The Impact of Empagliflozin on Renal Function and Kidney Injury Markers in Patients with Diabetic Nephropathy
DOI:
https://doi.org/10.54133/ajms.v7i1(Special).984Keywords:
Albuminuria, Diabetic nephropathy, Empagliflozin, Type 2 DMAbstract
Background: Diabetic nephropathy affects approximately 50% of type 2 diabetes patients. Early detection of kidney disease is crucial to reducing the deterioration of renal function. Reversing microalbuminuria towards normal showed beneficial effects in delaying the onset of renal impairment or even reversing the progression of the disease. Recently, empagliflozin, a sodium/glucose cotransporter-2 inhibitor, has received attention for its anti-inflammatory and reno-cardioprotective effects. Objective: This interventional open-label randomized clinical trial aimed to evaluate the clinical outcome of empagliflozin as an add-on therapy for renal function parameters and other injury markers in type 2 diabetic nephropathy patients. Methods: The study enrolled twenty-one type 2 diabetic patients with nephropathy and nineteen without nephropathy. Each group received empagliflozin 10 mg/day for 16 weeks as an add-on to the traditional treatment. Blood and urine samples were collected at baseline and at week 16 to evaluate the glycemic status, renal function, tubular injury markers, and inflammatory and oxidative stress markers. Results: After 16 weeks, empagliflozin significantly reduced glycated hemoglobin A1c and urinary albumin/creatinine ratios in the nephropathy group. Compared with the non-nephropathy group, empagliflozin showed a significant increase in serum creatinine and a significant decrease in eGFRcr. Empagliflozin significantly reduced serum kidney injury molecule-1, cystatin C, interleukin-18, c-reactive protein, and malondialdehyde in both groups. Conclusions: Adding empagliflozin to the traditional oral antidiabetic drugs in diabetic nephropathy improved albuminuria with a mild increment in serum creatinine. Empagliflozin also effectively reduced renal injury markers, as well as inflammatory and oxidative stress markers.
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Tuttle KR, Bakris GL, Bilous RW, Chiang JL, De Boer IH, Goldstein-Fuchs J, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care. 2014;37(10):2864–2883. doi: 10.2337/dc14-1296.
International Diabetes Federation. IDF Diabetes Atlas, (10th edn.), Brussels, Belgium: International Diabetes Federation. Int Diabetes Fed. 2021.
Fox CS, Matsushita K, Woodward M, Bilo HJ, Chalmers J, Heerspink HJ, et al. Chronic Kidney Disease Prognosis Consortium: Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: A meta-analysis. Lancet. 2012;380(9854):1662–1673. doi: 10.1016/S0140-6736(12)61350-6.
American Diabetes Association Professional Practice Committee. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S17-S38. doi: 10.2337/dc22-S002.
Ali MK, Bullard KM, Saydah S, Imperatore G, Gregg EW. Cardiovascular and renal burdens of prediabetes in the USA: analysis of data from serial cross-sectional surveys, 1988–2014. Lancet Diabetes Endocrinol. 2018;6(5):392–403. doi: 10.1016/S2213-8587(18)30027-5.
Hoogeveen EK. The epidemiology of diabetic kidney disease. Kidney Dial. 2022;2(3):433-442. doi: 10.3390/kidneydial2030038.
Martínez-Castelao A, Navarro-González JF, Luis Górriz J, De Alvaro F. The concept and the epidemiology of diabetic nephropathy have changed in recent years. J Clin Med. 2015;4(6):1207–1216. doi: 10.3390/jcm4061207.
Selby NM, Taal MW. An updated overview of diabetic nephropathy: Diagnosis, prognosis, treatment goals and latest guidelines. Diabetes Obes Metab. 2020;22:3–15. doi: 10.1111/dom.14007.
de Zeeuw D, Heerspink HJL. Time for clinical decision support systems tailoring individual patient therapy to improve renal and cardiovascular outcomes in diabetes and nephropathy. Nephrol Dial Transplant. 2020;35 (Supplement_2):ii38–42. doi: 10.1093/ndt/gfaa013.
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving H-H, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861–869. doi: 10.1056/NEJMoa01116.
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851–860. doi: 10.1056/NEJMoa011303.
Rando MM, Guthoff M, Tiwari V, Biscetti F. Editorial: Diagnosis, prevention and treatment in diabetic nephropathy. Front Endocrinol (Lausanne). 2022;13(September):1–3. doi: 10.3389/fendo.2022.1011665.
Association AD. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S135–151. doi: 10.2337/dc20-S011.
Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255–323. doi: 10.1093/eurheartj/ehz486.
Zhang Z, Cai CX. Kidney injury molecule-1 (KIM-1) mediates renal epithelial cell repair via ERK MAPK signaling pathway. Mol Cell Biochem. 2016;416(1–2):109–116. doi: 10.1007/s11010-016-2700-7.
Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323-334. doi: 10.1056/NEJMoa1515920.
Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388(2):117–127. doi: 10.1056/NEJMoa2204233.
Sampson EJ, Baird MA, Burtis CA, Smith EM, Witte DL, Bayse DD. A coupled-enzyme equilibrium method for measuring urea in serum: optimization and evaluation of the AACC study group on urea candidate reference method. Clin Chem. 1980;26(7):816–826.
Delanghe JR, Speeckaert MM. Creatinine determination according to Jaffe-what does it stand for? NDT Plus. 2011;4(2):83–86. doi: 10.1093/ndtplus/sfq211.
Goldstein DE, Little RR, Wiedmeyer HM, England JD, McKenzie EM. Glycated hemoglobin: methodologies and clinical applications. Clin Chem. 1986;32(10 Suppl):B64-70.
Benedict SR, Behre JA. Some applications of a new color reaction for creatinine. J Biol Chem. 1936;114(2):515–532. doi: 10.1016/s0021-9258(18)74824-2.
Mybiosource USA. Manual of enzyme immunoassay for the quantitative measurement of kidney injury molecule-1 in serum and plasma. 2021; Catalog No: MBS264966.
Mybiosource USA. Manual of enzyme immunoassay for the quantitative measurement of cystatin C in serum and plasma. 2020; Catalog No: MBS006197.
Mybiosource USA.Manual of enzyme immunoassay for the quantitative measurement of interleukin-18 in serum, plasma and saliva. 2020; Catalog No: MBS281497.
Mybiosource USA.Manual of enzyme immunoassay for the quantitative measurement of High sensitive C reactive protein in serum, plasma or tissue homogenates. 2020; Catalog No: MBS040244.
Mybiosource USA. Manual of enzyme immunoassay for the quantitative measurement of Malodialdehyde in serum and plasma. 2021; Catalog No: MBS263626.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–612. doi: 10.7326/0003-4819-150-9-200905050-00006.
Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367(1):20–29. doi: 10.1056/NEJMoa1114248.
van Ruiten CC, van der Aart-van der Beek AB, IJzerman RG, Nieuwdorp M, Hoogenberg K, van Raalte DH, et al. Effect of exenatide twice daily and dapagliflozin, alone and in combination, on markers of kidney function in obese patients with type 2 diabetes: A prespecified secondary analysis of a randomized controlled clinical trial. Diabetes Obes Metab. 2021;23(8):1851–1858. doi: 10.1111/dom.14410.
Li J, Liu H, Takagi S, Nitta K, Kitada M, Srivastava SP, et al. Renal protective effects of empagliflozin via inhibition of EMT and aberrant glycolysis in proximal tubules. JCI Insight. 2020;5(6):e129034. doi: 10.1172/jci.insight.129034.
Dekkers CCJ, Petrykiv S, Laverman GD, Cherney DZ, Gansevoort RT, Heerspink HJL. Effects of the SGLT‐2 inhibitor dapagliflozin on glomerular and tubular injury markers. Diabetes Obes Metab. 2018;20(8):1988–1993. doi: 10.1111/dom.13301.
Cherney DZI, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus M, von Eynatten M, et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017;5(8):610–621. doi: 10.1016/S2213-8587(17)30182-1.
Liu G, Zhong X, Zheng J, Zhang J, Kong W, Hu X, et al. Comparative efficacy of novel antidiabetic drugs on albuminuria outcomes in type 2 diabetes: A systematic review. Diabetes Ther Res Treat Educ Diabetes Relat Disord. 2023;14(5):789–822. doi: 10.1007/s13300-023-01391-8.
Idowu AA, Ajose AO, Adedeji AT, Adegoke AO, Jimoh KA. Microalbuminuria, other markers of nephropathy and biochemical derangements in type 2 diabetes mellitus: Relationships and determinants. Ghana Med J. 2017;51(2):56–63.
Ansar MM, Shahrokhi Rad R, Lebady MK. Risk factors of microalbuminuria and macroalbuminuria in type 2 diabetic patients in north of Iran-Rasht. Nephrourol Mon. 2017;9(1). doi: 10.5812/numonthly.40031.
Khan TM, Nawaz FK, Karim MS, Shafique Z, Anwar MS, Usman O. Incidence of microalbuminuria and factors affecting it in patients with type 2 diabetes mellitus. Cureus. 2022;14(7). doi: 10.7759/cureus.27294.
Lezaic V. Albuminuria as a biomarker of the renal disease BT- Biomarkers in Kidney Disease. In: Patel VB, Preedy VR, (eds.), Dordrecht: Springer Netherlands. 2016;427–44. doi: 10.1007/978-94-007-7699-9_31.
Mozawa K, Kubota Y, Hoshika Y, Tara S, Tokita Y, Yodogawa K, et al. Empagliflozin confers reno‐protection in acute myocardial infarction and type 2 diabetes mellitus. ESC Hear Fail. 2021;8(5):4161–4173. doi: 10.1002/ehf2.13509.
Lytvyn Y, Bjornstad P, van Raalte DH, Heerspink HL, Cherney DZI. The new biology of diabetic kidney disease—mechanisms and therapeutic implications. Endocr Rev. 2020;41(2):202–231. doi: 10.1210/endrev/bnz010.
van Bommel EJM, Lytvyn Y, Perkins BA, Soleymanlou N, Fagan NM, Koitka-Weber A, et al. Renal hemodynamic effects of sodium-glucose cotransporter 2 inhibitors in hyperfiltering people with type 1 diabetes and people with type 2 diabetes and normal kidney function. Kidney Int. U S. 2020;97:631–635. doi: 10.1016/j.kint.2019.12.021.
Shlipak MG, Matsushita K, Ärnlöv J, Inker LA, Katz R, Polkinghorne KR, et al. Cystatin C versus creatinine in determining risk based on kidney function. N Engl J Med. 2013;369(10):932–943. doi: 10.1056/NEJMoa1214234.
Mende C, Katz A. Cystatin C- and Creatinine-based estimates of glomerular filtration rate in dapagliflozin phase 3 clinical trials. Diabetes Ther Res Treat Educ diabetes Relat Disord. 2016;7(1):139–151. doi: 10.1007/s13300-016-0158-y.
Group K. Kidney Disease: Improving Global Outcomes (KDIGO) 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2013;3:1–150.
Currie G, McKay G, Delles C. Biomarkers in diabetic nephropathy: Present and future. World J Diabetes. 2014;5(6):763. doi: 10.4239/wjd.v5.i6.763.
Perkins BA, Ficociello LH, Ostrander BE, Silva KH, Weinberg J, Warram JH, et al. Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes. J Am Soc Nephrol. 2007;18(4):1353–1361. doi: 10.1681/ASN.2006080872.
MacIsaac RJ, Jerums G. Diabetic kidney disease with and without albuminuria. Curr Opin Nephrol Hypertens. 2011;20(3):246–257. doi: 10.1097/MNH.0b013e3283456546.
Tekce BK, Tekce H, Aktas G, Sit M. Evaluation of the urinary kidney injury molecule-1 levels in patients with diabetic nephropathy. Clin Investig Med. 2014;E377–383. doi: 10.25011/cim.v37i6.22242.
Ashrafi Jigheh Z, Ghorbani Haghjo A, Argani H, Roshangar L, Rashtchizadeh N, Sanajou D, et al. Empagliflozin attenuates renal and urinary markers of tubular epithelial cell injury in streptozotocin-induced diabetic rats. Indian J Clin Biochem. 2020;35(1):109–114. doi: 10.1007/s12291-018-0790-6.
Oraby MA, El-Yamany MF, Safar MM, Assaf N, Ghoneim HA. Dapagliflozin attenuates early markers of diabetic nephropathy in fructose-streptozotocin-induced diabetes in rats. Biomed Pharmacother. 2019;109:910–920. doi: 10.1016/j.biopha.2018.10.100.
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