Retrospective evaluation of microalbuminuria and GFR levels of diabetic patients taking DPP-4 Inhibitor, GLP-1 Analog, or SGLT-2 Inhibitor

Abstract

Background: In our study, we determined the changes in microalbuminuria and gfr (glomerular filtration rate) values, which are important for diabetic nephropathy, within 1 year after starting treatment in our patients taking DPP-4 inhibitor (linagliptin), GLP-1 analog (exenatide) and SGLT-2 inhibitor (empagliflozin). Material and Methods: We evaluated the urea, creatinine, gfr and microalbuminuria levels of our patients who were treated with linagliptin, exenatide and empagliflozin on their 0th, 6th and 12th month visits. We included patients who were followed up for nephropathy for at least 1 year after starting treatment in each drug group. Results: When the 0th and 12th month GFR values of our 98 patients who were prescribed linagliptin were compared, an increase of 4.57% was detected (p<0.01). In this group, there were 55 patients whose microalbuminuria could be followed up at 12 months, and no significant change was detected (p>0.05). While no statistically significant difference was found in the 0th and 12th month GFR follow-ups of our 97 patients using exenatide (p>0.05); in this group, it was determined that the microalbuminuria decreased significantly in 12 months in 33 of our patients who could be followed up in terms of microalbuminuria (p<0.05). No statistically significant change was observed in the 0th and 12th month GFR follow-ups of our 99 patients taking empagliflozin (p>0.05); however, it was determined that microalbuminuria decreased significantly at the end of 1 year in our 79 patients who could be followed up for microalbuminuria in this group (p<0.05). Conclusions: Although there was no improvement in microalbuminuria in our patients taking linagliptin, an increase in GFR was observed; however, it was observed that this situation was associated with the discontinuation of the nephrotoxic agents used by the patients for the treatment of diabetes and switching to linagliptin. In our patients taking exenatide and Empagliflozin, although no significant change was detected in the GFR value, a decrease in microalbuminuria was observed; this is important in order to prevent the progression of nephropathy in the early period. The results of our study suggest that the use of GLP-1 analog and SGLT-2 inhibitor in diabetic patients will provide a nephroprotective effect.

Keywords

• Diabetic nephropathy
• Empagliflozin
• Exenatide
• Linagliptin
• Renal failure

References

1. Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, Malanda B. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018 Apr;138:271-81. doi: 10.1016/j.diabres.2018.02.023.
2. Kramer HJ. Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA. 2003;289(24):3273. doi: 10.1001/jama.289.24.3273.
3. Krolewski AS. Progressive renal decline: The new paradigm of diabetic nephropathy in type 1 diabetes. Diabetes Care. 2015;38(6):954-62. doi: 10.2337/dc15-0184.
4. Tonneijck L, Muskiet MH, Smits MM, van Bommel EJ, Heerspink HJ, van Raalte DH, Joles JA. Glomerular hyperfiltration in diabetes: Mechanisms, clinical significance, and treatment. J Am Soc Nephrol. 2017 Apr;28(4):1023-39. doi: 10.1681/ASN.2016060666.
5. Ruggenenti P, Porrini EL, Gaspari F, Motterlini N, Cannata A, Carrara F, Cella C, Ferrari S, Stucchi N, Parvanova A, Iliev I, Dodesini AR, Trevisan R, Bossi A, Zaletel J, Remuzzi G; GFR Study Investigators. Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Diabetes Care. 2012 Oct;35(10):2061-8. doi: 10.2337/dc11-2189.
6. Fox CS, Matsushita K, Woodward M, Bilo HJ, Chalmers J, Heerspink HJ, Lee BJ, Perkins RM, Rossing P, Sairenchi T, Tonelli M, Vassalotti JA, Yamagishi K, Coresh J, de Jong PE, Wen CP, Nelson RG; 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 Nov 10;380(9854):1662-73. doi: 10.1016/S0140-6736(12)61350-6.
7. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR; UKPDS GROUP. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 2003 Jan;63(1):225-32.doi: 10.1046/j.1523-1755.2003.00712.x.
8. Ninomiya T, Perkovic V, de Galan BE, Zoungas S, Pillai A, Jardine M, Patel A, Cass A, Neal B, Poulter N, Mogensen CE, Cooper M, Marre M, Williams B, Hamet P, Mancia G, Woodward M, Macmahon S, Chalmers J; ADVANCE Collaborative Group. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol. 2009 Aug;20(8):1813-21. doi: 10.1681/ASN.2008121270.

9. Cea Soriano L, Johansson S, Stefansson B, Rodríguez LAG. Cardiovascular events and all-cause mortality in a cohort of 57946 patients with type 2 diabetes: associations with renal function and cardiovascular risk factors. Cardiovasc Diabetol. 2015 Apr 18;14:38. doi: 10.1186/s12933-015-0204-5.
10. Scirica BM, Mosenzon O, Bhatt DL, Udell JA, Steg PG, McGuire DK, Im K, Kanevsky E, Stahre C, Sjöstrand M, Raz I, Braunwald E. Cardiovascular outcomes according to urinary albumin and kidney disease in patients with type 2 diabetes at high cardiovascular risk: Observations from the SAVOR-TIMI 53 trial. JAMA Cardiol. 2018 Feb 1;3(2):155-63. doi: 10.1001/ jamacardio.2017.4228.
11. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Sabatine MS. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019 Jan 5;393(10166):31-9. doi: 10.1016/S0140-6736(18)32590-X.
12. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720.
13. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS; DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019 Jan 24;380(4):347-57. doi: 10.1056/NEJMoa1812389.
14. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-57. doi: 10.1056/NEJMoa1812389.
15. Rosenstock J, Kahn SE, Johansen OE, Zinman B, Espeland MA, Woerle HJ, Pfarr E, Keller A, Mattheus M, Baanstra D, Meinicke T, George JT, von Eynatten M, McGuire DK, Marx N; CAROLINA Investigators. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: The CAROLINA randomized clinical trial. JAMA. 2019 Sep 24;322(12):1155-66. doi: 10.1001/jama.2019.13772.
16. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, Lawson FC, Ping L, Wei X, Lewis EF, Maggioni AP, McMurray JJ, Probstfield JL, Riddle MC, Solomon SD, Tardif JC; ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015 Dec 3;373(23):2247-57. doi: 10.1056/NEJMoa1509225.
17. Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228-39. doi: 10.1056/NEJMoa1612917.
18. Nauck MA, Kahle M, Baranov O, Deacon CF, Holst JJ. Addition of a dipeptidyl peptidase-4 inhibitor, sitagliptin, to ongoing therapy with the glucagon-like peptide-1 receptor agonist liraglutide: A randomized controlled trial in patients with type 2 diabetes. Diabetes, Obes Metab. 2017;19(2):200-7. doi: 10.1111/ dom.12802.
19. Clar C, Gill JA, Court R, Waugh N. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open. 2012;2(5):e001007. doi: 10.1136/bmjopen-2012-001007.
20. Ueda P, Svanström H, Melbye M, Eliasson B, Svensson AM, Franzén S, Gudbjörnsdottir S, Hveem K, Jonasson C, Pasternak B. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ. 2018 Nov 14;363:k4365. doi: 10.1136/bmj.k4365.
21. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J, Riesmeyer JS, Riddle MC, Rydén L, Xavier D, Atisso CM, Dyal L, Hall S, Rao-Melacini P, Wong G, Avezum A, Basile J, Chung N, Conget I, Cushman WC, Franek E, Hancu N, Hanefeld M, Holt S, Jansky P; REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019 Jul 13;394(10193):121-30. doi: 10.1016/S0140-6736(19)31149-3.
22. Ural D. Systematic Review, Meta-analysis and Meta-regression of Epidemiological Studies for Cardiovascular Risk Factors conducted in Turkey: Obesity Data. Archives Turkish Soc Cardiol. 2018;46(7):577-90. doi: 10.5543/tkda.2018.62200.
23. Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, Alexander JH, Pencina M, Toto RD, Wanner C, Zinman B, Woerle HJ, Baanstra D, Pfarr E, Schnaidt S, Meinicke T, George JT, von Eynatten M, McGuire DK; CARMELINA Investigators. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk. JAMA. 2019 Jan 1;321(1):69-79. doi: 10.1001/jama.2018.18269.
24. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22. doi: 10.1056/ NEJMoa1603827.
25. Scheen AJ. Pharmacokinetics and clinical use of incretin-based therapies in patients with chronic kidney disease and type 2 diabetes. Clin Pharmacokinet. 2015;54(1):1-21. doi: 10.1007/ s40262-014-0198-2.
26. Tonneijck L, Smits MM, Muskiet MHA, Hoekstra T, Kramer MHH, Danser AHJ, Diamant M, Joles JA, van Raalte DH. Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial. Diabetologia. 2016 Jul;59(7):1412-21. doi: 10.1007/s00125-016-3938-z.
27. Bulum T, Prkačin I, Duvnjak L. Treatment with a glucagon-like peptıde-1 receptor agonist exenatide decreases albuminuria in overweight type 2 diabetic patients. Nephrol Dial Transplant. 2016;31(suppl_1):i487-i487. doi: 10.1093/ndt/gfw193.18.
28. Cherney DZI, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus M, von Eynatten M, Wanner C. 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 Aug;5(8):610- 21. doi: 10.1016/S2213-8587(17)30182-1.