Guideline sources The following summarized guidelines for the evaluation and management of hypertriglyceridemia are prepared by our editorial team based on guidelines from the European Society of Cardiology (ESC/EAS 2020), the Endocrine Society (ES 2020; 2012), and the American College of Preventive Medicine (ACPM/ADA/PCNA/ABC/ASPC/AAPA/AGS/AHA/ACC/APhA 2019). 1 2 3 4 5 5 6 7 8 Definition Hypertriglyceridemia is defined as fasting triglycerides 150 mg/dL, which is associated with an increased risk for coronary heart disease. 5 Epidemiology Underlying pathophysiology occurs through abnormalities in hepatic VLDL production, and intestinal chylomicron synthesis; dysfunctional LPL-mediated lipolysis or impaired remnant clearance. Primary etiology includes genetic mutations (LPL, APOC3, APOA5 genes), while secondary etiologies may consist of obesity, metabolic syndrome, diabetes, alcohol use, renal disease, pregnancy, and nonalcoholic fatty liver disorder. 6 Pathophysiology https://web.pathway.md/diseases/recbmLpNwNZ6SlgPv 1/6 6/24/23, 12:45 PM Hypertriglyceridemia Pathway The prevalence of hypertriglyceridemia in the United States is estimated at 29% in men and 21% in women. 5 Disease course Clinical manifestations include eruptive cutaneous xanthomata, lipemia retinalis, tuberous xanthoma, palmar crease xanthomas, hepatosplenomegaly, focal neurologic symptoms (irritability), and recurrent epigastric pain with an increased risk of pancreatitis seen mostly with both familial chylomicronemia and primary mixed hyperlipidemia. Hypertriglyceridemia is associated with an increased risk of coronary heart disease, T2DM mellitus, and acute pancreatitis with a reduction in health-related quality of life. 7 Prognosis and risk of recurrence Hypertriglyceridemia with high (150-500 mg/dL) and very high levels (> 500 mg/dL) is associated with increased risk of all-cause mortality with hazard ratio of 1.49 (95% CI 1.36-1.63, p < 0.001) and 3.08 (95% CI 1.46-6.50, p < 0.01), respectively. 8 Guidelines 1. Screening and diagnosis Indications for screening: screen adults for hypertriglyceridemia with measurement of serum triglycerides as part of a lipid panel at least every 5 years. B Diagnosis: base the diagnosis of hypertriglyceridemia on fasting rather than nonfasting triglyceride levels. B 2. Diagnostic investigations Initial evaluation: evaluate patients with elevation of fasting triglycerides for secondary causes of hypertriglyceridemia, including endocrine conditions and medications. Focus treatment on such secondary causes. B Lipoprotein levels: Avoid routine measurement of lipoprotein particle heterogeneity in patients with hypertriglyceridemia. D Consider measuring ApoB or lipoprotein A levels, whereas measurement of other apolipoprotein levels has little clinical value. C 3. Medical management General principles: https://web.pathway.md/diseases/recbmLpNwNZ6SlgPv 2/6 6/24/23, 12:45 PM Hypertriglyceridemia Pathway As per ES 2020 guidelines, initiate pharmacologic treatment as adjunct to dietary modifications and exercise to prevent pancreatitis in adult patients with fasting triglyceride levels > 500 mg/dL (5.6 mmol/L). B As per AHA 2019 guidelines, address and treat lifestyle factors (such as obesity and metabolic syndrome), secondary factors (such as diabetes mellitus, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism), and medications that increase triglycerides in 20 years old adult patients with moderate hypertriglyceridemia (fasting or nonfasting triglycerides 175-499 mg/dL; 2.0-5.6 mmol/L). A Show 3 more As per ES 2012 guidelines: Target a non-HDL-C level in agreement with published guidelines in patients with moderate hypertriglyceridemia. B Consider initiating the following drug classes alone or in combination with statins as treatment options in patients with moderately to severely elevated triglyceride levels: fibrates niacin n-3 fatty acids. C Fibrates: As per ESC 2020 guidelines: Consider adding fenofibrate or bezafibrate to statins for primary prevention in patients with triglyceride levels of > 2.3 mmol/L (> 200 mg/dL) achieved LDL cholesterol goal. C Consider adding fenofibrate or bezafibrate to statins in high risk patients with triglyceride levels of > 2.3 mmol/L (> 200 mg/dL) achieved LDL cholesterol goal. C Updated evidence: PROMINENT In patients with T2DM, mild-to-moderate hypertriglyceridemia, and high-density lipoprotein cholesterol levels 40 mg/dL, pemafibrate was not superior to placebo with respect to the composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. Aruna Das Pradhan et al. N Engl J Med. 2022 Nov 24. As per AHA 2019 guidelines, consider initiating fibrates if necessary to prevent acute pancreatitis in adult patients with severe hypertriglyceridemia (fasting triglycerides 500 mg/dL; 5.7 mmol/L), especially with fasting triglycerides 1,000 mg/dL ( 11.3 mmol/L), if triglycerides are persistently elevated or increasing after addressing other causes of hypertriglyceridemia. C As per ES 2012 guidelines, initiate fibrates as first-line therapy to reduce triglycerides in patients at risk for triglyceride-induced pancreatitis. B Polyunsaturated fatty acids: https://web.pathway.md/diseases/recbmLpNwNZ6SlgPv 3/6 6/24/23, 12:45 PM Hypertriglyceridemia Pathway As per ES 2020 guidelines, consider adding n-3 PUFAs (icosapent ethyl 2 2 g/day) in high or very high risk patients with triglyceride levels of 1.5-5.6 mmol/L (135-499 mg/dL) despite statin treatment. C As per ES 2020 guidelines, consider adding eicosapentaenoic acid ethyl ester to reduce the risk of CVD in adult patients with moderate hypertriglyceridemia (> 150 mg/dL; > 1.7 mmol/L) on statins and with either ASCVD or diabetes plus 2 additional risk factors. C As per AHA 2019 guidelines, advise consuming omega-3 fatty acids in adult patients with severe hypertriglyceridemia (fasting triglycerides 500 mg/dL; 5.7 mmol/L), especially with fasting triglycerides 1,000 mg/dL ( 11.3 mmol/L), if triglycerides are persistently elevated or increasing after addressing other causes of hypertriglyceridemia. B Statins: As per ESC 2020 guidelines, initiate statins as first-line therapy to reduce cardiovascular risk in high risk patients with hypertriglyceridemia (triglyceride levels > 2.3 mmol/L; > 200 mg/dL). B As per AHA 2019 guidelines: Consider initiating statin therapy in 40-75 years old adult patients with severe hypertriglyceridemia (fasting triglycerides 500 mg/dL; 5.6 mmol/L) and ASCVD risk of 7.5%. C Consider intensifying statin therapy in 40-75 years old adult patients with moderate-to-severe hypertriglyceridemia and ASCVD risk of 7.5% if triglyceride levels are persistently elevated despite addressing lifestyle and secondary factors. C As per ES 2012 guidelines: Avoid using statins as monotherapy in patients with severe or very severe hypertriglyceridemia. D Consider initiating statins for the treatment of patients with moderate hypertriglyceridemia, when indicated to modify the cardiovascular risks. B Bile acid sequestrants: consider measuring triglyceride levels before and after starting a bile acid sequestrant in patients with elevated triglycerides (> 150-499 mg/dL; 1.7-5.6 mmol/L). C 4. Nonpharmacologic interventions Lifestyle modification: As per AHA 2019 guidelines, advise implementing a very low-fat diet, avoiding refined carbohydrates and alcohol in adult patients with severe hypertriglyceridemia (fasting triglycerides 500 mg/dL; 5.7 mmol/L), especially with fasting triglycerides 1,000 mg/dL ( 11.3 mmol/L), if triglycerides are persistently elevated or increasing after addressing other causes of hypertriglyceridemia. B As per ES 2012 guidelines, advise dietary modification, physical activity, and weight reduction programs as first-line therapy in overweight and obese patients with mild-to-moderate hypertriglyceridemia. B https://web.pathway.md/diseases/recbmLpNwNZ6SlgPv 4/6 6/24/23, 12:45 PM Hypertriglyceridemia Pathway 5. Specific circumstances Patients with triglyceride-induced pancreatitis: Avoid performing acute plasmapheresis as first-line therapy to reduce triglyceride levels in patients with triglyceride-induced pancreatitis. D Avoid administering routine insulin infusion in patients with triglyceride-induced pancreatitis not having diabetes. D References 1. Lars Berglund, John D. Brunzell, Anne C. Goldberg et al. Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2012 Sep; 97 9 2969 2989. Open 2. Fran ois Mach, Colin Baigent, Alberico L Catapano et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020 Jan 1;41 1 111 188. Open 3. Connie B Newman, Michael J Blaha, Jeffrey B Boord et al. Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2020 Dec 1;105 12):dgaa674. Open 4. Scott M Grundy, Neil J Stone, Alison L Bailey et al. 2018 AHA/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. Circulation. 2019 Jun 18;139 25):e1082-e1143. Open 5. Wenjun Fan, Sephy Philip, Craig Granowitz et al. Hypertriglyceridemia in statin-treated US adults: the National Health and Nutrition Examination Survey. Jan-Feb 2019;13 1 100 108.Jan-Feb 2019;13 1 100 108. Open 6. H C Hassing, R P Surendran, H L Mooij et al. Pathophysiology of hypertriglyceridemia. 2012 May;1821 5 826 32.2012 May;1821 5 826 32. Open 7. George Yuan, Khalid Z Al-Shali, Robert A Hegele. Hypertriglyceridemia: its etiology, effects and treatment. 2007 Apr 10;176 8 1113 20.2007 Apr 10;176 8 1113 20. Open 8. Marcello Arca, Chiara Veronesi, Laura D'Erasmo et al. Association of Hypertriglyceridemia with All-Cause Mortality and Atherosclerotic Cardiovascular Events in a Low-Risk Italian Population: The TG REAL Retrospective Cohort Analysis. 2020 Oct 20;9 19):e015801.2020 Oct 20;9 19):e015801. Open 9. Ann C Skulas-Ray, Peter W F Wilson, William S Harris et al. Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association. Circulation. 2019 Sep 17;140 12):e673-e691. Open 10. Mahya Faghih, Vikesh K Singh. Do Elevated Triglycerides Truly Trigger Acute Pancreatitis?. Dig Dis Sci. 2019 Mar;64 3 616 618. Open 11. Susan Xiaoqin Lin, Mercedes Carnethon, Moyses Szklo et al. Racial/ethnic differences in the association of triglycerides with other metabolic syndrome components: the Multi-Ethnic Study of Atherosclerosis. Metab Syndr Relat Disord. 2011 Feb;9 1 35 40. Open https://web.pathway.md/diseases/recbmLpNwNZ6SlgPv 5/6 6/24/23, 12:45 PM Hypertriglyceridemia Pathway 12. Wenjun Fan, Sephy Philip, Craig Granowitz et al. Hypertriglyceridemia in statin-treated US adults: the National Health and Nutrition Examination Survey. J Clin Lipidol. Jan-Feb 2019;13 1 100 108. Open 13. Margaret D Carroll, David A Lacher, Paul D Sorlie et al. Trends in serum lipids and lipoproteins of adults, 1960 2002. JAMA. 2005 Oct 12;294 14 1773 81. Open 14. Lauren Elizabeth Kleess, Natasa Janicic. SEVERE HYPERTRIGLYCERIDEMIA IN PREGNANCY A CASE REPORT AND REVIEW OF THE LITERATURE. AACE Clin Case Rep. 2018 Oct 5;5 2):e99-e103. Open 15. George Yuan, Khalid Z Al-Shali, Robert A Hegele. Hypertriglyceridemia: its etiology, effects and treatment. CMA. 2007 Apr 10;176 8 1113 20. Open 16. Sujani Poonuru, Sumedha R Pathak, Hemender S Vats et al. Rapid reduction of severely elevated serum triglycerides with insulin infusion, gemfibrozil and niacin. Clin Med Res. 2011 Mar;9 1 38 41. Open 17. Bertha Wong, Teik C Ooi, Erin Keely. Severe gestational hypertriglyceridemia: A practical approach for clinicians. Obstet Med. 2015 Dec;8 4 158 67. Open 18. Klaus G Parhofer, Ulrich Laufs. The Diagnosis and Treatment of Hypertriglyceridemia. Dtsch Arztebl Int. 2019 Dec 6;116 49 825 832. Open 19. Marcello Arca, Chiara Veronesi, Laura D'Erasmo et al. Association of Hypertriglyceridemia with All- Cause Mortality and Atherosclerotic Cardiovascular Events in a Low-Risk Italian Population: The TG REAL Retrospective Cohort Analysis. J Am Heart Assoc. 2020 Oct 20;9 19):e015801. Open https://web.pathway.md/diseases/recbmLpNwNZ6SlgPv 6/6