Lviv clinical bulletin 2021, 3(35)-4(36): 8-15

https://doi.org/10.25040/lkv2021.03-04.008

Diabetic Cardiovascular Autonomic Neuropathy: Effects of Simvastatin and Omega-3 Polyunsaturated Fatty Acids on Insulin Resistance and Lipid Profile Parameters

V. Serhiyenko, M. Hotsko, S. Azhmi, O. Serhiyenko

Danylo Halytsky Lviv National Medical University

Introduction. Currently, there is no unified treatment algorithm of cardiac autonomic neuropathy (CAN) in patients with type 2 diabetes mellitus (T2DM).

The aim of the study was to investigate the effects of simvastatin (SIM) and w-3 polyunsaturated fatty acids (w-3 PUFAs) on blood lipid profile and insulin resistance (IR) in patients with type 2 diabetes mellitus and definite cardiac autonomic neuropathy.

Materials and methods. The study involved 72 patients with T2DM and definite CAN. Patients were divided into four groups: 1st – received standard hypoglycemic therapy – control (n = 15); 2nd (n = 22) – in addition simvastatin (SIM) 20.0 mg/q.d.; 3rd (n = 18) – in addition 1 capsule/q.d. of the ω-3 PUFAs; 4th (n = 17) – in addition SIM 10.0 mg/q.d and 1 capsule/q.d of the ω-3 PUFAs for three months. The concentration of glucose, glycated hemoglobin A1c, immunoreactive insulin (IRI), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) in the blood were determined. Homeostasis model assessment IR (HOMA-IR), atherogenic coefficient (AC), TG/LDL-C, TG/TC, TG/LDL-C and TG and glucose index (TyG) were calculated.

Results. Prescription of SIM was accompanied by a statistically significant decrease in TC, LDL-C, TG concentrations. In parallel, SIM induced a decrease of AC, TG/HDL-C, increase in HDL-C, and does not affect the IRI, HOMA-IR, TG/LDL-C, TG/TC, TC/LDL-C/HDL-C, TyG. The use of ω-3 PUFAs has contributed to a significant reduction in TG, AC, TG/LDL-C, TG/TC, TG/HDL-C, TyG index, increase in HDL-C, and was not accompanied by changes in IRI content, HOMA-IR, TC, LDL-C, and TC/LDL-C/HDL-C. The combined prescription of SIM and w-3 PUFAs was accompanied by more pronounced, statistically significant changes in the blood lipid spectrum, as well as a decrease in the IRI and HOMA-IR.

Conclusions. Obtained results justify the appropriateness of combined simvastatin and w-3 polyunsaturated fatty acids prescription to patients with type 2 diabetes mellitus and definite cardiac autonomic neuropathy.

References

  1. Abbasi F, Reaven GM. Comparison of two methods using plasma triglyceride concentration as a surrogate estimate of insulin action in nondiabetic subjects: triglycerides x glucose versus triglyceride/high-density lipoprotein cholesterol. Metabolism. 2011;60(8):1673-1676. https://doi.org/10.1016/j.metabol.2011.04.006
  2. American Diabetes Association’s Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;42(Suppl.1):S105-S118. https://doi.org/10.2337/dc19-S007
  3. Aung T, Halsey J, Kromhout D, Gerstein HC, Marchioli R, Tavazzi L et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks. JAMA Cardiol. 2018;3(3):225-234. https://doi.org/10.1001/jamacardio.2017.5205
  4. Bonafini S, Antoniazzi F, Maffeis C, Minuz P, Fava C. Beneficial effects of omega-3 PUFA in children on cardiovascular risk factors during childhood and adolescence. Prostaglandins Other Lipid Mediat. 2015;120:72-79. https://doi.org/10.1016/j.prostaglandins.2015.03.006
  5. Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochim Biophis Acta. 2015;1851(4):469-484. https://doi.org/10.1016/j.bbalip.2014.08.010
  6. Deo SH, Fisher JP, Vianna LC, Kim A, Chockalingam A, Zimmerman MC et al. Statin therapy lowers muscle sympathetic nerve activity and oxidative stress in patients with heart failure. Am J Physiol Heart Circ Physiol. 2012;303(4):H377-H385. https://doi.org/10.1152/ajpheart.00289.2012
  7. Elnaem MH, Mohamed MHN, Huri HZ, Azarisman SM, Elkalmi RM. Statin therapy prescribing for patients with type 2 diabetes mellitus: A review of current evidence and challenges. J Pharm Bioallied Sci. 2017;9(2):80-87.
  8. Endo J, Arita M. Cardioprotective mechanism of omega-3 polyunsaturated fatty acids. J Cardiol. 2016;67(1):22-27. https://doi.org/10.1016/j.jjcc.2015.08.002
  9. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):3168-3209. https://doi.org/10.1016/j.jacc.2018.11.002
  10. Handelsman Y, Shapiro MD. Triglycerides, atherosclerosis, and cardiovascular outcome studies: focus on omega-3 fatty acids. Endocr Pract. 2017;23(1):100-112. https://doi.org/10.4158/EP161445.RA https://doi.org/10.4158/EP161445.RA
  11. Jacobo-Cejudo MG, Valdes-Ramos R, Guadarrama-Lopez AL, Pardo-Morales RV, Martinez-Carrillo BE, Harbige LS. Effect of n-3 polyunsaturated fatty acid supplementation on metabolic and inflammatory biomarkers in type 2 diabetes mellitus patients. Nutrients. 2017;9(6):573. https://doi.org/10.3390/nu9060573
  12. Jeppesen C, Schiller K, Schulze MB. Omega-3 and omega-6 fatty acids and type 2 diabetes. Curr Diab Rep. 2013;13(2):279-288. https://doi.org/10.1007/s11892-012-0362-8
  13. Kim CH, Han KA, Yu J, Lee SH, Jeon HK, Kim SH et al. Efficacy and safety of adding omega-3 fatty acids in statin-treated patients with residual hypertriglyceridemia: ROMANTIC (Rosuvastatin-OMAcor iN residual hyperTrIglyCeridemia), a randomized, double-blind, and placebo-controlled trial. Clin Ther. 2018;40(1):83-94. https://doi.org/10.1016/j.clinthera.2017.11.007
  14. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-419. https://doi.org/10.1007/BF00280883
  15. Moreira ED, Mostarda CT, Moraes-Silva IC, Ferreira JB, Dos Santos F, Lacchini S et al. Effect of simvastatin in the autonomic system is dependent on the increased gain/sensitivity of the baroreceptors. Physiol Rep. 2013;1(3):e00045. https://doi.org/10.1002/phy2.45
  16. O’Mahoney LL, Matu J, Price OJ, Birch KM, Ajjan RA, Farrar D et al. Omega-3 polyunsaturated fatty acids favourably modulate cardiometabolic biomarkers in type 2 diabetes: a meta-analysis and meta-regression of randomized controlled trials. Cardiovasc Diabetol. 2018;17:98. https://doi.org/10.1186/s12933-018-0740-x
  17. Pop-Busui R, Boulton AJM, Feldman EL, Bril V, Freeman R, Malik RA et al. Diabetic neuropathy: A position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136-154. https://doi.org/10.2337/dc16-2042
  18. Poreba M, Mostowik M, Siniarski A, Golebiowska-Wiatrak R, Malinowski KP, Haberka M et al. Treatment with high-dose n-3PUFAs has no effect on platelet function, coagulation, metabolic status or inflammation in patients with atherosclerosis and type 2 diabetes. Cardiovasc Diabetol. 2017;16(1):50. https://doi.org/10.1186/s12933-017-0523-9
  19. Pursnani A, Massaro JM, D’Agostino RB Sr, O’Donnell CJ, Hoffmann U. Guideline-based statin eligibility, coronary artery calcification, and cardiovascular events. JAMA. 2015;314(2):134-141. https://doi.org/10.1001/jama.2015.7515
  20. Ramos R, Comas-Cufi M, Marti-Lluch R, Balló E, Ponjoan A, Alves-Cabratosa L et al. Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study. BMJ. 2018;362:k3359. https://doi.org/10.1136/bmj.k3359
  21. Sawada T, Tsubata H, Hashimoto N, Takabe M, Miyata T, Aoki K et al. Effects of 6-month eicosapentaenoic acid treatment on postprandial hyperglycemia, hyperlipidemia, insulin secretion ability, and concomitant endothelial dysfunction among newly-diagnosed impaired glucose metabolism patients with coronary artery disease. An open label, single blinded, prospective randomized controlled trial. Cardiovasc Diabetol. 2016;15(1):121. https://doi.org/10.1186/s12933-016-0437-y
  22. Serhiyenko VA, Serhiyenko AA. Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment. World J Diabetes. 2018;9(1):1-24. https://doi.org/10.4239/wjd.v9.i1.1
  23. Serhiyenko VA, Serhiyenko AA. Diabetic cardiac autonomic neuropathy: Do we have any treatment perspectives? World J Diabetes. 2015; 6(2):245-258. https://doi.org/10.4239/wjd.v6.i2.245
  24. Serhiyenko VA, Serhiyenko AA. Diabetic cardiac autonomic neuropathy. In: Saldaña JR, ed. Diabetes Textbook: Clinical principles, patient management and public health issues. Basel: Springer Nature Switzerland AG, 2019, Section 53. pp. 825-850. https://doi.org/10.1007/978-3-030-11815-0_53
  25. Simental-Mendia LE, Rodriguez-Moran M, Guerrero-Romero F. The product of fasting glucose and triglycerides as surrogate for identifying insulin resistance in apparently healthy subjects. Metab Syndr Relat Disord. 2008;6(4):299-304. https://doi.org/10.1089/met.2008.0034
  26. Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R et al. Toronto Consensus Panel on Diabetic Neuropathy. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011;27:639-653. https://doi.org/10.1002/dmrr.1239
  27. Tandon N, Ali MK, Narayan KM. Pharmacologic prevention of microvascular and macrovascular complications in diabetes mellitus: implications of the results of recent clinical trials in type 2 diabetes. Am J Cardiovasc Drugs. 2012;12(1):7-22. https://doi.org/10.2165/11594650-000000000-00000
  28. Tenenbaum A, Enrique Z. Fisman EZ. Omega-3 polyunsaturated fatty acids supplementation in patients with diabetes and cardiovascular disease risk: does dose really matter? Cardiovasc Diabetol. 2018;17:119. https://doi.org/10.1186/s12933-018-0766-0
  29. Vasques AC, Novaes FS, de Oliveira MS, Souza JR, Yamanaka A, Pareja JC et al. TyG index performs better than HOMA in a Brazilian population: a hyperglycemic clamp validated study. Diabetes Res Clin Pract. 2011;93(3):e98-e100. https://doi.org/10.1016/j.diabres.2011.05.030
  30. Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig. 2013;4(1):4-18. https://doi.org/10.1111/jdi.12042
  31. Yanai H, Masui Y, Katsuyama H, Adachi H, Kawaguchi A, Hakoshima M et al. An improvement of cardiovascular risk factors by omega-3 polyunsaturated fatty acids. J Clin Med Res. 2018;10(4):281-289. https://doi.org/10.14740/jocmr3362w
  32. Ziegler D, Keller J, Maier C, Pannek J; German Diabetes Association. Diabetic neuropathy. Exp Clin Endocrinol Diabetes. 2014;122(7):406-415. https://doi.org/10.1055/s-0034-1366435