A 60-year-old Caucasian man is referred for management of elevated cholesterol. He has history of obesity, hypertension, and hyperlipidemia. He had a non–ST-segment elevation myocardial infarction (NSTEMI) one year ago with drug-eluting stent placement in his right coronary artery. His current medications include aspirin 81 mg daily, lisinopril 20 mg daily, and metoprolol XL 50 mg daily. His physical exam is notable for a body mass index (BMI) of 32 kg/m2 but is otherwise unremarkable. His blood pressure is 135/85 mm Hg.
A recent lipid panel shows the following:
- Total Cholesterol: 226 mg/dL
- Triglycerides: 154 mg/dL
- High-Density Lipoprotein Cholesterol (HDL-C): 39 mg/dL
- Friedewald-Estimated Low-Density Lipoprotein Cholesterol (LDL-C): 156 mg/dL
- He has a normal creatinine and normal liver enzymes. His TSH and vitamin D levels are within normal limits.
He was advised to lose weight and referred to a weight loss counselor. He also started rosuvastatin 20 mg daily but developed severe aching in his thighs and calves muscles. He discontinued the medication with resolution of his aches. Then, he started atorvastatin 20 mg daily but again developed aching in his thighs. Similar aches occurred on a red yeast rice/CoQ10 combination and intermittent dosing of simvastatin 20 mg weekly and rosuvastatin 5 mg weekly. His creatine kinase levels were never elevated during his episodes of muscle aches. He is not willing to try any more statin therapy.
The correct answer is: C. Niacin.
The case presentation is an example of statin intolerance in the secondary prevention setting. Myalgia is defined as muscle pain without a concomitant rise in biomarkers of muscle injury (i.e., creatine kinase). It is the most common reason for statin intolerance and discontinuation. Randomized clinical trials of statins show a significant increase in risk of myositis (myalgia with elevation of creatine kinase) and rhabdomyolysis, but not myalgia.1 A meta-analysis of 18 clinical trials (301,374 person-years) found comparable rates of myalgia in statins and placebo groups.2
The actual incidence of statin-attributed myalgia in clinical practice outside of clinical trial settings is estimated to be 10-20%.3 The majority of patients who discontinue statins are able to tolerate re-challenge with either the same or another statin.4
This patient's presentation is unusual because he experienced recurrent symptoms with different statin regimens. Therefore, careful assessment of the patient history and physical examination looking for secondary causes of myalgia is warranted like hypothyroidism, vitamin D deficiency, primary rheumatologic disorders, drug-drug interactions, and renal and liver diseases. Given his history of coronary artery disease (CAD), he is at high risk for a recurrent atherosclerotic cardiovascular disease (ASCVD) event. Management of hypercholesterolemia in high-risk patients with statin intolerance is challenging given the paucity of clinical trials of alternative therapies, as reflected in the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline on the treatment of blood cholesterol.5 The guideline gives a class IIa recommendation based on expert opinion for the use of non-statin cholesterol-lowering drugs and recommends the use of drugs that have been shown to reduce ASCVD events in randomized clinical trials.
A. Bile Acid Sequestrants: There are no clinical trials of bile acid sequestrants monotherapy in secondary prevention. However, cholestyramine is a good choice for primary prevention in patients who are completely statin-intolerant. The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) was published in 1984 and randomized 3,000 men to cholestyramine versus placebo over 7.5 years. Cholestyramine resulted in significant reduction of coronary heart events by 19%.6 Hypertriglyceridemia is a relative contraindication to bile acid sequestrants. In addition, gastrointestinal side effects are common with those agents.
B. Fibrates: There are three trials of fibrate monotherapy in secondary prevention settings. A study of gemfibrozil therapy enrolled 2,531 patients with LDL-C <140 mg/dL and HDL-C <40 mg/dL, which resulted in 24% reduction of cardiovascular events compared to placebo.7 This beneficial effect has not been observed in two other larger secondary prevention trials. In the Coronary Drug Project research group, clofibrate showed no significant reduction in cardiovascular outcome compared to placebo.8 Furthermore, the Bezafibrate Infarction Prevention (BIP) study randomized 3,090 patients with CAD to bezafibrate and placebo. After a mean follow-up of 6.2 years, there was no significant difference in primary endpoint of fatal or nonfatal myocardial infarction or sudden death between the bezafibrate and placebo groups.9 In the BIP study, post hoc analysis showed that patients with triglyceride level of >200 mg/dl has a significant reduction in the primary endpoint.
C. Niacin: The two major trials of niacin therapy in secondary prevention included patients who were already well-treated with niacin.10,11 The Coronary Drug Project is the only randomized clinical trial on niacin monotherapy versus placebo in a secondary prevention population. It was published in 1975 in the pre-statin era. A total of 1,103 patients were randomized to niacin 3 gm daily. Compared to placebo, niacin therapy resulted in 26% reduction in the incidence of non-fatal myocardial infarction, 24% reduction in fatal and non-fatal stroke and no significant reduction in total cardiovascular mortality.8 However, niacin therapy reduced total mortality by 11% in a 15-year follow-up study (nine years after termination of the initial study) of patients who had received niacin therapy during the trial.12
D. Ezetimibe: Ezetimibe impairs dietary and biliary cholesterol absorption at the brush border of the intestine and results in a 17% reduction of LDL-C levels.13,14 However, there are no randomized clinical trials with clinical cardiovascular outcomes of ezetimibe monotherapy in secondary prevention. However, ezetimibe as an add-on to simvastatin was studied in the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial in a high-risk primary prevention population with heterozygous hypercholesterolemia.15 Carotid intima media thickness was not improved with ezetimibe/statin therapy compared to statin alone. The Subcutaneous Heparin and Angioplasty Restenosis Prevention (SHARP) trial, a primary prevention trial, randomized 4,650 patients with chronic kidney disease to simvastatin 20 mg plus ezetimibe 10 mg daily or placebo. After a median follow-up of 4.9 years, simvastatin/ezetimibe therapy reduced major ASCVD events by 17% compared to placebo.16 The 2013 ACC/AHA guideline concluded that there was "insufficient data to evaluate the efficacy and safety of Ezetimibe monotherapy."5 At the present time, the role of ezetimibe therapy in primary or secondary prevention is unclear.
D. PCKS9: PCSK9 inhibitors have not been approved by the FDA thus far. Additionally, there are no monotherapy trials of PCSK9 inhibitors in secondary (or even primary) prevention populations with a primary endpoint of event reduction. The Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects (GAUSS-2) trial randomly assigned 307 patients intolerant to at least two statins without a prior history of ASCVD to evolocumab or ezetimibe 10 mg daily.17 Evolocumab reduced LDL-C by approximately 56 % compared to 18% for ezetimibe (p<0.001) after 10 to 12 weeks. PCSK9 inhibitors need to show an improvement in cardiovascular clinical outcomes with a good safety profile before they can be adopted as an alternative to statin therapy in statin-intolerant patient. Given their potent LDL-C-lowering capacity, a safety record to date, they can be viewed as a promising class of medications for treatment of those patients.
- Desai CS, Martin SS, Blumenthal RS. Non-cardiovascular effects associated with statins. BMJ 2014;349:g3743.
- Silva MA, Swanson AC, Gandhi PJ, Tataronis GR. Statin-related adverse events: A meta-analysis. Clin Ther 2006;28:26-35.
- Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther 2005;19:403-14.
- Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med 2013;158:526-34.
- Stone NJ, Merz CNB, ScM F, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;63:2889-934.
- The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984;251:351-64.
- Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410-8.
- Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360-81.
- Bezafibrate Infarction Prevention (BIP) study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation 2000;102:21-7.
- AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.
- HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12.
- Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245-55.
- Dujovne CA, Ettinger MP, McNeer JF, et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol 2002;90:1092-7.
- Knopp RH, Gitter H, Truitt T, et al. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J 2003;24:729-41.
- Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-43.
- Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (study of heart and renal protection): a randomised placebo-controlled trial. Lancet 2011;377:2181-92.
- Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2541-8.