Statin adverse effects: Sorting out the evidence

A 2006 systematic review estimated the absolute risk of rhabdomyolysis to be 3.4 per 100,000 person-years, but the incidence was 10 times higher for patients taking both a statin and gemfibrozil.¹¹ (See TABLE 2^12,13 for more on drug-drug interactions.) But both the meta-analysis cited earlier⁴ and an earlier systematic review¹⁴ (35 RCTs and >74,000 patients) found that statins as a class do not increase the incidence of myalgia or rhabdomyolysis.

Differences in the way muscular disorders are defined has been suggested as one reason for the discrepancies.¹⁰ In addition, many clinical trials exclude patients at higher risk of statin-associated AEs, such as those with renal or hepatic insufficiency, prior muscular complaints, poorly controlled diabetes, or potential drug-drug interactions.¹

An FDA advisory. In a safety communication last updated in February 2012, the US Food and Drug Administration (FDA) cautioned against starting patients on the highest dose of simvastatin (80 mg).¹⁵ The warning is based on a large study (N=12,064) that found an increased risk of myopathy (0.9%) and rhabdomyolysis (0.2%) in patients on the 80-mg dose vs those taking 20 mg (0.02% and 0%, respectively).¹⁶

With the ACC/AHA now recommending intensive therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) to achieve an LDL reduction >50% for many patients,¹ it is important to be aware that this risk is specific to simvastatin. A recent meta-analysis of studies directly comparing patients receiving intensive statin therapy with those on low to moderate doses did not find any increased risk in rhabdomyolysis associated with more intensive therapy when those taking 80 mg simvastatin were excluded.¹⁷

THE BOTTOM LINE: Although rhabdomyolysis is rare, its severity—a fatality rate of 10%¹¹—makes it critical to educate patients about the disorder and instruct them to stop taking the statin and call the office immediately if they develop severe muscle pain or weakness.

Recommend CoQ10
 for statin-induced myopathy


Although the exact mechanism of statin-induced myopathy is unknown, the most likely explanation is a depletion of coenzyme Q10 (CoQ10), which has negative effects on mitochondrial energy production.¹⁸ While studies using CoQ10 to treat this AE have been small and had mixed results, the overall evidence suggests that it decreases the development and/or severity of symptoms.^18-20

In fact, CoQ10 supplementation is the only treatment that has shown promise in treating statin-induced muscle symptoms.^18-20 Doses of about 100 mg bid have been found to be beneficial and safe; no clinically relevant AEs have been seen with doses <300 mg/d.^18,20,21 A large placebo-controlled study is currently evaluating a 600 mg/d dose of CoQ10 in patients with statin-induced myopathy.¹⁹

CASE › On his next visit, Mr. L reports a new ache in his left shoulder and upper back, which he describes as mild, but annoying. He also tells you his memory seems to be getting worse and that he has developed an odd tingling in his hands. These symptoms began about a month after he started the medications, Mr. L says. He also began a new exercise program, but his BMI is unchanged.

On examination, you find the affected shoulder and upper back modestly and diffusely tender to palpation, but with no decline in strength. Mr. L’s BP has fallen to 134/84 mm Hg and his fasting glucose is 105 mg/dL. Lab tests reveal an LDL of 144 mg/dL and HDL of 36 mg/dL, HbA1c of 6.1%, ALT of 105 U/L, AST of 61 U/L, and a normal CK.

You recommend 100 mg CoQ10 bid. Because it is available only over the counter, you advise the patient to look for a product whose purity and potency have been verified by an external source, such as the US Pharmacopeial Convention. You also prescribe metformin 500 mg bid for insulin resistance, refer the patient to a nutritionist and diabetes specialist, and order tests to evaluate his other symptoms.

Hepatic effects are rare

CoQ10 supplementation is the only treatment that has shown promise in treating statin-induced muscle symptoms.Historically, statins have been linked to potential hepatotoxicity, with case reports of serum transaminase elevation, cholestasis, hepatitis, and acute liver failure. It is now recognized that hepatic AEs are rare and that statins are not associated with a risk of acute or chronic liver failure.^1,11 In patients with coronary heart disease, the incidence of hepatotoxicity with statin use is reported to be <1.5% over the course of 5 years, and appears to be dose-dependent.¹

In 2012, the FDA revised the labeling for most statins, relaxing its earlier recommendations for monitoring of liver function, clarifying the risk of myopathy, and providing additional information about drug-drug interactions.¹³