Mellor, J. orcid.org/0000-0003-1452-887X, Kuznetsov, D. orcid.org/0000-0002-9972-947X, Heller, S. orcid.org/0000-0002-2425-9565 et al. (15 more authors) (2024) Estimating risk of consequences following hypoglycaemia exposure using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials. Diabetologia, 67 (10). pp. 2210-2224. ISSN 0012-186X
Abstract
Aims/hypothesis
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, HbA1c, blood glucose, blood glucose variability and weight.
Methods
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 HbA1c 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.
Results
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 (p=0.002) to 2.81 (p=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 (p<0.0001) to 3.00 (p<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 (p=0.017) to 2.68 (p<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.
Conclusions/interpretation
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: | Consequences; Cox regression; Hypo-RESOLVE; Hypoglycaemia |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
Funding Information: | Funder Grant number EUROPEAN COMMISSION - HORIZON 2020 777460 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 21 Aug 2024 09:54 |
Last Modified: | 07 Oct 2024 10:41 |
Status: | Published |
Publisher: | Springer Science and Business Media LLC |
Refereed: | Yes |
Identification Number: | 10.1007/s00125-024-06225-1 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:216286 |