Case Study: Muscle-Related Statin Intolerance

Our patient is a 67-year-old African American female referred to the Duke Lipid Clinic for hypercholesterolemia and elevated creatine kinase (CK). She has a history of coronary heart disease with a prior non ST-elevation myocardial infarction (NSTEMI) and stent placement. She has a former 40-packs-a-year smoking history, hypertension, lumbar degenerative disk disease and constipation. She had lower extremity muscle pain with atorvastatin with elevated CK in the low 300s (reference 20-200 U/L). Her mild CK elevation persisted when she was off of statin therapy. She was unable to tolerate a statin re-challenge with pravastatin because of lower extremity muscle cramping that started within a few weeks of beginning statin therapy and stopped after statin discontinuation. CK levels never rose above her baseline of 290-330 U/L on statin therapy. However, her quality of life was impaired to the point of being unable to perform her activities of daily living (ADLs). At her initial visit, when she was off all lipid medications, her lipid profile results were: total cholesterol 287 mg/dL, low-density lipoprotein cholesterol (LDL-C) 209 mg/dL, triglycerides 108 mg/ dL; her high-density lipoprotein (HDL) was 56 mg/dL.

How common are statin-related muscle complaints?
There is little doubt that Statins are highly effective for cholesterol lowering. Clinical trials have demonstrated that they reduce the risk of ischemic heart disease events, coronary procedures and stroke by about one third.1 Clinical trials and experience have demonstrated that statin therapy is generally safe and well tolerated. However, muscle symptoms and associated myopathy can limit their use in clinical practice. While the incidence of severe myopathy is low, occurring in less than 0.1% of patients who receive statin therapy,2 mild to moderate muscular symptoms are quite common. The Prediction of Muscular Risk in Observational conditions (PRIMO) study, a large observational study of primary care patients on high-dose statin therapy, demonstrated that 10.5% of study patients had mild to moderate muscular symptoms.3

What are risk factors for muscular symptoms?
The PRIMO study highlights certain patient characteristics that are likely to be associated with muscle side effects from statin therapy. In PRIMO, the strongest independent risk factor for muscular symptoms was a personal history of muscle pain with another lipid-lowering therapy (statins or fibrates).This prior history was associated with a 10-fold increase in the risk of muscular symptoms. Other significant, independent risk factors in the PRIMO study were unexplained cramps (odds ratio [OR] 4.14), a history of CK elevation (OR 2.04), a family history of muscular symptoms (OR 1.89) and hypothyroidism (OR 1.71). Treatment with statins for more than three months and concomitant antidepressant medication use were associated with a significantly lower prevalence of muscular symptoms (OR 0.28 and 0.51, respectively). Importantly, no greater prevalence was found amongst patients with impaired kidney function or older age. Patients with muscle symptoms were more physically active and the incidence of muscle pain increased with the level of physical activity.

Clinical features of statin-induced myalgia
Usual Statin-related muscular pains are proximal, symmetric muscle weaknesses and soreness. In the PRIMO study, pains were most commonly described as heaviness, stiffness or cramps. However, weakness, loss of strength during exertion and tendon-associated pain were also frequently reported. Symptoms were most commonly in the lower extremities; however, upper extremity, truncal and diffuse pain also were also found.3 On physical exam, patients may have muscle tenderness and impairment in motor function, such as difficulty rising from a seated position or raising arms above the head. Most patients have no elevation – or only minor elevation – in serum CK.4

How do you evaluate a patient with statin intolerance?
Our approach to patients with statin intolerance because of muscle side effects consists of a detailed history, physical exam, medicine reconciliation and focused laboratory evaluation. Our history focuses on the timing of muscle effects related to statin initiation or dose titration, unusual physical activity or concurrent illness, as well as historical features that would point to a secondary cause of muscle pain (hypothyroidism, vitamin D deficiency, and family history of autoimmune or neuromuscular disease, symptoms of systemic illness). Medication reconciliation particularly focuses on drugs that inhibit cytochrome P450 3A4, fibrate therapy, drugs independently considered a risk factor for myopathy (i.e. glucocorticoids, cyclosporine, daptomycin, zidovudine) and diet history (daily consumption of grapefruit juice). During physical examination, we look for signs of systemic illness or inflammatory myositis (rash, joint effusions, fever, muscle redness or edema) as well as muscle weakness and pain. In a younger person, the ability to do six deep knee bends without using arms and hands to assist the legs is reassuring that proximal motor weakness is absent; in an older person, the ability to rise from a chair without using arms and hands is reassuring. A standard laboratory workup includes renal and liver function tests, and measurement of CK and thyroidstimulating hormone (TSH). Based on the history and physical examination, serum calcium, albumin, phosphorus, 25-hydroxyvitamin D, CBC, erythrocyte sedimentation rate (ESR), autoantibodies (such as antinuclear antibodies [ANA] for suspected lupus, rheumatoid factor [RF] for suspected rheumatoid arthritis, etc.), electromyogram or possibly muscle biopsy may be obtained.

Let’s get back to our patient. At her initial appointment, off statin therapy for several months, she had intermittent, chronic low back pain. She denied systemic complaints other than severe constipation. She rode a stationary bike for 30 minutes three times weekly without difficulty. She ate a low-fat, low-glycemic-index diet. Her medications consisted of Tylenol, tramadol, aspirin, carvedilol, lisinopril and a bowel regimen. Her blood pressure was 133/58, her body mass index (BMI) was 27 kg/m,2 and her physical examination was within normal limits, including the ability to rise from a chair without using her arms. There was no other muscle weakness or pain. Her basic metabolic profile, albumin, phosphorus, liver function and TSH were all within normal limits. She had an erythrocyte sedimentation rate (ESR) of 22 mm/h and CK 305 U/L off of statin therapy.

Rosuvastatin 2.5 mg twice weekly was prescribed5 but, within three weeks, she developed crampy lower-extremity pain and weakness that made it difficult for her to walk up the stairs in her home and take care of her other ADLs. Symptoms resolved several weeks after discontinuing rosuvastatin.

Based on National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), our patient’s LDL-C goal is less than 100mg/dL. Given her intolerance of low-dose pravastatin and even low-dose rosuvastatin twice weekly with symptoms that interfered with her ability to carry out ADLs, she was felt to be statin intolerant. Other medication possibilities include fibrates, bile acid sequestrants, niacin and cholesterol-absorption inhibitors. Given her severe constipation, bile acid sequestrants were not an option. She was counseled on therapeutic lifestyle changes and started on ezetimibe 10mg daily with immediate-release niacin titrated up to 1,000 mg twice daily. A mortality benefit from niacin was suggested from the follow-up of the Coronary Drug Project which demonstrated an 11% decrease in mortality in patients who received niacin after a myocardial infarction.6 Ezetimibe has been demonstrated to reduce LDL-C by 25% when added to niacin therapy.7

Over a period of about nine months, our patient lost weight, reaching a BMI of 25 kg/m2 and increasing her exercise to an hour five times weekly. She tolerated her medications and had no medical event. She recently had the following lipid profile: total cholesterol, 198; LDL-C, 102; HDL-C, 89; triglyceride, 36 mg/dL. The decrement in her LDL-C is surprisingly large for niacin-ezetimibe combination therapy; however, individual patient responses are variable. During a period of active weight loss, LDL-C can drop transiently for several months, and we warned her that long-term results may not sustained at this level.8 She is not at her NCEP ATP III goal; nevertheless, she has had vast improvement and, for the next six months, we will continue current medications. We suggest that adding psyllium to her bowel regimen may reduce LDL-C further.9

Disclosure statement: Dr. Greyshock has no disclosures to report. Dr. Guyton has received consulting fees from Merck & Co. Inc. and research grants from Merck & Co. Inc., Abbott Laboratories, GlaxoSmithKline, Amarin Corporation, Regeneron Pharmaceuticals, Inc., Amgen Inc., and Genzyme Corporation, A Sanofi Company. He is a stockholder in Eli Lilly and Company.