R3i Editorial

For too long, triglycerides (TG) have been the forgotten player in atherosclerotic cardiovascular disease (ASCVD). Times are now changing. Substantive evidence from epidemiologic surveys and Mendelian randomization studies supports a role for TG-rich lipoproteins and their remnants in the causal pathway of ASCVD ^1,2. Added to this, REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Interventional Trial) showed that lowering elevated TG with high-dose icosapent ethyl, an eicosapentaenoic acid (EPA) ethyl ester, significantly reduced cardiovascular events in high-risk patients ³. Controversy persists, however, as other clinical trials, including STRENGTH (A Long-Term Outcomes Study to Assess Statin Residual Risk Reduction with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) with a mixed omega-3 fatty acid formulation ⁴, did not show any cardiovascular benefit from lowering TG. It is, however, recognized by both European and North American guideline groups that elevated TG contribute to increased cardiovascular risk. For example, preceding REDUCE-IT, the 2018 American Heart Association/American College of Cardiology/multisociety cholesterol guideline categorized elevated TG as a “risk-enhancing factor” ⁵. The 2019 European Society of Cardiology/ European Atherosclerosis Society (ESC/EAS) dyslipidemia guidelines also recommended desirable TG levels in managing elevated TG ⁶.

Recently, the ACC published an Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients With Persistent Hypertriglyceridemia ⁷ to address gaps in the management of high-risk patients with mild to moderate hypertriglyceridemia (defined as fasting TG ≥150 mg/dL or nonfasting TG ≥175 mg/dL and <500 mg/dL). Specifically, this focused on therapeutic approaches when guideline-recommended lifestyle intervention and a stable dose of maximally tolerated statin therapy have failed to lower elevated TG. For ASCVD patients with persistent mild to moderate hypertriglyceridemia, treatment strategies are differentiated by LDL-C levels. For those with LDL-C levels <70 mg/dL on a statin, a TG-risk-based approach is recommended, with the use of high-dose icosapent ethyl. In contrast, for patients with LDL-C levels ≥100 mg/dL the approach is LDL-C-based, with optimization of statin therapy and consideration of non-statin LDL-lowering options. A joint strategy is recommended if LDL-C levels are between 70 and 99 mg/dL. This consensus document also considered the management of primary prevention patients with diabetes mellitus and persistent hypertriglyceridemia, as well as those with no ASCVD or diabetes mellitus and elevated TG levels. While there is some consistency with European recommendations, the latter do also take account the potential for microvascular benefits from other TG-lowering therapy ^6,8.

Why is this new guidance important? This document addresses many uncertainties that clinicians have in their daily management of patients with mild to moderate hypertriglyceridemia. The Editors welcome clarity on managing elevated TG, given the ongoing clinical development of several novel agents that lower TG. Not only do these include the selective peroxisome proliferator-activated receptor alpha agonist pemafibrate, currently being tested in the PROMINENT (Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patients With diabetes) study ⁹, but also RNA interference therapy (antisense oligonucleotides and small interfering RNAs) and monoclonal antibody therapy specific to key targets of TG metabolism. Results from these trials will be crucial to delineating the contribution of elevated TG – a surrogate for TG-rich lipoproteins and their remnants – to residual cardiovascular risk.

References

1. Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 2013;45:1345–52.
2. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.
3. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22.
4. Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA 2020;324:2268–80.
5. 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e285–e350.
6. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88.
7. Virani SS, Morris PB, Agarwala A et al. 2021 ACC Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients With Persistent Hypertriglyceridemia. A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021:S0735-1097²¹05323-7. doi: 10.1016/j.jacc.2021.06.011.
8. Averna M, Banach M, Bruckert E, et al. Practical guidance for combination lipid-modifying therapy in high- and very-high-risk patients: A statement from a European Atherosclerosis Society Task Force. Atherosclerosis 2021;325:99-109.
9. Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018;206:80-93.