Pearls & Oy-sters: Managing Cholesterol in a Patient With Statin Intolerance Due to Anti-HMG-CoA Reductase–Associated Myopathy

Discussion

Statins act by inhibiting HMG-CoA reductase, which leads to increased expression of the hepatic LDL-C receptor and increased clearance of LDL-C from circulation. The mechanism underlying the development of anti-HMGCR myopathy remains unknown, although statins up-regulate the expression of HMG-CoA reductase suggesting a mechanistic link between statins and the development of autoimmunity.¹ They are the first-line agents for the treatment of hypercholesterolemia and prevention of atherosclerotic cardiovascular disease (ASCVD).² It is estimated that 1 in 4 Americans aged older than 40 years use statins.³ Their most common adverse effects occur in skeletal muscle, usually called statin-associated muscle symptoms (SAMS), and include myalgia (muscle aches without elevated levels of CK), myopathy (muscle symptoms with CK >10 times the upper limit of normal [ULN]), myositis (muscle inflammation), and rhabdomyolysis.

Statins are also associated with anti-HMG-CoA reductase–associated myopathy. This is a rare disease with an estimated incidence of 2–3 cases for every 100,000 patients treated with statins,⁴ which generally occurs in adults in their 50s and 60s who have been taking statins for 1–2 years, but can also occur in patients with no history of statin use. In one case series, the median disease duration was 13 months at the time of biopsy.⁵ Patients usually have very high CK levels: > 10 times the ULN, usually around 45 times the ULN.^3,4 The clinical presentation consists of myalgia and a bilateral, proximal, symmetric weakness that helps to differentiate it from other forms of SAMS in which weakness is less common. Indicative laboratory test results include the presence of anti-HMGCR antibodies, which have a sensitivity of 94.4% and a specificity of 99.3% for anti-HMG-CoA reductase–associated myopathy.⁶ EMG is usually interpreted as an irritable myopathy, and magnetic resonance imaging may show muscle edema. Muscle biopsy may reveal muscle fibers of different sizes, necrosis, regeneration, myophagocytosis, and infiltration of macrophages and lymphocytes.⁴ Up to 25% of cases may present with neither muscle fiber necrosis nor perimysial pathology.⁷ Macrophages that are CD163-positive are the predominant infiltrating cell type and would play a role in muscle regeneration rather than mediate muscle injury. Sparse lymphocytic infiltration suggests that T and B cells play a lesser role in the pathogenesis of anti-HMG-CoA reductase–associated myopathy.⁴

In addition to the discontinuation of statins, immunosuppressive treatment is indicated, usually corticosteroids at a dose equivalent to 1 mg/kg/d of prednisone. Methotrexate and azathioprine are often given as immunosuppressant agents.^3,4 The use of IV immunoglobulin has also been described as a replacement for immunosuppressants or even as monotherapy,⁸ and rituximab has been used as a rescue treatment for patients with refractory anti-HMG-CoA reductase–associated myopathy,⁹ but effective treatment strategies have not yet been established in clinical trials. After muscle strength recovery, medications should be tapered, although a relapse may prompt long-term immunosuppressive therapy.

There are several caveats in the treatment of these patients. Corticosteroid treatment may adversely affect serum lipid levels.¹⁰ This should be considered if a patient treated with corticosteroids and LDL-lowering therapy continues with a high LDL-C level because this may prompt replacement or reduction of the dose of corticosteroids and/or intensification of the LDL-lowering therapy. Second, rechallenge with the same or another type of statin should be avoided because this may lead to a disease flare, with accelerated decline in weakness and worsening hyperCKemia,³ possibly by the upregulation of HMGCR levels. Third, although anti-HMGCR antibody levels are reported to correlate with disease activity, they rarely normalize even in patients who seem to have recovered. Thus, anti-HMGCR antibody titer may not be useful for therapeutic monitoring.

In anti-HMG-CoA reductase–associated myopathy, the aim of pharmacologic lipid modification is to reduce LDL-C as a means of primary or secondary prevention of ASCVD. Ezetimibe reduces LDL-C by selectively blocking the Niemann-Pick C1-like 1 protein and reducing intestinal cholesterol absorption. In addition, ezetimibe inhibits macrophage migration, decreasing vascular cell adhesion molecule 1 expression, and reducing the level of reactive oxygen species, which may reduce inflammation.¹¹ Although it has been shown to reduce LDL-C by 15%–20%, there is limited evidence on its role as monotherapy in the prevention of ASCVD.¹² Ezetimibe has a safety profile similar to placebo, and no significant drug interactions have been observed.¹²

A case series described the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which proved to be a safe cholesterol-lowering therapy for patients with anti-HMG-CoA reductase–associated myopathy.¹³ PCSK9 inhibitors have been proven to reduce LDL-C more effectively than ezetimibe.¹⁴ Although PCSK9 inhibitors are very effective and safe drugs that can reduce LDL-C and cardiovascular events, considering their cost, they may be cost-effective only in patients at very high-risk of ASCVD and their use may not be possible in countries with limited healthcare resources.²

A large retrospective cohort study¹⁵ found that patients with myocardial infarction (MI) who were prescribed statin but were found to be statin-intolerant after MI hospitalization and were therefore then treated with another LDL-lowering therapy had a 36% higher rate of recurrence of MI and a 43% higher rate of coronary heart disease events than those who were statin-adherent. Strategies for dealing with statin intolerance in secondary prevention are still needed.

The exponential use of statins makes it crucial for clinicians to remain aware of their possible and even dangerous side effects. Early recognition and treatment are key factors in decreasing the morbidity of anti-HMG-CoA reductase–associated myopathy, a rare disease that requires definitive statin withdrawal, plus immunosuppressive therapy, while maintaining the prevention of ASCVD.