Statin intolerance due to statin-associated muscle symptoms (SAMS) is low in randomized controlled trials (RCTs), but much higher in clinical observation studies. Statin nonadherence is associated with higher rates of cardiovascular events, and is most frequently attributed to SAMS. This can result in a need for extensive education and counseling during the patient visit. The following are key points to remember from this article on SAMS:

1. Recent RCTs of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in highly statin intolerant patients demonstrate that SAMS can occur when patients have a true intolerance, but also may be a result of misattribution of pain symptoms.
2. Common conditions with similar presentation to SAMS include osteoarthritis, rheumatoid arthritis, tendinitis, and chronic pain disorders. Musculoskeletal pain is associated with conditions that often overlap with patients at risk for cardiovascular disease such as obesity, diabetes, and aging.
3. Resources such as the National Lipid Association’s Statin Myalgia Clinical Index Score focus on location, symmetry, and timing of muscle pain as well as response to dechallenge and challenge, producing statin myalgia likelihood score.
4. Medication interaction with statins can increase musculoskeletal symptoms, and changing these medications may allow for statin treatment. CYP3A4A inhibitors, gemfibrozil, cyclosporins, and other lipid-lowering agents such as fibrates and less frequently niacin are possible culprits. In the case of fibrates or niacin, the authors suggest omega-3 fatty acids as an alternative to treat hypertriglyceridemia.
5. At this point, supplements given concomitantly with statins such as vitamin D and coenzyme Q10 (CoQ10) are not supported by RCTs. However, both have good safety profiles. Vitamin D is relatively inexpensive and low serum concentrations are associated with myalgias. CoQ10 is also anecdotally reported to provide relief from musculoskeletal symptoms. The authors suggest that a short-term trial of either may be warranted. Supplements such as phytosterols and viscous fiber supplements show a modest reduction in low-density lipoprotein cholesterol (LDL-C), while in one well-designed RCT, red yeast rice (RYR) has been shown to significantly lower LDL and reduce cardiovascular events. However, the variability of a potentially renal toxic substance in RYR makes its safety profile less clear.
6. Reintroduction of a statin after a minimum 2-week statin-free period can help identify truly statin-intolerant patients, and can also demonstrate statin tolerance to patients whose musculoskeletal complaints are not related.
7. Intermittent statin dosing is associated with a reduction in LDL-C by 20-40%. Statins with longer half-lives can be initially dosed once weekly, and up-titrated to as frequently as every other day dosing. For patients who experience a slower onset of symptoms, a drug holiday of about 25% of the time it takes to develop intolerable symptoms can at least allow for more time on a statin than not.
8. Ezetimibe is first-line in the statin-intolerant patient, but these patients should be advised that this medication is not a statin, and has an extremely low incidence of musculoskeletal symptoms. Intermittent ezetimibe dosing, or dosing with a half tab daily have both been shown to lower LDL-C from 20-25% as compared to 26% in the 10 mg daily dose.
9. There are a number of second-line agents to treat elevated LDL-C. Bile acid resins are effective, but raise triglyceride levels and are often not well-tolerated. PCSK9 inhibitors are powerful reducers of LDL-C, and have a lower incidence of discontinuation for musculoskeletal symptoms, but do not have compelling evidence of beneficial outcomes at this time. Niacin has long-term data showing no clinical benefit, and fibrates only minimally lower LDL-C.
10. Overall, a cornerstone in treating patients with SAMS is communication. This includes careful history taking, counseling regarding diet and other modifiable risk factors, shared decision making, realistic goal setting, and clear counseling about the benefits and low incidence of side-effect in statins.

Keywords: Arthritis, Rheumatoid, Bile Acids and Salts, Biological Products, Cholesterol, LDL, Chronic Pain, Cyclosporins, Diabetes Mellitus, Diet, Dyslipidemias, Fatty Acids, Omega-3, Gemfibrozil, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertriglyceridemia, Musculoskeletal Pain, Myalgia, Niacin, Obesity, Osteoarthritis, Primary Prevention, Proprotein Convertases, Risk Factors, Subtilisins, Triglycerides, Vitamin D

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