Introduction

Hypertriglyceridemia (HTG) is a very common problem in clinical practice with a prevalence of approximately 10%.¹ Plasma triglyceride (TG) concentration is a biomarker for TG rich lipoproteins (TRL) and their remnants, which have emerged as important contributors to atherosclerotic cardiovascular disease and pancreatitis. This summary reviews the underlying biochemistry, etiologies, current treatments and emerging therapies that was discussed in detail in Clinical review on triglycerides by Ulrich Laufs et al. published in the European Heart Journal early in 2020.

Biochemistry and Etiology

TGs are composed of three fatty acid molecules bound to a glycerol. TRLs, i.e. chylomicrons, and very low-density lipoproteins (VLDL) are composed of core TGs and cholesterol esters with surface apolipoproteins, phospholipids and free cholesterol. Dietary TGs absorbed via the intestinal lymphatics are transported in chylomicrons, while endogenous TGs synthesized in the liver are transported in VLDLs.

Hydrolysis of circulating chylomicrons and VLDLs by lipoprotein lipase (LPL) releases free fatty acids and produces chylomicron remnants and intermediate-density lipoprotein (IDL) particles, respectively. Chylomicron remnants are then cleared by the liver via an interaction between apolipoprotein E (apoE) on the chylomicron remnant and the low density lipoprotein receptor (LDLR) on the hepatocytes.

IDLs can be removed similarly by an interaction between apoE or apoB-100 with LDLR or instead could be further hydrolyzed by LPL to low-density lipoprotein (LDL), which is cleared by the LDLR, whose activity is reduced by proprotein convertase subtilisin kexin 9 (PCSK9). Hepatic uptake of TRLs is a saturable process; in general, increased VLDL production is the commonest initiation factor for HTG such as what is seen in those with insulin resistance, obesity, and type 2 diabetes mellitus.²

Several interacting proteins at the endothelial surface affect LPL activity. Lipolysis is enhanced by lipase maturation factor 1 (LMF1), a chaperone protein which ensures LPL is properly secreted. Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein-1 (GPIHBP1) stabilizes LPL on the endothelial surface. Apo C-II activates LPL and apo A-V serves as a stabilizing cofactor. In contrast, lipolysis is reduced by apo C-III, a component of TRLs, and by angiopoietin-like proteins 3 and 4 (ANGPTL3 and ANGPTL4). Peroxisome proliferator-activated receptors (PPAR), particularly alpha and delta types, influence several of these molecules. Many of the emerging therapies discussed below target these molecular pathways.

Though the European cutoff levels for specific categories do not completely overlap with the 2018 AHA/ACC Multi-society Cholesterol Guideline,³ normal fasting TG levels can be defined as <150 mg/dL (1.7 mmol/L), mild-to-moderate HTG 175-885 mg/dL (TG 2.0–9.9 mmol/L), severe >885 mg/dL (>10 mmol/L) or very severe >1770 mg/dL (>20 mmol/L). Secondary causes (see Table 1) alone may cause mild to moderate HTG; however, they frequently interact with polygenic susceptibility factors to produce an HTG phenotype.

Table 1: Secondary Causes For Hypertriglyceridemia

Lifestyle	Obesity	Metabolic syndrome	Alcohol
Secondary Disorders	Diabetes mellitus or Hypothyroidism	Chronic liver disease	Chronic kidney disease and/or nephrotic syndrome
Medications	Hormone related: Oral estrogens Tamoxifen Raloxifene Retinoids Glucocorticoids	Immune related: Cyclosporine Tacrolimus Sirolimus Cyclophosphamide Interferon	Other: Beta blockers Thiazides Atypical antipsychotics Rosiglitazone Bile acid sequestrants L-asparaginase

Familial HTG (classically Fredrickson Levy Lees / WHO Type 4), dysbetalipoproteinemia (Type 3) and familial combined hyperlipidemia (Type 2B) are all examples of primary HTG presenting with mild to moderate HTG. They are mainly caused by a number of complex genetic susceptibility factors with the exception of dysbetalipoproteinemia, which is classically described as autosomal recessive with defects in APOE.

Although secondary factors contribute significantly to mild to moderate HTG, severe HTG is more commonly primary in nature (see Table 2). The vast majority of severe HTG is a result of complex genetic susceptibility factors as is seen with mixed hyperlipidemia (Type 5).⁴ However, approximately 2% of these patients have a monogenic cause, such as familial chylomicronemia syndrome (FCS, Type 1). An autosomal recessive mutation in LPL accounts for 80% of the cases of FCS while the remainder of this autosomal recessive disorder is caused by mutations in four other genes; APOC2, APOA5, LMF1 and GPIHBP1, which are all involved in lipolysis as described above.

Table 2: Primary Causes of Hypertriglyceridemia

Severe HTG severe >885 mg/dL (>10 mmol/L) Monogenic chylomicronemia (formerly HLP Type 1 or familial chylomicronemia syndrome) via Lipoprotein lipase deficiency (80% of cases) Apo C-II deficiency Apo A-V deficiency Lipase maturation factor 1 deficiency (LMF1) GPIHBP1 deficiency Multifactorial or polygenic chylomicronemia (formerly HLP Type 5 or mixed hyperlipidemia) via complex genetic susceptibility, including Heterozygous rare large-effect gene variants for monogenic chylomicronemia (see above); and/or Accumulated common small-effect TG-raising polymorphisms Mild-to-moderate HTG 175-885 mg/dL (TG 2.0–9.9 mmol/L) Multifactorial or polygenic HTG (formerly HLP Type 4 or familial HTG) via complex genetic susceptibility Dysbetalipoproteinemia (formerly HLP Type 3 or dysbetalipoproteinemia) via complex genetic susceptibility, plus APOE E2 mutation Combined hyperlipoproteinemia (formerly HLP Type 2B or familial combined hyperlipidemia) via complex genetic susceptibility plus accumulation of common small effect LDL-C-raising polymorphisms

Serum TRL levels are consistently associated with ASCVD risk. For example, in large cohort studies from Copenhagen non-fasting TGs of 6.6 vs. 0.8 mmol/L (585 vs.70 mg/dL) were associated with a five-, three-, and two-fold increased adjusted risk for myocardial infarction, ischemic stroke, and all-cause mortality, respectively.⁵

All TRL particles, as well as LDL particles, contain a single apoB molecule. Non-high density lipoprotein cholesterol, calculated as TC minus HDL-C, captures the cholesterol on apo B-containing lipoproteins. Such particles infiltrate the arterial wall and promote atherogenesis via pro-inflammatory and pro-thrombotic pathways.

It was thought for many years that only severe HTG was associated with acute pancreatitis; however, newer data suggest an increased risk of acute pancreatitis in a dose related fashion even at mild to moderate TG levels. Despite this, the absolute numbers remain small until TG >885 mg/dL (10 mmol/L) and clinical presentations are often accompanied by additional risk factors such as alcohol use, gallstone disease or certain medications. The mechanism by which HTG causes acute pancreatitis is not clear but changes in the microenvironment, particularly pH changes due to concentrations of the fatty acids, have been postulated as the main factor.⁶

Diagnosis of Hypertriglyceridemia

It is well known that non-fasting samples have higher TG levels. However, the increase in post-prandial TG is highly correlated with fasting TG concentrations with similar prognostic value.⁷ Therefore, non-fasting samples are recommended for general screening for practical reasons with repeat fasting samples when the initial screen exceeds 400 mg/dL or higher (≥4.5 mmol/L).

Therapy – Lifestyle

Both the US and European guidelines highlight the management of lifestyle factors such as weight loss, alcohol abstinence, and increased exercise as the most important principle for the management of HTG.^3,8 A reduction of approximately 8 mg/dL is seen with each kilogram of weight loss. Alcohol abstinence is associated with a variable response but a decrease of up to 80% has been seen in those with prior excessive intake. A decrease in TG levels by 10-20% or more can be seen with an increase in aerobic exercise. Lastly, the contributions from comorbidities such as renal disease and medicines such as thiazides, hormone therapy, beta-blockers and steroids should be considered.

Therapy – Approved Pharmacologic Therapy

LDL-C lowering agents such as statins, ezetimibe and PCSK9 inhibitors decrease TG levels by 5-15%, whereas specific TG lowering agents such as fibrates, omega-3 fatty acids and niacin decrease levels by 25-45%. The first step in the initiation of a medication is determining ASCVD risk and initiation of an LDL-C lowering therapy. Once LDL-C is optimized, the addition of a specific TG lowering agent can be considered for further reduction in ASCVD and/or acute pancreatitis risk.

There is a paucity of evidence demonstrating a reduction in ASCVD or acute pancreatitis when these medications are added to a statin.⁹ A subgroup analysis of patients with HTG and low HDL-C did, however, suggest a benefit with the addition of fibrate therapy.¹⁰ Therefore, many lipid clinics in the US and Canada used to consider fibrate therapy, in particular fenofibrate, in those with elevated ASCVD risk and persistent TG concentrations >200 mg/dL despite optimizing LDL-C.

Use of omega-3-fatty acids has in general not been shown to decrease ASCVD events.¹¹ In contrast, the 2019 REDUCE-IT trial, which assessed the effects of 4g icosapent ethyl (Vascepa®) in high risk patients with persistently elevated TGs despite statin therapy, demonstrated a dramatic risk reduction (HR 0.75) in ASCVD events over a mean of 4.9 years.¹² It is unclear whether the benefits seen in this trial are related to the higher EPA dosage of 4g, the specific formulation chosen, the selected study population, or in part the possible deleterious effects of the mineral oil used as a placebo.

As previously discussed, acute pancreatitis secondary to HTG is seen primarily in patients with very high levels of TGs. Beyond standard therapies for acute pancreatitis and avoidance of glucose containing fluids which may stimulate hepatic VLDL production, specific therapies to rapidly decrease TGs include heparin, which releases endothelial bound LPL, or insulin, which blocks the release of free fatty acids.^13,14 Plasmapheresis is an alternative strategy typically reserved for severe HTG in pregnancy.

Therapy – Novel and Emerging Strategies

Epanova®, similar to Vascepa®, is a 4g daily formulation of omega-3 fatty acids but includes both EPA (the active agent in Vascepa®) and docosahexaenoic acid. A phase 3 trial, STRENGTH (Statin Residual Risk Reduction with EpaNova in High Cardiovascular Risk Patients with Hypertriglyceridaemia) was stopped earlier this year for futility. This suggests that the formulation of these omega-3 fatty acids was not as effective as EPA alone. Pemafibrate, a PPAR modulator, is being evaluated in the phase 3 clinical trial, PROMINENT (Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts with diabetes). Both are large ASCVD outcome trials with >10,000 participants.

As described above, apo C-III negatively affects lipolysis through its interaction with LPL. Volanesorsen is a subcutaneously injected anti-apo C-III antisense oligonucleotide which impairs translation of apo C-III mRNA. APPROACH was a 52 week randomized controlled trial of 66 FCS patients.¹⁵ TGs were reduced by 77% in the volanesorsen group compared with 18% in the placebo group. The primary adverse reactions from the drug include injection site reactions and thrombocytopenia potentially related to the antisense formulation.

As a result of the thrombocytopenia, the US Food and Drug Administration did not approve volanesorsen for FCS while the European Medicines Agency has recommended conditional marketing authorization. It is hoped that a next-generation N-acetylgalactosamine (GalNac)-conjugated allele-specific oligonucleotide (ASO) targeting apo C-III (AKCEA-APOCIII-LRx) will not have the same adverse reactions. Notably, AKCEA-APOCIII-LRx will focus on patients with ASCVD risk rather than FCS.

Angiopoietin-like protein 3 (ANGPTL3) decreases lipolysis through its interaction with LPL and other unclear mechanisms. The monoclonal antibody evinacumab and GalNac modified antisense oligonucleotide IONIS-ANGPTL3-LRx are anti-ANGPTL3 therapies, which reduce both severely elevated TGs and LDL such as in familial hypercholesterolemia. Both agents are in phase 2-3 trials.

Alipogene tiparvovec was a gene therapy for LPL deficiency available in Europe until 2017 when the sponsor declined to renew market authorization. While TG levels normalized in 12 weeks, levels then returned to prior baseline by 6 months after therapy. Pradigastat and AZD7687 are oral inhibitors of diacylglycerol acyltransferase which govern fat absorption and intestinal TG synthesis. GI side effects predictably have been a difficulty with these agents.

Finally, whereas many of the above discussed agents focus on inhibiting the proteins involved in the inhibition of LPL, there are several agents in early stages of development that target apo C-II and apo A-V and in doing so seek to promote LPL activity.

Table 3: Emerging Treatments for Hypertriglyceridemia

Name	Mechanism of action	Indication	Stage	Biochemical effect
Icosapent ethyl	Not fully defined	Elevated TG	Phase 3 CVOT completed (REDUCE-IT)	Reduces TG
Pemafibrate	Selective PPAR modulator	Elevated TG	CVOT in progress (PROMINENT)	Reduces TG, increases HDL-C
Volanesorsen	First-generation anti-APOC3 ASO	FCS	Approved in Europe, not in North America	Reduces TG, increases HDL-C
AKCEA-APOCIII-LRx	N-acetylgalactosamine (GalNac)-conjugated antiAPOC3 ASO	ASCVD	Phase 3 CVOT planned	Reduces TG, increases HDL-C
Evinacumab	Anti-ANGPTL3 antibody	FH, FCS, severe HTG	Phase 2-3	Reduces TG, LDL-C, and HDL-C
IONIS-ANGPTL3-LRx	N-acetylgalactosamine (GalNac)-conjugated antiANGPTL3 ASO	FH, FCS, severe HTG	Phase 2-3	Reduces TG, LDL-C, and HDL-C
Alipogene tiparvovec	LPL gene therapy	FCS	Approved; but no longer marketed	Reduces TG

Conclusion

It is well established that TRL and their remnants are important contributors to ASCVD. The first step of treatment involves implementing lifestyle changes. Next, LDL-C reduction with statins +/- non-statins is indicated to decrease ASCVD risk. Although previous agents targeting lower TG levels, such as niacin and fibrates, did not show significant reductions in vascular events, high dose icosapent ethyl was much more successful in reducing vascular events in patients already being treated with at least moderate intensity statin therapy. Lastly, familiarity with the biochemistry underlying TG metabolism is key to understanding the novel and emerging therapies targeting TRL that are currently under investigation.

References

1. Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. Eur Heart J 2020;41:99-109c.
2. Xiao C, Dash S, Morgantini C, Hegele RA, Lewis GF. Pharmacological targeting of the atherogenic dyslipidemia complex: the next frontier in CVD prevention beyond lowering LDL cholesterol. Diabetes 2016;65:1767-78.
3. 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. Circulation 2019:139:e1082-e1143.
4. Dron JS, Wang J, Cao H, et al. Severe hypertriglyceridemia is primarily polygenic. J Clin Lipidol 2019;13:80-88.
5. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.
6. Havel RJ. Pathogenesis, differentiation and management of hypertriglyceridemia. Adv Intern Med 1969;15:117-54.
7. Nordestgaard BG, Langsted A, Mora S, et al. Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cut-points - a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Eur Heart J 2016;37:1944-58.
8. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J 2016;37:2999-3058.
9. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
10. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010;375:1875-84.
11. Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol 2018;3:225-34.
12. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
13. Tornvall P, Olivecrona G, Karpe F, Hamsten A, Olivecrona T. Lipoprotein lipase mass and activity in plasma and their increase after heparin are separate parameters with different relations to plasma lipoproteins. Arterioscler Thromb Vasc Biol 1995;15:1086-93.
14. Wolfgram PM, Macdonald MJ. Severe hypertriglyceridemia causing acute pancreatitis in a child with new onset type I diabetes mellitus presenting in ketoacidosis. J Pediatr Intensive Care 2013;2:77-80.
15. Witztum JL, Gaudet D, Freedman SD, et al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med 2019;381:531-42.

Clinical Topics: Anticoagulation Management, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins, Diet, Exercise

Keywords: Dyslipidemias, Acetylgalactosamine, Acute Disease, Acetates, Alleles, Aminopyridines, Alcohol Abstinence, Antibodies, Monoclonal, Antipsychotic Agents, Apolipoproteins, Apolipoproteins A, Apolipoproteins B, Apolipoproteins E, Apolipoprotein B-100, Apolipoprotein C-II, Apolipoprotein C-III, Asparaginase, Atherosclerosis, Benzoxazoles, Bile Acids and Salts, Brain Ischemia, Butyrates, Cardiovascular Diseases, Cholesterol, Cholesterol, Dietary, Cholesterol Esters, Cholesterol, LDL, Chylomicron Remnants, Chylomicrons, Cohort Studies, Cyclophosphamide, Cyclosporins, Diabetes Mellitus, Diabetes Mellitus, Type 2, Diacylglycerol O-Acyltransferase, Docosahexaenoic Acids, Eicosapentaenoic Acid, Estrogens, Exercise, Fasting, Fatty Acids, Fatty Acids, Nonesterified, Fatty Acids, Omega-3, Fenofibrate, Fibric Acids, Gallstones, Genetic Predisposition to Disease, Glucocorticoids, Glucose, Glycerol, Glycosylphosphatidylinositols, Glycosylphosphatidylinositols, Heparin, Hepatocytes, Hydrogen-Ion Concentration, Hydrolysis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipidemias, Hyperlipoproteinemia Type I, Hyperlipoproteinemia Type II, Hyperlipoproteinemia Type III, Hypertriglyceridemia, Hypothyroidism, Insulin, Insulin Resistance, Life Style, Lipase, Lipolysis, Lipoprotein Lipase, Lipoproteins, Lipoproteins, VLDL, Lipoproteins, LDL, Lipoproteins, IDL, Liver Diseases, Medical Futility, Metabolic Syndrome, Mineral Oil, Mutation, Myocardial Infarction, Nephrotic Syndrome, Niacin, Obesity, Oligonucleotides, Oligonucleotides, Antisense, Peptide Initiation Factors, Peroxisome Proliferator-Activated Receptors, Phenotype, Phospholipids, Plasmapheresis, Pregnancy, Prevalence, Prognosis, Receptors, LDL, Renal Insufficiency, Chronic, Retinoids, Risk Factors, Risk Reduction Behavior, RNA, Messenger, Sirolimus, Stroke, Subtilisins, Tacrolimus, Tamoxifen, Thiazides, Thrombocytopenia, Triglycerides, United States Food and Drug Administration, Weight Loss

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