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
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 outcomes7,9
- 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
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
- 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
- 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
- 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.
- 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.
- 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
- 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.
- 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
- 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
- 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
- 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.
- Das Pradhan A, Glynn RJ, Fruchart JC et al. Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk. N Engl J Med. 2022; 387:1923-1934
- Virani SS. The Fibrates Story – A Tepid End to a PROMINENT Drug. N Engl J Med. 2022; 387:1991-1992
- Bhatt DL, Steg PG, Miller M et al; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22.
- Taskinen MR, Borén J. Why Is apolipoprotein CIII emerging as a novel therapeutic target to reduce the burden of cardiovascular disease? Curr Atheroscler Rep 2016;18:59.
- 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.
- Witztum JL, Gaudet D, Freedman SD, et al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med 2019;381:531-42.
- 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.
- 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.
- 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
- Kersten S. New insights into angiopoietin-like proteins in lipid metabolism and cardiovascular disease risk. Curr Opin Lipidol 2019;30:205-11.
- 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.