{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T09:21:52Z","timestamp":1792142512321,"version":"4.4.0"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T00:00:00Z","timestamp":1721606400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T00:00:00Z","timestamp":1721606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","award":["777460"],"award-info":[{"award-number":["777460"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Aims\/hypothesis<\/jats:title>\n                <jats:p>Whether hypoglycaemia increases the risk of other adverse outcomes in diabetes remains controversial, especially for hypoglycaemia episodes not requiring assistance from another person. An objective of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project was to create and use a dataset of pooled clinical trials in people with type 1 or type 2 diabetes to examine the association of exposure to all hypoglycaemia episodes across the range of severity with incident event outcomes: death, CVD, neuropathy, kidney disease, retinal disorders and depression. We also examined the change in continuous outcomes that occurred following a hypoglycaemia episode: change in eGFR, HbA<jats:sub>1c<\/jats:sub>, blood glucose, blood glucose variability and weight.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Data from 84 trials with 39,373 participants were pooled. For event outcomes, time-updated Cox regression models adjusted for age, sex, diabetes duration and HbA<jats:sub>1<jats:italic>c<\/jats:italic><\/jats:sub> were fitted to assess association between: (1) outcome and cumulative exposure to hypoglycaemia episodes; and (2) outcomes where an acute effect might be expected (i.e. death, acute CVD, retinal disorders) and any hypoglycaemia exposure within the last 10 days. Exposures to any hypoglycaemia episode and to episodes of given severity (levels 1, 2 and 3) were examined. Further adjustment was then made for a wider set of potential confounders. The within-person change in continuous outcomes was also summarised (median of 40.4 weeks for type 1 diabetes and 26 weeks for type 2 diabetes). Analyses were conducted separately by type of diabetes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The maximally adjusted association analysis for type 1 diabetes found that cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of neuropathy, kidney disease, retinal disorders and depression, with risk ratios ranging from 1.55 (<jats:italic>p<\/jats:italic>=0.002) to 2.81 (<jats:italic>p<\/jats:italic>=0.002). Associations of a similar direction were found when level 1 episodes were examined separately but were significant for depression only. For type 2 diabetes cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of death, acute CVD, kidney disease, retinal disorders and depression, with risk ratios ranging from 2.35 (<jats:italic>p<\/jats:italic>&lt;0.0001) to 3.00 (<jats:italic>p<\/jats:italic>&lt;0.0001). These associations remained significant when level 1 episodes were examined separately. There was evidence of an association between hypoglycaemia episodes of any kind in the previous 10 days and death, acute CVD and retinal disorders in both type 1 and type 2 diabetes, with rate ratios ranging from 1.32 (<jats:italic>p<\/jats:italic>=0.017) to 2.68 (<jats:italic>p<\/jats:italic>&lt;0.0001). These associations varied in magnitude and significance when examined separately by hypoglycaemia level. Within the range of hypoglycaemia defined by levels 1, 2 and 3, we could not find any evidence of a threshold at which risk of these consequences suddenly became pronounced.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions\/interpretation<\/jats:title>\n                <jats:p>These data are consistent with hypoglycaemia being associated with an increased risk of adverse events across several body systems in diabetes. These associations are not confined to severe hypoglycaemia requiring assistance.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical Abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1007\/s00125-024-06225-1","type":"journal-article","created":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T04:01:39Z","timestamp":1721620899000},"page":"2210-2224","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Estimating risk of consequences following hypoglycaemia exposure using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical 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The repository will be maintained for a 2 year period following the end of the Hypo-RESOLVE project. Enquiries about third-party researcher data access and associated access criteria should be sent to the Hypo-RESOLVE data access committee (Chair: Jakob Haardt, J.Haardt@eurice.eu\/Mark Ibberson, Mark.Ibberson@sib.swiss; or via ).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 777460. The JU receives support from the European Union\u2019s Horizon 2020 research and innovation programme and EFPIA and T1DExchange, JDRF, IDF, HCT. The industry partners supporting the JU include Abbott Diabetes Care, Eli Lilly, Medtronic, Novo Nordisk and Sanofi-Aventis. Results reflects only the authors\u2019 view and JU is not responsible for any use that may be made of the information it contains. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"HMC has research grants from JDRF and Diabetes UK. She has participated in a speakers' bureau, on an advisory board for Novo Nordisk and on an advisory panel for Bayer AG, and is a shareholder of Roche Pharmaceuticals and Bayer AG. SH has participated on advisory boards for Eli Lilly and Novo Nordisk and in a speakers' bureau for Novo Nordisk, and received an honorarium via his institution from Medtronic. He has consulted for Vertex Pharma, Zucara Pharmaceuticals and Zealand Pharma. AS is an employee of, and holds shares in, Novo Nordisk. UP-B received a personal honorarium for lectures, presentations and for expert testimony from Sanofi and Novo Nordisk, and is a member of the editorial board of <i>Diabetologia<\/i>. BEdG is a member of the editorial board of <i>Diabetologia<\/i>. RJM received a personal honorarium for lectures and presentations from Sanofi and Novo Nordisk, and support for travel to lecture at an educational event from Sanofi. He is a non-executive member of NHS Tayside Health Board. MR is an employee of, and holds shares in, Eli Lilly and Company. SAA has served on advisory boards for Vertex Pharmaceuticals and spoken at educational events sponsored by Sanofi and Novo Nordisk. M-AG is an employee of, and holds shares in, Novo Nordisk. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"BEdG, UP-B, M-AG, MR, SAA, SH, JL, YQ, RJM, PMM and HMC contributed to the initial analysis plan including the literature review on important risk factors of hypoglycaemia that informed this analysis. DK, AS and MI were involved in data cleaning, harmonisation, quality control and databasing of the data. JM coded the data analysis. BEdG, UP-B, M-AG, MR, SAA, SH, JL, YQ, RJM, SM, LB, WB, PMM and HMC contributed to the interpretation of the data. JM and HMC drafted the initial manuscript. All authors made critically important contributions to manuscript revision and all authors approved the final version. HMC is the guarantor and, as such, is responsible for the integrity of the work as a whole.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}