A 62-year-old woman presents to your office for follow-up. She has stable multivessel coronary artery disease (normal stress echocardiogram four months ago and no angina symptoms), hypertension, noninsulin dependent diabetes mellitus, and dyslipidemia. She has stents deployed in her proximal RCA and mid LAD. She has nonobstructive plaque in multiple other regions of her coronary vasculature. She has been diabetic for approximately 13 years. She had difficulty controlling her blood glucose levels until one year ago. She lost 45 lbs, quit smoking, and now ambulates two miles daily. Her BMI is 29 kg/m2. She has microalbuminuria, hepatic steatosis, and early proliferative retinopathy that has not yet required laser photocoagulation. She has no history of peripheral vascular disease or claudication. Blood pressure is 120/70 mm Hg and resting pulse is 68 bpm.
Current medications include ramipril 10 mg po qd, aspirin 81 mg po qd, clopidogrel 75 mg po qd, carvedilol 12.5 mg po bid, rosuvastatin 40 mg po qd, metformin 1000 mg po bid, and exenatide 10 mg SQ bid. Hemoglobin A1c is 6.8%, creatinine 1.0 mg/dL, and serum electrolytes and normal thyroid indices. Lipid profile shows LDL-C 67 mg/dL, non-HDL-C 93 mg/dL, HDL-C 29 mg/dL, and triglycerides 370 mg/dL.
The patient's BP and diabetes are both well controlled. Given her comorbidities and lipid profile results, which of the following medications would you consider adding in order to more optimally control all components of her lipid profile?
The correct answer is: C. Initiate fenofibrate therapy
A. According to the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, this patient should be treated with the highest dose of a high-intensity statin, which includes rosuvastatin 40 mg or atorvastatin 80 mg.1 Although the new guideline does not recommend treatment to specific atherogenic lipoprotein targets, she clearly meets target levels for a very high risk patients according to the criteria established by NCEP ATPIII.2
B. High dose omega-3 fish oils are indicated to reduce serum triglycerides > 500 mg/dL. With a baseline fasting triglyceride level of 379 mg/dL, 4.0 g of fish oil will reduce her serum triglyceride levels. There are no available randomized, placebo controlled trials to show whether or not omega-3 fish oils would provide incremental risk reduction in the type of patient we are evaluating. The results of GISSI-3 do not apply as she is not status post an acute coronary syndrome.3 The REDUCE-IT trial will hopefully clarify this situation, but this trial will not be completed for at least another three to four years.4
C. The addition of fenofibrate would be an appropriate choice. In both the FIELD5 and ACCORD trials,6 fenofibrate reduced risk of progression of retinopathy in diabetic patients by approximately one-third. Fenofibrate has also been shown to reduce microalbuminuria.5,7 Reducing the risk of blindness and progression of albuminuria are important therapeutic considerations in patients with diabetes mellitus. Among patients with low HDL-C and high triglycerides, post hoc subgroup analyses demonstrated that fenofibrate reduced risk for the primary composite endpoint of cardiovascular events by 27% and 31% in the FIELD and ACCORD trials, respectively. Although post hoc findings must be considered hypothesis generating only, there is remarkable consistency of benefit in patients given fibrate therapy when triglycerides are high and HDL-C is low. In addition to benefit for reducing morbidity from microangiopathy, it is possible that fibrate therapy might also provide incremental risk reduction for macrovascular events. This requires confirmation in a prospective randomized trial.
D. Given the patient's current LDL-C and non-HDL-C levels, both the AIM-HIGH8 and HPS2-THRIVE9 studies show that adjuvant nicotinic acid therapy does not provide incremental benefit. In a post hoc analysis from AIM-HIGH10, among patients with high triglycerides and low HDL-C, nicotinic acid therapy did provide a 37% incremental risk reduction for the primary composite endpoint. However, this finding is tempered by the fact that in HPS2-THRIVE, this subgroup did not experience any incremental benefit from nicotinic acid therapy. This lack of consistency between the two trials is a matter of current debate and requires further study.
E. Cholestyramine is not indicated for this patient since her LDL-C and non-HDL-C are already well controlled. Bile acid binding resins are contraindicated in patients with hypertriglyceridemia. Any expected reduction in her hemoglobin A1c would be minimal because her blood glucose levels are already fairly well controlled.
Stone NJ, Robinson J, Lichtenstein AH, Merz CN, Blum CB, Eckel RH, 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; [Epub Ahead of Print].
Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.
Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002;105:1897-903.
www.clinicaltrials.gov/show/NCT01492361. A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. (REDUCE-IT)
Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-61.
Ginsberg HN, Elam MB, Lovato LC, Crouse JR, 3rd, Leiter LA, Linz P, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
Ansquer JC, Foucher C, Rattier S, Taskinen MR, Steiner G. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis 2005;45:485-93.
Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.
Guyton JR, Slee AE, Anderson T, Fleg JL, Goldberg RB, Kashyap ML, et al. Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). J Amer Coll Cardiol 2013;62:1580-4.