Statin therapy and musculoskeletal side effects

The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, has had a major role in decreasing cardiovascular risk over the past three decades. Statins have become one of the most prescribed medication classes in modern medicine. However, the efficacy of statins is limited in part by statin discontinuation.

Juan P. Brito Campana, MBBS, of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic's campus in Rochester, Minnesota, says: "In some cohorts, half of all patients discontinue statin therapy within two years of their prescription. Discontinuation is frequently due to the development of musculoskeletal complaints. The incidence of these complaints is between 1 percent and 5 percent in randomized controlled trials and 10 percent in large observational studies. The key challenge for the clinician is to find a way to preserve the cardiovascular benefits of statins in patients experiencing musculoskeletal side effects attributed to statins."

A practical definition

Statin-associated musculoskeletal syndrome (SAMS) comprises musculoskeletal symptoms or signs (muscle or tendon discomfort, pain, or impaired function) that develop while the patient is taking statins, decrease the health-related quality of life of the patient and resolve after statin discontinuation. Most complaints are not associated with abnormalities of creatine kinase (CK), which is an imperfect marker of muscle damage.

Risk factors for SAMS

Vinaya Simha, MBBS, M.D., of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic in Rochester, Minnesota, explains: "A systematic review of 27,548 patients found a greater incidence of SAMS (odds ratio = 9.97; 95 percent confidence interval, 1.28 to 77.92) in patients receiving intensive-dose statin therapy compared with standard-dose therapy. In addition, the risk of SAMS may depend on the type of statin used.

"An article published in Cardiovascular Drugs and Therapy in 2005 about the Prediction of Muscular Risk in Observational conditions (PRIMO) study reported different rates of SAMS with fluvastatin 40 mg (5 percent), pravastatin 40 mg (11 percent) and simvastatin 40 to 80 mg (18 percent). A meta-analysis including 71,108 people, 36,062 on statins and 35,046 on placebo, reported the greatest risk of SAMS with atorvastatin and the least risk with fluvastatin.

"Different rates have been attributed to pharmacological differences between statins. For example, rosuvastatin and pravastatin are primarily metabolized by cytochrome 2C9, a site with fewer drug-drug interactions than cytochrome 3A4, which metabolizes simvastatin, lovastatin and atorvastatin. Drugs inhibiting glucuronidation, such as gemfibrozil, or drugs affecting cytochrome 3A4 activity, such as amiodarone, protease inhibitors, niacin, azole antifungals, macrolides and nondihydropyridine calcium channel blockers, affect the clearance and increase the blood levels of statins."

Other important risk factors for SAMS are:

  • Age > 65 years
  • Family or personal history of SAMS
  • Unexplained muscle cramps
  • Hypothyroidism
  • Vitamin D deficiency
  • Rare hereditary metabolic muscle diseases

Establishing the diagnosis of SAMS

Dr. Simha highlights: "The clinician needs to consider whether the patient complaint represents SAMS or an alternative diagnosis. After excluding alternative diagnoses, clini­cians should determine the extent to which the musculoskeletal symptoms experienced affect the quality of life of the patient. This would include disruptions or impairments during work, recreation or sleep attributed to SAMS."

Assess and consider the potential benefit from statins

Clinicians and patients should review the potential value of statins. Using state-of-the-art risk communication tools, such as the Statin Choice Decision Aid, clinicians can explain to patients what the cardiovascular risk reduction means so that patients can consider whether the pursuit of this reduction is worth the work and potential side effects associated with therapeutic trials of other statins.

Dr. Brito Campana notes: "Patients at very low cardiovascular risk will likely opt to focus their health efforts in areas other than lowering lipid fractions and cardiovascular risk. Clinicians should reassure these patients because some might have been mistakenly informed that they were at high risk of cardiovascular events. Patients at high cardiovascular risk who value the risk reduction afforded by statins and are willing to run the risk of SAMS to find the right statin will proceed with restarting statins. Patients at high risk who are less willing to experience SAMS may instead choose to focus on other ways to reduce cardiovascular risk."

Restarting statins

If the diagnosis of SAMS was correct and there were no risk factors to modify, SAMS will likely recur after the same statin is resumed at the same dose. Dr. Simha suggests: "Two modifications may reduce the risk of recurrence of SAMS: switching to another statin and decreasing the dose. The statins with the lowest rates of SAMS include pravastatin, fluvastatin and rosuvastatin. Using a low dose — either by reducing the daily dose or by reducing the frequency of administration — of any of these could achieve the goal of SAMS-free adherence to statins."


Dr. Brito Campana concludes: "Instead of taking a purely technical approach, we suggest that clinicians engage the patient in a dialog about the promised quantified benefits of statins in light of their potential to cause SAMS. Patients should recognize there are other interventions also capable of reducing their cardiovascular risk that they may have already implemented or may be available to them to use instead of statins. For patients who value the risk reduction with statins, clinicians should prescribe therapeutic trials with statins associated with low risk of SAMS and administered at lower doses or frequency. A close partnership with the patient may lead to a greater proportion of patients who are able to achieve their goals with therapies that do more good than harm."

For more information

Bruckert E, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients — The PRIMO study. Cardiovascular Drugs and Therapy. 2005;19:403.

Statin Choice Decision Aid. Mayo Clinic.