The following are key points to remember from this American College of Cardiology (ACC) Expert Consensus Decision Pathway on the management of atherosclerotic cardiovascular disease (ASCVD) risk reduction in patients with persistent hypertriglyceridemia:

1. Elevated triglycerides (TGs) are one of the risk-enhancing factors identified by the 2018 American Heart Association (AHA)/ACC cholesterol guideline, which used the Pooled Cohort Equation to estimate 10-year ASCVD risk in primary prevention. This ACC consensus recommendation (for adults ≥20 years old) emphasizes the necessary lifestyle interventions for hypertriglyceridemia and the use of statins and TG risk-based nonstatin therapies for ASCVD risk reduction in persistent hypertriglyceridemia for: 1) established ASCVD, 2) diabetes as an additional risk factor, 3) high-risk primary prevention, and 4) severe hypertriglyceridemia.
2. Despite the use of statin therapy, ASCVD event rates remain high in patients with elevated TGs. Epidemiological and Mendelian randomization studies suggest a causal role of elevated TG in atherosclerosis due to an increase in highly atherogenic cholesterol-rich remnant particles (very low-density lipoprotein [VLDL]-remnants), which are associated with a decrease in high-density lipoprotein cholesterol (HDL-C) and increase in small dense LDL particles.
3. TG elevation is defined as mild to moderate when fasting is ≥150 mg/dl or nonfasting is ≥175 mg/dl to <500 mg/dl, and severe as ≥500 mg/dl and especially ≥1000 mg/dl. Persistent hypertriglyceridemia is defined as ≥175 mg/dl after a minimum of 4-12 weeks of lifestyle intervention on a stable dose of maximally tolerated statins when indicated, and management of secondary causes. Use of risk-based nonstatin therapy is based on ≥2 measures of fasting lipids ≥2 weeks apart. Fasting lipids are also necessary to diagnose the metabolic syndrome; identify lipid disorders without ASCVD in persons with a family history of premature ASCVD or genetic lipid disorders; assess effects of and adherence to recommended lifestyle and lipid-lowering medication; and identify persons with TG ≥500 mg/dl who are at risk for pancreatitis, and monitor response to therapy. Levels >1000 mg/dl are associated with chylomicronemia, which when >1500 mg/dl, is often associated with the chylomicronemia syndrome including eruptive xanthomas, lipemia retinalis, and pancreatitis. The most common trigger is a secondary cause in the setting of a genetic cause of hypertriglyceridemia known as multifactorial chylomicronemia syndrome, while much less common are familial chylomicronemia syndrome and familial partial lipodystrophy. It is important that these be clarified considering treatment is markedly different for each.
4. An excellent table provides the list of secondary causes of hypertriglyceridemia (see Table 1 in the document). Each of them can result in or increase the severity of hypertriglyceridemia in genetic or familial lipid disorders. Among the common causes include diabetes, chronic kidney disease, metabolic syndrome/obesity, pregnancy, and chronic inflammatory diseases; alcohol and diets high in saturated fat; and high-glycemic index foods. Medications include beta-blockers, diuretics, bile resins, steroids, estrogens, HIV protease inhibitors, tamoxifen, cyclophosphamide, and immunosuppressives.
5. Lifestyle intervention and control of secondary causes are the foundation of management of patients with hypertriglyceridemia. Referral to a registered dietitian is necessary to educate patients on the heart-healthy diet, exercise (moderate 150 minutes/week or vigorous 75 minutes/week), and weight control (5-10% loss), and provide individualized recommendations for hypertriglyceridemia. Alcohol should be limited and eliminated when triglycerides are markedly elevated. The diet requirement for severe hypertriglyceridemia (limiting all fats to ≤20-30 g) differs markedly from moderate hypertriglyceridemia (low saturated fat with 30-35% fat calories, high protein intake, and marked limiting of foods with high glycemic index particularly fructose and starches).
6. Prior to considering TG levels, the guideline stresses the use of LDL-C–based therapy for primary prevention following the ACC/AHA cholesterol guidelines and secondary prevention in ASCVD. The following are recommended:
   • In adults without ASCVD or diabetes, there is no indication for nonstatin TG-lowering treatment in mild to moderately elevated TGs (>150-<500 mg/dl).
   • In adults 20-39 years old with persistent fasting TGs 500-999 mg/dl, emphasize low-fat diet and consider fenofibrate or prescribed omega-3 fatty acids (OM-3FAs) to reduce risk of pancreatitis. In those 40-75 years old with 10-year risk of ≥5%, ASCVD, or diabetes, initiate or intensify statins, emphasize low-fat or very low-fat diet, and consider fenofibrate or prescription OM-3FA (icosapent ethyl [IPE] or omega-3 acid ethyl esters) to reduce risk of pancreatitis.
   • For TGs ≥1000 mg/dl, implement very low-fat diet (10-15% of calories, ≤20-30 g, consider <5% until TGs are <1000 mg/dl (chylomicron clearing diet). Treat hyperglycemia and re-evaluate TGs. Begin prescription OM-3FA and consider fenofibrate but not gemfibrozil if statins are used, and consider potential of fibrate–statin drug interaction.
7. TG risk-based therapies including fibrates and prescription grade OM-3FA have been useful for severe hypertriglyceridemia, but until recently, were of little value for reducing risk and prevention of ASCVD. Prescription grade OM-3FA includes mixtures of EPA and DHA as ethyl esters and carboxylic acids and purified EPA (IPE); 2 g twice daily of available OM-3FA reduces high TGs by about 30%. Clinical trials have not shown a benefit for primary or secondary prevention of ASCVD by low-dose OM-3FA, whether combined with statins in healthy persons or diabetics. However, two outcome trials with EPA alone showed a reduction in major CV events.
   • The JELIS trial, conducted in Japan with 1.8 g of EPA as an ethyl ester in patients with cholesterol >250 mg/dl on a low-intensity statin in whom the baseline EPA was high because of a high fish diet, found the benefit was primarily when TGs were ≥150 mg/dl and HDL-C was low.
   • The REDUCE-IT trial was designed to confirm the JELIS trial using IPE compared to placebo in about 8,000 persons with prespecified groups and elevated TGs on statins (93%); 71% were secondary prevention with age ≥45 years and 29% primary prevention in diabetes with age ≥50 years and ≥1 other CV risk factor. LDL-C ranged from 41-100 mg/dl and TGs 135-499 mg/dl with median level of TGs 216 mg/dl in both groups. Baseline EPA was 26 µg/ml compared to JELIS 95 mg/L. Patients were randomized to 2 g IPE twice daily versus mineral oil placebo. Primary composite endpoint of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or unstable angina was reduced by 25% over a follow-up of 4.9 years with a number needed to treat of 21; similarly, secondary endpoints were defined as hard events as well as individual endpoints including CV mortality. The risk of atrial fibrillation was significantly higher with IPE than placebo (5.3% vs 3.9%), as was bleeding-related serious events (2.7% vs. 2.1%). TGs were reduced by about 20% more with IPE than placebo at 1 year. A relative increase of 5 mg/dl in LDL-C and non–HDL-C of about 16 mg/dl were predominantly related to the placebo group. The event reduction was associated with the marked rise in EPA (26-144 µg/ml), but not the change in TGs from baseline or on-treatment.
   • The EVAPORATE study was conducted to assess the effect of IPE versus placebo on progression of coronary atherosclerosis using computed tomography over an 18-month period. The IPE group showed a significant difference in plaque as well as fibrosis and fibrofatty volumes without significant differences in lipid levels between groups.
   • The STRENGTH trial, with a similar design, failed to show a benefit of combination EPA + DHA; 13,000 men and women were randomized to 4 g of OM-3 carboxylic acid (550 mg EPA and 200 mg DHA) versus 4 g corn oil. The trial was halted because of futility when 1,384 subjects had reached the primary endpoint.
   • Considerations for the different results from REDUCE-IT included the value of very high levels of EPA, the ethyl ester pure EPA versus the carboxylic acid for the EPA + DHA, a negative effect of DHA, and possible adverse effects of a mineral oil placebo in REDUCE-IT, which is unlikely, based on the magnitude of benefit.
8. Fibrates have been shown to be of benefit as monotherapy but not combined with statins.
   • The impressive VA-HIT trial of gemfibrozil versus placebo in coronary heart disease prior to the statin era found a significant 32% reduction in death or nonfatal MI, mortality by 41%, and stroke by 40%. The benefit was not attributable to changes in HDL-C or TGs.
   • In the ACCORD study of fenofibrate in diabetics on 40 mg simvastatin with a median TG of 162 mg/dl, there was no benefit of fenofibrate in the primary outcome of hard CV events, but with a possible benefit in those with a high baseline TG and low HDL-C.
   • The FIELD study of nearly 10,000 patients with type 2 diabetes mellitus not on statins were randomized to fenofibrate or placebo. There was no significant reduction in coronary events but a reduction in nonfatal MI. Fenofibrate was associated with less microvascular complications including microalbuminuria and retinopathy. The use of nonstudy statins resulted in a significant attenuation of the differences in lipids.
   • A promising study of the novel pemafibrate (selective PPAR alpha modulator) in high-risk diabetes patients with mild to moderate elevation of TGs and optimal treatment, will be completed in mid 2022.
9. The guidelines stress the use of high-dose prescription OM-3FA and not over-the-counter fish oil for hypertriglyceridemia, and pure EPA as IPE for reducing CV events in ASCVD and diabetes with persistently elevated mild to moderately elevated TGs.

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

Keywords: Atherosclerosis, Blood Glucose, Cholesterol, HDL, Cholesterol, LDL, Diabetes Mellitus, Type 2, Diet, Drug Therapy, Dyslipidemias, Exercise, Fatty Acids, Omega-3, Fenofibrate, Fibric Acids, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type I, Life Style, Lipids, Lipoproteins, Metabolic Syndrome, Myocardial Infarction, Pancreatitis, Primary Prevention, Risk Reduction Behavior, Risk Factors, Secondary Prevention, Stroke, Therapeutics, Triglycerides, Vascular Diseases

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