Renal hemodynamic effects differ between antidiabetic combination strategies: randomized controlled clinical trial comparing empagliflozin/linagliptin with metformin/insulin glargine
Christian Ott, Susanne Jung, Manuel Korn, Dennis Kannenkeril, Agnes Bosch, Julie Kolwelter, Kristina Striepe, Peter Bramlage, Mario Schiffer, Roland E Schmieder, Christian Ott, Susanne Jung, Manuel Korn, Dennis Kannenkeril, Agnes Bosch, Julie Kolwelter, Kristina Striepe, Peter Bramlage, Mario Schiffer, Roland E Schmieder
Abstract
Background: Type 2 diabetes causes cardio-renal complications and is treated with different combination therapies. The renal hemodynamics profile of such combination therapies has not been evaluated in detail.
Methods: Patients (N = 97) with type 2 diabetes were randomized to receive either empagliflozin and linagliptin (E+L group) or metformin and insulin glargine (M+I group) for 3 months. Renal hemodynamics were assessed with para-aminohippuric acid and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR). Intraglomerular hemodynamics were calculated according the Gomez´ model.
Results: Treatment with E+L reduced GFR (p = 0.003), but RPF remained unchanged (p = 0.536). In contrast, M+I not only reduced GFR (p = 0.001), but also resulted in a significant reduction of RPF (p < 0.001). Renal vascular resistance (RVR) decreased with E+L treatment (p = 0.001) but increased with M+I treatment (p = 0.001). The changes in RPF and RVR were different between the two groups (both padjust < 0.001). Analysis of intraglomerular hemodynamics revealed that E+L did not change resistance of afferent arteriole (RA) (p = 0.116), but diminished resistance of efferent arterioles (RE) (p = 0.001). In M+I group RA was increased (p = 0.006) and RE remained unchanged (p = 0.538). The effects on RA (padjust < 0.05) and on RE (padjust < 0.05) differed between the groups.
Conclusions: In patients with type 2 diabetes and preserved renal function treatment with M+I resulted in reduction of renal perfusion and increase in vascular resistance, in contrast to treatment with E+I that preserved renal perfusion and reduced vascular resistance. Moreover, different underlying effects on the resistance vessels have been estimated according to the Gomez model, with M+I increasing RA and E+L predominantly decreasing RE, which is in contrast to the proposed sodium-glucose cotransporter 2 inhibitor effects.
Trial registration: The study was registered at www.clinicaltrials.gov (NCT02752113) on April 26, 2016.
Keywords: Hemodynamics; Intraglomerular; Renal; Type 2 diabetes.
Conflict of interest statement
PB received research funding from Boehringer for this and other studies; RES has received speaker fees and advisory board fees from Boehringer Ingelheim Pharma GmbH & Co KG.
© 2021. The Author(s).
Figures
References
- Global Burden of Metabolic Risk Factors for Chronic Diseases Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment. Lancet Diabetes Endocrinol. 2014;2(8):634–47. doi: 10.1016/S2213-8587(14)70102-0.
- Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2015;58(3):429–42. doi: 10.1007/s00125-014-3460-0.
- Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Diabetologia. 2018;61(12):2461–98. doi: 10.1007/s00125-018-4729-5.
- Tonneijck L, Muskiet MH, Smits MM, van Bommel EJ, Heerspink HJ, van Raalte DH, et al. Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment. J Am Soc Nephrol. 2017;28(4):1023–1039. doi: 10.1681/ASN.2016060666.
- 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.
- Brenner BM, Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA. The role of glomerular hyperfiltration in the initiation and progression of diabetic nephropathy. Acta Endocrinol Suppl. 1981;242:7–10.
- Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–2128. doi: 10.1056/NEJMoa1504720.
- Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, 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.
- Giugliano D, De Nicola L, Maiorino MI, Bellastella G, Garofalo C, Chiodini P, et al. Preventing major adverse cardiovascular events by SGLT-2 inhibition in patients with type 2 diabetes: the role of kidney. Cardiovasc Diabetol. 2020;19(1):35. doi: 10.1186/s12933-020-01010-x.
- Giorgino F, Vora J, Fenici P, Solini A. Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk. Cardiovasc Diabetol. 2020;19(1):196. doi: 10.1186/s12933-020-01163-9.
- Yamada T, Wakabayashi M, Bhalla A, Chopra N, Miyashita H, Mikami T, et al. Cardiovascular and renal outcomes with SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and network meta-analysis. Cardiovasc Diabetol. 2021;20(1):14. doi: 10.1186/s12933-020-01197-z.
- Denic A, Mathew J, Lerman LO, Lieske JC, Larson JJ, Alexander MP, et al. Single-nephron glomerular filtration rate in healthy adults. N Engl J Med. 2017;376(24):2349–2357. doi: 10.1056/NEJMoa1614329.
- Arakawa K, Ishihara T, Oku A, Nawano M, Ueta K, Kitamura K, et al. Improved diabetic syndrome in C57BL/KsJ-db/db mice by oral administration of the Na(+)-glucose cotransporter inhibitor T-1095. Br J Pharmacol. 2001;132(2):578–586. doi: 10.1038/sj.bjp.0703829.
- Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129(5):587–597. doi: 10.1161/CIRCULATIONAHA.113.005081.
- van Bommel EJM, Muskiet MHA, van Baar MJB, Tonneijck L, Smits MM, Emanuel AL, et al. The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial. Kidney Int. 2020;97(1):202–212. doi: 10.1016/j.kint.2019.09.013.
- Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. The Diabetes Control and Complications (DCCT) Research Group. Kidney international. 1995;47(6):1703–20.
- Erpeldinger S, Rehman MB, Berkhout C, Pigache C, Zerbib Y, Regnault F, et al. Efficacy and safety of insulin in type 2 diabetes: meta-analysis of randomised controlled trials. BMC Endocr Disord. 2016;16(1):39. doi: 10.1186/s12902-016-0120-z.
- Jung S, Bosch A, Kannenkeril D, Karg MV, Striepe K, Bramlage P, et al. Combination of empagliflozin and linagliptin improves blood pressure and vascular function in type 2 diabetes. J Eur Heart J Cardiovasc Pharmacother. 2020;6(6):364–371. doi: 10.1093/ehjcvp/pvz078.
- Schmieder RE, Gatzka C, Schobel H, Schachinger H, Weihprecht H. Renal hemodynamic response to stress is influenced by ACE-inhibitors. Clin Nephrol. 1994;42(6):381–388.
- Delles C, Klingbeil AU, Schneider MP, Handrock R, Schaufele T, Schmieder RE. The role of nitric oxide in the regulation of glomerular haemodynamics in humans. Nephrol Dial transpl. 2004;19(6):1392–1397. doi: 10.1093/ndt/gfh187.
- Ott C, Schneider MP, Delles C, Schlaich MP, Schmieder RE. Reduction in basal nitric oxide activity causes albuminuria. Diabetes. 2011;60(2):572–576. doi: 10.2337/db09-1630.
- Smith HW, Finkelstein N, Aliminosa L, Crawford B, Graber M. The renal clearances of substituted hippuric acid derivatives and other aromatic acids in dog and man. J Clin Investig. 1945;24(3):388–404. doi: 10.1172/JCI101618.
- Gomez DM. Evaluation of renal resistances, with special reference to changes in essential hypertension. J Clin Investig. 1951;30(10):1143–1155. doi: 10.1172/JCI102534.
- Guidi E, Cozzi MG, Minetti EE, Civati G, Busnach G, Brando B. Effect of familial hypertension on glomerular hemodynamics and tubulo-glomerular feedback after uninephrectomy. Am J Hypertens. 2001;14(2):121–128. doi: 10.1016/S0895-7061(00)01238-3.
- Ott C, Ritt M, Titze SI, Schaufele T, Schmieder RE. Rosuvastatin does not affect intrarenal hemodynamics in patients with hypercholesterolemia. J Nephrol. 2009;22(5):675–681.
- Ott C, Schneider MP, Raff U, Ritt M, Striepe K, Alberici M, et al. Effects of manidipine vs. amlodipine on intrarenal haemodynamics in patients with arterial hypertension. Br J Clin Pharmacol. 2013;75(1):129–35. doi: 10.1111/j.1365-2125.2012.04336.x.
- Ott C, Kistner I, Keller M, Friedrich S, Willam C, Bramlage P, et al. Effects of linagliptin on renal endothelial function in patients with type 2 diabetes: a randomised clinical trial. Diabetologia. 2016;59(12):2579–2587. doi: 10.1007/s00125-016-4083-4.
- Cohen AJ, McCarthy DM, Stoff JS. Direct hemodynamic effect of insulin in the isolated perfused kidney. Am J Physiol. 1989;257(4 Pt 2):F580–F585.
- Juncos LA, Ito S. Disparate effects of insulin on isolated rabbit afferent and efferent arterioles. J Clin Investig. 1993;92(4):1981–1985. doi: 10.1172/JCI116792.
- Kidokoro K, Cherney DZI, Bozovic A, Nagasu H, Satoh M, Kanda E, et al. Evaluation of glomerular hemodynamic function by empagliflozin in diabetic mice using in vivo imaging. Circulation. 2019;140(4):303–315. doi: 10.1161/CIRCULATIONAHA.118.037418.
- Skrtic M, Yang GK, Perkins BA, Soleymanlou N, Lytvyn Y, von Eynatten M, et al. Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration. Diabetologia. 2014;57(12):2599–2602. doi: 10.1007/s00125-014-3396-4.
- Klessens CQ, Woutman TD, Veraar KA, Zandbergen M, Valk EJ, Rotmans JI, et al. An autopsy study suggests that diabetic nephropathy is underdiagnosed. Kidney Int. 2016;90(1):149–156. doi: 10.1016/j.kint.2016.01.023.
- Tonneijck L, Smits MM, Muskiet MH, Hoekstra T, Kramer MH, Danser AH, et al. Renal effects of DPP-4 inhibitor sitagliptin or GLP-1 receptor agonist liraglutide in overweight patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2016;39(11):2042–2050. doi: 10.2337/dc16-1371.
- Muskiet MHA, Tonneijck L, Smits MM, Kramer MHH, Ouwens DM, Hartmann B, et al. Effects of DPP-4 inhibitor linagliptin versus sulfonylurea glimepiride as add-on to metformin on renal physiology in overweight patients with type 2 diabetes (RENALIS): a randomized double-blind trial. Diabetes Care. 2020;43(11):2889–2893. doi: 10.2337/dc20-0902.
- Bjornstad P, Skrtic M, Lytvyn Y, Maahs DM, Johnson RJ, Cherney DZ. The Gomez' equations and renal hemodynamic function in kidney disease research. Am J Physiol Renal Physiol. 2016;311(5):F967–F975. doi: 10.1152/ajprenal.00415.2016.
- Cooper ME, Inzucchi SE, Zinman B, Hantel S, von Eynatten M, Wanner C, et al. Glucose control and the effect of empagliflozin on kidney outcomes in type 2 diabetes: an analysis from the EMPA-REG OUTCOME trial. Am J Kidney Dis. 2019;74(5):713–715. doi: 10.1053/j.ajkd.2019.03.432.
- Zhang Y, Nakano D, Guan Y, Hitomi H, Uemura A, Masaki T, et al. A sodium-glucose cotransporter 2 inhibitor attenuates renal capillary injury and fibrosis by a vascular endothelial growth factor-dependent pathway after renal injury in mice. Kidney Int. 2018;94(3):524–535. doi: 10.1016/j.kint.2018.05.002.
- Heerspink HJL, Perco P, Mulder S, Leierer J, Hansen MK, Heinzel A, et al. Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease. Diabetologia. 2019;62(7):1154–1166. doi: 10.1007/s00125-019-4859-4.
Source: PubMed