevention and undoubtedly one of the most influential advancements in therapeutic cardiovascular medicine. However, intolerance to therapy does occur in some patients and requires careful consideration.

For the purpose of this discussion, most cases of intolerance are related to muscle complaints and changes in liver and muscle enzymes. Controversy surrounds the very existence of 'statin intolerance.' This should not be unexpected. Definitions for intolerance vary widely;^1-5 therefore, establishing a diagnosis remains challenging. Consequently, inconsistencies with respect to the true incidence have been reported – ranging from as low as 1.5% in randomized trials (compared to placebo)⁶ to as high as 25-30% in observational studies (likely because strict definition for criteria to define myotoxic effects were not followed, but more so because of the inherent bias found in these study types, i.e., their value is limited in demonstrating a causal relationship between treatment and outcomes).^2,7 Once a diagnosis of statin intolerance (SI) is established, an adequate treatment approach is equally complex. Management plans largely hinge on stain discontinuation and repetitive re-challenge, and include low or intermittent dosing strategies, or the use of ezetimibe.^2,3,8 Recently, there has been a call for a clinical definition for SI;⁹ Table 1 summarizes a unified definition of the inability to tolerate at least two different statins.¹

Table 1: Unified Definition of Statin Intolerance*

1	The inability to tolerate at least two different statins; one statin at the lowest starting average daily dose and the other statin at any dose.
2	Intolerance associated with confirmed, intolerable statin-related adverse effect(s) or significant biomarker abnormalities as recently suggested by the European Atherosclerosis Society Consensus Panel and the National Lipid Association.†
3	Symptom or biomarker changes; resolution or significant improvement upon dose decrease or discontinuation.
4	Symptoms or biomarker changes not attributable to established predispositions such as drug-drug interactions and recognized conditions increasing the risk of statin intolerance.

In this setting, the GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3) trial was comprehensively designed to 1) identify to development of muscle symptoms with both statin and non-statin therapy, and 2) compare the lipid lowering capability of two non-statin medications, ezetimibe and evolocumab, among those with clinical intolerance.¹⁰ The majority of patients (63%) were classified as high Framingham risk – patients who would otherwise benefit from lipid lowering therapy. To summarize, this was a two-stage randomized clinical trial that included patients with documented muscle-related adverse effects to two or more statins or uncontrolled low-density lipoprotein cholesterol (LDL-C) levels. After an initial 4-week period in which all lipid-lowering therapy was discontinued, a total of 511 participants entered phase A. Phase A was composed of two periods: patients were randomized to receive either atorvastatin (20 mg daily) or placebo for 10 weeks (period 1), followed by a 2-week washout, followed by crossover to the alternate treatment for 10 weeks (period 2). After a second 2-week washout period, eligible patients for Phase B included participants from Phase A who developed intolerable muscle symptoms while taking atorvastatin and those with a prior history of CK >10x ULN and muscle symptoms, followed by resolution of both indices, respectively. Participants were randomized in a 2:1 fashion to ezetimibe (10 mg daily) or evolocumab (420 mg monthly) for 24 weeks during Phase B. Importantly, the authors rigorously classified SI on a clinical basis; for Phase A, the majority of enrolled patients were previously unable to tolerate ≥3 statins (82%), with similar numbers found in those who qualified for Phase B. Laboratory data (i.e., liver and muscle enzymes) were collected in all participants. Ultimately, the results of this study were informative and the following findings should be considered:

1. Statin Intolerance

During Phase A, muscle intolerance developed with atorvastatin in 51% (126/246) and 34% (83/246) of participants who received atorvastatin and placebo first, respectively; overall 209 patients (43%) had muscle adverse effects while taking atorvastatin and 130 (27%) developed symptoms on placebo but not atorvastatin. It is interesting to note that the time to first muscle adverse event was highest between 30-60 days while on atorvastatin therapy, earlier than reported in the literature.^11,12 The incidence appears to be inflated and competes with arguments that most statin treated patient can be safely re-challenged with the same or an alternative statin and demonstrate tolerance.^8,12,13 Specifically, atorvastatin (used in this study) and rosuvastatin are recommended for those with documented SI, given their long half-life, tolerability after reinitiation, and significant improvements in LDL-C and total cholesterol levels (see discussion on the nocebo effect below).^14-16 Alternatively, Nissen et al.¹⁰ have established a relationship between statin therapy and muscle symptoms (i.e., it is no longer controversial) – which is not possible in clinical practice or observational studies because blinding is not present.¹⁷ While muscle complaints may be subjective or genuine, physicians should continue to stress the cardiovascular benefits of statin therapy with patients; as suggested in this study, 60% of patients with previous intolerance were able to tolerate therapy.

2. The Nocebo Effect

When statin therapy is indicated, patients should be informed about the potential side effects that may occur. Inadvertently, this raises concerns for the nocebo effect (side effects experienced by patients if they anticipate a medication to be harmful) and may explain the variable rates of myopathy observed when comparing cases in clinical practice and observational studies with randomized trials.¹⁸ In the current study, 27% of patients experienced muscle related effects while taking placebo. The proportion of patients with SI ranges between 2% in Japan and Sweden to 10-12% in industrialized countries such as Canada, the United Kingdom, and the United States.¹⁹ This variability may be influenced by many factors, such as warnings about adverse effects, information disseminated by various media outlets (social and broadcast) about the dangers of treatment, and the patients' perception. Overall, effective physician–patient communication about the potential side effects and the benefits conferred by long-term statin therapy is necessary to improve both adherence and outcomes.¹⁷

3. Evolucumab vs Ezetimibe

In phase B, 218 patients were randomized to receive subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). The mean LDL-C level (mg/dL) at 22 weeks after treatment was 103.6 for the evolocumab group vs 183.0 for the ezetimibe group (mean % change from baseline: -54.5% vs -16.7%, respectively, p <0.001); at 24 weeks, the mean % change was -52.8% vs -16.7%, respectively, p <0.001). The reduction in LDL-C is consistent with previous reports for ezetimibe,^20,21 evolocumab,^22,23 or alirocumab in statin intolerant patients.²¹ Important to these findings, reported muscle symptoms were not eliminated with the PCSK9 inhibitor and ezetimibe (20.7% vs 28.8%, respectively); in GAUSS-2, muscle adverse events occurred in 12% vs 23% of evolocumab- and ezetimibe-treated patients,²² respectively, albeit a stringent protocol that identified patients who were statin intolerant was used in GAUSS-3. Altogether, the results suggest promise from this emerging drug class.

4. PCSK-9 Inhibitors for a Niche Population

Currently, the FDA and European Medicine Agency (EMA) have approved the use of evolocumab as an adjunct to diet and maximally tolerated statin therapy for the management of familial hypercholesterolemia and for those with clinical atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-C. Additionally, alirocumab was recognized by the EMA for use in patients unable to tolerate statin therapy and for use in whom a statin is contraindicated. The main arguments against its use for SI are largely three-fold: 1) difficulty defining SI due to a lack of established biomarkers for use in clinical practice (i.e., statin therapy should be reconsidered as a first line agent); 2) lack of hard cardiovascular outcome data with PCSK-9 therapy; and 3) PCSK-9 treatment is not costs effective at its current price.²³ Financial burden aside, the exclusive use of non-statin therapy has been considered for high-risk patients unable to tolerate alternative statin dosing regimens. To date, ezetimibe represented the best non-statin alternative, despite unavailable outcome data assessing ASCVD events with this specific monotherapy. To clarify, patients with SI represent a very small proportion of all statin treated patients. As such, when clinically appropriate, evolocumab appears favorable for further lowering LDL-C levels (3-times greater than ezetimibe).

Encouraged by early primary prevention trials with statin therapy, which demonstrated a reduction in short term CVD events and long term total and CVD mortality, PCSK9 inhibitors are likely poised to follow a similar trajectory. Evidence supports improved cardiovascular outcomes with lower LDL-C,²⁴ with greater clinical benefit found with greater reduction in cholesterol.^7,25 Indeed, evidence from randomized studies has revealed that statin therapy reduces the risk of major cardiovascular events by about 25% for each 1 mmol/L reduction in LDL–C during each year it is taken (after the first year).⁷ As such, the robust LDL-C reduction seen with PCSK9 inhibitors may be of importance when determining alternative therapy plans in otherwise high-risk patients who develop statin associated muscle symptoms (as seen in the current study, for example).

In summary, the GAUSS-3 randomized clinical trial confirms the existence of statin intolerance (despite a relatively narrow wash out period during Phase A), supports the notion of the nocebo effect, demonstrates similar rates of intolerance between two non-statin therapies, further demonstrates greater LDL-C reductions with evolocumab compared with ezetimibe, and provides definitive evidence that despite multiple attempts to develop an acceptable statin regimen, many patients can indeed safely tolerate statin therapy. While we await outcome data for PCSK9 inhibitors, practicing physicians should recall the lessons offered by Sir William Osler who suggested to "listen to your patient, he is telling you the diagnosis," emphasizing the importance of patience during history acquisition. Physicians must provide the balanced information that patients deserve in order to improve statin adherence and reduce CVD risk that is otherwise undermined by the onset of (perceived) muscle side effect.

References

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2. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Etiology and Management. Eur Heart J 2015;36:1012–22.
3. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:S1–45.
4. Rosenson RS, Baker SK, Jacobson TA, et al. An assessment by the statin muscle safety task force: 2014 update. J Clin Lipidol 2014;8:S58–71.
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15. Ferrer-Garcia JC, Perez-Silvestre J, Martinez-Mir I, et al. Alternate-day dosing of atorvastatin: effects in treating type 2 diabetic patients with dyslipidemia. Acta Diabetol 2006;43:75–8.
16. Jafari M, Ebrahimi R, Ahmadi-Kashani M, et al. Efficacy of alternate-day dosing versus daily dosing of atorvastatin. J Cardiovasc Pharmacol Ther 2003;8:123–6.
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18. Tobert JA, Newman CB. The nocebo effect in the context of statin intolerance. J Clin Lipidol 2016;10:739-47.
19. Hovingh GK, Gandra SR, McKendrick J, et al. Identification and management of patients with statin-associated symptoms in clinical practice: a clinician survey. Atherosclerosis 2016;245:111-7.
20. Venero CV, Venero JV, Seip RL, Thompson PD. Effectiveness of thrice weekly ezetimibe. Am J Cardiol 2008;102:1205-6.
21. Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol 2015;9:758-69.
22. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2541-8.
23. Waters DD, Hsue PY, Bangalore S. PCSK9 inhibitors for statin intolerance? JAMA 2016;315:1571-2.
24. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
25. Ridker PM, Mora S, Rose L, JUPITER Trial Study Group. Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents. Eur Heart J 2016;37:1373-9.
26. Hays H, Cohen DE, Chalasani N, et al. An assessment by the statin liver safety task force: 2014 update. J Clin Lipidol 2014;8:S47–57.

Keywords: Antibodies, Monoclonal, Atherosclerosis, Biomarkers, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Diet, Drug Interactions, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Muscular Diseases, Nocebo Effect, Primary Prevention, Secondary Prevention, Dyslipidemias

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