Dealing with statin-induced myopathy

Let’s start with a patient case.  An 82 year old female patient presents to clinic with complaints of weakness in her lower extremities. She describes her weakness as symmetrical heaviness and identifies some stiffness and cramping. Other causes of her complaints are ruled out except for her medications. Her hyperlipidemia is currently being managed with simvastatin 40 mg orally daily and niacin ER 1 g orally daily. What are our options for dealing with suspected statin-induced myopathy?

Clinical features of statin-induced myopathy:

• Symmetrical heaviness, stiffness, and cramping
• +/- elevations in CPK, urinary myoglobin, AKI
• Incidence is related to serum concentration & statin dose
• Generally occurs within first 1-6 months but can occur any time

The Prediction of Muscular Risk in Observational Conditions (PRIMO study) observed 7900 patients on high-dose statins for 12 months and found the following rates of myopathy:

• Fluvastatin (5.1%)
• Pravastatin (10.9%)
• Atorvastatin (14.9%)
• Simvastatin (18.2%)

While rates of rhabdomyolysis are low, drug-interactions are estimated to be responsible for ~60% of cases. Lova-, simva-, and atorvastatin are metabolized by CYP450 3A4 and fluva- and rosuvastatin are metabolized by CYP450 2C9 and inhibitors of these enzymes will increase serum concentrations. Note pravastatin is not metabolized by any of these enzymes. There is also a synergistic effect with other lipid-lowering agents. Depending on the agent, check for drug-interactions with:

• Cyclosporine, amiodarone, macrolides, azole antifungals, calcium channel blockers, fibrates, niacin, red yeast rice, nefazodone

Options for management of statin-induced myopathy (when you would still like to keep the patient on a statin) include:

• Reduced dosing frequency
• Alternate statin trial
• Vitamin D supplementation
• Coenzyme Q10 supplementation

Reduced dosing frequency

• Studies have prospectively or retrospectively attempted every other day, twice-weekly, or once-weekly dosing of some statins to assess tolerability in patients previously experiencing statin intolerance. Patients generally tolerated the less frequent dosing and LDL reductions persisted. However, it is unknown if the pleiotropic effects of statins remain intact at this reduced frequency. No study has been done to examine hard endpoints like CV events.

Alternate statin trial

• Results are mixed when switching to a different statin. If switching, it is reasonable to select one of the more hydrophilic statins such as prava-, fluva-, or rosuvastatin.

Vitamin D supplementation

• Low 25-OH vitamin D levels have been independently associated with myalgia. A prospective study identified patients with statin intolerance who also had low 25-OH vitamin D. They were treated with vitamin D and the same statin was reinitiated. Statins were tolerated by 87% at the end of the study.

Coenzyme Q10 supplementation

• Patients on statins have decreased CoQ10 so supplementing it makes sense. However, studies are conflicting and generally do not increase statin tolerability.

Back to the patient case

Our patient has multiple risk factors for statin-induced myopathy including female, >80 years old, simvastatin (lipophilic), and on niacin (drug-interaction). The need for niacin should be questioned as it increases the risk for myopathy, has multiple side effects, and recent studies have not demonstrated any benefits to cardiovascular outcomes (as discussed in previous posts niacin for dyslipidemia and results from the HPS2-THRIVE study). In a geriatric patient, it should always be assessed if her statin is still indicated for primary or secondary prevention based on her risk factors. If planning on continuing treatment, it is reasonable to briefly discontinue her statin, check a 25-OH vitamin D level and supplement if necessary, and switch to a statin that has been shown to have better tolerability.

Take home points:

Options for management of statin-induced myopathy include:

• Reduced dosing frequency – works but may be missing pleiotropic effects
• Alternate statin trial – good option but patients frequently intolerant to multiple statins
• Vitamin D supplementation – good option & safe to check vitamin D and supplement
• Coenzyme Q10 supplementation – data not encouraging – avoid use

Note: The above does not address indications for stopping statin therapy or the treatment of myositis or rhabdomyolysis. These strategies above are for those trying to continue statin therapy when it is still indicated in the face of muscle-related intolerance.

References:

Bruckert E, Hayem G, Dejager S, et al.: Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients–the PRIMO study. Cardiovasc Drugs Ther 2005, 19:403–

414.

Others are available on request. 

photo by kev-shine