Sugar rush: are we one step closer to understanding the relationship between diabetes and ARDS?

There are syndromes within critical care that are defined by similar clinical features but lack a unifying pathology. One such example is ARDS, where heterogeneity in individual patient risk factors and underlying biology may be limiting success in identifying an effective pharmacotherapy.2Calfee C.S. Janz D.R. Bernard G.R. et al.Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies.Chest. 2015; 147: 1539-1548Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar,3Boyle A.J. Mac Sweeney R. McAuley D.F. Pharmacological treatments in ARDS; a state-of-the-art update.BMC Med. 2013; 11: 166Crossref PubMed Scopus (115) Google Scholar Ideally, clinicians and researchers would have a sophisticated taxonomy for patients with ARDS, enabling them to group patients based on a similar phenotype, genotype, or metabolome, before evaluating whether a targeted intervention works in that specific subgroup of patients.4Boyle A.J. Ferris P. Bradbury I. et al.Baseline plasma IL-18 may predict simvastatin treatment response in patients with ARDS: a secondary analysis of the HARP-2 randomised clinical trial.Crit Care. 2022; 26: 164Crossref Scopus (15) Google Scholar As part of this, there remains a need to improve our understanding about how individual patient characteristics modify their risk of developing ARDS. Such advances should assist with grouping similar patients, improving risk stratification, and identifying those patients most likely to respond to a specific intervention. One example of where there remains uncertainty about individual patient characteristics that may modify their risk for ARDS is diabetes, where existing data are conflicting.7Yu S. Christiani D.C. Thompson B.T. Bajwa E.K. Gong M.N. Role of diabetes in the development of acute respiratory distress syndrome.Crit Care Med. 2013; 41: 2720-2732Crossref PubMed Scopus (46) Google Scholar,8Boyle A.J. Madotto F. Laffey J.G. et al.Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database.Crit Care. 2018; 22: 268Crossref Scopus (21) Google Scholar Like ARDS, diabetes comprises different pathologies (eg, autoimmune, gestational), different phenotypes, and various complications arising from the condition. Given associations between diabetes and ARDS have only been inconsistently reported, in this issue of CHEST Critical Care, Bogart et al9Bogart AM, Lopez CR, Obeidalla SN, et al. Elevated hemoglobin A1c and the risk of developing acute respiratory distress syndrome in two cohort studies. CHEST Crit Care. https://doi.org/10.1016/j.chstcc.2024.100082.Google Scholar took a more nuanced approach. To reduce inherent heterogeneity, they evaluated whether chronic hyperglycemia, quantified using glycated hemoglobin (HbA1c) as a continuous variable, was associated with the development of ARDS. In this analysis of two prospective observational cohort studies, patients were included if they had at least one risk factor for ARDS and measured HbA1c in the preceding 6 months (or in the subsequent 14 days) after enrollment in either of the observational cohort studies. Patients were categorized by HbA1c as either nondiabetic, prediabetic, diabetic with adequate glycemic control, or diabetic with inadequate glycemic control.10ElSayed N.A. Aleppo G. Aroda V.R. et al.2. Classification and diagnosis of diabetes: standards of care in diabetes—2023.Diabetes Care. 2022; 46: S19-S40Google Scholar For patients in both cohorts, a prior diagnosis of diabetes was not associated with an increased risk for developing ARDS. Instead, in the discovery cohort (Validating Acute Lung Injury biomarkers for Diagnosis), Bogart et al9Bogart AM, Lopez CR, Obeidalla SN, et al. Elevated hemoglobin A1c and the risk of developing acute respiratory distress syndrome in two cohort studies. CHEST Crit Care. https://doi.org/10.1016/j.chstcc.2024.100082.Google Scholar identified that there was a nonlinear relationship between baseline HbA1c and development of ARDS, with more ARDS developing in patients with an HBA1c reflective of either prediabetes or diabetes with inadequate glycemic control. The association between the diabetic with inadequate glycemic control group and development of ARDS persisted after adjusting for confounding factors, including an existing diagnosis of diabetes.9Bogart AM, Lopez CR, Obeidalla SN, et al. Elevated hemoglobin A1c and the risk of developing acute respiratory distress syndrome in two cohort studies. CHEST Crit Care. https://doi.org/10.1016/j.chstcc.2024.100082.Google Scholar Although these findings were not statistically significant in the validation cohort (Early Assessment of Renal and Lung Injury), which may be explained by an insufficient sample size, the study by Bogart et al9Bogart AM, Lopez CR, Obeidalla SN, et al. Elevated hemoglobin A1c and the risk of developing acute respiratory distress syndrome in two cohort studies. CHEST Crit Care. https://doi.org/10.1016/j.chstcc.2024.100082.Google Scholar offers important insights into any potential relationship between diabetes and ARDS. First, they reiterate the findings from a large global study that a simple categorization of patients with and without diabetes is too blunt to identify patients at greater risk of ARDS.8Boyle A.J. Madotto F. Laffey J.G. et al.Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database.Crit Care. 2018; 22: 268Crossref Scopus (21) Google Scholar Second, they report that the relationship between diabetes and ARDS is likely to be complex, and influenced by many of the factors that contribute to heterogeneity in diabetes, including chronic hyperglycemia preceding critical illness. These data suggest that long-term glycemia is more important than a diagnosis of diabetes per se. For example, it is conceivable that patients labeled as having diabetes, but who have excellent glycemic control prior to ICU admission, have less risk of developing ARDS than patients without such a label (ie, not known to have diabetes) but who have chronic hyperglycemia. Taken further, it is possible that certain prophylactic interventions to reduce the risk of ARDS may be more likely to be effective in those patients with chronic hyperglycemia. Equally, long-term glycemic control may be a surrogate index for other factor(s) that affect a patient's risk for developing ARDS. In this analysis, 18.7% of patients with a nondiabetic HbA1c had a prior chart diagnosis of diabetes. For these patients, and those with diabetes and adequate glycemic control, it is plausible that lifestyle or therapeutic interventions that occurred in the time between HbA1c measurement and ICU admission were the factors that attenuated their risk for developing ARDS. Although long-term glycemic control may be more important than a diagnosis of diabetes, it could be the interventions used to achieve glycemic control that reduce the risk of developing ARDS, rather than glycemic control itself. In preclinical models of ARDS, certain glucose-lowering drugs have been shown to attenuate lung injury.11Chen X. Walther F.J. Sengers R.M.A. et al.Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response.Am J Physiol Lung Cell Mol Physiol. 2015; 309: L262-L270Crossref Scopus (38) Google Scholar,12Baer B. Putz N.D. Riedmann K. et al.Liraglutide pretreatment attenuates sepsis-induced acute lung injury.Am J Physiol Lung Cell Mol Physiol. 2023; 325: L368-L384Crossref PubMed Scopus (4) Google Scholar It is therefore feasible that similar treatments in patients modified their risk for developing ARDS, rather than glycemic control itself acting as the risk modifier. Future evaluations of the relationship between diabetes, glycemic control, and risk of developing ARDS may reduce heterogeneity through greater categorization of patients. These studies should consider including longitudinal glycemic data control. There also remains a need to further evaluate the relationship between the various glucose-lowering drugs and ARDS. If feasible, there may be value in combining this resource with stored biological samples. This might allow the measurement of additional indexes of glycemic control and help identify biological modifications caused by poor glycemic control that could be novel treatable targets in ARDS. In doing so, we may move closer to identifying patients at risk of developing ARDS that share similar pathologic features which can be targeted with more precise interventions. 1Matthay M.A. Arabi Y. Arroliga A.C. et al.A new global definition of acute respiratory distress syndrome.Am J Respir Crit Care Med. 2024; 209: 37-47Crossref PubMed Google Scholar5Bellani G. Laffey J.G. Pham T. et al.Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.JAMA. 2016; 315: 788-800Crossref PubMed Scopus (3536) Google Scholar6Poole A.P. Finnis M.E. Anstey J. et al.The effect of a liberal approach to glucose control in critically ill patients with type 2 diabetes: a multicenter, parallel-group, open-label randomized clinical trial.Am J Respir Crit Care Med. 2022; 206: 874-882Crossref Scopus (13) Google Scholar. None declared. Author contributions: A. J. B. contributed to conceptualization, first draft, review, and editing. A. M. D. contributed to conceptualization, review, and editing. All authors approved the final manuscript. Elevated Hemoglobin A1c and the Risk of Developing ARDS in Two Cohort StudiesCHEST Critical CareVol. 2Issue 3