Extreme hypertriglyceridemia: frequency of occurrence, clinical aspects, and efficacy of different therapeutic approaches

Aim. To evaluate the prevalence, clinical features, and effectiveness of various lipid-lowering therapy (LLT) regimens in patients with extreme hypertriglyceridemia (EHTG).
Material and methods. A retrospective analysis of a database comprising 170,640 patients from a cardiology inpatient unit and outpatient clinics was conducted (2018-2024) to identify cases of EHTG. The study included 155 patients with triglyceride (TG) levels exceeding 10 mmol/L. Twenty-three patients receiving cascade plasmafiltration were excluded from the analysis of pharmacological therapy effectivenesse. The final analysis of the efficacy of various LLT regimens was performed in 114 patients with maintained treatment adherence. Clinical characteristics, lipid profiles, over a follow-up period of at least 12 months were assessed.
Results. The prevalence of EHTG was 0.1%. The median age of patients was 50 [43-59] years, with 62% being men. The frequency of risk factors was as follows: obesity (58%), arterial hypertension (64%), type 2 diabetes mellitus (44%), and smoking (41%). A history of acute pancreatitis was present in 41% of patients, and pancreatic necrosis in 18%. Coronary artery disease was diagnosed in 56% of patients, with its onset preceding hyperlipidemic therapy (HLT) in 92% of cases. Atherosclerosis of carotid and lower limb arteries was detected in 52% and 55% of patients, respectively. Initially, there was a significant elevation in triglyceride levels (13.1 [11.3-26.4] mmol/L), while high-density lipoprotein cholesterol levels were low (0.8 [0.6–0.9] mmol/L). LLT resulted in a threefold reduction of TG levels to 4.2 [2.9–6.0] mmol/L. The highest treatment effectiveness was observed with a combination of fibrates, statins, and omega-3 polyunsaturated fatty acids (PUFAs), resulting in a 79.3% reduction in triglycerides; this was followed by a combination of fibrates with omega-3 PUFAs (71.5%). The smallest triglyceride reduction was recorded with statin monotherapy (51.6%). An analysis of the various regimens effectiveness also highlighted the importance of dietary adherence and lifestyle modification for achieving optimal results. A significant reduction in TG levels was revealed with combination therapy compared to monotherapy or no treatment.
Conclusion. EHTG is a rare condition (0.1%) but is associated with a high frequency of pancreatitis and atherosclerotic lesions. Combination therapy including fibrates, statins, and omega-3 PUFAs demonstrates the highest effectiveness in reducing TG levels.

1. Berglund L, Brunzell JD, Goldberg AC, et al.; Endocrine society. Evaluation and treatment of hypertriglyceridemia: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(9):2969-89. DOI: 10.1210/jc.2011-3213. Erratum in: J Clin Endocrinol Metab. 2015;100(12):4685. DOI:10.1210/jc.2015-3649.

2. Miller M, Stone NJ, Ballantyne C, et al.; American Heart Association Clinical Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Nursing; Council on the Kidney in Cardiovascular Disease. Triglycerides and cardiovascular disease: а scientific statement from the American Heart Association. Circulation. 2011;123(20):2292-333. DOI:10.1161/CIR.0b013e3182160726.

3. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet. 2014;384(9943):626-35. DOI:10.1016/s0140-6736(14)61177-6.

4. Hegele RA, Ginsberg HN, Chapman MJ, et al.; European Atherosclerosis Society Consensus Panel. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014;2(8):655-66. DOI:10.1016/s2213-8587(13)70191-8.

5. Valdivielso P, Ramírez-Bueno A, Ewald N. Current knowledge of hypertriglyceridemic pancreatitis. Eur J Intern Med. 2014;25(8):689-94. DOI:10.1016/j.ejim.2014.08.008.

6. Chubykina UV, Ezhov MV, Sokolov AA, et al. Russian extreme hypertriglyceridemia registy (REGGI): a call to action. Rational Pharmacotherapy in Cardiology. 2024;20(5):566-73 (In Russ.)

7. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 western prospective studies. Circulation. 2007;115(4):450-8. DOI:10.1161/circulationaha.106.637793.

8. Talayero BG, Sacks FM. The role of triglycerides in atherosclerosis. Curr Cardiol Rep. 2011;13(6):544-52. DOI:10.1007/s11886-011-0220-3.

9. Keech A, Simes RJ, Barter P, et al.; FIELD study investigators. Effects of longterm fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366(9500):1849-61. DOI:10.1016/s0140-6736(05)67667-2. Erratum in: Lancet. 2006;368(9545):1420. Erratum in: Lancet. 2006;368(9545):1415. DOI:10.1016/S0140-6736(06)69594-9.

10. Ginsberg HN. The ACCORD (Action to Control Cardiovascular Risk in Diabetes) Lipid trial: what we learn from subgroup analyses. Diabetes Care. 2011;34 Suppl 2(Suppl 2):S107-8. DOI:10.2337/dc11-s203.

11. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet. 2001;357(9260):905-10. Erratum in: Lancet 2001;357(9271):1890.

12. Bhatt DL, Steg PG, Miller M, et al.; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. DOI:10.1056/NEJMoa1812792.

13. Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA. 2020;324(22):2268-80. DOI:10.1001/jama.2020.22258.

14. Das Pradhan A, Glynn RJ, Fruchart JC, et al.; PROMINENT Investigators. Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk. N Engl J Med. 2022;387(21):1923-34. DOI:10.1056/NEJMoa2210645.

15. Ezhov MV, Batluk TI, Tokmin DS, et al. The significance of dyslipidemia before and during the COVID-19 pandemic. Analysis of a big laboratory dataset. Atherosclerosis and dyslipiemias. 2023;(2):31-42 (In Russ.)

16. Wiggins BS, Saseen JJ, Page RL, 2nd, et al.; American Heart Association Clinical Pharmacology Committee of the Council on Clinical Cardiology; Council on Hypertension; Council on Quality of Care and Outcomes Research; and Council on Functional Genomics and Translational Biology. Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease: A Scientific Statement From the American Heart Association. Recommendations for management of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease: A scientific statement from the american heart association. Circulation. 2016;134(21):e468-95. DOI:10.1161/cir.0000000000000456.

17. Bashir B, Ho JH, Downie P, et al. Severe Hypertriglyceridaemia and Chylomicronaemia Syndrome-Causes, Clinical Presentation, and Therapeutic Options. Metabolites. 2023;13(5):621. DOI:10.3390/metabo13050621.

18. Bashir B, Ferdousi M, Durrington P, et al. Pancreatic and cardiometabolic complications of severe hypertriglyceridaemia. Curr Opin Lipidol. 2024;35(4):208-18. DOI:10.1097/MOL.0000000000000939.

19. Gaudet D, Pall D, Watts GF, et al. Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia: The SHASTA-2 Randomized Clinical Trial. JAMA Cardiol. 2024;9(7):620-30. DOI:10.1001/jamacardio.2024.0959.

20. Ezhov MV, Kukharchuk VV, Sergienko IV, et al. Disorders of lipid metabolism. Clinical Guidelines 2023. Russian Journal of Cardiology. 2023;28(5):5471 (In Russ.)

21. Mach F, Baigent C, Catapano AL, et al.; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111-88. DOI:10.1093/eurheartj/ehz455.

22. Chubykina UV, Tyurina AV, Ezhov MV. The era of targeted therapy for hyperlipidemia. Russian Journal of Cardiology. 2024;29(8):6038 (In Russ.)