Introduction

Statins are considered to be a cornerstone therapy in patients with coronary artery disease. The efficacy of statins for the prevention of recurrent myocardial infarction (MI) has been demonstrated in several randomized controlled trials.1 Large-scale analyses of > 170,000 patients have demonstrated that for each 1.0-mmol/L (39-mg/dL) reduction in low-density lipoprotein (LDL) cholesterol, statins reduce the rates of major adverse cardiovascular events (MACEs) by 20 to 25%.2 Based on this evidence, guidelines recommend high-intensity statins following acute coronary syndromes.3 4 Statins are generally well tolerated, but as many as 20% of patients report adverse muscle side effects.5 6

Effect of Discontinuation of Statins in High-Risk Patients

Statin intolerance may lead to discontinuation of therapy, which is associated with an increased risk of cardiovascular outcomes.7 Serban et al showed discontinuation or downtitration of statin in patients of MI within 1 year increases the risk of recurrent MI by 36% and coronary heart disease (CHD) events by 46%.8 It evaluated 1,741 patients of statin intolerance, with 55,567 patients of high statin adherence over a median of 1.9 to 2.3 years of follow-up. The multivariate adjustment showed that hazard ratio (HR) comparing beneficiaries with statin intolerance with those with high statin adherence was 1.50 (95% confidence interval [CI]: 1.30–1.73) for recurrent MI, 1.51 (95% CI: 1.34–1.70) for CHD events, and 0.96 (95% CI: 0.87–1.06) for all-cause mortality (Fig. 1). Misdiagnosing statin intolerance and its inappropriate discontinuation can lead to increased cardiac events. Therefore, the issue of statin intolerance is of great clinical importance.

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Fig. 1 Flowchart for management of statin-attributed muscle symptoms. (Adapted from EAS Consensus Panel 2015.) CETP, cholesteryl ester transfer protein; CK, creatinine kinase; LDL-C, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9; ULN, upper limit of normal range.

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Fig. 1 Flowchart for management of statin-attributed muscle symptoms. (Adapted from EAS Consensus Panel 2015.) CETP, cholesteryl ester transfer protein; CK, creatinine kinase; LDL-C, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9; ULN, upper limit of normal range.

How Common Is Statin Intolerance?

Statin intolerance is defined as inability of a patient to tolerate a statin, either because of the development of a side effect or because of evidence on a blood test elevated markers of liver function or muscle function (creatinine kinase).9 The intolerance can be either partial (i.e., only some statins at some doses) or complete (i.e., all statins at any dose). The most common presentation of statin intolerance includes muscle aches, pains, weakness, or cramps, often called myalgias. Muscle symptoms are also known as statin-associated myalgia/myopathy, statin-induced myalgia/myopathy, or statin-related myalgia/myopathy or muscle symptoms (SAMS).10 The recent statement of the European Atherosclerosis Society (EAS) has focused on SAMS, and avoided the use of the term “statin intolerance,” as it is not specific for muscle symptoms.11 Although muscle syndromes are the most common adverse effects observed after statin therapy, excluding other side effects might underestimate the number of patients with true statin intolerance. The incidence of statin intolerance in clinical trials varies between 5 and 10%, whereas in observational studies the statin intolerance can be seen up to 20%.5 A recent, large, observational survey reports that statin-associated muscle pain affects 29% of statin users and causes 15% of these individuals to stop statin therapy.12 The reason for lower incidence of statin intolerance in randomized clinical trials (RCTs) can be multifactorial. First, patients with history of any statin related side are excluded in RCTs. Second, patients who are at risk of developing muscle-related symptoms, such as women, elderly patients, and patients with significant comorbidities (e.g., liver failure, kidney failure, or thyroid disease), are underrepresented in RCTs. Definition of statin intolerance is not uniform in trials. Some studies ignored statin-associated myalgia and only considered elevated serum creatine kinase (CK) activity as a side effect. To overcome these issues, International Lipid Panel came with a unified definition of statin intolerance in 2015, which is listed as follows.13

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.

3. Symptoms 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.

Statin Adverse Effects

Table 1 summarizes the other side effects mentioned in the literature. Most common adverse effect of statins is muscle related. The symptoms are usually mild and are rarely associated with muscle inflammation (myositis) and markers of muscle injury (creatinine kinase).9 These symptoms are completely reversible shortly after the statin discontinuation. Serious muscle damage or rhabdomyolysis associated with statin treatment is extremely rare, for instance, occurring in 1 in 23 million individuals with prescriptions for atorvastatin. Mild to moderate increases in creatinine kinase may be occasionally seen in patients taking statins who have no muscle-related side effects, and this should not be grounds to stop statin therapy.

1. Muscle-related side effects: The most common statin-related adverse event is muscle weakness; however, due to the many potential reasons for this symptom, it is sometimes difficult to definitely state that it is indeed statin-related. EAS integrated all muscle-related complaints (e.g., pain, weakness, or cramps) as “muscle symptoms,” subdivided by the presence or absence of CK elevation (Table 2).11 Pain and weakness in typical SAMS are usually symmetrical and proximal and generally affect large muscle groups, including the thighs, buttocks, calves, and back muscles. Discomfort and weakness typically occur early (within 4–6 weeks after starting statin therapy) but may still occur after many years of treatment. Onset of new symptoms may occur with an increase in statin dose or initiation of an interacting drug. The symptoms appear to be more frequent in physically active individuals. Statin-associated muscle symptoms often appear more promptly when patients are reexposed to the same statin. Commonly SAMS are not accompanied by marked CK elevation.14 If CK elevations >10 × ULN with muscle symptoms it is usually referred to as myopathy, the incidence is approximately 1 per 10,000 per year with a standard statin dose. Rhabdomyolysis is a severe form of muscle damage associated with very high CK levels with myoglobinemia and/or myoglobinuria with a concomitantly increased risk of renal failure. The incidence of rhabdomyolysis in association with statin therapy is 1 in 100,000 per year.15 In view of the rarity of CK elevations during statin therapy, routine monitoring of CK is not recommended. Even if an asymptomatic elevation of CK is detected, the clinical significance is unclear.

How to Manage Statin Adverse Effects?

Statin adverse effects depends on the dose of statin, class of statin, age, sex, other comorbidities, and cotreatment with other drugs or foods. Extraneous factors causing rise in CK or liver enzyme levels should be ruled out. Vitamin deficiency, hypothyroidism, and extreme physical exertion can lead to marked increase in CK levels and should be ruled out before discontinuing the therapy.

Patients should be counseled regarding the benefit and harm of statins. Cardiovascular benefits of statins and harms on its discontinuation should be discussed with patients. Reduction in fatal and nonfatal heart attack and stroke by statin treatment cannot be achieved with other currently available medications, nutraceuticals, or dietary modifications. The risk of drug discontinuation versus the benefits must be weighed before making permanent decisions about the management of statin intolerance. The long-term safety and absence of “organ damage” with statins, even when discomfort/pain is present should be reemphasized. There is high likelihood of successful rechallenge with statin and should be explained to the patient. Before considering the use of a second-line alternative drug, patients should try statin rechallenge, alternative regimens, doses, or types of statins. In most cases, rechallenge with a statin after a brief period of drug discontinuation (“drug holiday”) can be successful. In a study of 11,124 patients in whom statins were discontinued at least temporarily because of clinical events or symptoms believed to have been caused by statin use, 92% of those who were rechallenged were still taking a statin 12 months after the statin-related event and 47% were on same statin to which they had statin-related adverse effects.5

Management of Statin-Associated Muscle Symptoms

Depending on the symptoms and serum CK levels, patients should be stratified (Table 3). In patients at low cardiovascular disease (CVD) risk with muscle symptoms and CK < 4 × ULN, their need for a statin should be reassessed and the benefits of therapeutic lifestyle changes, such as cessation of cigarette smoking, blood pressure control, and adoption of a Mediterranean style diet, should be balanced against the risk of continuing statin therapy. For patients at high CVD risk, the benefits of ongoing statin therapy need to be weighed against the burden of muscle symptoms. Withdrawal of statin therapy followed by one or more rechallenges (after a washout) can often help in determining causality. Alternative approaches include the use of an alternative statin, a statin at lowest dose, intermittent (i.e., nondaily) dosing of a highly efficacious statin, or the use of other lipid lowering medications. For patients at low CVD risk who have symptoms with CK > 4 × ULN, the statin should be stopped and its need reassessed. If considered important, a lower dose of an alternative statin should be tried and CK monitored. For patients at high CVD risk with muscle symptoms and a CK of > 4 × ULN (but < 10 × ULN), statin therapy can be continued with concomitant monitoring of CK, but it can be stopped (at least temporarily) if the levels exceed 10 × ULN. In this case, that particular statin regimen should not be restarted. If CK levels decrease after stopping the statin, restarting at a lower statin dose with CK monitoring should be tried. In patients with a CK > 10 × ULN, statin therapy should be stopped because of the potential risk of rhabdomyolysis. If the CK level returns to normal, rechallenge with a lower dose of an alternative statin and careful monitoring of symptoms and CK may be considered. If rhabdomyolysis is suspected, statin should not be reintroduced. If there is severe muscular pain, general weakness, and signs of myoglobinemia or myoglobinuria, rhabdomyolysis should be considered. Evaluation of renal damage (urinalysis, serum creatinine levels) should be done. Intravenous hydration and urine alkalinization are recommended for the treatment of rhabdomyolysis depending on severity and the presence of kidney injury.21 If indicated, nonstatin low-density lipoprotein cholesterol (LDL-C)–lowering agents should be used (see the following text).

If symptoms/CK abnormalities resolve after discontinuation of statin, either treatment with the same statin at a lower dose or switching to an alternative statin should be started. If tolerated, doses need to be uptitrated to achieve LDL-C goal or as much LDL-C reduction that can be achieved with minimal muscle complaints. If these strategies are not tolerated, alternate-day or twice-weekly dosing can be considered to achieve the LDL-C goal. Studies have shown that either alternate-day or twice-weekly dosing strategies can reduce LDL-C by 12 to 38%, and, importantly, are tolerated by > 70% of previously intolerant patients.22 However, LDL-C reduction is much lower than the ideal LDL-C target in alternate dosing, and it has not been established through clinical trials. Thus alternate-day dosing strategy should be used only as a secondary option in specific high-risk patients who are intolerant to lower/alternative statin therapy.

Switching Therapy

Statins vary in their metabolism, and this affects their potential for drug interaction. Simvastatin and atorvastatin are metabolized via the CYP3A4 pathway. Concurrent therapy with drugs that interfere with CYP3A4 pathway (such as anti retrovirals, cyclosporine, digoxin, diltiazem, and antifungals) may lead to statin accumulation and an increased propensity for myopathic side effects. Statins not metabolized via this pathway such as pravastatin, rosuvastatin, and fluvastatin should be considered in these patients. Similarly, statins that are lipophilic (atorvastatin) have increased incidence of rhabdomyolysis as compared with statins that are hydrophilic (rosuvastatin). Therefore, patients' intolerant to one statin can be switched over to a more hydrophilic statins.

Alternate-Day Dosing

Statins with longer half-life maintain lipid-lowering effect over a longer period of time, enabling alternate-day dosing strategy with statin. Atorvastatin with a mean half-life of 14 hours is metabolized into two active metabolites: orthohydroxy and parahydroxy forms. Both these active metabolites contribute to 70% activity of atorvastatin and have a half-life of 20 to 30 hours. This pharmacokinetic parameter of atorvastatin makes it suitable for an alternate-day dosage regimen and continues its lipid-lowering activity for considerably a longer period of time. Rosuvastatin, a third-generation statin, possesses a long half-life period of around 19 hours and can be tried as alternate-dose or twice-weekly dosing.

Complementary Therapies

Evidence for the effectiveness of vitamin D is also controversial, although many patients with SAMS are found to have low blood levels of vitamin D. Hence, routine use of CoQ10 or vitamin D supplementation is not recommended to treat or prevent SAMS.

Future Low-Density Lipoprotein–Lowering Therapies

Two classes of novel therapies, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and cholesteryl ester transfer protein (CETP) inhibitors, has shown to decrease LDL levels similar to statins, and they offer as an alternative to patients with statin intolerance.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors

Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels in patients who are treated with statins. Studies have shown LDL-C reductions of 50 to 60% in a patient groups, including those identified as statin intolerant, with a very low rate of muscle symptoms, thus reinforcing the concept that statin rather than LDL-C lowering is implicated in the causation of myopathy.26 In recent two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to MACEs in the trial involving lower-risk patients but had a significant benefit in the trial involving higher-risk patients (Studies of PCSK9 inhibition and the reduction of vascular events [SPIRE 1 and SPIRE 2 trial]).27 Therefore, for high-risk patients with statin intolerance, PCSK9 inhibitors can be used as an alternative.

Cholesteryl Ester Transfer Protease Inhibitor

Cholesteryl ester transfer protein mediates the heteroexchange of triglycerides and cholesteryl esters between lipoproteins. Inhibitors of CETP markedly increases high-density lipoprotein cholesterol (HDL-C), and two members of this class in advanced development, anacetrapib and evacetrapib, equally lower LDL-C by 25 to 40%.28 Although it decreased LDL-C and increased HDL-C, evacetrapib failed to reduce MACEs when compared with placebo in high vascular risk patients.

Statin Intolerance and Liver Disease

All patients prior to starting statin should have baseline alanine transaminase/aspartate transaminase (ALT/AST) levels done. Regular monitoring of liver enzymes is not recommended until there is clinical worsening. In patients with chronic liver disease (CLD), guidelines recommend more frequent ALT/AST monitoring; every month during the first 3 months of therapy and four times per year thereafter. In CLD patients, statin therapy should be stopped if AST/ALT activities rise for more than or equal to two times than the baseline value. After AST/ALT activities return to normal/baseline values, it is recommended to consider another statin to establish whether patient is (liver) statin intolerant. With regard to hepatitis B virus (HBV), hepatitis C virus (HCV), and primary biliary cirrhosis (PBC), there are common benefits related to statin therapy in high-risk CV patients.29 Statins confer a more efficient treatment of viral hepatitis, and it is related with reduced risk of cirrhosis and hepatocellular carcinoma (HCC). In patients with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH), statin treatment is safe, contributes to the resolution of NAFLD/NASH, and substantially reduces CVD risk to a level higher than in those with normal liver function.

Conclusion

Statin intolerance (predominantly muscle symptoms) is a major reason for statin nonadherence/discontinuation; it contributing to decreased CVD benefits from statins. In patients with symptoms of statin intolerance, indication for statin use should be assessed and patients should be made fully aware of the expected benefit in CVD risk reduction that can be achieved with this treatment. Contraindications to use of statin should be ruled out. Patients should be counseled regarding the risk of “side effects” and the high probability that these can be dealt with successfully. Dietary and other lifestyle measures should be emphasized. Statin should be reintroduced after drug washout period. If rechallenge does not work, a low or intermittent dosing should be used preferably of a different (potent or efficacious) statin. Nonstatin therapies should be used as adjuncts as needed to achieve LDL-C goal. Role of supplements is not recommended to alleviate muscle symptoms as there is no good evidence to support their use. Golden principles in management of statin intolerance is always strive to continue “maximally tolerated” statin therapy and always apply repetitive rechallenges. To achieve LDL-C target, different optimal therapy should be combined with maximally tolerated, or even nondaily statin dose, or with nonstatin-based lipid-lowering therapies.