Current treatment of hypertriglyceridaemia

Current treatment of hypertriglyceridaemia is based on lifestyle modification and lipid lowering therapies.^1-4 There is no specific triglyceride (TG) target but a level <1.7 mmol/L (<150 mg/dL) indicates lower risk of cardiovascular (CV) disease,¹ and it has been proposed that a level <1.2 mmol/l (<100 mg/dL) should be considered optimal.⁴

Lifestyle modification

European guidelines recommend the following lifestyle interventions aimed at reducing plasma levels of triglyceride-rich lipoproteins (TRL):¹

	Effect on plasma TRL	Evidence level
Reduce excessive body weight	≤5%	A
Reduce alcohol intake	>10%	A
Increase habitual physical activity	5-10%	A
Reduce total dietary carbohydrate intake	5-10%	A
Use supplements of n-3 polyunsaturated fats	5-10%	A
Reduce intake of mono- and disaccharides	5-10%	B
Replace saturated fats with mono- or polyunsaturated fats	≤5%	B

US guidance recommends lifestyle interventions for patients, according to TG level:²

	TG <5.6 mmol/L (500 mg/dL)	TG 5.6 -11.2 mmol/L (500-999 mg/dL)	TG ≥11.2 mmol/L (1000 mg/dL)
Added sugars (% cals)	<6%	<5%	Eliminate
Total fat (% cals)	30%-35%	20%-25%	10%-15%
Alcohol	Restrict	Abstain completely	Abstain completely
Aerobic activity	≥150 min/week of moderate intensity or 75 min/week of vigorous intensity (or equivalent combination of both)
Weight loss (% body weight)	Recommended weight loss goal of 5-10%

Lipid lowering therapy (LLT)

European guidelines recommend initiating LLT in high risk patients with a TG level >2.3 mmol/L (>200 mg/dL) after excluding secondary causes.¹ US guidance recommends initiating LLT in patients with atherosclerotic cardiovascular disease (ASCVD) and persistently elevated fasting TG ≥1.7 mmol/L (150 mg/dL) or non-fasting TG ≥2 mmol/L (175 mg/dL) and TG <5.6 mmol/L (500 mg/dL) after excluding secondary causes.²

Statins are the mainstay of lipid lowering therapies for dyslipidaemia, including hypertriglyceridaemia, and have been shown to reduce TG levels by 10-30%.⁵ In patients with hypertriglyceridaemia, European and US guidance recommends maximising statin therapy, preferably with high intensity statins (eg. atorvastatin, rosuvastatin, and pitavastatin).^1-3

Ezetimibe is recommended in addition to maximally tolerated statin therapy:²

• As additional drug of choice in very high risk patients with clinical ASCVD and persistent hypertriglyceridaemia (TG ≥1.7 mmol/L [150 mg/dL] and <5.6 mmol/L [500 mg/dl]) whose LDL-C has been reduced by <50% from baseline and is ≥1.8 mmol/L (70 mg/dL)
• As a reasonable additional option in patients with clinical ASCVD and persistent hypertriglyceridaemia (TG ≥1.7 mmol/l [150 mg/dL] and <5.6 mmol/L [500 mg/dL]) not considered at very high risk but whose LDL-C is ≥1.8 mmol/L (70 mg/dL)

In the IMPROVE-IT study in patients following acute coronary syndrome, reduction from baseline in TG at 1 year was a mean 0.2 mmol/L (14 mg/dL) greater with simvastatin+ezetimibe than simvastatin alone (p<0.001).⁶

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) also reduce TG levels, and are recommended for consideration in addition to statins in patients with persistent hypertriglyceridaemia, depending on ASCVD risk.^1,2

• In patients with CV disease on statin therapy, TG was reduced from baseline by 15.5% at 48 weeks in patients taking evolocumab, compared to placebo⁷  
• In patients at high risk of CV events on statin therapy, TG was reduced from baseline by 17.2% at 24 weeks in patients taking alirocumab, compared to placebo.⁸ Both evolocumab and alirocumab have been associated with beneficial effects on CV outcomes^7,9
• In patients with, or at high risk of, ASCVD on statin therapy, TG was reduced from baseline by 7.0-12.6% at day 510 in patients taking inclisiran, compared to placebo.¹⁰ CV outcomes studies of inclisiran are ongoing.

Fibrates reduce TG levels by up to 50%, though the magnitude of effect is highly dependent on baseline lipid levels.¹ European guidelines recommend:¹

• Fenofibrate or bezafibrate may be considered in combination with statins for primary prevention in patients who are at LDL-C goal with TG levels >2.3 mmol/L (>200 mg/dL)
• Fenofibrate or bezafibrate may be considered in combination with statins in high-risk patients who are at LDL-C goal with TG levels >2.3 mmol/L (>200 mg/dL)

In the PROMINENT trial in patients with type 2 diabetes and mild-to-moderate hypertriglyceridaemia, the addition of the selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα), pemafibrate, to guidelines-recommended LLT reduced TG levels by 26.2% compared to placebo.¹¹ However, at a median 3.4 years follow up, pemafibrate did not reduce CV events compared to placebo (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15). It was suggested that the failure to reduce apoB may have been responsible for the lack of effect on CV outcomes with pemafibrate.¹²

Omega-3 fatty acids in doses of 2-4 g/day reduce serum TG levels by up to 45% in a dose-dependent way.¹ In the REDUCE-IT trial in high CV risk patients with hypertriglyceridaemia, the addition of icosapent ethyl (IPE) 2 g bd to statin treatment reduced TG by 20.5% at one year, compared to placebo, and significantly reduced the risk of ischaemic events, including CV death, by 25% compared to placebo over a median follow-up of 4.9 years (p<0.001).¹³

European guidance suggests that in high-risk patients with TG levels of 1.5-5.6 mmol/L (135-499 mg/dL) despite statin treatment, IPE (2×2 g/day) should be considered in combination with a statin.¹ US guidance suggests that patients with ASCVD, and persistent fasting hypertriglyceridaemia after lifestyle management, statin optimisation and glycaemic control, should be stratified according to their residual LDL-cholesterol (LDL-C) level:²

• For patients with LDL-C ≥100 mg/dL (2.6 mmol/L), an LDL-C risk-based approach is recommended, with further optimisation of statin therapy and adherence, and LDL-C-guided non-statin therapy to be considered in line with the 2018 American Heart Association/ACC cholesterol management guidelines³
• For patients with LDL-C of 70-99 mg/dL (1.8-2.6 mmol/L), a combined TG/LDL-C risk-based approach is recommended, based on patient preference. Options are for an LDL-C risk-based approach as above or a TG risk-based approach including consideration of medication known to reduce CV risk in patients with elevated TG, eg. IPE
• For patients with LDL-C <70 mg/dL (1.8 mmol/L), a TG risk-based approach is recommended with consideration given to treatment with IPE

Novel agents

ApoC3 inhibitors (eg. volanesorsen, olezarsen and ARO-APOC3) target apoC3, which determines how efficiently TGs are cleared from the plasma, through direct inhibition of lipoprotein lipase (LPL), as well as indirect mechanisms, such as promoting secretion of TG-rich lipoproteins, provoking proinflammatory responses in vascular cells and impairing lipoprotein lipase-independent hepatic clearance of TRL remnants.¹⁴ Mendelian randomisation studies have shown that loss-of-function variants in the APOC3 gene were associated with low TG, as well as a reduced risk of coronary artery disease.¹⁵

• In clinical trials, volanesorsen reduced TG levels by 77% in patients with familial chylomicronaemia syndrome,¹⁶ and by approximately 70% in patients with multifactorial chylomicronaemia¹⁷
• In a dose-ranging study, olezarsen reduced TG levels by up to 60% in patients at high CV risk with moderate hypertriglyceridaemia¹⁸
• In a Phase 1 trial, ARO-APOC3 reduced TG levels by 92% in patients with severe hypertriglyceridaemia¹⁹

ANGPTL3 inhibitors (eg. Evinacumab and ARO-ANG3) target ANGPTL3 (produced in the liver) which plays a key role in the regulation of lipid metabolism by inhibiting lipoprotein lipase (LPL) and endothelial lipase in adipose and muscle tissue. Mendelian randomisation studies have shown that loss-of-function variants in ANGPTL3 are associated with low levels of LDL-C, HDL-C and TG, as well as a reduced risk of coronary artery disease.^20,21

References

1. Mach F, Baigent C, Catapano AL et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. European Heart Journal 2020; 41: 111-188
2. 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. J am Coll Cardiol 2021; Aug, 78 (9) 960–993
3. Grundy SM, Stone NJ, Bailey AL et al. 2018  HA/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.
4. Ginsberg HN, Packard CJ, Chapman MJ et al. Triglyceride-rich lipoproteins and their remnants:metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies—a consensus statement from the European Atherosclerosis Society. European Heart Journal 2021 Dec 14;42(47):4791-4806. 
5. Miller M, Stone NJ, Ballantyne C et al; American Heart Association Clinical Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Nursing; Council on the Kidney in Cardiovascular Disease. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011 May 24;123(20):2292-333
6. Cannon CP, Blazing MA, Giugliano RP et al; IMPROVE-IT Investigators. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18;372(25):2387-97.
7. Sabatine MS, Giugliano RP, Keech AC et al; FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722
8. Robinson JG, Farnier M, Krempf M et al; ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16;372(16):1489-99
9. Schwartz GG, Steg PG, Szarek M et al; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018 Nov 29;379(22):2097-2107
10. Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, Bisch JA, Richardson T, Jaros M, Wijngaard PLJ, Kastelein JJP; ORION-10 and ORION-11 Investigators. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020 Apr 16;382(16):1507-1519. 
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15. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;37132-41.
16. Witztum JL, Gaudet D, Freedman SD, et al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med 2019;381:531-42.
17. Gouni-Berthold I, Alexander VJ, Yang Q, et al. Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol;9:264-75.
18. Tardif JC, Karwatowska-Prokopczuk E, Amour ES et al. Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J. 2022 Apr 6;43(14):1401-1412.
19. Spagnuolo CM, Hegele RA. Recent advances in treating hypertriglyceridemia in patients at high risk of cardiovascular disease with apolipoprotein C-III inhibitors. Expert Opin Pharmacother. 2023 Jun;24(9):1013-1020
20. Kersten S. New insights into angiopoietin-like proteins in lipid metabolism and cardiovascular disease risk. Curr Opin Lipidol 2019;30:205-11.
21. Dewey FE, Gusarova V, Dunbar RL et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017; 377: 211-21.