Diabetic dyslipidemia: focus on pathogenesis and treatment

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Prof. Zhuravlyova L.V., PHD Sokolnikova N.V., PHD Rogachova T.A.

Kharkiv National Medical University

Atherosclerotic cardiovascular diseases are the most common cause of death in the developed countries of the world. Patients with diabetes mellitus 2 type are 2-4 times more likely to die from these diseases compared to patients without diabetes. This review discusses the pathophysiology of lipid disorders, which are the main cause of cardiovascular disease in patients with diabetes mellitus 2 type, and the current approaches to the medical therapy of these disorders. Obesity, metabolic syndrome, and diabetes mellitus 2 type are characterized by insulin resistance, which leads to excessive lipolysis of visceral adipose tissue. The consequence of this disorder is the excessive production of free fatty acids, which become the source for excessive synthesis of proatherogenic lipoproteins saturated with triglycerides. These lipid profile abnormalities are the main pathogenetic link between diabetes and increased risk of atherosclerosis. Chronically elevated levels of free fatty acids reduce insulin synthesis, glucose-stimulated insulin secretion, and β-cell sensitivity to glucose, resulting in a very high risk of developing diabetes mellitus 2 type. Numerous factors contribute to elevated plasma free fatty acid levels and subsequent impairment of metabolic health, such as unhealthy diet, obesity, low physical activity, obstructive sleep apnea, sleep deprivation, and smoking. Currently, lifestyle changes are the best tool for long-term normalization of the concentration of free fatty acids in the blood plasma. The results of modern research have proven that a healthy lifestyle and glycemic control, treatment with statins, ezetimibe, and hypoglycemic drugs improve the lipid profile, reduce insulin resistance and inflammation, which reduces the risk of cardiovascular diseases.

Key words: insulin resistance, type 2 diabetes, free fatty acids, inflammation

https://dx.doi.org/10.15407/internalmed2022.02.049

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Для цитування:

  1. Журавльова, Л.В. Діабетична дисліпідемія: фокус на патогенез і лікування / Л.В. Журавльова, Н.В. Сокольнікова, Т.А. Рогачова // Східноєвропейський журнал внутрішньої та сімейної медицини. – 2022. – № 2. – С. 49-57. doi: 15407/internalmed2022.02.049
  2. Zhuravlyova LV, Sokolnikova NV, Rogachova TA. [Diabetic dyslipidemia: focus on pathogenesis and treatment]. Shidnoevr. z. vnutr. simejnoi med. 2022;2:49-57. Ukrainian. doi: 10.15407/internalmed2022.02.049

References

  1. Stefanovski D, Punjabi N, Boston R, Watanabe R. Insulin Action, Glucose Homeostasis and Free Fatty Acid Metabolism: Insights From a Novel Model. Frontiers in Endocrinology. 2021;12:. http://dx.doi.org/10.3389/fendo.2021.625701
  2. Chueire V, Muscelli E. Effect of free fatty acids on insulin secretion, insulin sensitivity and incretin effect – a narrative review. Archives of Endocrinology and Metabolism. 2020;:. http://dx.doi.org/10.20945/2359-3997000000313
  3. Xin Y, Wang Y, Chi J, Zhu X, Zhao H, Zhao S, Wang Y. Elevated free fatty acid level is associated with insulin-resistant state in nondiabetic Chinese people. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2019;Volume 12:139-147. http://dx.doi.org/10.2147/dmso.s186505
  4. Newsholme E, Dimitriadis G. Integration of biochemical and physiologic effects of insulin on glucose metabolism. Experimental and Clinical Endocrinology & Diabetes. 2001;109(Suppl 2):S122-S134. http://dx.doi.org/10.1055/s-2001-18575
  5. Sears B, Perry M. The role of fatty acids in insulin resistance. Lipids in Health and Disease. 2015;14(1):. http://dx.doi.org/10.1186/s12944-015-0123-1
  6. Welsh P, Grassia G, Botha S, Sattar N, Maffia P. Targeting inflammation to reduce cardiovascular disease risk: a realistic clinical prospect?. British Journal of Pharmacology. 2017;174(22):3898-3913. http://dx.doi.org/10.1111/bph.13818
  7. Moore K. Targeting inflammation in CVD: advances and challenges. Nature Reviews Cardiology. 2018;16(2):74-75. http://dx.doi.org/10.1038/s41569-018-0144-3
  8. Ridker P. Clinician’s Guide to Reducing Inflammation to Reduce Atherothrombotic Risk. Journal of the American College of Cardiology. 2018;72(25):3320-3331. http://dx.doi.org/10.1016/j.jacc.2018.06.082
  9. Sharif S, Van der Graaf Y, Cramer M, Kapelle L, de Borst G, Visseren F, Westerink J, van Petersen R, Dinther B, Algra A, van der Graaf Y, Grobbee D, Rutten G, Visseren F, de Borst G, Kappelle L, Leiner T, Nathoe H. Low-grade inflammation as a risk factor for cardiovascular events and all-cause mortality in patients with type 2 diabetes. Cardiovascular Diabetology. 2021;20(1):. http://dx.doi.org/10.1186/s12933-021-01409-0
  10. Aday A, Ridker P. Targeting Residual Inflammatory Risk: A Shifting Paradigm for Atherosclerotic Disease. Frontiers in Cardiovascular Medicine. 2019;6:. http://dx.doi.org/10.3389/fcvm.2019.00016
  11. Ridker P. From C-Reactive Protein to Interleukin-6 to Interleukin-1. Circulation Research. 2016;118(1):145-156. http://dx.doi.org/10.1161/circresaha.115.306656
  12. Lorey M, Öörni K, Kovanen P. Modified Lipoproteins Induce Arterial Wall Inflammation During Atherogenesis. Frontiers in Cardiovascular Medicine. 2022;9:. http://dx.doi.org/10.3389/fcvm.2022.841545
  13. Doran A. Inflammation Resolution: Implications for Atherosclerosis. Circulation Research. 2022;130(1):130-148. http://dx.doi.org/10.1161/circresaha.121.319822
  14. Hirano T. Pathophysiology of Diabetic Dyslipidemia. Journal of Atherosclerosis and Thrombosis. 2018;25(9):771-782. http://dx.doi.org/10.5551/jat.rv17023
  15. Ye X, Kong W, Zafar M, Chen L. Serum triglycerides as a risk factor for cardiovascular diseases in type 2 diabetes mellitus: a systematic review and meta-analysis of prospective studies. Cardiovascular Diabetology. 2019;18(1):. http://dx.doi.org/10.1186/s12933-019-0851-z
  16. American Diabetes Association. Standards of Medical Care in Diabetes—2022 Abridged for Primary Care Providers. Clin Diabetes. 2022; 40 (1): 10–38.
  17. Stahel P, Xiao C, Nahmias A, Lewis G. Role of the Gut in Diabetic Dyslipidemia. Frontiers in Endocrinology. 2020;11:. http://dx.doi.org/10.3389/fendo.2020.00116
  18. Arpón A, Santos J, Milagro F, Cataldo L, Bravo C, Riezu-Boj J, Martínez J. Insulin Sensitivity Is Associated with Lipoprotein Lipase (LPL) and Catenin Delta 2 (CTNND2) DNA Methylation in Peripheral White Blood Cells in Non-Diabetic Young Women. International Journal of Molecular Sciences. 2019;20(12):2928. http://dx.doi.org/10.3390/ijms20122928
  19. Malhotra P, Boddy C, Dudeja A, Saksena S, Dudeja P, Gill R, Alrefai W. D-Glucose Increases Intestinal Niemann-Pick C1 Like 1 (NPC1L1) Gene Expression via Transcriptional Regulation. Gastroenterology. 2011;140(5):S-658-S-659. http://dx.doi.org/10.1016/s0016-5085(11)62731-5
  20. Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World Journal of Diabetes. 2015;6(3):456. http://dx.doi.org/10.4239/wjd.v6.i3.456
  21. Park K, Steffes M, Lee D, Himes J, Jacobs D. Association of inflammation with worsening HOMA-insulin resistance. Diabetologia. 2009;52(11):2337-2344. http://dx.doi.org/10.1007/s00125-009-1486-5
  22. Lee S, Kim H, Park Y, Kwon H, Yoon K, Han K, Kim M. HDL-Cholesterol, Its Variability, and the Risk of Diabetes: A Nationwide Population-Based Study. The Journal of Clinical Endocrinology & Metabolism. 2019;104(11):5633-5641. http://dx.doi.org/10.1210/jc.2019-01080
  23. Femlak M, Gluba-Brzózka A, Ciałkowska-Rysz A, Rysz J. The role and function of HDL in patients with diabetes mellitus and the related cardiovascular risk. Lipids in Health and Disease. 2017;16(1):. http://dx.doi.org/10.1186/s12944-017-0594-3
  24. Xepapadaki E, Nikdima I, Sagiadinou E, Zvintzou E, Kypreos K. HDL and type 2 diabetes: the chicken or the egg?. Diabetologia. 2021;64(9):1917-1926. http://dx.doi.org/10.1007/s00125-021-05509-0
  25. Cochran B, Ong K, Manandhar B, Rye K. High Density Lipoproteins and Diabetes. Cells. 2021;10(4):850. http://dx.doi.org/10.3390/cells10040850
  26. Russo G, Piscitelli P, Giandalia A, Viazzi F, Pontremoli R, Fioretto P, De Cosmo S. Atherogenic dyslipidemia and diabetic nephropathy. Journal of Nephrology. 2020;33(5):1001-1008. http://dx.doi.org/10.1007/s40620-020-00739-8
  27. Arnold N, Lechner K, Waldeyer C, Shapiro M, Koenig W. Inflammation and Cardiovascular Disease: The Future. European Cardiology Review. 2021;16:. http://dx.doi.org/10.15420/ecr.2020.50
  28. Suiter C, Singha S, Khalili R, Shariat-Madar Z. Free Fatty Acids: Circulating Contributors of Metabolic Syndrome. Cardiovascular & Hematological Agents in Medicinal Chemistry. 2018;16(1):20-34. http://dx.doi.org/10.2174/1871525716666180528100002
  29. Boden G. Effects of Free Fatty Acids (FFA) on Glucose Metabolism: Significance for Insulin Resistance and Type 2 Diabetes. Experimental and Clinical Endocrinology & Diabetes. 2003;111(03):121-124. http://dx.doi.org/10.1055/s-2003-39781
  30. Samuel V, Shulman G. Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases. Cell Metabolism. 2018;27(1):22-41. http://dx.doi.org/10.1016/j.cmet.2017.08.002
  31. Hagman E, Besor O, Hershkop K, Santoro N, Pierpont B, Mata M, Caprio S, Weiss R. Relation of the degree of obesity in childhood to adipose tissue insulin resistance. Acta Diabetologica. 2019;56(2):219-226. http://dx.doi.org/10.1007/s00592-018-01285-3
  32. Rider O, Holloway C, Emmanuel Y, Bloch E, Clarke K, Neubauer S. Increasing Plasma Free Fatty Acids in Healthy Subjects Induces Aortic Distensibility Changes Seen in Obesity. Circulation: Cardiovascular Imaging. 2012;5(3):367-375. http://dx.doi.org/10.1161/circimaging.111.971804
  33. Høgild M, Gudiksen A, Pilegaard H, Stødkilde‐Jørgensen H, Pedersen S, Møller N, Jørgensen J, Jessen N. Redundancy in regulation of lipid accumulation in skeletal muscle during prolonged fasting in obese men. Physiological Reports. 2019;7(21):. http://dx.doi.org/10.14814/phy2.14285
  34. Smart N, King N, McFarlane J, Graham P, Dieberg G. Effect of exercise training on liver function in adults who are overweight or exhibit fatty liver disease: a systematic review and meta-analysis. British Journal of Sports Medicine. 2016;52(13):834-843. http://dx.doi.org/10.1136/bjsports-2016-096197
  35. Borel A. Sleep Apnea and Sleep Habits: Relationships with Metabolic Syndrome. Nutrients. 2019;11(11):2628. http://dx.doi.org/10.3390/nu11112628
  36. Zhu B, Shi C, Park C, Zhao X, Reutrakul S. Effects of sleep restriction on metabolism-related parameters in healthy adults: A comprehensive review and meta-analysis of randomized controlled trials. Sleep Medicine Reviews. 2019;45:18-30. http://dx.doi.org/10.1016/j.smrv.2019.02.002
  37. Haj Mouhamed D, Ezzaher A, Hellara I, Neffati F, Douki W, Gaha L, Najjar M. 1980 – Effect of cigarette smoking on insulin resistance risk. European Psychiatry. 2013;28:1. http://dx.doi.org/10.1016/s0924-9338(13)76917-7
  38. Rincón, Krook, Galuska, Wallberg-Henriksson, Zierath. Altered skeletal muscle glucose transport and blood lipid levels in habitual cigarette smokers. Clinical Physiology. 1999;19(2):135-142. http://dx.doi.org/10.1046/j.1365-2281.1999.00161.x
  39. Rao M, Neylan T, Grunfeld C, Mulligan K, Schambelan M, Schwarz J. Subchronic Sleep Restriction Causes Tissue-Specific Insulin Resistance. The Journal of Clinical Endocrinology & Metabolism. 2015;100(4):1664-1671. http://dx.doi.org/10.1210/jc.2014-3911
  40. Egan B, Greene E, Goodfriend T. Nonesterified fatty acids in blood pressure control and cardiovascular complications. Current Hypertension Reports. 2001;3(2):107-116. http://dx.doi.org/10.1007/s11906-001-0021-y
  41. Henderson G. Plasma Free Fatty Acid Concentration as a Modifiable Risk Factor for Metabolic Disease. Nutrients. 2021;13(8):2590. http://dx.doi.org/10.3390/nu13082590
  42. MacDonald P, El-kholy W, Riedel M, Salapatek A, Light P, Wheeler M. The Multiple Actions of GLP-1 on the Process of Glucose-Stimulated Insulin Secretion. Diabetes. 2002;51(suppl_3):S434-S442. http://dx.doi.org/10.2337/diabetes.51.2007.s434
  43. Taskinen M, Björnson E, Matikainen N, Söderlund S, Pietiläinen K, Ainola M, Hakkarainen A, Lundbom N, Fuchs J, Thorsell A, Andersson L, Adiels M, Packard C, Borén J. Effects of liraglutide on the metabolism of triglyceride‐rich lipoproteins in type 2 diabetes. Diabetes, Obesity and Metabolism. 2021;23(5):1191-1201. http://dx.doi.org/10.1111/dom.14328
  44. Colhoun H, Betteridge D, Durrington P, Hitman G, Neil H, Livingstone S. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685–696. doi: 10.1016/S0140-6736(04)16895-5.
  45. Kandelouei T, Abbasifard M, Imani D, Aslani S, Razi B, Fasihi M, Shafiekhani S, Mohammadi K, Jamialahmadi T, Reiner Ž, Sahebkar A. Effect of Statins on Serum level of hs-CRP and CRP in Patients with Cardiovascular Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Mediators of Inflammation. 2022;2022:1-20. http://dx.doi.org/10.1155/2022/8732360
  46. Shakour N, Ruscica M, Hadizadeh F, Cirtori C, Banach M, Jamialahmadi T, Sahebkar A. Statins and C-reactive protein: in silico evidence on direct interaction. Archives of Medical Science. 2020;16(6):1432-1439. http://dx.doi.org/10.5114/aoms.2020.100304
  47. Momtazi-Borojeni A, Sabouri-Rad S, Gotto A, Pirro M, Banach M, Awan Z, Barreto G, Sahebkar A. PCSK9 and inflammation: a review of experimental and clinical evidence. European Heart Journal – Cardiovascular Pharmacotherapy. 2019;5(4):237-245. http://dx.doi.org/10.1093/ehjcvp/pvz022
  48. Everett B, MacFadyen J, Thuren T, Libby P, Glynn R, Ridker P. Inhibition of Interleukin-1β and Reduction in Atherothrombotic Cardiovascular Events in the CANTOS Trial. Journal of the American College of Cardiology. 2020;76(14):1660-1670. http://dx.doi.org/10.1016/j.jacc.2020.08.011
  49. Pradhan A, Paynter N, Everett B, Glynn R, Amarenco P, Elam M, Ginsberg H, Hiatt W, Ishibashi S, Koenig W, Nordestgaard B, Fruchart J, Libby P, Ridker P. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. American Heart Journal. 2018;206:80-93. http://dx.doi.org/10.1016/j.ahj.2018.09.011
  50. Szymczak-Pajor I, Wenclewska S, Śliwińska A. Metabolic Action of Metformin. Pharmaceuticals. 2022;15(7):810. http://dx.doi.org/10.3390/ph15070810
  51. Sato D, Morino K, Ogaku S, Tsuji A, Nishimura K, Sekine O, Ugi S, Maegawa H. Efficacy of metformin on postprandial plasma triglyceride concentration by administration timing in patients with type 2 diabetes mellitus: A randomized cross‐over pilot study. Journal of Diabetes Investigation. 2019;10(5):1284-1290. http://dx.doi.org/10.1111/jdi.13016
  52. Patel V, Joharapurkar A, Shah G, Jain M. Effect of GLP-1 Based Therapies on Diabetic Dyslipidemia. Current Diabetes Reviews. 2014;10(4):238-250. http://dx.doi.org/10.2174/1573399810666140707092506
  53. Onoviran O, Li D, Toombs Smith S, Raji M. Effects of glucagon-like peptide 1 receptor agonists on comorbidities in older patients with diabetes mellitus. Therapeutic Advances in Chronic Disease. 2019;10:204062231986269. http://dx.doi.org/10.1177/2040622319862691
  54. Basu D, Huggins L, Scerbo D, Obunike J, Mullick A, Rothenberg P, Di Prospero N, Eckel R, Goldberg I. Mechanism of Increased LDL (Low-Density Lipoprotein) and Decreased Triglycerides With SGLT2 (Sodium-Glucose Cotransporter 2) Inhibition. Arteriosclerosis, Thrombosis, and Vascular Biology. 2018;38(9):2207-2216. http://dx.doi.org/10.1161/atvbaha.118.311339
  55. Sánchez-García A, Simental-Mendía M, Millán-Alanís J, Simental-Mendía L. Effect of sodium-glucose co-transporter 2 inhibitors on lipid profile: A systematic review and meta-analysis of 48 randomized controlled trials. Pharmacological Research. 2020;160:105068. http://dx.doi.org/10.1016/j.phrs.2020.105068
  56. Skelley J, Carter B, Roberts M. Clinical potential of canagliflozin in cardiovascular risk reduction in patients with type 2 diabetes. Vascular Health and Risk Management. 2018;Volume 14:419-428. http://dx.doi.org/10.2147/vhrm.s168472
  57. Sugizaki T, Watanabe M, Horai Y, Kaneko-Iwasaki N, Arita E, Miyazaki T, Morimoto K, Honda A, Irie J, Itoh H. The Niemann-Pick C1 Like 1 (NPC1L1) Inhibitor Ezetimibe Improves Metabolic Disease Via Decreased Liver X Receptor (LXR) Activity in Liver of Obese Male Mice. Endocrinology. 2014;155(8):2810-2819. http://dx.doi.org/10.1210/en.2013-2143
  58. Mangat R, Warnakula S, Wang Y, Russell J, Uwiera R, Vine D, Proctor S. Model of intestinal chylomicron over-production and Ezetimibe treatment: Impact on the retention of cholesterol in arterial vessels. Atherosclerosis Supplements. 2010;11(1):17-24. http://dx.doi.org/10.1016/j.atherosclerosissup.2010.04.043
  59. Tie C, Gao K, Zhang N, Zhang S, Shen J, Xie X, Wang J. Ezetimibe Attenuates Atherosclerosis Associated with Lipid Reduction and Inflammation Inhibition. PLOS ONE. 2015;10(11):e0142430. http://dx.doi.org/10.1371/journal.pone.0142430