Can HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, commonly referred to as statins, cause myasthenia (muscle weakness)?

From the Guidelines

Yes, statins can cause muscle weakness as a side effect, occurring in approximately 5-10% of patients taking these cholesterol-lowering medications. This is supported by the 2019 American College of Cardiology/American Heart Association guideline on the management of blood cholesterol, which reports that statin-associated muscle symptoms (SAMS) occur in 5% to 10% of patients in clinical settings 1. The muscle symptoms typically range from mild discomfort to more severe weakness, and in rare cases can progress to a serious condition called rhabdomyolysis.

Risk Factors and Mechanism

The mechanism behind statin-induced muscle weakness involves the medication's interference with muscle cell energy production and possibly increased muscle cell breakdown. Risk factors for developing muscle symptoms include being over 65, having a small body frame, kidney or liver disease, diabetes, or taking certain medications that interact with statins, as noted in the 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering 1.

Management and Prevention

If you experience persistent muscle pain, tenderness, or weakness while taking a statin, you should contact your healthcare provider promptly. They may recommend temporarily stopping the medication, reducing the dose, or switching to a different statin. Some patients find that taking the medication every other day or switching to a less potent statin reduces muscle symptoms. The 2022 ACC expert consensus decision pathway also suggests that clinicians should strive to find the highest tolerated statin dose that is as close to the guideline recommendation as possible and work with patients to help understand the nature and severity of symptoms 1.

Key Considerations

It's essential to note that true complete statin intolerance is uncommon, and a careful history can help determine whether symptoms are consistent with statin-related effects, which tend to be symmetric myalgias or weakness in large proximal muscle groups. Other causes of muscle symptoms must be ruled out, and drug–drug interactions that can increase systemic statin exposure must be considered. The approach to statin-associated side effects should include discontinuation of statin therapy until resolution of symptoms and subsequent rechallenge to verify recurrence of muscle-related symptoms, as recommended in the 2022 ACC expert consensus decision pathway 1.

From the FDA Drug Label

Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CK) to greater than 10 times the upper limit of normal (ULN), occurred <0. 1% in pravastatin-treated patients in clinical trials. There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

Statins can cause muscle weakness. The risk of myopathy, including muscle weakness, is increased with the use of statins, such as simvastatin and pravastatin. Patients should be instructed to report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.

• Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher statin dosage.
• Immune-mediated necrotizing myopathy (IMNM), a rare condition characterized by proximal muscle weakness and elevated serum creatine kinase, has been reported with statin use. 2, 3, 3

From the Research

Statin-Associated Muscle Weakness

• Statins are generally safe and well-tolerated, but some patients experience muscle complaints that can be attributed to their use 4.
• Muscle complaints can range from muscle discomfort to statin-associated myotoxicity, characterized by elevated creatine kinase (CK) levels, with or without muscle discomfort or weakness 4.
• Rare patients have statin-associated autoimmune myopathy, a disease characterized by proximal muscle weakness, elevated CK levels, and autoantibodies recognizing hydroxy-methyl-glutaryl coenzyme A reductase 4.
• The side effects most commonly associated with statin use involve muscle cramping, soreness, fatigue, weakness, and, in rare cases, rapid muscle breakdown that can lead to death 5.

Prevalence and Mechanisms

• The incidence of myopathy associated with statin treatment typically ranges between 1.5% and 10% 6.
• The pathophysiology of statin-related myopathy is incompletely understood, but may involve a dose-dependent and proapoptotic effect, direct effects on mitochondria, drug interactions, and genetic factors 6.
• Discrepancies between clinical trials and daily practice may emanate from inconsistent definitions or exclusion criteria, and further research is needed to develop alternative LDL-lowering drugs when statins are not well tolerated 6.

Diagnosis and Management

• The appropriate evaluation of the patient before starting statins and proactive utilization of available diagnostic tests to rule out alternate etiologies mimicking adverse effects are essential for accurate diagnosis of statin-associated side effects 7.
• In patients with true statin-associated side effects, timely intervention with modified statin or non-statins is beneficial 7.
• Exchange of statin may be beneficial, although all statins have been associated with muscle pain, and reduction of dose is worth trying, especially in primary prevention 8.