{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T04:54:14Z","timestamp":1777870454313,"version":"3.51.4"},"reference-count":11,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T00:00:00Z","timestamp":1744416000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T00:00:00Z","timestamp":1744416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100001003","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001003","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Nephrol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Renin-angiotensin system inhibitors (RASi) and sodium glucose cotransporter inhibitors (SGLT2i) are known for their kidney protective properties, but both show significant residual risk in large outcome trials. In these trials, SGLT2i were introduced on top of RASi; the individual response to each drug is currently unclear. We therefore aimed to investigate the individual reactions to the angiotensin II receptor blocker (ARB) losartan and the SGLT2i empagliflozin and their combination on measured GFR (mGFR) and systolic blood pressure (SBP).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this double-blind, randomized, 4-armed, crossover study, 24 participants received 7\u00a0days of empagliflozin 10\u00a0mg once daily, losartan 50\u00a0mg once daily, combination therapy or matching placebo. We visualized individual drug response variability. We further explored predictors of mGFR and SBP changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>During empagliflozin administration, a greater than 10% reduction in mGFR was observed in 26% of participants receiving empagliflozin, in 30% of those receiving losartan, and in 39% among participants on combination therapy. In comparison, a greater than 10% reduction in SBP was observed in\u00a035% of participants on empagliflozin, in\u00a039% of those receiving losartan and in\u00a043% on combination therapy.\u00a0A large part of the participants who did not respond to one drug, did respond to the other drug or their combination. Monotherapy SGLT2i did not correlate with monotherapy ARB in mGFR change or SBP change.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our data show large individual variability in response to treatment with the ARB losartan and the SGLT2i empagliflozin. Clinicians should monitor treatment responses in patients and consider switching from one kidney protective drug to another in non-responders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s40620-025-02289-3","type":"journal-article","created":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T17:30:52Z","timestamp":1744479052000},"page":"1647-1653","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The systemic and kidney hemodynamic response to empagliflozin, losartan and their combination varies between individuals"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1128-2482","authenticated-orcid":false,"given":"Britt Eveline","family":"Wever","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosalie Annemien","family":"Scholtes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte Michelle","family":"Mosterd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne Clasien","family":"Hesp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark Martinus","family":"Smits","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiddo Jan Lambers","family":"Heerspink","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dani\u00ebl Henri","family":"van Raalte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,4,12]]},"reference":[{"issue":"4","key":"2289_CR1","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1681\/ASN.2016060666","volume":"28","author":"L Tonneijck","year":"2017","unstructured":"Tonneijck L, Muskiet MH, Smits MM, van Bommel EJ, Heerspink HJ, van Raalte DH, Joles JA (2017) Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment. J Am Soc Nephrol 28(4):1023\u20131039","journal-title":"J Am Soc Nephrol"},{"issue":"12","key":"2289_CR2","doi-asserted-by":"publisher","first-page":"3075","DOI":"10.2337\/dci22-0027","volume":"45","author":"IH de Boer","year":"2022","unstructured":"de Boer IH, Khunti K, Sadusky T, Tuttle KR, Neumiller JJ, Rhee CM, Rosas SE, Rossing P, Bakris G (2022) Diabetes management in chronic kidney disease: a consensus report by the american diabetes association (ADA) and kidney disease: improving global outcomes (KDIGO). Diabetes Care 45(12):3075\u20133090","journal-title":"Diabetes Care"},{"issue":"12","key":"2289_CR3","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1056\/NEJMoa011161","volume":"345","author":"BM Brenner","year":"2001","unstructured":"Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345(12):861\u2013869","journal-title":"N Engl J Med"},{"issue":"5","key":"2289_CR4","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1111\/nep.13839","volume":"26","author":"RA Scholtes","year":"2021","unstructured":"Scholtes RA, van Baar MJB, Kok MD, Bjornstad P, Cherney DZI, Joles JA, van Raalte DH (2021) Renal haemodynamic and protective effects of renoactive drugs in type 2 diabetes: Interaction with SGLT2 inhibitors. Nephrology (Carlton) 26(5):377\u2013390","journal-title":"Nephrology (Carlton)"},{"issue":"1","key":"2289_CR5","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1111\/dom.14864","volume":"25","author":"RA Scholtes","year":"2023","unstructured":"Scholtes RA, Mosterd CM, Hesp AC, Smits MM, Heerspink HJL, van Raalte DH (2023) Mechanisms underlying the blood pressure-lowering effects of empagliflozin, losartan and their combination in people with type 2 diabetes: a secondary analysis of a randomized crossover trial. Diabetes Obes Metab 25(1):198\u2013207","journal-title":"Diabetes Obes Metab"},{"issue":"6","key":"2289_CR6","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1097\/MNH.0000000000000447","volume":"27","author":"NMA Idzerda","year":"2018","unstructured":"Idzerda NMA, Pena MJ, Heerspink HJL (2018) Personalized medicine in diabetic kidney disease: a novel approach to improve trial design and patient outcomes. Curr Opin Nephrol Hypertens 27(6):426\u2013432","journal-title":"Curr Opin Nephrol Hypertens"},{"issue":"24","key":"2289_CR7","doi-asserted-by":"publisher","first-page":"1895","DOI":"10.1161\/CIRCULATIONAHA.122.061033","volume":"146","author":"RA Scholtes","year":"2022","unstructured":"Scholtes RA, Hesp AC, Mosterd CM, Geurts F, Hoorn EJ, Touw DJ, Krebber MM, Joles JA, Heerspink HJL, van Raalte DH (2022) Kidney hemodynamic effects of angiotensin receptor blockade, sodium-glucose cotransporter-2 inhibition alone, and their combination: a crossover randomized trial in people with type 2 diabetes. Circulation 146(24):1895\u20131897","journal-title":"Circulation"},{"issue":"8","key":"2289_CR8","doi-asserted-by":"publisher","first-page":"e129","DOI":"10.2337\/dc18-0394","volume":"41","author":"P Bjornstad","year":"2018","unstructured":"Bjornstad P, Laffel L, Tamborlane WV, Simons G, Hantel S, von Eynatten M, George J, Marquard J, Cherney DZI (2018) Acute effect of empagliflozin on fractional excretion of sodium and egfr in youth with type 2 diabetes. Diabetes Care 41(8):e129\u2013e130","journal-title":"Diabetes Care"},{"issue":"2","key":"2289_CR9","doi-asserted-by":"publisher","first-page":"440","DOI":"10.2337\/dc20-2604","volume":"44","author":"RA Scholtes","year":"2021","unstructured":"Scholtes RA, Muskiet MHA, van Baar MJB, Hesp AC, Greasley PJ, Karlsson C, Hammarstedt A, Arya N, van Raalte DH, Heerspink HJL (2021) Natriuretic effect of two weeks of dapagliflozin treatment in patients with type 2 diabetes and preserved kidney function during standardized sodium intake: results of the dapasalt trial. Diabetes Care 44(2):440\u2013447","journal-title":"Diabetes Care"},{"issue":"6","key":"2289_CR10","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1016\/j.kint.2024.03.019","volume":"105","author":"K Yau","year":"2024","unstructured":"Yau K, Cherney DZI, van Raalte DH, Wever BE (2024) Kidney protective mechanisms of SGLT2 inhibitors: evidence for a hemodynamic effect. Kidney Int 105(6):1168\u20131172","journal-title":"Kidney Int"},{"issue":"3","key":"2289_CR11","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1038\/ki.2011.79","volume":"80","author":"FA Holtkamp","year":"2011","unstructured":"Holtkamp FA, de Zeeuw D, Thomas MC, Cooper ME, de Graeff PA, Hillege HJ, Parving HH, Brenner BM, Shahinfar S, Lambers Heerspink HJ (2011) An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int 80(3):282\u2013287","journal-title":"Kidney Int"}],"container-title":["Journal of Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40620-025-02289-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40620-025-02289-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40620-025-02289-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T15:59:31Z","timestamp":1777564771000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/joneph\/article\/38\/6\/1647\/8457517"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,12]]},"references-count":11,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["2289"],"URL":"https:\/\/doi.org\/10.1007\/s40620-025-02289-3","relation":{},"ISSN":["1724-6059"],"issn-type":[{"value":"1724-6059","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,12]]},"assertion":[{"value":"24 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 March 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 April 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"B.E.W., R.A.S., A.C.H., and C.M.M. report no conflicts of interest. M.M.S. has acted as a consultant for Novo Nordisk. D.H.vR. has acted as a consultant for and received honoraria from Boehringer Ingelheim-Eli Lilly Alliance, Merck, Sanofi, and AstraZeneca, and has received research operating funds from Boehringer Ingelheim-Lilly Diabetes Alliance, AstraZeneca, and Merck. All honoraria are paid to the employer Amsterdam University Medical Center. HJLH reports funding to conduct clinical trials from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and Novo Nordisk (all to the University of Groningen); consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Behring, DImerix, Eli Lilly, Fresenius, Gilead, Janssen, Novo Nordisk, Novartis, and Travere Therapeutics; payment of honoraria for lectures from AstraZeneca, Novo Nordisk, and Bayer; support for traveling to and attending the American Diabetes Association meeting and American Society of Nephrology meeting from AstraZeneca and Eli Lilly (to HJLH and the University of Groningen); and receipt of the study drug from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and Novo Nordisk.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"The RECOLAR study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of the VU University Medical Center (RECOLAR: protocol code DC2019RECOLAR01, date of approval 16 September, 2020).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"The study was registered at ClincialTrials.gov (ID: NCT04238702). The local authorities and medical ethical review board of the VU University Medical Center (Amsterdam, The Netherlands METc no. NL71049.029.19) approved all protocol-specific documents, and all study procedures were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and animal rights"}},{"value":"Informed consent was obtained from all subjects involved in the study.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}