Why do statins (HMG-CoA reductase inhibitors) cause rhabdomyolysis?

From the Guidelines

Statins can cause rhabdomyolysis, a serious condition involving muscle breakdown, through several mechanisms, and the risk is increased with higher statin doses, certain medications, and in patients with kidney disease or hypothyroidism, as noted in the 2019 guideline on the management of blood cholesterol 1.

Mechanisms of Rhabdomyolysis

The exact mechanisms by which statins cause rhabdomyolysis are not fully understood, but they are thought to involve the inhibition of HMG-CoA reductase, which blocks cholesterol synthesis and also reduces the production of coenzyme Q10 and other isoprenoids essential for muscle cell energy production and membrane integrity. This metabolic disruption can trigger mitochondrial dysfunction, leading to increased oxidative stress and cellular damage in muscle tissue. Additionally, statins may impair calcium signaling in muscle cells and activate inflammatory pathways that contribute to muscle fiber breakdown.

Risk Factors for Rhabdomyolysis

The risk of rhabdomyolysis increases with higher statin doses, when combined with certain medications (like fibrates, cyclosporine, or azole antifungals), in elderly patients, those with kidney disease, hypothyroidism, or genetic factors affecting statin metabolism. According to the 2019 guideline, the incidence of rhabdomyolysis is rare, occurring in less than 0.1% of patients 1.

Monitoring and Prevention

While rhabdomyolysis is rare, it's essential to monitor for symptoms like severe muscle pain, weakness, and dark urine, especially when starting therapy or increasing doses. Routine monitoring of creatine kinase levels isn't recommended for asymptomatic patients, but should be checked if concerning symptoms develop. The 2016 recommendations for management of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease also emphasize the importance of careful monitoring when combining statins with other medications that may increase the risk of myopathy 1.

Key Points

• Statins can cause rhabdomyolysis through several mechanisms, including the inhibition of HMG-CoA reductase and the reduction of coenzyme Q10 production.
• The risk of rhabdomyolysis increases with higher statin doses, certain medications, and in patients with kidney disease or hypothyroidism.
• Monitoring for symptoms like severe muscle pain, weakness, and dark urine is essential, especially when starting therapy or increasing doses.
• Routine monitoring of creatine kinase levels is not recommended for asymptomatic patients, but should be checked if concerning symptoms develop.

From the FDA Drug Label

Atorvastatin calcium may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including atorvastatin

Simvastatin may cause myopathy and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including simvastatin

Rhabdomyolysis is a serious side effect associated with statin use, including simvastatin and atorvastatin. The exact mechanism of why statins cause rhabdomyolysis is not directly stated in the drug labels, but risk factors for myopathy and rhabdomyolysis include:

• Age 65 years or greater
• Uncontrolled hypothyroidism
• Renal impairment
• Concomitant use with certain other drugs (including other lipid-lowering therapies)
• Higher statin dosage
• Drug interactions that increase statin exposure due to inhibition of cytochrome P450 enzyme 3A4 (CYP3A4) and/or transporters 2 3 3

It is essential to carefully evaluate the benefits and risks of statin use, especially in patients with underlying risk factors, and to monitor for signs of myopathy and rhabdomyolysis.

From the Research

Mechanism of Statin-Induced Rhabdomyolysis

• The primary mechanism of statin-induced rhabdomyolysis is believed to be a decrease in ubiquinone (coenzyme Q) produced by the HMG-CoA pathway 4.
• Different types of lipophilic and hydrophilic statins play a role in causing rhabdomyolysis 4.

Risk Factors for Rhabdomyolysis

• Using CYP3A4 inhibitors, such as macrolide antibiotics, increases the risk of rhabdomyolysis 5, 6.
• Using high-dose statins increases the risk of rhabdomyolysis 4, 7.
• Strenuous physical activities increase the risk of rhabdomyolysis 4.
• Combining statins with other drugs that are myotoxic or that elevate the concentration of the statin increases the risk of rhabdomyolysis 5, 7.
• Renal insufficiency, diuretics, and hypothyroidism are also predisposing factors to the development of myopathy from the combination of statins and other drugs 7.

Prevention and Management

• Reducing the risk factors, such as using lower doses of statins, can prevent rhabdomyolysis 4, 7.
• Alternate-day therapy with a statin and fibrate, spacing of doses in a single day, or use of lower doses of statins may prevent the development of myopathy 7.
• Patients should be advised to watch for generalized muscle pain or weakness, and if it occurs, stop medications and report symptoms immediately 7.
• Early recognition and management of rhabdomyolysis are crucial to prevent the development of complications 6.