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International Journal of Diabetes in Developing Countries

Open Access 02-03-2024 | Rosuvastatin | Original Article

Effect of rosuvastatin on sortilin and fetuin-A in type 2 diabetic patients: a randomized controlled trial

Authors: Rehab H. Werida, Ola Mohamed Elattar, Reem Ahmed Abdelghafour, Asser Ghoneim

Published in: International Journal of Diabetes in Developing Countries

Abstract

Objective

Rosuvastatin is a drug used for decreasing the risk of cardiovascular complications in type 2 diabetes mellitus (T2DM) patients. It is hypothesized that fetuin-A encourages lipid-induced insulin resistance and sortilin may increase the risk of atherosclerotic-related disorders. The aim of this study is to investigate the safety and efficacy of rosuvastatin co-treatment in T2DM patients and its effect on levels of sortilin and fetuin-A.

Methods

Seventy T2DM patients treated with glimepiride and metformin were randomly assigned to either co-treated with rosuvastatin 10 mg tablets (rosuvastatin group, n = 40), or placebo (placebo group, n = 30) daily for 3 months in a parallel, double-blind randomized controlled trial. Blood was collected for biochemical analysis. Serum sortilin and fetuin-A levels, glycemic and lipid profiles were measured before and 3 months after intervention.

Results

Fasting blood glucose (FBG, mg/dl) significantly decreased in placebo and rousvastatin groups from (104 ± 7.24 to 96.67 ± 7.14 vs 102.8 ± 6.43 to 93.0 ± 4.71), respectively, compared with baseline (p < 0.05). BMI and HbA1c decreased in placebo vs rosuvastatin group (29.20 ± 3.18 to 28.10 ± 3.08, p=0.08 vs 28.67 ± 3.56 to 27.66 ± 3.16, p = 0.27), and (6.59 ± 0.27 to 6.36 ± 0.27 vs 6.56 ± 0.26 to 6.29 ± 0.25), respectively, compared with baseline (p ≤ 0.001) with no significance difference between both groups (p = 0.58 and p = 0.25, respectively). Sortilin and fetuin-A levels significantly decreased in rosuvastatin vs placebo group from (1.77 ± 0.41 to 0.64 ± 0.37 vs 1.70 ± 0.36 to 1.65 ± 0.36) and from (295.33 ± 52.04 to 179.75 ± 60.22 vs 307.22 ± 50.11 to 288.94 ± 49.53), respectively, compared with baseline with significance difference between both groups (p < 0.001) compared with placebo. Significant positive correlation was found between sortilin with fetuin-A, low-density lipoprotein (LDL-C), and atherogenic index (p < 0.001). Significant positive correlation was observed between fetuin-A with FBG (p < 0.05) and atherogenic index (p < 0.001).

Conclusion

Rosuvastatin co-treatment in T2DM patients improves glycemic control and aids in decreasing the atherogenic biomarkers sortilin and fetuin-A levels, so it can be considered tolerable and efficient in improving lipid profile and atherogenic index.

Trial registration

ClinicalTrials.gov identifier (NCT number): NCT03907423, (The registration date: April 9, 2019). https://clinicaltrials.gov/ct2/show/NCT03907423.

GBD. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2016;390(10100):1345–422. https://doi.org/10.1016/S0140-6736(17)32366-8. (Erratum in: Lancet. 2017; 390(10104):1736. Erratum in: Lancet. 2017; 390(10106): e38).CrossRef

Hernández C, Candell-Riera J, Ciudin A, Francisco G, Aguadé-Bruix S, Simó R. Prevalence and risk factors accounting for true silent myocardial ischemia: a pilot case-control study comparing type 2 diabetic with non-diabetic control subjects. Cardiovasc Diabetol. 2011;10:9. https://doi.org/10.1186/1475-2840-10-9.CrossRefPubMedPubMedCentral

Bommer C, Sagalova V, Heesemann E, et al. Global economic burden of diabetes in adults: projections from 2015 to 2030. Diabetes Care. 2018;41(5):963–70. https://doi.org/10.2337/dc17-1962.CrossRefPubMed

Kaze AD, Santhanam P, Musani SK, Ahima R, Echouffo-Tcheugui JB. Metabolic dyslipidemia and cardiovascular outcomes in type 2 diabetes mellitus: findings from the look AHEAD study. J Am Heart Assoc. 2021;10(7): e016947. https://doi.org/10.1161/JAHA.120.016947. (Erratum in: J Am Heart Assoc. 2021;10(14):e020749).CrossRefPubMedPubMedCentral

Aguilar-Ballester M, Hurtado-Genovés G, Taberner-Cortés A, Herrero-Cervera A, Martínez-Hervás S, González-Navarro H. Therapies for the treatment of cardiovascular disease associated with type 2 diabetes and dyslipidemia. Int J Mol Sci. 2021;22(2):660. https://doi.org/10.3390/ijms22020660.CrossRefPubMedPubMedCentral

Simsek Z, Alizade E, Güner A, Zehir R. Correlation between serum sortilin levels and severity of extracranial carotid artery stenosis. Int J Clin Pract. 2021;75(11): e14733. https://doi.org/10.1111/ijcp.14733.CrossRefPubMed

Shi R, Gao Y, Shen LL, et al. The effect of LDL-C status on the association between increased coronary artery calcium score and compositional plaque volume progression in statins-treated diabetic patients: evaluated using serial coronary CTAs. Cardiovasc Diabetol. 2022;21(1):121. https://doi.org/10.1186/s12933-022-01556-y.CrossRefPubMedPubMedCentral

Bahiru E, Hsiao R, Phillipson D, Watson KE. Mechanisms and treatment of dyslipidemia in diabetes. Curr Cardiol Rep. 2021;23(4):26. https://doi.org/10.1007/s11886-021-01455-w.CrossRefPubMed

Tuomilehto J, Leiter LA, Kallend D. A review of the efficacy of rosuvastatin in patients with type 2 diabetes. Int J Clin Pract Suppl. 2004;143:30–40. https://doi.org/10.1111/j.1368-504x.2004.00390.x.CrossRef

10.

Mitok KA, Keller MP, Attie AD. Sorting through the extensive and confusing roles of sortilin in metabolic disease. J Lipid Res. 2022;63(8): 100243. https://doi.org/10.1016/j.jlr.2022.100243.CrossRefPubMedPubMedCentral

11.

Su X, Chen L, Chen X, Dai C, Wang B. Emerging roles of sortilin in affecting the metabolism of glucose and lipid profiles. Bosn J Basic Med Sci. 2022;22(3):340–52. https://doi.org/10.17305/bjbms.2021.6601.CrossRefPubMed

12.

Goettsch C, Kjolby M, Aikawa E. Sortilin and its multiple roles in cardiovascular and metabolic diseases. Arterioscler Thromb Vasc Biol. 2018;38(1):19–25. https://doi.org/10.1161/ATVBAHA.117.310292.CrossRefPubMed

13.

Bourebaba L, Marycz K. Pathophysiological implication of fetuin-A glycoprotein in the development of metabolic disorders: a concise review. J Clin Med. 2019;8(12):2033. https://doi.org/10.3390/jcm8122033.CrossRefPubMedPubMedCentral

14.

Zheng J, Huang M, Huang Q, Chen Q, Chen Z. The relationship between fetuin-A and coronary atherosclerotic heart disease (CHD) and CHD-related risk factors: a retrospective study. Medicine (Baltimore). 2021;100(43): e27481. https://doi.org/10.1097/MD.0000000000027481.CrossRefPubMed

15.

Icer MA, Yıldıran H. Effects of fetuin-A with diverse functions and multiple mechanisms on human health. Clin Biochem. 2021;88:1–10. https://doi.org/10.1016/j.clinbiochem.2020.11.004.CrossRefPubMed

16.

Karadeniz H, Güler AA, Koca G, et al. Serum levels of fetuin-A as a novel biomarker for disease activity in patients with Takayasu arteritis and granulomatous polyangiitis. Clin Rheumatol. 2022;41(4):1169–76. https://doi.org/10.1007/s10067-021-06020-y.CrossRefPubMed

17.

Chekol Abebe E, Tilahun Muche Z, Behaile T/Mariam TA, et al. The structure, biosynthesis, and biological roles of fetuin-A: a review. Front Cell Dev Biol. 2022;10:945287. https://doi.org/10.3389/fcell.2022.945287.CrossRefPubMedPubMedCentral

18.

Gillett MJ. International Expert Committee report on the role of the A1c assay in the diagnosis of diabetes: Diabetes Care 2009; 32(7): 1327–1334. Clin Biochem Rev. 2009; 30(4):197–200

19.

Kim KJ, Yoon J, Won KH, Lim SW, Chae IH, Lee SY, Kim SW, Kim HS. Assessment of the efficacy of lowering LDL cholesterol with rosuvastatin 10 mg in Four Korean Statin Benefit Groups as per ACC/AHA Guidelines (NewStaR4G). J Clin Med. 2020;9(4):916. https://doi.org/10.3390/jcm9040916.PMID:32230818;PMCID:PMC7230727.CrossRefPubMedPubMedCentral

20.

Knopfholz J, Disserol CC, Pierin AJ, et al. Validation of the Friedewald formula in patients with metabolic syndrome. Cholesterol. 2014;2014: 261878. https://doi.org/10.1155/2014/261878.CrossRefPubMedPubMedCentral

21.

Kazemi T, Hajihosseini M, Moossavi M, Hemmati M, Ziaee M. Cardiovascular risk factors and atherogenic indices in an Iranian population: Birjand East of Iran. Clin Med Insights Cardiol. 2018;20(12):1179546818759286. https://doi.org/10.1177/1179546818759286.CrossRef

22.

Thambiah SC, Lai LC. Diabetic dyslipidaemia. Pract. Lab Med. 2021;26:e00248. https://doi.org/10.1016/j.plabm.2021.e00248.CrossRef

23.

Celik O, Acbay O. Effects of metformin plus rosuvastatin on hyperandrogenism in polycystic ovary syndrome patients with hyperlipidemia and impaired glucose tolerance. J Endocrinol Invest. 2012;35(10):905–10. https://doi.org/10.3275/8371.CrossRefPubMed

24.

Werida R, Khairat I, Khedr NF. Effect of atorvastatin versus rosuvastatin on inflammatory biomarkers and LV function in type 2 diabetic patients with dyslipidemia. Biomed Pharmacother. 2021;135: 111179. https://doi.org/10.1016/j.biopha.2020.111179.CrossRefPubMed

25.

Adams SP, Sekhon SS, Wright JM. Lipid-lowering efficacy of rosuvastatin. Cochrane Database Syst Rev. 2014; 21;2014(11):CD010254. https://doi.org/10.1002/14651858.CD010254.pub2

26.

Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207. https://doi.org/10.1056/NEJMoa0807646.CrossRefPubMed

27.

Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7–22. https://doi.org/10.1016/S0140-6736(02)09327-3.CrossRef

28.

Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentration, in the anglo-Scandinavian cardiac outcomes trial. Lipid lowering arm (ASCOT-LLA): a multicenter randomized controlled trial. Lancet. 2003;361(9364):1149–58. https://doi.org/10.1016/S0140-6736(03)12948-0.CrossRefPubMed

29.

Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495–504. https://doi.org/10.1056/NEJMoa040583.CrossRefPubMed

30.

Salunkhe VA, Mollet IG, Ofori JK, et al. Dual effect of rosuvastatin on glucose homeostasis through improved insulin sensitivity and reduced insulin secretion. EBioMedicine. 2016;10:185–94. https://doi.org/10.1016/j.ebiom.2016.07.007.CrossRefPubMedPubMedCentral

31.

Her AY, Kim JY, Kang SM, et al. Effects of atorvastatin 20 mg, rosuvastatin 10 mg, and atorvastatin/ezetimibe 5 mg/5 mg on lipoproteins and glucose metabolism. J Cardiovasc Pharmacol Ther. 2010;15(2):167–74. https://doi.org/10.1177/1074248409357922.CrossRefPubMed

32.

Milionis HJ, Rizos E, Kostapanos M, et al. Treating to target patients with primary hyperlipidemia: comparison of the effects of atorvastatin and rosuvastatin (the ATOROS study). Curr Med Res Opin. 2006;22(6):1123–31. https://doi.org/10.1185/030079906X112462.CrossRefPubMed

33.

Khokhar SA, Farooq Ur Rehman RM, Masood S. Comparison of efficiency between rosuvastatin and atorvastatin in reducing low-density lipoprotein (LDL-C) in patients with diabetes mellitus. J Pak Med Assoc. 2022;72(11):2288–90. https://doi.org/10.47391/JPMA.4823.CrossRefPubMed

34.

Sindhu S, Singh HK, Salman MT, Fatima J, Verma VK. Effects of atorvastatin and rosuvastatin on high-sensitivity C-reactive protein and lipid profile in obese type 2 diabetes mellitus patients. J Pharmacol Pharmacother. 2011;2(4):261–5. https://doi.org/10.4103/0976-500X.85954.CrossRefPubMedPubMedCentral

35.

Shah SN, Arneja J. Efficacy of rosuvastatin in achieving target HDL, LDL, triglycerides and total cholesterol levels in type 2 diabetes mellitus (T2DM) with newly diagnosed dyslipidaemia: an open label, nonrandomised, non-interventional and observational study in India. J Assoc Physicians India. 2013;61(10):721-6,732.PubMed

36.

Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol. 2003;92(2):152–60. https://doi.org/10.1016/s0002-9149(03)00530-7.CrossRefPubMed

37.

Long SB, Blaha MJ, Blumenthal RS, Michos ED. Clinical utility of rosuvastatin and other statins for cardiovascular risk reduction among the elderly. Clin Interv Aging. 2011;6:27–35. https://doi.org/10.2147/CIA.S8101.CrossRefPubMed

38.

Oh TJ, Ahn CH, Kim BR, et al. Circulating sortilin level as a potential biomarker for coronary atherosclerosis and diabetes mellitus. Cardiovasc Diabetol. 2017;16(1):92. https://doi.org/10.1186/s12933-017-0568-9.CrossRefPubMedPubMedCentral

39.

Goettsch C, Iwata H, Hutcheson JD, et al. Serum sortilin associates with aortic calcification and cardiovascular risk in men. Arterioscler Thromb Vasc Biol. 2017;37(5):1005–11. https://doi.org/10.1161/ATVBAHA.116.308932.CrossRefPubMedPubMedCentral

40.

Werida RH, Omran A, El-Khodary NM. Sortilin and homocysteine as potential biomarkers for coronary artery diseases. Int J Gen Med. 2021;27(14):6167–76. https://doi.org/10.2147/IJGM.S324889.CrossRef

41.

El-Khodary NM, Dabees H, Werida RH. Folic acid effect on homocysteine, sortilin levels and glycemic control in type 2 diabetes mellitus patients. Nutr Diabetes. 2022;12(1):33. https://doi.org/10.1038/s41387-022-00210-6.CrossRefPubMedPubMedCentral

42.

Kjolby M, Andersen OM, Breiderhoff T, et al. Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export. Cell Metab. 2010;12(3):213–23. https://doi.org/10.1016/j.cmet.2010.08.006.CrossRefPubMed

43.

Goettsch C, Hutcheson JD, Aikawa M, et al. Sortilin mediates vascular calcification via its recruitment into extracellular vesicles. J Clin Invest. 2016;126(4):1323–36. https://doi.org/10.1172/JCI80851.CrossRefPubMedPubMedCentral

44.

Ogawa K, Ueno T, Iwasaki T, et al. Soluble sortilin is released by activated platelets and its circulating levels are associated with cardiovascular risk factors. Atherosclerosis. 2016;249:110–5. https://doi.org/10.1016/j.atherosclerosis.2016.03.041.CrossRefPubMed

45.

Patel KM, Strong A, Tohyama J, et al. Macrophage sortilin promotes LDL uptake, foam cell formation, and atherosclerosis. Circ Res. 2015;116(5):789–96. https://doi.org/10.1161/CIRCRESAHA.116.305811.CrossRefPubMedPubMedCentral

46.

Musunuru K, Strong A, Frank-Kamenetsky M, et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature. 2010;466(7307):714–9. https://doi.org/10.1038/nature09266.CrossRefPubMedPubMedCentralADS

47.

Demir İ, Yildirim Akan O, Guler A, Bozkaya G, Aslanipour B, Calan M. Relation of decreased circulating sortilin levels with unfavorable metabolic profiles in subjects with newly diagnosed type 2 diabetes mellitus. Am J Med Sci. 2020;359(1):8–16. https://doi.org/10.1016/j.amjms.2019.10.003.CrossRefPubMed

48.

Sardana O, Goyal R, Bedi O. Molecular and pathobiological involvement of fetuin-A in the pathogenesis of NAFLD. Inflammopharmacology. 2021;29(4):1061–74. https://doi.org/10.1007/s10787-021-00837-4.CrossRefPubMed

49.

Liu S, Hu W, He Y, et al. Serum fetuin-A levels are increased and associated with insulin resistance in women with polycystic ovary syndrome. BMC Endocr Disord. 2020;20(1):67. https://doi.org/10.1186/s12902-020-0538-1.CrossRefPubMedPubMedCentral

50.

Demirbaş A, Kurtipek GS, Tunçez A, Akyürek F, Demirbaş GU. The role of cystatin-C and fetuin-A in the determination of early atherosclerotic risk in psoriasis patients. Dermatol Ther. 2020;33(6): e13898. https://doi.org/10.1111/dth.13898.CrossRefPubMed

51.

Shim YS, Kang MJ, Oh YJ, Baek JW, Yang S, Hwang IT. Fetuin-A as an alternative marker for insulin resistance and cardiovascular risk in prepubertal children. J Atheroscler Thromb. 2017;24(10):1031–8. https://doi.org/10.5551/jat.38323.CrossRefPubMedPubMedCentral

52.

Jirak P, Stechemesser L, Moré E, et al. Clinical implications of fetuin-A. Adv Clin Chem. 2019;89:79–130. https://doi.org/10.1016/bs.acc.2018.12.003.CrossRefPubMed

53.

Filardi T, Panimolle F, Tiberti C, et al. Circulating levels of fetuin-A are associated with moderate-severe hepatic steatosis in young adults. J Endocrinol Invest. 2021;44(1):105–10. https://doi.org/10.1007/s40618-020-01274-w.CrossRefPubMed

54.

Trepanowski JF, Mey J, Varady KA. Fetuin-A: a novel link between obesity and related complications. Int J Obes (Lond). 2015;39(5):734–41. https://doi.org/10.1038/ijo.2014.203.CrossRefPubMed

55.

Priya E, Jayashree K, Senthilkumar GP, Yasir M, Babu KR, Devi TD. Role of fetuin-A and vascular endothelial growth factor in type 2 diabetes mellitus patients without and with retinopathy. Diabetes Metab Syndr. 2019;13(4):2699–703. https://doi.org/10.1016/j.dsx.2019.07.026.CrossRefPubMed

56.

Neves KB, Lopes RA, Strembitska A, et al. Fetuin-a induces vascular dysfunction through toll-like receptor 4 and Nox1/4 activation. Hypertension. 2020;76:AP083. https://doi.org/10.1161/hyp.76.suppl_1.P083.CrossRef

57.

Kadoglou NP, Kottas G, Lampropoulos S, Vitta I, Liapis CD. Serum levels of fetuin-A, osteoprotegerin and osteopontin in patients with coronary artery disease: effects of statin (HMGCoA-reductase inhibitor) therapy. Clin Drug Investig. 2014;34(3):165–71. https://doi.org/10.1007/s40261-013-0157-y.CrossRefPubMed

58.

Mukhuty A, Fouzder C, Kundu R. Fetuin-A excess expression amplifies lipid induced apoptosis and β-cell damage. J Cell Physiol. 2022;237(1):532–50. https://doi.org/10.1002/jcp.30499.CrossRefPubMed

Title: Effect of rosuvastatin on sortilin and fetuin-A in type 2 diabetic patients: a randomized controlled trial
Authors: Rehab H. Werida
Ola Mohamed Elattar
Reem Ahmed Abdelghafour
Asser Ghoneim
Publication date: 02-03-2024
Publisher: Springer India
Keywords: Rosuvastatin
Arterial Occlusive Disease
Glimepiride
Insulins
Insulins
Biomarkers
Published in: International Journal of Diabetes in Developing Countries
Print ISSN: 0973-3930
Electronic ISSN: 1998-3832
DOI: https://doi.org/10.1007/s13410-024-01324-6

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