Statin-Induced Myopathy: What It Is and Possible Treatment

Cholesterol is a major risk factor for heart disease and stroke, which causes nearly 1 in 3 deaths among Americans. Too much cholesterol in the blood causes plaque (cholesterol deposits) buildup in the walls of the arteries. Plaque buildup can harden or clog the arteries and reduce blood flow to the heart. As a result, a person experiences chest pain, shortness of breath, and a heart attack.

To lower cholesterol levels and risks of cardiovascular complications, doctors prescribe statins. Unfortunately, in some people statins can induce a side effect called myopathy, the weakness of muscular tissues. Here, we discuss statin-induced myopathy and potential treatments to relieve this adverse effect.

What are statins?

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Statins are a class of drugs that effectively lower the blood level of low-density lipoprotein (LDL) cholesterol, otherwise known as the 'bad' cholesterol. Statins are also known as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, targeting the enzyme responsible for cholesterol production in the human body. They work by inhibiting cholesterol production in the liver. With statins, the risks of stroke, heart attack, and even death from cardiovascular disease are significantly lowered.

While statins are effective in managing cholesterol levels, they may also come with side effects, which can vary in frequency and severity. The potential side effects of statins include both common and rare occurrences, such as:

  • Headache
  • Fatigue
  • Nausea or vomiting
  • Sleep problems
  • Constipation
  • Diarrhea
  • Bloating or gas
  • Liver inflammation
  • Low platelet count
  • Muscle pain
  • Muscle weakness

What is myopathy?

The National Institute of Neurological Disorders and Stroke (NINDS) under the National Institutes of Health (NIH) defines myopathy as a neuromuscular disorder characterized by muscle weakness as the primary symptom. Myopathy is due to muscular dysfunction — specifically, the muscle fibers do not function properly, resulting in muscular weakness. It may also include muscle stiffness, spasms, and cramps.

Myopathy affects muscle structure, metabolism, or physiological functions. Depending on risk factors, myopathy can present with mild discomfort or severe enough pain to interfere with daily life activities. Myopathy primarily afflicts the voluntary muscles needed to perform movements, so patients with myopathy may experience difficulty even in simple tasks such as taking a bath, walking, or standing up from bed.

What is statin-induced myopathy?

According to the American College of Cardiology, statin-induced myopathy is the most common complaint of patients undergoing statin treatment. In general, around 27.8% of patients taking statins develop myopathy. When patients develop myopathy, they experience muscle-related symptoms that didn’t exist before they started statin treatment.

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Statins are generally safe and well tolerated, but they are also associated with undesirable side effects. The following are the symptoms of statin-induced myopathy:

  • Fatigue
  • Muscle pain, tenderness, or weakness
  • Muscle cramps or leg cramps, especially at night
  • Muscle stiffness or spasms

On the other hand, here are the most important risk factors that increase the likelihood of statin-induced myopathy:

  • Advanced age (80 and above)
  • Female sex
  • Small body frame and frailty
  • Having multisystem disease (particularly involving the liver, kidney, or both)
  • High consumption of grapefruit juice (>1 quart/day)
  • Hypothyroidism (underactive thyroid)
  • Alcohol use disorder (excessive alcohol consumption)
  • Diagnosis of type 1 or type 2 diabetes
  • History of major surgery
  • Excessive physical activity
  • Family history or previous myopathy experience with other cholesterol-lowering drugs
  • History of elevated blood creatine kinase (CK) levels
  • Cramps with no known cause
  • Receiving high-dose statin treatment
  • Polypharmacy or drug interaction with other drugs concurrently taken, such as cyclosporine, HIV protease inhibitors, nefazodone, verapamil, amiodarone, macrolide antibiotics, fibrates, and antifungals.

Myopathy classifications

Statins can contribute to the development of muscle-related conditions (myalgia, myositis, and rhabdomyolysis) by impairing muscle cell functions leading to muscle breakdown. Blood levels of creatine kinase (CK), an enzyme associated with muscle damage, are indicative of the severity of the damage and condition type.

Based on severity, muscle-related conditions can be classified into three categories: myalgia, myositis, and rhabdomyolysis.

  • Myalgia. Myalgia is the medical term for general muscle pain. Muscle symptoms may include spasms, tenderness, or weakness. Myalgia is usually diagnosed when there's no creatine kinase (CK) elevation.
  • Myositis. Myositis is distinguished by muscle pain, weakness, and increased levels of CK, typically up to 10 times the upper limit of reference blood levels.
  • Rhabdomyolysis. Rhabdomyolysis is rare but the most life-threatening condition, accompanied by severe muscle pain and weakness throughout the body, dark urine, and even kidney damage. It is identified by significantly elevated blood levels of CK and myoglobinuria, indicating high levels of myoglobin, a muscle cell protein, in the urine. Typically, CK levels surpass 10 times the upper reference limit in blood tests.

Statin-induced necrotizing myopathy is a rare complication associated with high CK levels in the blood, which may occur during statin treatment and persist even after cessation of therapy. Additionally, statin-induced necrotizing myositis can develop when the muscle cells undergo excessive cell death or necrosis. Muscle biopsies of necrotizing myopathies show a low level of inflammation but high levels of necrosis or muscle cell death.

There are also clinical cases suggesting that statins may trigger increased synthesis of the HGMCR enzyme, which they initially block, leading to autoimmunity. This may result in necrotizing myopathy/myositis due to the development of specific antibodies (anti-HGMCR antibodies), which then bind to muscle cells and inform our immune system to attack them. This is often seen in genetically susceptible patients.

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Why do statins cause myopathy?

The exact molecular mechanism of how statins induce myopathy is not fully understood. Studies have demonstrated several mechanisms that impair critical molecular functions related to muscle physiology.

Research findings suggest that statins can:

  • Reduce levels of coenzyme Q10 (coQ10), an essential molecule in the mitochondrial generation of energy.
  • Exist in lactone form, the non-therapeutic form, once inside the body, which can also impair mitochondria function.
  • Promote leakage of calcium from the muscle, which may ultimately cause damage and result in muscle pain and weakness.

Some researchers have suggested that statins might harm muscles and destroy muscle cells. However, the likelihood of this muscle problem varies depending on which statin is taken.

Which statin is less likely to cause muscle pain?

A 2022 study on statin therapy, which monitored 400 patients for 12 months, found that myopathy was most commonly observed with Simvastatin 40 mg. Approximately 50% of patients taking this dosage developed myopathy.

The lowest incidences of myopathy were observed with Rosuvastatin 10 mg and Fluvastatin XL 80 mg, where only 10.8% and 8% of the patients developed myopathy, respectively.

For the other statins, the incidences of myopathy are as follows:

  • Rosuvastatin: 10 mg — 10.8%; 20 mg — 14.6%
  • Atorvastatin: 10 mg — 12.5%; 20 mg — 21.2%; 40 mg — 28.9%
  • Simvastatin: 20 mg — 25.3%; 40 mg — 50%

However, this study had a small sample size, and the majority of participants had obesity or diabetes; therefore, the findings are not applicable to the general public. Some large clinical trials that included a more diverse range of people report statin-induced myopathy incidence of only 1–5%.

Determining the exact incidence of statin-induced myopathy in real-world situations can be challenging. Hence, understanding the risk factors associated with the development of this condition is crucial.

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Will the muscle pain go away?

Symptoms of statin-related muscle pain start to show soon after beginning the treatment. Generally speaking, within the first few months of statin treatment, patients susceptible to myopathy experience weak or achy muscles in their arms, shoulders, lower back, thighs, or buttocks.

In the majority of patients, muscle aches go away on their own after the first few weeks of statin medication. If statins are discontinued, muscle pain usually, but not always, resolves within 1–2 weeks.

Statin-induced myopathy treatment

Statins are important drugs to significantly reduce LDL cholesterol levels and cut the risk of cardiovascular diseases (CVDs) and CVD-related mortality. However, due to adverse effects like myopathy, patients may opt to stop their statin treatment, which can lead to serious consequences. Some treatments may help manage statin-induced myopathy. However, the treatments vary depending on the severity of the condition.

If you experience muscle pain or weakness during your statin treatment, it is important to discuss it with your healthcare provider as soon as possible. Your healthcare provider will help you manage the symptoms or rule out other underlying factors or conditions while ensuring your LDL cholesterol levels are under control.

Here are some treatment strategies that can be discussed with your doctor to alleviate statin-induced myopathy:

  1. Lowering the dosage of statin.
  2. Switching to other statins with lower myopathy risks.
  3. Switching to non-statin cholesterol-lowering drugs.
  4. Temporarily halting statin (e.g., for 3–4 weeks) or taking statins every other day.
  5. Reviewing your other medications and discussing potential interactions with statins.
  6. Supplementation with CoQ10 or vitamin D.
  7. Implementing diet and lifestyle changes that may help.
  8. Engaging in regular, moderate exercise and avoiding extensive physical activity.
  9. Getting a blood test to assess the severity of symptoms or other underlying conditions that may contribute to your condition.

Recovering from statin-induced myopathy

Many individuals who experience statin-induced myopathy typically recover fully within three months after discontinuing treatment. However, for those who require long-term statin therapy to manage high LDL cholesterol levels, myopathy may persist. Nonetheless, it can potentially be managed with the previously mentioned strategies under the guidance of healthcare providers. Additionally, recovery from statin-induced myopathy while effectively managing LDL cholesterol levels is more likely if patients are prescribed alternative non-statin lipid-lowering medications.

In extremely rare cases (estimated incidence of 2–3 cases per 100,000 people using statins), a patient may develop statin-induced necrotizing autoimmune myopathy (SINAM), severe progressive muscle weakness, and wasting, even after statins have been discontinued. This may require treatment with steroids and immunomodulatory drugs, but intravenous immunoglobulin treatment has also been demonstrated to be successful.

Key takeaways:

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