The correct answer is: C. Start omega-3 fatty acid prescription 2 g PO twice daily.

Highly purified omega-3 fatty acid prescriptions containing either a mixture of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) or EPA alone are effective agents that have been used in the treatment of hypertriglyceridemia. More recently, the REDUCE-IT trial (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease), a randomized placebo controlled trial of 8,179 individuals with either established ASCVD or high risk diabetes, assessed the efficacy and safety of pure EPA ethyl ester, icosapent ethyl, at 2 g twice daily versus placebo in reduction of ASCVD risk.⁵ Participants also had elevated fasting TG levels (135-499 mg/dL) but relatively well-controlled LDL cholesterol (LDL-C) levels (41-100 mg/dL). Over a median follow-up of 4.9 years, those randomized to icosapent ethyl showed a 25% relative risk reduction (4.8% absolute risk reduction) of major adverse cardiovascular events compared to placebo. There was also significant reduction of individual endpoint events of cardiovascular death, fatal or non-fatal MI, fatal or nonfatal stroke, hospitalization for unstable angina and urgent or emergent revascularization. Treatment on icosapent ethyl was further associated with reduction in total (first and subsequent) ischemic events compared to placebo.⁶ The overall rates of adverse events were not significantly different between the treatment and control arms of REDUCE-IT. However, there were increased rates of atrial fibrillation and peripheral edema associated with patients taking icosapent ethyl observed in the trial. The results of REDUCE-IT builds upon the findings of the JELIS trial (Effect of Eicosapentaenoic Acid (EPA) on Major Cardiovascular Events in Hypercholesterolemic Patients: the Japan EPA Lipid Intervention Study), which demonstrated efficacy of pure EPA in risk reduction of major coronary events in individuals with hypercholesterolemia.⁷ It should be noted that it is not yet known whether EPA+DHA mixtures given at prescription doses (4 g daily) will have a similar efficacy in ASCVD risk reduction as purified EPA. The STRENGTH trial (Long-Term Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh Cardiovascular Risk PatienTs With Hypertriglyceridemia), a cardiovascular outcomes trial of EPA+DHA mixture is ongoing. Based on the findings of the REDUCE-IT trial, icosapent ethyl may be considered in this patient with a history of ASCVD, diabetes, and hypertriglyceridemia to further reduce residual ASCVD risk sincethe evidence is strongest for icosapent ethyl.

Option A is incorrect. While the patient does have elevated triglycerides (TGs), and fibrates are effective agents in lowering TGs, randomized controlled trials on fibrates have not consistently demonstrated efficacy in risk reduction of ASCVD events.^1,2 Although one could argue that fibrate therapy may be associated with a reduction in ASCVD events, in the subgroup of patients with elevated triglycerides and low levels of high-density lipoprotein cholesterol (HDL-C), those data were from subgroup analyses and were post-hoc in most cases. Moreover, the use of gemfibrozil with a statin increases the risk for rhabdomyolysis. In situations where a fibrate and a statin are used together (i.e. severe hypertriglyceridemia), a fenofibrate derivative may be preferred.

Option B is incorrect. While niacin also effectively lowers TGs and increases HDL-C, the addition of niacin to statin therapy has not demonstrated efficacy in risk reduction of ASCVD events in recent randomized controlled trials.^3,4 In addition, niacin is associated with notable side effects, including flushing, which can lead to poor adherence as well as elevation of blood sugar.

Option D is incorrect. Non-statin medications may be considered in select clinical scenarios based on the AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines (i.e. very-high risk secondary prevention patients with LDL-C ≥ 70 mg/dL or non-HDL-C ≥ 100 mg/dL).⁸ Current clinical trial evidence supports the use of ezetimibe and/or PCSK9 inhibitors in adjunct to maximally tolerated statin therapy in these patients. However, this patient has well controlled LDL-C on a high-intensity statin. Moreover, there is a lack of clinical trial evidence supporting the use of bile acid resins such as colesevelam in addition to statin therapy for the reduction of ASCVD events. One previous trial (LRC-CPPT) did show a cardioprotective benefit of the bile acid resin, cholestyramine, in patients with primary hypercholesterolemia; however, this trial was performed prior to the advent of statin therapy.⁹ Lastly, one potential side effect of bile acid resins is hypertriglyceridemia, which should be taken into account when treating patients who already have elevated TGs.

Option E is incorrect. Omega-3 fatty acid prescriptions, in particular icosapent ethyl, have been shown in clinical trials to reduce risk for ASCVD. However, omega-3 prescriptions are tightly regulated and are taken at a much higher dose (4 g daily) compared with fish oil supplements. Previous clinical trials assessing efficacy in ASCVD risk reduction of lower doses of omega-3 fatty acid (~1 g daily) have been inconsistent.¹⁰ Also of note, earlier trials that did show efficacy were performed in the setting of low rates of statin use. Therefore, given the present evidence, omega-3 fatty acid supplements should not be used as a substitute for omega-3 fatty acid prescriptions in this patient.

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References

1. Keech A, Simes RJ, Barter P, 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.
2. Group AS, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
3. 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.
4. 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.
5. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med 2019;380:11-22.
6. Bhatt DL, Steg PG, Miller M, et al. Effects of Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT. J Am Coll Cardiol 2019;73:2791-802.
7. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-8.
8. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018 Nov 3. pii: S0735-1097(18)39033-8. doi: 10.1016/j.jacc.2018.11.002. [Epub ahead of print]
9. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984;251:351-64.
10. Ganda OP, Bhatt DL, Mason RP, Miller M, Boden WE. Unmet Need for Adjunctive Dyslipidemia Therapy in Hypertriglyceridemia Management. J Am Coll Cardiol 2018;72:330-43.