Mechanisms of Statin-Related Muscle Injury
As many as 10% of patients on statin therapy suffer muscle-related adverse effects. There are several proposed statin-induced mechanisms:
Decreases in cholesterol content of skeletal muscle membranes making them unstable and thus more prone to injury;
Depletion of coenzyme Q10 with subsequent deleterious effects on mitochondrial function; and
Reduced bioavailability of isoprenoids (farnesyl pyrophosphate and geranyl pyrophosphate), which can lead to cell death in vitro.
Genetics play a role. A 2010 FDA drug safety communication emphasized that patients of Chinese descent are more likely to suffer simvastatin-induced muscle side effects. A recent study showed carriers of the SLCO1B1 gene polymorphism had increased risk for muscle-related statin adverse effects. The greatest risk was seen in patients on simvastatin, whereas the risk for patients on pravastatin was almost negligible.
Statin-related muscle adverse effects are dose related: The higher the dose, the greater the risk for muscle-related side effects. The type of statin used also matters. In the PRIMO (Paricalcitol Capsules Benefits in Renal Failure Induced Cardiac Morbidity in Subjects With Chronic Kidney Disease) study, the lowest rate of muscle symptoms was seen in patients on fluvastatin.
Who is at greatest risk? Women, older patients, patients on high statin doses, people with a family history of statin intolerance, and patients on multiple medications are among those at greatest risk of suffering statin-related muscle side effects.
Muscle Aches: Ordinary vs Problematic
Muscle soreness due to physical activity usually peaks 2 days after strenuous activity and lasts about 3-4 days. Creatine kinase (CK) levels can be increased. Soreness can be generalized but usually resolves in several days. How to distinguish "ordinary" muscle soreness from statin-related effects can be difficult. The most commonly reported locations of statin-related symptoms are in the thighs and calves. The most commonly reported symptoms included heaviness, stiffness, or muscle cramps.
Extreme physical exertion can also trigger statin side effects. Patients who engage in more physical activity are more likely to suffer symptoms. This could be because a regular exercise regimen leads to low-level muscle inflammation, which is in turn, magnified by statin therapy side effects.
Knowing your patients' baseline CK levels may be helpful. When evaluating muscle symptoms in patients taking statins, checking their CK levels should be considered. A CK level of 10 times the upper limit of normal should sound warning bells.
No Consensus on Muscle Inflammation Terminology
From myalgias to myopathy to myositis to rhabdomyolysis, there's a lot of confusion in the terminology with no consensus on definitions. Definitions vary from the American College of Cardiology (ACC)/ American Heart Association (AHA)/National Heart, Lung, and Blood Institute (NHLBI), the National Lipid Association (NLA), and the FDA.
The June 2011 FDA Drug Safety Communication on simvastatin defines myopathy as "muscle pain, tenderness, or weakness, and an elevation of CK." Likewise, rhabdomyolysis is defined as "the most serious form of myopathy (that) can damage the kidneys and lead to kidney failure." Other sources further specify that in rhabdomyolysis, CK elevations are markedly elevated to at least 10 times the upper limit of normal. Fortunately, rhabdomyolysis is rare.
The Role of CK Levels in Managing Statin Side Effects
The decision on whether to check baseline "pretreatment" CK level is controversial. The NLA does not recommend checking baseline CK levels, but the ACC/AHA/NHLBI recommend a baseline CK level to aid in later clinical decision-making. Neither guideline recommends routine monitoring in asymptomatic patients. Some experts choose to stratify who should be screened with CK levels and recommend baseline CK levels for high-risk patients including older patents, patients on multiple medications (most of my internal medicine practice), and patents with impaired renal or hepatic function.
Checking CK levels can be confusing. There are many non-statin-related causes of elevated CK levels: vigorous exercise, hypothyroidism, alcoholism, trauma, seizures, and use of illicit drugs such as cocaine and amphetamines.
Additional Hints for Staving Off Muscle-Related Side Effects
Try every-other-day statin dosing. Alternate-day dosing is an option for reducing side effects especially for patients taking statins with long half-lives such as atorvastatin (half-life, 15 hours) and rosuvastatin (half-life, 20 hours).
Check for thyroid imbalance. Patients with uncontrolled hypothyroidism are at increased risk for muscle-related statin side effects.
Check vitamin D status. Anecdotal reports have found that some "statin-related" muscle side effects resolve with correction of vitamin D deficiency.
Consider coenzyme Q10. Several small clinical trials have suggested that coenzyme Q10 in doses of 100-200 mg/day can help prevent statin-related muscle side effects. More studies are needed to confirm this protective effect. Coenzyme Q10 is an antioxidant that helps stabilize membrane. It also has a role in mitochondrial function and adenosine triphosphate generation. Coenzyme Q10 supplements are considered to be relatively safe. Side effects include nausea, vomiting, diarrhea, pain, anorexia, allergic rash, and headache.[3,14]
Medscape Internal Medicine © 2011 WebMD, LLC
Cite this: Sandra A. Fryhofer. Switching From Simvastatin 80 mg: How to Shop for Statins - Medscape - Aug 12, 2011.