Approach

The two main objectives in the management of individuals with HTG are:

  • Prevention of adverse atherosclerotic cardiovascular disease (ASCVD) outcomes such as myocardial infarction, stroke, and revascularisation procedures

  • Prophylaxis of acute pancreatitis episodes.

For both aims, there are no specific evidence-based, guideline-recommended treatment target levels for triglyceride (TG).

Triglyceride targets

The 2018 American Heart Association/American College of Cardiology (AHA/ACC) guidelines suggest a framework consisting of two HTG categories: moderate HTG (fasting or non-fasting TG 2.0 to 5.6 mmol/L [175-499 mg/dL]) and severe HTG (fasting TG ≥5.6 mmol/L [≥500 mg/dL]).[2] For moderate HTG, the 2021 ACC expert consensus uses a definition of fasting TG ≥1.7 mmol/L (≥150 mg/dL) or non-fasting TG ≥2.0 mmol/L (≥175 mg/dL) and TG <5.6 mmol/L (<500 mg/dL).[9] The AHA/ACC guidelines state that there are many causes of elevated very low-density lipoprotein (VLDL), and recommend that it is reasonable to reduce VLDL levels to reduce risk of ASCVD.[2] In patients with severe HTG, elevated VLDL and remnant particles raise ASCVD risk, and fasting chylomicrons increase the risk of acute pancreatitis; therefore, the AHA/ACC guidelines suggest that therapies should address excesses in all classes of TG-rich lipoproteins.[2]

The 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines recommend that TG levels <1.7 mmol/L (<150 mg/dL) are associated with lower ASCVD risk.[11] They further state that if TG levels are higher than this, efforts at global cardiovascular risk modification should be undertaken, focusing on other risk factors such as LDL-cholesterol and blood pressure. The 2017 American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) guidelines explicitly state that TG <1.7 mmol/L (<150 mg/dL) is a goal for patients at risk of ASCVD.[58] In patients with severe HTG and TG ≥5.6 mmol/L (≥500 mg/dL), reduction of TG levels is recommend to reduce risk of acute pancreatitis.[2][9]

Non-pharmacological approaches

Epidemiological studies show that patients with mild-to-moderate HTG generally are at increased risk of ASCVD.[53] In patients with mild-to-moderate HTG, it is therefore reasonable to reduce both atherogenic VLDL and associated risk factors by non-pharmacological means where possible. This can best be achieved by identification and treatment of the multiple underlying causes of elevated TG. Secondary causes of HTG include medical conditions, lifestyle factors, and drugs:[4][5][9]

  • Medical conditions: diabetes mellitus, metabolic syndrome, insulin resistance, obesity, chronic kidney disease, nephrotic syndrome, hypothyroidism, pregnancy (particularly in the third trimester when TG elevation associated with pregnancy is peaking), myeloma, systemic lupus erythematosus, liver disease, HIV infection, Cushing syndrome, sarcoidosis

  • Lifestyle factors: excessive alcohol consumption; diet high in saturated fat, sugar, or high glycaemic index foods; sedentary lifestyle

  • Drugs: glucocorticoids, anabolic steroids, oral oestrogens, thiazide and loop diuretics, non-cardioselective beta-blockers, isotretinoin, bexarotene, propofol, bile acid sequestrants, cyclophosphamide, asparaginase, capecitabine, interferon, tacrolimus, sirolimus, ciclosporin, protease inhibitors, second-generation antipsychotic agents (e.g., clozapine, olanzapine).

The same initial approach applies to patients with severe HTG. Most patients with severe HTG also have multiple ASCVD risk factors and are at risk of developing ASCVD. This risk is imparted by atherogenic VLDL and remnant particles, plus other factors such as obesity, metabolic syndrome, and hyperglycaemia. While chylomicrons themselves are not atherogenic, in adult patients chylomicronaemia is associated with other atherogenic factors. As in individuals with mild-to-moderate HTG, in those with severe HTG it is reasonable to reduce TG by non-pharmacological means where possible. This is achieved by identification and treatment of the multiple underlying causes of elevated TG, as indicated above.

Non-pharmacological management in all HTG patients therefore includes: limitation or abstinence of alcohol; avoidance of simple carbohydrates; low-fat diet (<30% of total daily caloric intake) and when TG level >11.3 mmol/L (>1000 mg/dL), a very low-fat diet (<15% of total daily caloric intake); weight loss; strict glycaemic control in patients with diabetes or impaired glucose metabolism; treatment of hypothyroidism; control of other secondary causes; and avoidance of drugs that increase TG, if possible, or substitution with an available metabolically neutral alternative.[9][14]​ Referral to a registered dietitian nutritionist should be considered depending on TG level.

Individuals with familial chylomicronaemia syndrome (FCS) are a special case because of the severe genetic deficiency of lipolytic capacity. These individuals must follow a stringent low-fat diet (<15% of daily caloric intake from fat), which presents a challenge over a lifetime.[5][14][21] Medium-chain fatty acids can provide an alternate source of dietary fat given their direct absorption into the portal circulation with no reliance on chylomicron formation.[21] Given this strict dietary regimen, supplementation with essential fatty acids and fat-soluble vitamins can be considered.[21] Referral to a lipid specialist should be considered.

Pharmacological management of mild-to-moderate HTG to reduce ASCVD risk

The ACC defines persistent HTG as fasting TG ≥1.7 mmol/L (≥150 mg/dL) following a minimum of 4-12 weeks of lifestyle intervention, a stable dose of maximally tolerated statin therapy when indicated, and evaluation and management of secondary causes.[9] There are few contemporary randomised studies that have primarily recruited patients with HTG and treated them with TG-lowering drugs. Therefore, the 2018 AHA/ACC guidelines do not specifically address mild-to-moderate HTG directly.[2] Instead, patients are treated based on their ASCVD risk and LDL-cholesterol levels, primarily using statins. In patients with mild-to-moderate HTG, statin therapy reduces VLDL to a similar degree as fibrates, and statin trials have included HTG patients. Therefore, the 2018 AHA/ACC guidelines suggest that if an adult patient with moderate HTG has poorly controlled risk factors for ASCVD and a 10-year risk of ASCVD ≥7.5%, it is reasonable to either initiate or intensify statin therapy.[2] For those with a 10-year ASCVD risk 5% to <7.5% and persistent HTG, patient-clinician discussion is recommended regarding the initiation of moderate-intensity statin therapy.[2][9]

To further reduce LDL-cholesterol, it may be necessary to add adjunctive treatments such as ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, or bempedoic acid; however, these have only minimal impact on TG and are not recommended for treatment of HTG.[60]​

For information on calculating the 10-year risk of ASCVD, see Hypercholesterolaemia.

The ESC/EAS guidelines concur with AHA/ACC guidelines and recommend statins as the first drug of choice to reduce ASCVD risk in high-risk individuals with TG levels >2.3 mmol/L (>200 mg/dL).[11]

The REDUCE-IT trial found that among patients with elevated triglyceride (TG) levels despite the use of statins, addition of high-dose icosapent ethyl led to a significant reduction in the risk of ASCVD events and cardiovascular mortality.[61] The REDUCE-IT trial also reported that patients on active treatment had a slight but statistically significant increased risk of hospitalisation with atrial fibrillation (AF; 5.3% vs. 3.9% in placebo) and in mild bleeding events (2.7% vs. 2.1% in placebo).[61]​ While some jurisdictions have issued warnings regarding these risks, it is noted that the marked overall cardiovascular benefits have largely offset these concerns.[61]​ The US guidelines advise that addition of icosapent ethyl may be considered in patients with persistent TG ≥1.7 mmol/L (≥150 mg/dL) despite maximally tolerated statin therapy and consideration of lifestyle factors. Patients with moderate HTG considered for icosapent ethyl in US guidelines include those with ASCVD and either LDL-cholesterol <1.8 mmol/L (<70 mg/dL) or LDL-cholesterol 1.8 to 2.6 mmol/L (70-99 mg/dL), or those age >50 years without ASCVD, but with diabetes and one or more high-risk factors for ASCVD.[9][62]​ The ESC/EAS recommends that in high-risk patients with TG levels between 1.5 to 5.6 mmol/L (135-499 mg/dL) despite statin treatment, icosapent ethyl should be considered in combination with a statin.[11][61]​ In contrast to the AHA/ACC, the ESC/EAS also recommends that in patients who are at LDL-cholesterol goal and still have TG levels >2.3 mmol/L (>200 mg/dL), fenofibrate may be considered in combination with a statin.[11]

Pharmacological management of severe HTG

In severe HTG the most pressing issue is reduction of the risk of acute pancreatitis.[5][52]​​ Statins alone cannot reduce TG levels in individuals with severe HTG, especially in the face of unmanaged secondary causes. Statins alone cannot prevent acute pancreatitis in individuals with severe HTG. Fibrates and possibly omega-3 fatty acids are the most effective current drug treatments to achieve this.[63][64]​​​ Once TG has been lowered well into the mild-to-moderate HTG range, ASCVD risk reduction (see above) can be subsequently considered.[2][11][58]​​ In patients with poorly controlled diabetes, optimising glycaemic control (e.g., with weight loss, metformin, sodium-glucose transporter-2 [SGLT2] inhibitors, glucagon-like peptide-1 [GLP-1] receptor agonists, or insulin) can be associated with dramatic improvements in TG levels, although the mechanism(s) underlying improvement are not directly in the lipoprotein metabolism pathway.[65]​ See Type 2 diabetes in adults.

To prevent acute pancreatitis, the AHA/ACC guidelines suggest it is reasonable to reduce TG levels in patients with TG >5.6 mmol/L (>500 mg/dL).[2] This reduction can be partially achieved by the above non-pharmacological approaches, implementing a very low-fat diet, and then by adding a fibrate and/or omega-3 fatty acids for patients with persistently severe HTG. These are the most reliable pharmacological therapies to reduce TG to a safer level. If a fibrate is necessary for a patient being treated with a statin, fenofibrate is safer than gemfibrozil, with a lower risk of statin-associated muscle complications, particularly severe myositis and rhabdomyolysis.[2]

The AHA/ACC recommends that in adults with severe HTG and ASCVD risk >7.5%, it is reasonable to re-evaluate ASCVD risk after lifestyle and secondary factors are addressed and to consider a persistently elevated TG level as a factor favouring initiation or intensification of statin therapy.[2] For those with a 10-year ASCVD risk 5% to <7.5% and persistent HTG, patient-clinician discussion is recommended regarding the initiation of moderate-intensity statin therapy.[2][9]

The AHA/ACC further recommends that in adults with TG ≥5.6 mmol/L (≥500 mg/dL), and especially fasting TG ≥11.3 mmol/L (≥1000 mg/dL), it is reasonable to further reduce TG by implementing a very low-fat diet, avoiding refined carbohydrates and alcohol, taking prescription omega-3 fatty acids, and, if necessary, fibrate therapy.[2][9]​ In individuals with TG ≥5.6 mmol/L (≥500 mg/dL), a ≥30% reduction in TG is possible with prescription omega-3 fatty acids.[62]​ One European regulatory review found that omega-3 ethyl esters, used in the treatment of hypertriglyceridaemia, are associated with a dose-dependent increased risk of AF.[66]

Severe or life-threatening HTG during pregnancy is best managed in consultation with a lipid specialist.[2][48]

Patients with acute pancreatitis due to chylomicronaemia should be admitted to hospital. They should have intravenous hydration and take nothing by mouth during the acute phase of illness (first 48-72 hours). Plasmapheresis or plasma exchange is generally not necessary because TG levels will fall with a half-life of 24-30 hours with cessation of oral intake and supportive care alone. Patients should then be transitioned to clear fluids, followed by a low-fat diet with advice for long-term lifestyle modification. Intravenous insulin infusion in patients with poorly controlled diabetes may help reduce TG levels. See Complications.

Once TG levels are <5 mmol/L (<440 mg/dL), LDL-cholesterol-lowering drugs such as statins can be commenced to achieve non-high-density lipoprotein (non-HDL) cholesterol target goals as recommended according to cardiac risk factor status. Optimal goal is TG <1.7 mmol/L (<150 mg/dL), but is typically not realistic. Fibrate therapy is recommended as prophylaxis against future pancreatitis episodes.[2][9]​ 

Use of this content is subject to our disclaimer