New Statin Intolerance Clinic

The first 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, lovastatin, obtained approval from the US Food and Drug Administration in 1987. Now, after a little more than 2 decades of clinical availability, the statins, as this group of drugs is more commonly known, have emerged at the forefront of pharmacologic treatment of high cholesterol.

Statin therapy is estimated to be indicated in up to 25% of the US adult population. Statin therapy significantly reduces the incidence of heart attack, stroke, and cardiovascular death.

Because hypercholesterolemia is largely asymptomatic, any unpleasant effects of pharmacologic agents used to manage it can undermine patient compliance.

In several cohort studies, the reported rate of adherence to statin therapy at 1 year ranged from 26% to 85%, with a rapid decline in adherence rates typically observed within the first few months.

In the Lipid Research Clinics Coronary Primary Prevention Trial, the reduction in risk of coronary events was 39.3% among patients fully compliant with lipid-lowering therapy, compared with risk reductions of 10.9% and 26.1% among patients with approximately 25% and 5% adherence, respectively.

In the West of Scotland Coronary Prevention Study of men without a history of coronary artery disease, the risk of all-cause mortality was reduced 33% more among those who took 75% or more of their prescribed medication compared with those taking less than 75%.

The majority of adverse effects reported to be associated with statins are musculoskeletal, hepatic, gastrointestinal, and psychiatric. The most prevalent are musculoskeletal, and the spectrum of statin-associated myotoxicity ranges from the more common but less severe myalgia (5%-10%) to the less common but more severe myopathy (0.1%) and its potentially fatal complication, rhabdomyolysis (0.01%).

Among patients who develop myalgias, the most common symptom is muscle aches in slightly more than half and clinically noticeable muscle weakness in one-third, while 10% report cramping as the predominant symptom. Muscle-related symptoms in clinical trials, which involve highly selected patient groups with high treatment adherence and statin tolerance, do not reflect the true prevalence of myalgia in the clinic, as evidenced by findings in observational studies. Although only 3% of patients in randomized research studies developed intolerance, in clinical practice up to 15% of outpatients receiving statins have reported muscle pain.

One reason that higher rates of adverse effects are observed in general use is that many clinical studies involving statins had a run-in phase and excluded patients if intolerance to the drug developed. Clinical trial protocols also often exclude patients who may be more prone to myopathy (such as the elderly) or who may have abnormal liver test results at baseline.

Among patients taking high-dose statins (atorvastatin, 40-80 mg; extended-release fluvastatin, 80 mg; pravastatin, 40 mg; or simvastatin, 40-80 mg), the proportion of patients reporting muscle-related symptoms is even higher:

• 5% in those taking extended-release fluvastatin vs 10% of those taking high-dose pravastatin
• 15% for atorvastatin
• 18% for simvastatin

The median time to onset of muscle symptoms is 1 month after either initiation of statin therapy or titration to a higher dosage, although approximately 15% of patients have symptoms that appear more than 6 months after the start of treatment. When discomfort occurs, it is widespread in 60% of patients, with 24% reporting pain all over. Pain is more common in the lower extremities, including the thighs and calves, than in the upper extremities or trunk.

Although more than 100,000 patients have been studied in randomized trials of statins, research on the mechanism or treatment of statin intolerance has been limited. Adding to the uncertainty, the National Lipid Association, US Food and Drug Administration, and ACC/AHA/NHLBI have all come out with different definitions of statin-associated myalgia, myopathy, and myositis.

In the Prediction of Muscular Risk in Observational Conditions (PRIMO) study, patients with a family history of muscle pain during lipid-lowering therapy had double the risk of muscle-related symptoms compared with patients who did not have this family history. This finding implies the prospect of identifying particular genes or single-nucleotide polymorphisms that may increase the risk of myopathy or reduce the maximal tolerated dose.

To better care for these patients, Mayo Clinic has established a Statin Intolerance Clinic as part of the Cardiovascular Health Clinic to better diagnose, risk stratify, and treat patients with statin-associated adverse effects.

In addition to evaluating muscle symptoms with a validated questionnaire, standard work-up includes levels of creatine kinase and vitamin D, along with renal and thyroid function testing. When appropriate, genetic testing for statin efficacy and potential toxicity, proximal muscle strength evaluation, and percutaneous outpatient muscle biopsy are important assessment tools.

"Treatment depends on the individual patient and the patient's history of statin intolerance symptoms and may include either changing the dose or type of statin or switching to a nonstatin agent to treat hyperlipidemia," according to Stephen L. Kopecky, M.D., director of the new Statin Intolerance Clinic.

Other treatment options include supplements to reduce the myotoxicity symptoms attributable to impairment of fatty acid oxidation or mitochondrial dysfunction that result from the statin therapy. Patients who are either on statin therapy or have a family history of severe reactions to these agents but have never actually taken a statin drug can be referred to the Statin Intolerance Clinic by calling 507-284-4443.