What is the likelihood of developing muscle cramping with HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, commonly referred to as statins?

From the Guidelines

Muscle cramping from statins typically develops within weeks to months after starting treatment, with approximately 5-10% of patients experiencing some form of muscle symptoms 1. The severity of muscle cramping varies widely among individuals, and risk factors that may accelerate cramping include older age, female gender, low body weight, kidney or liver disease, hypothyroidism, vitamin D deficiency, and taking multiple medications. Some key points to consider when evaluating muscle cramping in patients taking statins include:

• The frequency of statin-associated muscle symptoms (SAMS) is infrequent (1% to 5%) in randomized controlled trials (RCTs), but more frequent (5% to 10%) in observational studies and clinical settings 1.
• Predisposing factors for SAMS include age, female sex, low body mass index, high-risk medications, comorbidities, and Asian ancestry 1.
• If muscle symptoms develop during statin therapy, it is recommended to discontinue the statin until the symptoms can be evaluated, and to consider other causes of muscle symptoms, such as hypothyroidism, reduced renal or hepatic function, or primary muscle diseases 1.
• The most effective way to manage muscle cramping while maintaining cardiovascular benefits is to work with a healthcare provider to adjust the statin dose or switch to a different statin, rather than discontinuing the medication altogether 1.

From the FDA Drug Label

The following adverse reactions have been identified during post-approval use of simvastatin... Musculoskeletal and Connective Tissue Disorders muscle cramps, immune-mediated necrotizing myopathy, polymyalgia rheumatica, arthritis In clinical studies with a median follow-up of at least 4 years, in which 24,747 patients received simvastatin, the incidence of myopathy (defined as unexplained muscle weakness, pain, or tenderness accompanied by CK increases greater than 10xULN) was approximately 0.03%, 0.08%, and 0.61% for the simvastatin 20 mg, 40 mg, and 80 mg daily groups, respectively. The time to develop muscle cramping with statins is not explicitly stated in the label. However, myopathy (which includes muscle weakness and pain) was most common in the first year of treatment, with the incidence decreasing in subsequent years 2.

• The exact time to develop muscle cramps is not provided.
• Myopathy incidence was highest during the first year of treatment. It is not possible to determine the exact time to develop muscle cramping based on the information provided in the label.

From the Research

Statin-Associated Muscle Cramping

• The development of muscle cramping with statins can vary depending on several factors, including the type of statin, dosage, and individual patient characteristics 3, 4.
• Studies have reported that statin-associated muscle symptoms, including cramping, can occur in 10% to 29% of patients in clinical practice 5.
• The onset of muscle cramping with statins can be difficult to predict, as the evidence in support of muscle pain caused by statins is often equivocal and not particularly strong 6.
• However, it is known that statins can lead to a range of neuromuscular side effects, including asymptomatic elevation of muscle enzymes, mild-moderate myalgias and cramps, and rare cases of rhabdomyolysis 3.

Risk Factors and Mechanisms

• The exact mechanisms underlying statin-associated muscle cramping are not fully understood, but it is thought that multiple, interactive, and potentially additive mechanisms are involved 4.
• Risk factors for developing muscle cramping with statins may include underlying muscle or neuromuscular junction disorders, as well as certain genetic predispositions 3, 7.
• The discovery of anti-HMGCR antibodies has led to a better understanding of clinical aspects of statin-associated anti-HMGCR myopathy and its treatment 3.

Management and Treatment

• The management of statin-associated muscle cramping typically involves a range of strategies, including switching to another statin, reducing the dose, or discontinuing the statin altogether 5, 7.
• In some cases, adding supplements such as vitamin D or coenzyme Q10 may be recommended, although the evidence for their effectiveness is limited 5.
• It is essential to weigh the benefits of statin therapy against the potential risks and to carefully monitor patients for signs of muscle cramping or other adverse effects 6, 7.