Case Study: The Intolerance for Statin Intolerance

A colleague recently asked us to comment on an interesting case. The patient was a 68-year-old woman hospitalized for abdominal pain and new-onset atrial fibrillation. She had a medical history significant for longstanding hypertension and non-obstructive coronary artery disease (CAD) by angiography one year prior to admission. Her home medications included simvastatin 20 mg daily and omeprazole 40 mg daily for dyspepsia. Her physical exam on admission revealed a blood pressure of 135/85 mmHg, an irregular pulse at 72 beats per minute, and a body mass index of 22 kg/m2. Her physical exam was notable for epigastric tenderness. Her lab values were normal, except for the following:

Hemoglobin – 10 g/dL

Total cholesterol – 305 mg/dL

Triglycerides – 250 mg/dL

High-density lipoprotein cholesterol (HDLC) – 35 mg/dL

Low-density lipoprotein cholesterol (LDLC) – 220 mg/dL

She was placed on diltiazem 180 mg daily and her simvastatin dose was increased to 40 mg daily. She converted to normal sinus rhythm. A pharmacological stress test was negative for ischemia. An esophagogastroduodenoscopy demonstrated a duodenal ulcer that was positive for helicobacter pylori (H. Pylori). She was placed on antibiotics for H. pylori, including clarithromycin, and discharged to home. She was not anticoagulated because of concerns of bleeding related to her ulcer. One month later, the patient presented to the emergency department with severe muscle pain and weakness, most notably in her arms and thighs, and “rusty-colored” urine. At that time, she appeared acutely ill with a blood pressure of 98/60 and a regular pulse at 52 beats per minute. Her labs now revealed the following:

Hemoglobin – 10.9 g/dL

White blood cell count – 12,100 per mcL

Total cholesterol – 198 mg/dL

Triglycerides – 200 mg/dL

HDL-C – 32 mg/dL

LDL-C – 154 mg/dL

Troponin x 2 – < 0.01

Creatine kinase U/L – 12,000

Urinalysis positive for myoglobin

A diagnosis of rhabdomyolysis was established and the patient was admitted to the hospital. The rhabdomyolysis was thought to be secondary to the interaction between simvastatin and diltiazem and both were discontinued. It also was discovered that she was still taking clarithromycin, despite finishing her course of therapy for H. pylori, and it was discontinued. She received aggressive fluid resuscitation and made a full recovery. Two months later she remained stable and her creatine kinase was normal. She was placed on atorvastatin 20 mg daily and ezetimibe 10 mg daily. No anti-arrhythmic drugs were initiated and she remained in sinus bradycardia. Her only complaint was constipation, which was treated symptomatically.

She had a recurrence of severe myalgia one month later. The atorvastatin and ezetimibe were discontinued. Her labs were as follows:

Total cholesterol – 210 mg/dl

Triglycerides – 140 mg/dL

HDL-C – 37 mg/dl

LDL-C – 145 mg/dl

It was felt that her LDL-C was unacceptably high despite her best attempts at diet and exercise and it appeared to be a roadblock for more aggressive statin therapy. Additional laboratory testing revealed thyroid-stimulating hormone (TSH) of 24 mIU/L and 25-hydroxy vitamin D level of 20 ng/ml. Thyroid and vitamin D3 supplementation were started and both levels normalized within three months. She then was started on pravastatin 40 mg qHS. Despite these interventions, she developed recurrent myalgia within five weeks. Before committing to a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, one last attempt at statin therapy was made. She was placed on rosuvastatin 10 mg three times weekly. After two months, she remained asymptomatic and her lipid panel now demonstrated:

Total cholesterol – 150 mg/dl

Triglycerides – 120 mg/dL

HDL-C – 41 mg/dl

LDL-C – 85mg/dl

This case illustrates that true statin intolerance may be less common than expected if a clinician takes a careful and comprehensive approach to evaluation and management of this condition.1–3

 This patient developed complications at the outset because of multiple drug-drug interactions, most common with statins metabolized by the cytochrome P450 3A4 pathway (lovastatin, simvastatin and, less commonly, atorvastatin). Many cardiovascular drugs, such as diltiazem, amlodipine, and amiodarone, as well as anti-fungals and macrolide antibiotics, have important interactions with statins.4 Additionally, providers should search for subclinical hypothyroidism in such cases.5 A tip-off that hypothyroidism was present in this patient was the relatively slow atrial fibrillation (untreated) and constipation. Recent reports suggest that low 25-hydroxy vitamin D levels also may predispose to statin-associated muscle symptoms.6 However, we lack robust data demonstrating that vitamin D supplementation for this purpose is beneficial. Finally, the effectiveness and tolerability of intermittent statin therapy has been well documented, especially for those who are slow metabolizers.7

 On her current regimen of rosuvastatin, she has achieved significantly better control of her LDL-C. If further LDL-C lowering is desired, therapeutic options include intensification of therapeutic lifestyle changes and a cautious increase in the rosuvastatin dose or frequency and/ or the addition of ezetimibe. By diligently pursuing evaluation and treatment of statin-associated muscle symptoms, one can get most patients on cost-effective, evidence-based therapies that are tolerable and efficacious.

Disclosure statement: Dr. Shapiro has received compensation for advisory activities from Alexion, Amgen, Bracco, GE Health Care, and Synta Pharmaceuticals. Dr. Greenfield has no disclosures to report.