{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T18:36:31Z","timestamp":1793903791315,"version":"4.8.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"vor","delay-in-days":33,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100007797","name":"University of Helsinki","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007797","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cardiovasc Diabetol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Soluble receptor for advanced glycation end-products (sRAGE) modulates RAGE-mediated inflammation and oxidative stress. We investigated if sRAGE stratifies cardiovascular and kidney disease risk in individuals with type 1 diabetes and baseline treatment-resistant hypertension (TRH).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study included 1262 adults with type 1 diabetes from the FinnDiane study who were on antihypertensive therapy and whose sRAGE concentration was measured at baseline. Participants were divided into groups: controlled blood pressure (BP) (n\u2009=\u2009295), uncontrolled BP (n\u2009=\u2009730) or TRH (n\u2009=\u2009237). Prospective analyses were performed in those with baseline TRH. Of them, 62 developed coronary artery disease (CAD) and 38 stroke (median follow-up 12\u00a0years), while 99 progressed to end-stage kidney disease (ESKD) (median follow-up 9.2\u00a0years).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Every 100 units increase in baseline sRAGE was associated with 4% higher odds for TRH, compared to those with uncontrolled BP (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.003), and 6% higher odds than those with controlled BP (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0006). Associations attenuated after adjusting for kidney markers. In the competing risk analysis, higher sRAGE was associated with greater risk of CAD (SHR 1.05,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.01) in those with TRH. After adjusting for eGFR, the association attenuated (SHR 1.04,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.052), but the same trend remained. sRAGE was not associated with stroke. Furthermore, sRAGE was associated with higher risk of ESKD (SHR 1.06,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.0001), but no longer after adjusting for eGFR (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.4).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Elevated sRAGE is associated with increased odds of TRH in individuals with type 1 diabetes. sRAGE further stratifies high risk of incident CAD and ESKD, even after accounting for clinical variables. Along with eGFR, sRAGE may help to identify individuals at the highest risk of adverse cardiovascular and kidney outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12933-025-03017-8","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T10:47:35Z","timestamp":1765536455000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Soluble RAGE further stratifies risk of coronary artery and end-stage kidney disease in high-risk individuals with type 1 diabetes and treatment-resistant hypertension"],"prefix":"10.1186","volume":"25","author":[{"given":"Krishna","family":"Adeshara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raija","family":"Lithovius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Mutter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valma","family":"Harjutsalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markku","family":"Lehto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per-Henrik","family":"Groop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niina","family":"Sandholm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the FinnDiane Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"3017_CR1","doi-asserted-by":"publisher","first-page":"709","DOI":"10.2337\/dc13-2023","volume":"37","author":"R Lithovius","year":"2014","unstructured":"Lithovius R, Harjutsalo V, Forsblom C, Saraheimo M, Groop PH, FinnDiane Study Group. Antihypertensive treatment and resistant hypertension in patients with type 1 diabetes by stages of diabetic nephropathy. Diabetes Care. 2014;37:709\u201317.","journal-title":"Diabetes Care"},{"key":"3017_CR2","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1016\/j.jash.2014.03.003","volume":"8","author":"MR Irvin","year":"2014","unstructured":"Irvin MR, Booth JN III, Shimbo D, et al. Apparent treatment-resistant hypertension and risk for stroke, coronary heart disease, and all-cause mortality. J Am Soc Hypertens. 2014;8:405\u201313.","journal-title":"J Am Soc Hypertens"},{"issue":"6","key":"3017_CR3","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1093\/ajh\/hpae020","volume":"37","author":"G Bakris","year":"2024","unstructured":"Bakris G, Chen C, Campbell AK, Ashton V, Haskell L, Singhal M. Real-world impact of blood pressure control in patients with apparent treatment-resistant or difficult-to-control hypertension and stages 3 and 4 chronic kidney disease. Am J Hypertens. 2024;37(6):438\u201346.","journal-title":"Am J Hypertens"},{"issue":"8","key":"3017_CR4","doi-asserted-by":"publisher","first-page":"1885","DOI":"10.2337\/dc20-0170","volume":"43","author":"R Lithovius","year":"2020","unstructured":"Lithovius R, Harjutsalo V, Mutter S, Gordin D, Forsblom C, Groop PH, et al. resistant hypertension and risk of adverse events in individuals with type 1 diabetes: a nationwide prospective study. Diabetes Care. 2020;43(8):1885\u201392.","journal-title":"Diabetes Care"},{"key":"3017_CR5","doi-asserted-by":"publisher","first-page":"1184","DOI":"10.2741\/e178","volume":"2","author":"S Yamagishi","year":"2010","unstructured":"Yamagishi S, Matsui T. Soluble form of a receptor for advanced glycation end products (sRAGE) as a biomarker. Front Biosci (Elite Ed). 2010;2:1184\u201395.","journal-title":"Front Biosci (Elite Ed)"},{"issue":"16","key":"3017_CR6","doi-asserted-by":"publisher","first-page":"3942","DOI":"10.3390\/ijms20163942","volume":"20","author":"B Gryszczy\u0144ska","year":"2019","unstructured":"Gryszczy\u0144ska B, Budzy\u0144 M, Begier-Krasi\u0144ska B, Osi\u0144ska A, Boruczkowski M, Kaczmarek M, et al. Association between advanced glycation end products, soluble RAGE receptor, and endothelium dysfunction, evaluated by circulating endothelial cells and endothelial progenitor cells in patients with mild and resistant hypertension. Int J Mol Sci. 2019;20(16):3942.","journal-title":"Int J Mol Sci"},{"issue":"7","key":"3017_CR7","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1007\/s00125-019-4883-4","volume":"62","author":"JM Wad\u00e9n","year":"2019","unstructured":"Wad\u00e9n JM, Dahlstr\u00f6m EH, Elonen N, Thorn LM, Wad\u00e9n J, Sandholm N, et al. Soluble receptor for AGE in diabetic nephropathy and its progression in Finnish individuals with type 1 diabetes. Diabetologia. 2019;62(7):1268\u201374.","journal-title":"Diabetologia"},{"issue":"3","key":"3017_CR8","doi-asserted-by":"publisher","first-page":"102441","DOI":"10.1016\/j.dsx.2022.102441","volume":"16","author":"KA Adeshara","year":"2022","unstructured":"Adeshara KA, Bangar N, Diwan AG, Tupe RS. Plasma glycation adducts and various RAGE isoforms are intricately associated with oxidative stress and inflammatory markers in type 2 diabetes patients with vascular complications. Diabetes Metab Syndr. 2022;16(3):102441.","journal-title":"Diabetes Metab Syndr"},{"issue":"453","key":"3017_CR9","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.cca.2015.12.002","volume":"30","author":"FN Wong","year":"2016","unstructured":"Wong FN, Tan JA, Keng TC, Ng KP, Chua KH, Kuppusamy UR. Association between plasma soluble RAGE and renal function is unaffected by medication usage and enzymatic antioxidants in chronic kidney disease with type 2 diabetes. Clin Chim Acta. 2016;30(453):56\u201361.","journal-title":"Clin Chim Acta"},{"issue":"10","key":"3017_CR10","doi-asserted-by":"publisher","first-page":"2669","DOI":"10.1007\/s00125-011-2186-5","volume":"54","author":"MC Thomas","year":"2011","unstructured":"Thomas MC, S\u00f6derlund J, Lehto M, M\u00e4kinen VP, Moran JL, Cooper ME, et al. Soluble receptor for AGE (RAGE) is a novel independent predictor of all-cause and cardiovascular mortality in type 1 diabetes. Diabetologia. 2011;54(10):2669\u201377.","journal-title":"Diabetologia"},{"issue":"9","key":"3017_CR11","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1038\/2012","volume":"4","author":"L Park","year":"1998","unstructured":"Park L, Raman KG, Lee KJ, Lu Y, Ferran LJ Jr, Chow WS, et al. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat Med. 1998;4(9):1025\u201331.","journal-title":"Nat Med"},{"issue":"2","key":"3017_CR12","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1097\/MCA.0b013e32834f114e","volume":"23","author":"SJ Yoon","year":"2012","unstructured":"Yoon SJ, Park S, Park C, Chang W, Cho DK, Ko YG, et al. Association of soluble receptor for advanced glycation end-product with increasing central aortic stiffness in hypertensive patients. Coron Artery Dis. 2012;23(2):85\u201390.","journal-title":"Coron Artery Dis"},{"issue":"2","key":"3017_CR13","doi-asserted-by":"publisher","first-page":"14","DOI":"10.4238\/gmr.15028414","volume":"15","author":"Q Liu","year":"2016","unstructured":"Liu Q, Chen HB, Luo M, Zheng H. Serum soluble RAGE level inversely correlates with left ventricular hypertrophy in essential hypertension patients. Genet Mol Res. 2016;15(2):14.","journal-title":"Genet Mol Res"},{"issue":"9","key":"3017_CR14","doi-asserted-by":"publisher","first-page":"604","DOI":"10.7326\/0003-4819-150-9-200905050-00006","volume":"150","author":"AS Levey","year":"2009","unstructured":"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\u201312.","journal-title":"Ann Intern Med"},{"issue":"Suppl. 1","key":"3017_CR15","first-page":"S32","volume":"23","author":"American Diabetes Association","year":"2000","unstructured":"American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2000;23(Suppl. 1):S32\u201342.","journal-title":"Diabetes Care"},{"issue":"446","key":"3017_CR16","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1080\/01621459.1999.10474144","volume":"94","author":"JP Fine","year":"1999","unstructured":"Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94(446):496\u2013509.","journal-title":"J Am Stat Assoc"},{"key":"3017_CR17","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1002\/dmrr.690","volume":"23","author":"K Nakamura","year":"2007","unstructured":"Nakamura K, Yamagishi S, Adachi H, Kurita-Nakamura Y, Matsui T, Yoshida T, et al. Elevation of soluble form of receptor for advanced glycation end products (sRAGE) in diabetic subjects with coronary artery disease. Diabetes Metab Res Rev. 2007;23:368\u201371.","journal-title":"Diabetes Metab Res Rev"},{"issue":"1","key":"3017_CR18","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1186\/s12933-022-01535-3","volume":"21","author":"J Sabbatinelli","year":"2022","unstructured":"Sabbatinelli J, Castiglione S, Macr\u00ec F, Giuliani A, Ramini D, Vinci MC, et al. Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study. Cardiovasc Diabetol. 2022;21(1):95.","journal-title":"Cardiovasc Diabetol"},{"issue":"9","key":"3017_CR19","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1016\/j.metabol.2014.05.011","volume":"63","author":"BI Hudson","year":"2014","unstructured":"Hudson BI, Dong C, Gardener H, Elkind MS, Wright CB, Goldberg R, et al. Serum levels of soluble receptor for advanced glycation end-products and metabolic syndrome: the Northern Manhattan Study. Metabolism. 2014;63(9):1125\u201330.","journal-title":"Metabolism"},{"issue":"4","key":"3017_CR20","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1055\/s-0042-1756175","volume":"31","author":"K Prasad","year":"2022","unstructured":"Prasad K. Involvement of AGE and Its receptors in the pathogenesis of hypertension in elderly people and its treatment. Int J Angiol. 2022;31(4):213\u201321.","journal-title":"Int J Angiol"},{"issue":"639","key":"3017_CR21","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.gene.2017.09.066","volume":"10","author":"Y Wang","year":"2018","unstructured":"Wang Y, Zhang W, Zhao H, Wang Y, Lu C, Li X, et al. Fasting blood soluble RAGE may be causally implicated in impaired glucose metabolism in Chinese patients with primary hypertension. Gene. 2018;10(639):11\u20137.","journal-title":"Gene"},{"key":"3017_CR22","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1097\/01.hjh.0000177535.45785.64","volume":"23","author":"D Geroldi","year":"2005","unstructured":"Geroldi D, Falcone C, Emanuele E, D\u2019Angelo A, Calcagnino M, Buzzi MP, et al. Decreased plasma levels of soluble receptor for advanced glycation end-products in patients with essential hypertension. J Hypertens. 2005;23:1725\u20139.","journal-title":"J Hypertens"},{"issue":"1\u20132","key":"3017_CR23","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.jns.2014.03.006","volume":"340","author":"L Xiao","year":"2014","unstructured":"Xiao L, Sun W, Lan W, Xiong Y, Duan Z, Zhang Z, et al. Correlation between cerebral microbleeds and S100B\/RAGE in acute lacunar stroke patients. J Neurol Sci. 2014;340(1\u20132):208\u201312.","journal-title":"J Neurol Sci"},{"issue":"1\u20132","key":"3017_CR24","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.jns.2009.09.013","volume":"287","author":"C Yokota","year":"2009","unstructured":"Yokota C, Minematsu K, Tomii Y, Naganuma M, Ito A, Nagasawa H, et al. Low levels of plasma soluble receptor for advanced glycation end products are associated with severe leukoaraiosis in acute stroke patients. J Neurol Sci. 2009;287(1\u20132):41\u20134.","journal-title":"J Neurol Sci"},{"issue":"4","key":"3017_CR25","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1007\/s12017-017-8471-9","volume":"19","author":"SC Tang","year":"2017","unstructured":"Tang SC, Yang KC, Hu CJ, Chiou HY, Wu CC, Jeng JS. Elevated plasma level of soluble form of RAGE in ischemic stroke patients with dementia. Neuromolecular Med. 2017;19(4):579\u201383.","journal-title":"Neuromolecular Med"},{"issue":"8","key":"3017_CR26","doi-asserted-by":"publisher","first-page":"2280","DOI":"10.1161\/STROKEAHA.107.505354","volume":"39","author":"J Montaner","year":"2008","unstructured":"Montaner J, Perea-Gainza M, Delgado P, Rib\u00f3 M, Chac\u00f3n P, Rosell A, et al. Etiologic diagnosis of ischemic stroke subtypes with plasma biomarkers. Stroke. 2008;39(8):2280\u20137.","journal-title":"Stroke"},{"issue":"5","key":"3017_CR27","doi-asserted-by":"publisher","first-page":"107061","DOI":"10.1016\/j.jstrokecerebrovasdis.2023.107061","volume":"32","author":"XH Chu","year":"2023","unstructured":"Chu XH, Hu HY, Godje ISG, Zhu LJ, Zhu JB, Feng YL, et al. Elevated HMGB1 and sRAGE levels in cerebrospinal fluid of aneurysmal subarachnoid hemorrhage patients. J Stroke Cerebrovasc Dis. 2023;32(5):107061.","journal-title":"J Stroke Cerebrovasc Dis"},{"issue":"1","key":"3017_CR28","doi-asserted-by":"publisher","first-page":"2353836","DOI":"10.1080\/08037051.2024.2353836","volume":"33","author":"Z Ram\u00edk","year":"2024","unstructured":"Ram\u00edk Z, V\u00e1clav\u00edk J, Kvapil T, Jel\u00ednek L, Koci\u00e1nov\u00e1 E, Kamasov\u00e1 M, et al. Long-term trajectory of renal dysfunction and related risk factors in patients with apparently treatment-resistant and non-resistant arterial hypertension. Blood Press. 2024;33(1):2353836.","journal-title":"Blood Press"},{"key":"3017_CR29","doi-asserted-by":"publisher","first-page":"2461","DOI":"10.1016\/j.jacc.2012.12.061","volume":"61","author":"L De Nicola","year":"2013","unstructured":"De Nicola L, Gabbai FB, Agarwal R, Chiodini P, Borrelli S, Bellizzi V, et al. Prevalence and prognostic role of resistant hypertension in chronic kidney disease patients. J Am Coll Cardiol. 2013;61:2461\u20137. https:\/\/doi.org\/10.1016\/j.jacc.2012.12.061.","journal-title":"J Am Coll Cardiol"},{"issue":"1","key":"3017_CR30","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1093\/ndt\/gfu282","volume":"30","author":"CM Rebholz","year":"2015","unstructured":"Rebholz CM, Astor BC, Grams ME, Halushka MK, Lazo M, Hoogeveen RC, et al. Association of plasma levels of soluble receptor for advanced glycation end products and risk of kidney disease: the Atherosclerosis risk in communities study. Nephrol Dial Transplant. 2015;30(1):77\u201383.","journal-title":"Nephrol Dial Transplant"},{"key":"3017_CR31","doi-asserted-by":"publisher","first-page":"638","DOI":"10.3390\/biomedicines8120638","volume":"8","author":"E Dozio","year":"2020","unstructured":"Dozio E, Vettoretti S, Caldiroli L, Nerini-Molteni S, Tacchini L, Ambrogi F, et al. Advanced glycation end products (AGE) and soluble forms of AGE receptor: emerging role as mortality risk factors in CKD. Biomedicines. 2020;8:638.","journal-title":"Biomedicines"},{"issue":"1","key":"3017_CR32","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1053\/j.ajkd.2008.06.018","volume":"53","author":"RD Semba","year":"2009","unstructured":"Semba RD, Ferrucci L, Fink JC, Sun K, Beck J, Dalal M, et al. Advanced glycation end products and their circulating receptors and level of kidney function in older community-dwelling women. Am J Kidney Dis. 2009;53(1):51\u20138.","journal-title":"Am J Kidney Dis"},{"issue":"1","key":"3017_CR33","first-page":"113","volume":"14","author":"M Gissler","year":"2004","unstructured":"Gissler M, Haukka J. Finnish health and social welfare registers in epidemiological research. Norsk epidemiol. 2004;14(1):113\u201320.","journal-title":"Norsk epidemiol"},{"key":"3017_CR34","doi-asserted-by":"crossref","unstructured":"Carey\u2008RM, Calhoun\u2008DA, Bakris\u2008GL, et al.; American heart association professional\/public education and publications committee of the council on hypertension; council on cardiovascular and stroke nursing; council on clinical cardiology; council on genomic and precision medicine; council on peripheral vascular disease; council on quality of care and outcomes research; and stroke council. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American heart association. Hypertension 2018; 72:e53\u2013e90","DOI":"10.1161\/HYP.0000000000000084"},{"key":"3017_CR35","unstructured":"Core R. Team. R: a language and environment for statistical computing [Internet]. Vienna, Austria, R Foundation for Statistical Computing, 2019."}],"container-title":["Cardiovascular Diabetology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12933-025-03017-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12933-025-03017-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12933-025-03017-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T15:07:06Z","timestamp":1768403226000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12933-025-03017-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,12]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3017"],"URL":"https:\/\/doi.org\/10.1186\/s12933-025-03017-8","relation":{},"ISSN":["1475-2840"],"issn-type":[{"value":"1475-2840","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,12]]},"assertion":[{"value":"4 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 December 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":"The study protocol is in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Helsinki and Uusimaa Hospital District (HUS) (491\/E5\/2006, 238\/13\/03\/00\/2015, and HUS-3313\u20132018, July 3rd 2019). All participants gave their informed written consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Not applicable. This study has not been registered as a clinical trial.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Clinical trial number"}},{"value":"P\u2013H.G. has received investigator-initiated research grants from Eli Lilly and Roche, lecture fees from Astellas, Astra Zeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Eli Lilly, Elo Water, Genzyme, Medscape, Menarini, Merck Sharp & Dohme, Mundipharma, Novartis, Novo Nordisk, PeerVoice, Sanofi and Sciarc. He is an advisory board member for AbbVie, Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, Cebix, Eli Lilly, Janssen, Medscape, Merck Sharp & Dohme, Mundipharma, Nestl\u00e9, Novartis, Novo Nordisk, and Sanofi. S.M. received lecture honoraria from Encore Medical Education. All other authors declared that they had no conflict of interest.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"13"}}