A 53-year-old woman is referred for management of elevated cholesterol. She has a history of obesity, hypertension, and dyslipidemia. She reports a strong family of premature coronary artery disease with both her mother and father suffering myocardial infarctions in their 50s. A calcium score performed prior to this visit showed coronary artery calcium in the proximal left anterior descending with a total Agatston score of 49 (Figure 1). This placed her in the 93rd percentile for her age, race, and gender.
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Figure 1: Axial slice from coronary artery calcium CT scan shows area of calcification in the proximal LAD (arrow) |
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Her medications include aspirin 81 mg daily and hydrochlorothiazide 25 mg daily. Her physical exam is notable for a body mass index (BMI) of 33 kg/m
2, but is otherwise unremarkable. Her blood pressure is 128/88 mm Hg.
Her hemoglobin A1c is 6.2%.
A recent lipid panel shows:
- TC: 253 mg/dL
- High-Density Lipoprotein Cholesterol (HDL-C): 51 mg/dL
- Trig: 150 mg/dL
- Friedewald-Estimated Low-Density Lipoprotein Cholesterol (LDL-C): 172 mg/dL
Non-HDL-C: 202 mg/dL
LDL particle concentration: 3,086 nmol/L (reference lab standard for very high >2,000 nmol/L)
Her estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk is 3.1% by the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Pooled Cohort Equations.
Coronary artery calcium score: Total Agatston Score 49 located in the LAD (93rd percentile for age, race, and gender)
She was advised to lose weight and referred to a weight loss counselor. She also started rosuvastatin 20 mg daily, but developed aching in her thighs and discontinued the medication with resolution of her aches. She then started atorvastatin 40 mg daily, but again developed aching in her thighs. Similar aches occurred on a red yeast rice/CoQ10 combination and intermittent dosing of simvastatin 20 mg weekly. Her creatine kinase levels were never elevated during her episodes of thigh pain.
The correct answer is: A. Bile acid sequestrant.
The case presentation serves as an example of statin intolerance. Myalgias, or muscle pain without a concomitant rise in biomarkers of muscle damage (i.e. creatine kinase), are the most commonly cited reason for discontinuation of statin use, though the actual incidence attributable to statins is unclear. Prospective, randomized clinical trials show an increase in incidence of rhabdomyolysis and myositis (muscle pain with a 10-fold increase in biomarkers), but do not demonstrate an increase in myalgias.1 This may be partly due to exclusion of patients experiencing myalgias during a "run-in" phase. However, several large, prospective statin RCTs did not have a pre-enrollment run-in phase and reported equivalent myalgia incidence among statin and placebo groups.2 "Real world" estimates of statin intolerance suggests 10-20% of patients experience side effects that are attributed, rightly or wrongly, to statin use.3 However, the majority of patients who discontinue statins are able to tolerate re-challenge with either the same or another statin.4
The patient in the case above represents the exception in that she experienced recurrent myalgias with several statin regimens. Nevertheless, her extremely high LDL particle levels, family history of premature CHD, and, particularly, the presence of subclinical atherosclerosis (CAC) all suggest that she is at higher risk of ASCVD events than her estimated 10-year risk suggests. The 2013 ACC/AHA guideline on the treatment of blood cholesterol broadly addresses the scenario of statin intolerance in those that are candidates for statin therapy.5 In such individuals, the committee gave a IIa recommendation based on Expert opinion to the use of "non-statin cholesterol-lowering drugs that have been shown to reduce ASCVD events in RCTs if the ASCVD risk-reduction benefits outweigh the potential for adverse effects."
There are multiple non-statin lipid-lowering drugs available to the clinician; however, the extent of evidence for ASCVD risk reduction is less than for statins, and the data are older.
A. Bile Acid Sequestrants: Published in the 1980s, the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) randomized more than 3,800 men to cholestyramine versus placebo over 7.5 years.6 Cholestyramine treatment led to a 19% reduction in hard CHD events (p<0.05). Notably, entry criteria included an LDL-C ≥190 mg/dL (indicative of familial hypercholesterolemia), and only men aged 35-59 years were enrolled. Hypertriglyceridemia is a relative contraindication to bile acid sequestrants, and there are notable GI side effects with this class. Bile acid sequestrants represent the best potential therapeutic option for the patient in the case above.
B. Ezetimibe: There are no monotherapy trials of ezetimibe in primary prevention populations with a primary endpoint of event reduction. In primary prevention patients with renal disease, the Study of Heart And Renal Protection (SHARP) trial showed a reduction in the combined primary endpoint of CHD, non-hemorrhagic stroke, and revascularization with combination simvastatin 20 mg/ezetimibe 10 mg daily compared with placebo.7 The risk reduction that was reported per LDL-C lowering was beyond what would be expected from statin therapy alone and compatible with combination therapy. Nevertheless, direct randomized evidence for ASCVD risk reduction from ezetimibe monotherapy is lacking.
C. Niacin: There are no monotherapy trials of niacin in primary prevention populations with a primary endpoint of event reduction. Two large recent trials in secondary prevention populations who were already well-treated with statins (i.e., low levels of apoB) have been negative.8,9 In the pre-statin era, the Coronary Drug Project randomized a secondary prevention population with an average serum cholesterol concentration of 250 mg/dL to niacin versus placebo.10 Randomization to niacin resulted in a statistically significant reduction in coronary events, though mortality was no different than that of placebo. In follow-up nine years after the trial completion, mortality was lower in those randomized to niacin during the trial.11 It remains to be seen whether niacin carries a similar impact in a primary prevention population with elevated cholesterol and statin intolerance; however, given recent failures, it is unlikely that such a trial will be conducted.
D. PCSK9 inhibitors: PCSK9 inhibitors have not been approved by the FDA thus far. Furthermore, there are no monotherapy trials of PCSK9 inhibitors in primary prevention populations with a primary endpoint of event reduction. While trials have been conducted in statin-intolerant subjects, these were powered to demonstrate LDL-C reduction rather than event driven outcomes.12,13 Initial outcomes trials of these compounds are primarily in secondary prevention populations and on background lipid-lowering therapy. However, PCSK9 inhibition delivers the most potential for lipid lowering among non-statin therapies for statin-intolerant subjects such as the one described in the case and represent a promising class of medications with outcomes data pending.
E. There is no recommendation for nonstatin therapies in the latest guidelines: As stated above, the guidelines give a IIa recommendation for the use of lipid lowering therapy in statin intolerant subjects deemed to have high enough risk to warrant statin therapy.5
Note: Regarding fibrates, two large trials in the pre-statin era tested fibrates in primary prevention populations of men: The World Health Organization (WHO) Cooperative Trial comparing clofibrate with placebo and the Helsinki Heart Study (HHS) comparing gemfibrozil with placebo.14-16 Both trials showed a decrease in CHD events; however, there were concerns over statistically non-significant increases in overall mortality. During the statin era, the FIELD study of fenofibrate versus placebo in diabetic patients (both primary and secondary prevention) was negative for the primary endpoint of CHD reduction. However, post hoc analyses suggest a benefit in certain subgroups, including women with diabetes.17 Fibrates may be a reasonable therapeutic option in the case described. However, it is the opinion of the authors that a trial of a bile acid sequestrant is the single next best step.
As noted above, there is a dearth of evidence for non-statin medications in primary prevention of coronary events, particularly in the statin era. Given the tremendous success of statin therapy, providers will likely have to rely on extrapolation of data from trials of secondary prevention or statin-treated populations. Finally, if the patient were to reconsider statin therapy after discussion with her clinician, then fluvastatin or intermittent, low-dose rosuvastatin would be better options than simvastatin.
References
- Desai CS, Martin SS, Blumenthal RS. Non-cardiovascular effects associated with statins. BMJ 2014;349:g3743.
- Kashani A, Phillips CO, Foody JM, et al. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation 2006;114:2788-97.
- Eckel RH. Approach to the patient who is intolerant of statin therapy. J Clin Endocrinol Metab 2010;95:2015-22.
- 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, Robinson JG, Lichtenstein AH, 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 2014;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.
- 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.
- Investigators A-H, 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.
- Group HTC, 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.
- Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360-81.
- 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.
- Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 2012;308:2497-506.
- 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.
- A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Report from the Committee of Principal Investigators. Br Heart J 1978;40:1069-118.
- W.H.O. cooperative trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterol: mortality follow-up. Report of the Committee of Principal Investigators. Lancet 1980;2:379-85.
- Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237-45.
- d'Emden MC, Jenkins AJ, Li L, et al. Favourable effects of fenofibrate on lipids and cardiovascular disease in women with type 2 diabetes: results from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetologia 2014.
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