Separate and combined effects of semaglutide and empagliflozin on kidney oxygenation and perfusion in people with type 2 diabetes: a randomised trial.
Glucagon-like peptide-1 receptor agonist
Kidney
MRI
Sodium–glucose cotransporter 2 inhibitor
Type 2 diabetes
Journal
Diabetologia
ISSN: 1432-0428
Titre abrégé: Diabetologia
Pays: Germany
ID NLM: 0006777
Informations de publication
Date de publication:
05 2023
05 2023
Historique:
received:
26
09
2022
accepted:
30
11
2022
pubmed:
7
2
2023
medline:
28
3
2023
entrez:
6
2
2023
Statut:
ppublish
Résumé
Glucagon-like peptide-1 receptor agonists (GLP-1ras) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown kidney-protective effects. Improved kidney oxygenation and haemodynamic changes are suggested mechanisms; however, human data are scarce. We therefore investigated whether semaglutide (GLP-1ra), empagliflozin (SGLT2i) or their combination improve kidney oxygenation and perfusion. The trial was undertaken at Aarhus University Hospital, Denmark. A total of 120 people with type 2 diabetes (HbA Our model estimated a common baseline R2* value across all four groups in the cortex and the medulla. At baseline, the value was 24.5 (95% CI 23.9, 24.9) Hz in the medulla. After 32 weeks, the R2* values in the medulla were estimated to be 25.4 (95% CI 24.7, 26.2) Hz in the empagliflozin group and 24.5 (95% CI 23.9, 25.1) Hz in the placebo group (p=0.016) (higher R2* corresponds to a lower oxygenation). Semaglutide decreased perfusion in both the cortex and the medulla. Empagliflozin increased erythropoietin and haematocrit. All three active treatments decreased GFR but not UACR. Ten serious adverse events were reported, among them two occurrences of semaglutide-associated obstipation. Our hypothesis, that semaglutide, empagliflozin or their combination improve kidney oxygenation, was rejected. On the contrary, empagliflozin induced a reduction in medullary kidney oxygenation. Semaglutide substantially reduced kidney perfusion without affecting oxygenation. Clinicaltrialsregister.eu EudraCT 2019-000781-38 FUNDING: Novo Nordisk Foundation, Central Denmark Region Research Fund and Danish Medical Associations Research Foundation.
Identifiants
pubmed: 36746803
doi: 10.1007/s00125-023-05876-w
pii: 10.1007/s00125-023-05876-w
doi:
Substances chimiques
Hypoglycemic Agents
0
semaglutide
53AXN4NNHX
empagliflozin
HDC1R2M35U
Erythropoietin
11096-26-7
Types de publication
Randomized Controlled Trial
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
813-825Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 14(2):88–98. https://doi.org/10.1038/nrendo.2017.151
doi: 10.1038/nrendo.2017.151
pubmed: 29219149
Porrini E, Ruggenenti P, Mogensen CE et al (2015) Non-proteinuric pathways in loss of renal function in patients with type 2 diabetes. Lancet Diabetes Endocrinol 3(5):382–391. https://doi.org/10.1016/s2213-8587(15)00094-7
doi: 10.1016/s2213-8587(15)00094-7
pubmed: 25943757
López-Novoa JM, Martínez-Salgado C, Rodríguez-Peña AB, Hernández FJL (2010) Common pathophysiological mechanisms of chronic kidney disease: therapeutic perspectives. Pharmacol Ther 128(1):61–81. https://doi.org/10.1016/j.pharmthera.2010.05.006
doi: 10.1016/j.pharmthera.2010.05.006
pubmed: 20600306
Perkovic V, Jardine MJ, Neal B et al (2019) Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 380(24):2295–2306. https://doi.org/10.1056/NEJMoa1811744
doi: 10.1056/NEJMoa1811744
pubmed: 30990260
Heerspink HJL, Stefansson BV, Correa-Rotter R et al (2020) Dapagliflozin in patients with chronic kidney disease. N Engl J Med 383(15):1436–1446. https://doi.org/10.1056/NEJMoa2024816
doi: 10.1056/NEJMoa2024816
pubmed: 32970396
Herrington WG, Staplin N, Wanner C et al (2022) Empagliflozin in patients with chronic kidney disease. N Engl J Med. https://doi.org/10.1056/NEJMoa2204233
Sattar N, Lee MMY, Kristensen SL et al (2021) Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol 9(10):653–662. https://doi.org/10.1016/s2213-8587(21)00203-5
doi: 10.1016/s2213-8587(21)00203-5
pubmed: 34425083
Fine LG, Orphanides C, Norman JT (1998) Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int Suppl 65:S74–S78
pubmed: 9551436
Yin WJ, Liu F, Li XM et al (2012) Noninvasive evaluation of renal oxygenation in diabetic nephropathy by BOLD-MRI. Eur J Radiol 81(7):1426–1431. https://doi.org/10.1016/j.ejrad.2011.03.045
doi: 10.1016/j.ejrad.2011.03.045
pubmed: 21470811
Milani B, Ansaloni A, Sousa-Guimaraes S et al (2017) Reduction of cortical oxygenation in chronic kidney disease: evidence obtained with a new analysis method of blood oxygenation level-dependent magnetic resonance imaging. Nephrol Dial Transplant 32(12):2097–2105. https://doi.org/10.1093/ndt/gfw362
doi: 10.1093/ndt/gfw362
pubmed: 27798200
Sørensen SS, Gullaksen S, Vernstrøm L et al (2022) Evaluation of renal oxygenation by BOLD–MRI in high-risk patients with type 2 diabetes and matched controls. Nephrol Dial Transplant. https://doi.org/10.1093/ndt/gfac186
Prasad PV, Thacker J, Li LP et al (2015) Multi-parametric evaluation of chronic kidney disease by MRI: a preliminary cross-sectional study. PLoS One 10(10):1–14. https://doi.org/10.1371/journal.pone.0139661
doi: 10.1371/journal.pone.0139661
Pruijm M, Milani B, Pivin E et al (2018) Reduced cortical oxygenation predicts a progressive decline of renal function in patients with chronic kidney disease. Kidney Int 93(4):932–940. https://doi.org/10.1016/j.kint.2017.10.020
doi: 10.1016/j.kint.2017.10.020
pubmed: 29325997
Thelwall PE, Taylor R, Marshall SM (2011) Non-invasive investigation of kidney disease in type 1 diabetes by magnetic resonance imaging. Diabetologia 54(9):2421–2429. https://doi.org/10.1007/s00125-011-2163-z
doi: 10.1007/s00125-011-2163-z
pubmed: 21533898
Hesp AC, Schaub JA, Prasad PV et al (2020) The role of renal hypoxia in the pathogenesis of diabetic kidney disease: a promising target for newer renoprotective agents including SGLT2 inhibitors? Kidney Int 98(3):579–589. https://doi.org/10.1016/j.kint.2020.02.041
doi: 10.1016/j.kint.2020.02.041
pubmed: 32739206
pmcid: 8397597
Laursen JC, Søndergaard-Heinrich N, de Melo JML et al (2021) Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: a randomised, double-blind, placebo-controlled crossover trial. eClinicalMedicine 37:100895. https://doi.org/10.1016/j.eclinm.2021.100895
doi: 10.1016/j.eclinm.2021.100895
pubmed: 34386735
pmcid: 8343250
Zhou S, Zhang Y, Wang T et al (2021) Canagliflozin could improve the levels of renal oxygenation in newly diagnosed type 2 diabetes patients with normal renal function. Diabetes Metab 47(5):101274. https://doi.org/10.1016/j.diabet.2021.101274
doi: 10.1016/j.diabet.2021.101274
pubmed: 34481963
Zanchi A, Burnier M, Muller ME et al (2020) Acute and chronic effects of SGLT2 inhibitor empagliflozin on renal oxygenation and blood pressure control in nondiabetic normotensive subjects: a randomized, placebo-controlled trial. J Am Heart Assoc 9(13):e016173. https://doi.org/10.1161/JAHA.119.016173
doi: 10.1161/JAHA.119.016173
pubmed: 32567439
pmcid: 7670540
Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R (2016) SGLT2 inhibitors and the diabetic kidney. Diabetes Care 39(Suppl 2):S165–S171. https://doi.org/10.2337/dcS15-3006
doi: 10.2337/dcS15-3006
pubmed: 27440829
van Bommel EJM, Muskiet MHA, van Baar MJB et al (2020) 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 97(1):202–212. https://doi.org/10.1016/j.kint.2019.09.013
doi: 10.1016/j.kint.2019.09.013
pubmed: 31791665
Lee MMY, Gillis KA, Brooksbank KJM et al (2022) Effect of empagliflozin on kidney biochemical and imaging outcomes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF). Circulation 146(4):364–367. https://doi.org/10.1161/CIRCULATIONAHA.122.059851
doi: 10.1161/CIRCULATIONAHA.122.059851
pubmed: 35877829
Skov J, Pedersen M, Holst JJ et al (2016) Short-term effects of liraglutide on kidney function and vasoactive hormones in type 2 diabetes: a randomized clinical trial. Diabetes Obes Metab 18(6):581–589. https://doi.org/10.1111/dom.12651
doi: 10.1111/dom.12651
pubmed: 26910107
Asmar A, Simonsen L, Asmar M et al (2016) Glucagon-like peptide-1 does not have acute effects on central or renal hemodynamics in patients with type 2 diabetes without nephropathy. Am J Physiol Endocrinol Metab 310(9):E744–E753. https://doi.org/10.1152/ajpendo.00518.2015
doi: 10.1152/ajpendo.00518.2015
pubmed: 26956188
Wen J, Trolle C, Viuff MH et al (2018) Impaired aortic distensibility and elevated central blood pressure in Turner Syndrome: a cardiovascular magnetic resonance study. J Cardiovasc Magn Reson 20(1):80. https://doi.org/10.1186/s12968-018-0497-0
doi: 10.1186/s12968-018-0497-0
pubmed: 30541571
pmcid: 6292015
Nery F, Buchanan CE, Harteveld AA et al (2020) Consensus-based technical recommendations for clinical translation of renal ASL MRI. MAGMA 33(1):141–161. https://doi.org/10.1007/s10334-019-00800-z
doi: 10.1007/s10334-019-00800-z
pubmed: 31833014
Geist BK (2019) Calculation of GFR via the slope-intercept method in nuclear medicine. IntechOpen, London
Pruijm M, Hofmann L, Maillard M et al (2010) Effect of sodium loading/depletion on renal oxygenation in young normotensive and hypertensive men. Hypertension 55(5):1116–1122. https://doi.org/10.1161/HYPERTENSIONAHA.109.149682
doi: 10.1161/HYPERTENSIONAHA.109.149682
pubmed: 20308608
Pruijm M, Hofmann L, Charollais-Thoenig J et al (2013) Effect of dark chocolate on renal tissue oxygenation as measured by BOLD-MRI in healthy volunteers. Clin Nephrol 80(3):211–217. https://doi.org/10.5414/CN107897
doi: 10.5414/CN107897
pubmed: 23557792
Fitzmaurice G, Laird N, Ware J (2011) Applied longitudinal analysis, 2nd edn. John Wileys, Hoboken, NJ
doi: 10.1002/9781119513469
Wang ZJ, Kumar R, Banerjee S, Hsu C-Y (2011) Blood oxygen level-dependent (BOLD) MRI of diabetic nephropathy: preliminary experience. J Magn Reson Imaging 33(3):655–660. https://doi.org/10.1002/jmri.22501
doi: 10.1002/jmri.22501
pubmed: 21563249
pmcid: 3573698
Pruijm M, Hofmann L, Piskunowicz M et al (2014) Determinants of renal tissue oxygenation as measured with BOLD-MRI in chronic kidney disease and hypertension in humans. PLoS One 9(4):e95895. https://doi.org/10.1371/journal.pone.0095895
doi: 10.1371/journal.pone.0095895
pubmed: 24760031
pmcid: 3997480
Khatir DS, Pedersen M, Jespersen B, Buus NH (2015) Evaluation of renal blood flow and oxygenation in CKD using magnetic resonance imaging. Am J Kidney Dis 66(3):402–411. https://doi.org/10.1053/j.ajkd.2014.11.022
doi: 10.1053/j.ajkd.2014.11.022
pubmed: 25618188
O'Neill J, Fasching A, Pihl L, Patinha D, Franzén S, Palm F (2015) Acute SGLT inhibition normalizes O
doi: 10.1152/ajprenal.00689.2014
pubmed: 26041448
Hare GMT, Zhang Y, Chin K et al (2021) Impact of sodium glucose linked cotransporter-2 inhibition on renal microvascular oxygen tension in a rodent model of diabetes mellitus. Physiol Rep 9(12):e14890. https://doi.org/10.14814/phy2.14890
doi: 10.14814/phy2.14890
pubmed: 34184431
pmcid: 8239445
Layton AT, Vallon V, Edwards A (2016) Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron. Am J Physiol Renal Physiol 310(11):F1269–F1283. https://doi.org/10.1152/ajprenal.00543.2015
doi: 10.1152/ajprenal.00543.2015
pubmed: 26764207
pmcid: 4935777
Inzucchi SE, Zinman B, Fitchett D et al (2017) How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 41(2):356–363. https://doi.org/10.2337/dc17-1096
doi: 10.2337/dc17-1096
pubmed: 29203583
Vallon V, Thomson SC (2020) The tubular hypothesis of nephron filtration and diabetic kidney disease. Nat Rev Nephrol 16(6):317–336. https://doi.org/10.1038/s41581-020-0256-y
doi: 10.1038/s41581-020-0256-y
pubmed: 32152499
pmcid: 7242158
Hviid AVR, Sorensen CM (2020) Glucagon-like peptide-1 receptors in the kidney: impact on renal autoregulation. Am J Physiol Renal Physiol 318(2):F443–F454. https://doi.org/10.1152/ajprenal.00280.2019
doi: 10.1152/ajprenal.00280.2019
pubmed: 31841385
Carretero Gómez J, Ena J, Seguí Ripoll JM et al (2020) Early biomarkers of diabetic kidney disease. A focus on albuminuria and a new combination of antidiabetic agents. Int J Clin Pract 74(10):e13586. https://doi.org/10.1111/ijcp.13586
doi: 10.1111/ijcp.13586
pubmed: 32533906
van Ruiten CC, van der Aart-van der Beek AB, IJzerman RG et al (2021) 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 23(8):1851–1858. https://doi.org/10.1111/dom.14410
doi: 10.1111/dom.14410
pubmed: 33908691
pmcid: 8360098
Levey AS, Coresh J, Tighiouart H, Greene T, Inker LA (2020) Measured and estimated glomerular filtration rate: current status and future directions. Nat Rev Nephrol 16(1):51–64. https://doi.org/10.1038/s41581-019-0191-y
doi: 10.1038/s41581-019-0191-y
pubmed: 31527790
Bane O, Mendichovszky IA, Milani B et al (2020) Consensus-based technical recommendations for clinical translation of renal BOLD MRI. MAGMA 33(1):199–215. https://doi.org/10.1007/s10334-019-00802-x
doi: 10.1007/s10334-019-00802-x
pubmed: 31768797
van Dam RM, Hu FB, Willett WC (2020) Coffee, caffeine, and health. N Engl J Med 383(4):369–378. https://doi.org/10.1056/NEJMra1816604
doi: 10.1056/NEJMra1816604
pubmed: 32706535