New Approaches in Targeting Triglycerides for the Reduction of Cardiovascular Risks

Atherosclerotic cardiovascular disease (ASCVD), the leading global cause of morbidity and mortality in the United States is largely attributed to avariety of cardiovascular risk factors, including hypertriglyceridemia, elevated low-density lipoprotein cholesterol (LDL-C), insulin resistance, hypertension, and obesity.^1,2 Coronary heart disease (CHD) isthe most common manifestation of cardiovascular disease (CVD), comprising approximately 50% of patients’ first CVD events.³ Risk factors include a familyhistory of premature ASCVD (men < 55 years old, women < 65 years old), metabolic syndrome (increased body mass index, elevated triglycerides >150 mg/dL, elevated blood pressure), hypercholesterolemia, and chronic kidney disease.²

Risk of ASCVD is categorized as low (<5%), borderline (5%-< 7.5%), intermediate (>7.5%-< 20%) or high (>20%) over a 10-year period.² These risk stratifications can help determine the most appropriate interventions for patients. Those with minimal or borderline ASCVD risk may beeligible for lifestyle modifications, including dietary improvements, physical activity, and smoking cessation if applicable.² In addition to lifestyle changes, several therapies are used to lower LDL-C and/or triglyceride levels, but only select agents have demonstrated a significant effect in reducingcardiovascular mortality.^4-7

This article reviews the evolving therapeutic landscape for lowering LDL-C and cardiovascular risk, with an emphasis on the role of omega-3 fatty acids.

THE ROLE OF STATINS IN REDUCING LDL-C

Cholesterol-lowering statin therapy is frequently used in patients with or without a history of CHD,⁸ primarily because their ability to markedly lower LDL-C levels.9 These reductions in LDL-C levels are generally linearly related to the reductions in atherosclerotic plaques and atherosclerotic events (eg, stroke or myocardial infarction).10

Meta analyses suggest that statins reduce major adverse cardiovascular events and all-cause mortality in patients at risk for ASCVD.^11,12 Additionally, reductions in LDL-C levels associated with the use of statins are generally irrespective of comorbidities, such as diabetes, chronic kidney disease, or previous vascular disease.¹²

The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommend moderate or high intensity statins in addition to lifestyle modifications for those at moderate and high risk for recurring cardiovascular events.²

THERAPEUTIC TARGETING OF HYPERTRIGLYCERIDEMIA

Beyond LDL-cholesterol lowering, therapeutic targeting of triglyceride levels can reduce cardiovascular risk,⁴ as triglyceride levels of 150 mg/dL or more are considered a marker of persistent cardiovascular risk despite controlled LDL-C.¹³ In high-risk patients, such as those with established cardiovascular disease or diabetes, lowering triglyceride levels, along with decreasing LDL-C levels and raising HDL-C levels, produces trends suggesting reduced cardiovascular mortality. In addition to lifestyle changes, several therapies including ezetimibe, fibrates, and niacin; omega-3 fatty acids have been shown to lower triglyceride and non–HDL-C levels, but only select agents have demonstrated an effect inimproving cardiovascular morbidity and mortality.^4-7,15,16

• When ezetimibe therapy is added to statin or fibrate therapy, decreases in total cholesterol, LDL-C, and triglycerides, as well as increases in HDL-C levels, have been observed; however, the risk of cardiovascular events is only minimally improved and no effect on cardiovascular mortality has been observed.⁶
• Fibrate therapy has been associated with a 10% relative risk reduction for major cardiovascular events.¹⁷
• Although niacin, in combination with statin therapy, may increase in serum HDL-C levels, it does not reduce cardiovascular mortality or recurrent events in patients with/at high-risk for ASCVD.
• As a class, omega-3 fatty acids (eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA]), have been shown to decrease triglyceride levels. Recent data on EPA/DHA combination regimens generally confer no evidence of a significant effect on cardiovascular disease composite end points or all-cause mortality.^15,16

THE CARDIOVASCULAR BENEFITS OF OMEGA-3 FATTY ACIDS

Another intervention that has shown efficacy toward lowering triglyceride levels is omega-3 fatty acids, which can be used for patients with high (200-499 mg/dL) or very high (≥ 500 mg/dL) triglyceride levels.¹⁸ Omega-3 fatty acid products are available as prescription or as dietary supplements.^18,19 DHA and EPA are the primary long-chain fatty acids components of omega-3 fatty acids.¹⁸ The effects of omega-3 fatty acids on LDL-C vary based on the specific long-chain fatty acid (ie, DHA or EPA) component. Findings from a systematic review of head-to-head studies of omega-3 fatty acid products revealed that DHA increased LDL-C by 2.6%, whereas EPA decreased LDL-C by 0.7%.²⁰

Four FDA-approved omega-3 fatty acid therapies are currently available via prescription in the United States, and all are indicated to decrease triglyceride levels. They include omega-3 acid ethyl esters, omega-3 acid ethyl esters A, omega-carboxylic acids and icosapent ethyl (Table 1).^21-24

Early studies, such as the GISSI-Prevenzione study, demonstrated reductions in cardiovascular events with omega-3 fatty acid supplements²⁵;however, in the era of statin therapy, these results have generally not been replicated.¹⁸ Results from more recent studies have found that EPA/DHA combination products do not confer significant cardiovascular benefits.^15,16 For example, the ASCEND trial (NCT00135226) evaluated the use of omega-3 fatty acids in 15,480 patients with type 2 diabetes. Patients were randomized to either 840 mg of omega-3 fatty acids (EPA, 460 mg; DHA,380 mg) once daily or placebo. Compared with placebo, those in the omega-3 fatty acid group had no significant difference in the risk of serious vascular events.¹⁵ Additionally, the VITAL trial (NCT01169259) evaluated the use of vitamin D3 plus omega-3 fatty acids for the primary prevention ofcardiovascular disease and cancer. Overall 25,871 patients were randomized to either vitamin D3 2000 IU plus omega-3 fatty acids (EPA, 460 mg; DHA, 380 mg) once daily or placebo. Use of omega-3 fatty acids did not result in a decreased incidence of either cardiovascular events or cancer.¹⁶

Icosapent ethyl, the most recent product in the omega-3 landscape, is indicated as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride levels and established CV disease or diabetes mellitus and 2 or more additional risk factors for CV disease. It is also indicated as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia.²⁴ Unlike other omega-3 fatty acid formulations that contain DHA and EPA, icosapent ethyl is a purified ethyl ester of EPA.^21-24

The approval of icosapent ethyl was based on data from the multicenter, randomized, double-blind REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention) trial (NCT01492361) that demonstrated a reduction of risk of ischemic events, including cardiovascular mortality, in patients receiving icosapent ethyl.²⁶ Investigators evaluated the use of icosapent ethyl in patients with either (1) established cardiovascular disease or (2) diabetes and other risk factors who had triglyceride levels of 135-499 mg/dL and were currently receiving statin therapy.²⁶ Overall, 8179 patients were randomized to statin plus icosapent ethyl 2 g twice daily (n = 4089) or statin plus placebo (n = 4090).²⁶ The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina, while the secondary end point was a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.²⁶

After a median of 4.9 years, patients randomized to statin plus icosapent had significantly fewer primary composite(17.2% vs 22%, respectively; P <.001) and secondary composite events (11.2% vs 14.8%, respectively; P <.001) versus those randomized to statin plus placebo.²⁶ This represented a 25% relative risk reduction in primary composite end point ofcardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina.²⁶ At a median follow-up of approximately 5 years, the number needed to treat to avoid 1 primary end point was 21.²⁶

Because some results from international trials have shown poorer outcomes in patients in the United States, a subgroup analysis of the US-only population (REDUCE-IT USA) was conducted.²⁷ Primary and secondary composite events were significantly reduced in patients randomized to statin plusicosapent ethyl versus those randomized to statin plus placebo (P = .000001 and P = .00008, respectively).²⁷ In addition, the US population demonstrated particularly robust risk reductions across a variety of individual and composite end points, including cardiovascular death (P = .007), myocardial infarction (P = .01), stroke (P = .02), and all-cause mortality (P = .004).²⁷

In the overall international population and in the US-only cohort, overall rates of adverse events, and serious adverse events leading to discontinuation did not significantly differ between groups.^26,27 Icosapent ethyl was generally well tolerated and presented with no polypharmacy issues when combined with statins.

Following the REDUCE-IT findings, numerous guidelines were updated to include recommendations for the use of icosapent ethyl to reduce cardiovascular risks (Table 2).^19,28-30

CONCLUSIONS

With the approval of icosapent ethyl, the role of omega-3 fatty acids in the evolving spectrum of ASCVD management and prevention is expanding. Moreover, the continued research and integration of icosapent ethyl in combination with other approaches could potentially reduce risks of CV events.

References

1. 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. 2019;73(24):3168-3209.doi:10.1016/j.jacc.2018.11.002

2. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140(11):e596-e646. doi:10.1161/cir.0000000000000678

3. Gaziano TA, Bitton A, Anand S, Abrahams-Gessel S, Murphy A. Growing epidemic of coronary heart disease in low- and middle-income countries. Curr Probl Cardiol. 2010;35(2):72-115. doi:10.1016/j. cpcardiol.2009.10.002

4. Reiner Ž. Hypertriglyceridaemia and risk of coronary artery disease. Nat Rev Cardiology. 2017;14(7):401-411. doi:10.1038/nrcardio.2017.31

5. Vallejo-Vaz AJ, Corral P, Schreier L, Ray KK. Triglycerides and residual risk. Curr Opin Endocrinol Diabetes Obes. 2020;27(2):95-103. doi:10.1097/med.0000000000000530

6. Zhan S, Tang M, Liu F, Xia P, Shu M, Wu X. Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events. Cochrane Database Syst Rev.2018;11(11):Cd012502. doi:10.1002/14651858.CD012502.pub2

7. Garg A, Sharma A, Krishnamoorthy P, et al. Role of niacin in current clinical practice: a systematic review. Am J Med. 2017;130(2):173-187. doi:10.1016/j.amjmed.2016.07.038

8. Virani SS. Statins in the primary and secondary prevention of cardiovascular disease in women. Texas Heart Institute Journal. 2013;40(3):288-289.

9. Stroes E. Statins and LDL-cholesterol lowering: an overview. Curr Med Res Opin. 2005;21(suppl 6):S9-S16. doi:10.1185/030079905x59102

10. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. aconsensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-2472. doi:10.1093/eurheartj/ehx144

11. Chou R, Dana T, Blazina I, Daeges M, Jeanne TL. Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US Preventive Services TaskForce. JAMA. 2016;316(19):2008-2024. doi:10.1001/jama.2015.15629

12. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vasculardisease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581–90. doi:10.1016/S0140-6736(12)60367-5

13. Talayero BG, Sacks FM. The role of triglycerides in atherosclerosis. Curr Cardiol Rep. 2011;13(6):544-552. doi:10.1007/s11886-011- 0220-3

14. Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR, Kjekshus J. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation. 2001;104(25):3046-3051. doi:10.1161/hc5001.100624

15. Bowman L, Mafham M, Stevens W, et al. ASCEND: A Study of Cardiovascular Events in Diabetes: characteristics of a randomized trial of aspirin and of omega-3 fatty acidsupplementation in 15,480 people with diabetes. Am Heart J. 2018;198:135-144. doi:10.1016/j. ahj.2017.12.006

16. Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2019;380(1):23-32. doi:10.1056/NEJMoa1811403

17. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010;375:1875-1884. doi:10.1016/S0140-6736(10)60656-3

18. Ito MK. A comparative overview of prescription omega-3 fatty acid products. P T. 2015;40(12):826-857.

19. Prescription omega-3 medications work for high triglycerides, advisory says. News release. American Heart Association. August 19, 2019. Accessed July 10, 2020. https://www.heart. org/en/news/2019/08/19/prescription-omega3-medica- tions-work-for-high-triglycerides-advisory-says

20. Jacobson TA, Glickstein SB, Rowe JD, Soni PN. Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review. J Clin Lipidol. 2012;6(1):5-18. doi:10.1016/j.jacl.2011.10.018

21. Lovaza. Package insert. GlaxoSmithKline. 2019.

22. Omtryg. Package insert. Trygg Pharma Inc. 2014.

23. Epanova. Package insert. AstraZeneca Pharmaceuticals LP. 2017.

24. Vascepa. Package insert. Amarin Pharma Inc. 2019.

25. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet. 1999;354(9177):447-455.

26. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. doi:10.1056/NEJMoa1812792

27. Bhatt DL, Miller M, Brinton EA, et al. REDUCE-IT USA: results from the 3146 patients randomized in the United States. Circulation. 2020;141(5):367-375.doi:10.1161/circulationaha.119.044440

28. Garber AJ, Handelsman Y, Grunberger G, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on thecomprehensive type 2 diabetes management algorithm - 2020 executive summary. Endocr Pract. 2020;26(1):107-139. doi:10.4158/cs-2019-0472

29. Arnold SV, Bhatt DL, Barsness GW, et al. Clinical management of stable coronary artery disease in patients with type 2 dia- betes mellitus: a scientific statement from theAmerican Heart Association. Circulation. 2020;141(19):e779-e806. doi:10.1161/ cir.0000000000000766

30. Orringer CE, Jacobson TA, Maki KC. National Lipid Association scientific statement on the use of icosapent ethyl in statin-treated patients with elevated triglycerides and high or very-high ASCVD risk. J Clin Lipidol. 2019;13(6):860-872. doi:10.1016/j.jacl.2019.10.014