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 plozasiran) 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 the Phase 3 Balance trial, olezarsen 80 mg significantly reduced TG levels at 6 months by 43.5% (95% confidence interval [CI], −69.1 to −17.9; P<0.001) compared with placebo in patients with familial chylomicronaemia syndrome (FCS).¹⁸ In 2024, these results supported the approval of olezarsen as an adjunct to diet in patients with FCS in the USA.
• In the Phase 3 PALISADE trial in patients with persistent chylomicronaemia, plozasiran 25 mg reduced fasting TG by 80% at month 10, compared with a 17% reduction with placebo (P<0.001). There was also a reduction in the incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P = 0.03).¹⁹

ANGPTL3 inhibitors (eg. evinacumab, zodasiran and solbinsiran) target ANGPTL3 (produced in the liver) which plays a key role in the regulation of lipid metabolism by inhibiting 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.^20-22

• In clinical trials in patients with severe hypertriglyceridaemia, homozygous familial hypercholesterolaemia (HoFH) and refractory hypercholesterolaemia, evinacumab at highest doses reduced TG levels by more than 50%.²³
• In the ARCHES-2 trial of zodasiran in patients with mixed dyslipidaemia, zodasiran 50 mg-200 mg reduced TG levels at week 24 by 51%-63% compared with placebo (P<0.001 for all comparisons).²⁴
• In the PROLONG-ANG trial of solbinsiran in patients with mixed dyslipidaemia, solbinsiran 100 mg-800 mg reduced TG levels at day 180 by 36.3%-52.5% compared to placebo (P<0.0001 for all comparisons).²⁵

The gene editing medicine, VERVE-201, is designed to permanently inactivate ANGPTL3 in the liver via a precise A-to-G DNA base pair edit and thereby lower LDL-C and TG concentrations.

References

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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
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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. 
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