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Diabetes Increases Risk of Sepsis, But Not Mortality, Inflammatory or Lipid Responses
44 Pages Posted: 15 May 2019More...
Background: Diabetes may increase sepsis risk, but it is unknown whether and how diabetes alters sepsis mortality. Our hypotheses were: (1) diabetes increases risk of sepsis and mortality; during sepsis (2) diabetes alters the inflammatory response; (3) hyperglycemia is associated with altered lipid levels.
Methods: We studied four cohorts (Population-based, multi-center, and single center cohorts; 2000-2016) with minimum 28-day follow-up: UK Biobank Cohort 1 (n =484,857; diabetics n = 25,430; non-diabetics n = 459,407), Single Centre Cohort 2 (n = 727; diabetics = 37; non-diabetics n = 690), Inflammation Mechanism Cohort 3 (n = 779; diabetics n = 165; non-diabetics n = 614), Lipid Mechanism Cohort 4 (n = 200; diabetics n = 49; non-diabetics n = 151). Twenty eight-day mortality and days-alive-and-free (DAF) of vasopressors, ventilation and renal replacement therapy (RRT) of diabetics and non-diabetics were compared. Hierarchical clustering was done on 39 cytokines and glucose association with HDL and triglyceride levels was evaluated early in sepsis.
Findings: Diabetics increased sepsis admission risk (n = 478/25,430 [1.89%] vs. n = 3,179/459,407 [0.70%], odds ratio (OR)[95% CI]: 2.75 [2.50 to 3.03], p<1E-15) but not mortality in UK Biobank Cohort 1 (15.8% vs. 13.7%; OR [95% CI]: 1.18 [0.91 - 1.54]], p=0.21), Single Centre Cohort 2 (24.3% vs. 19.3%, OR 1.35 [ 95% CI]: 0.63-2.92] p=0.452), Inflammation Mechanism Cohort 3 (38.8% vs. 36.9%, OR 1.09 [95%CI: 0.76, 1.55] p=0.651); or Lipid Mechanism Cohort 4 ((90-day) 17% vs. 14%, OR 1.59 [0.70-3.65], p=0.28), or in DAF vasopressors, ventilation and RRT (Cohort 3). Diabetics and non-diabetics had similar cytokine levels, hierarchical clustering and principal components analyses. There was no association of hyperglycemia with HDL or triglycerides levels.
Interpretation: Despite increased risk of sepsis, diabetic patients did not have increased 28-day mortality perhaps because inflammatory and lipid responses of diabetics and non-diabetics were similar.
Funding Statement: Support for VASST: Canadian Institutes of Health Research, Grant number: MCT 44152, Trial Registration: ISRCTN94845869. John Boyd is a recipient of a Providence Health Care Research Scholarship. Liam Brunham is supported by a Canada Research Chair in Precision Cardiovascular Disease Prevention and is a Michael Smith Foundation for Health Research Scholar. Keith Walley is supported by CIHR FDN 154311. Joe Hsu is supported by a grant from the National Institutes of Health, National Heart Lung and Blood Institute (1K08HL122528-01A1).
Support for current study: Department of Anesthesia and Department of Medicine, Division of Pulmonary and Critical Care, Stanford University; James A. Russell (overhead funds UBC/PHC); Canadian Institutes of Health Research (CIHR)(SONRIS).
Declaration of Interests: Dr. Russell reports patents owned by the University of British Columbia (UBC) that are related to the use of PCSK9 inhibitor(s) in sepsis and related to the use of vasopressin in septic shock. Dr. Russell is an inventor on these patents. Dr. Russell was a founder, Director and shareholder in Cyon Therapeutics Inc. Dr. Russell is a shareholder in Molecular You Corp. Dr. Russell reports receiving consulting fees in the last 3 years from: 1. Asahi Kesai Pharmaceuticals of America (AKPA)(developing recombinant thrombomodulin in sepsis). 2. SIB Therapeutics LLC (developing a sepsis drug). 3. Ferring Pharmaceuticals (manufactures vasopressin and developing selepressin). No longer actively consulting for the following: 4. La Jolla Pharmaceuticals (developing angiotensin II; Dr. Russell chaired the DSMB of a trial of angiotensin II from 2015 - 2017) - no longer actively consulting. 5. Cubist Pharmaceuticals (now owned by Merck; formerly was Trius Pharmaceuticals; developing antibiotics) – no longer actively consulting. 6. Grifols (sells albumin) - no longer actively consulting. 7. CytoVale Inc. (developing a sepsis diagnostic) - no longer actively consulting. 8. PAR Pharma (sells prepared bags of vasopressin) - no longer actively consulting. Dr. Russell reports having received an investigator-initiated grant from Grifols (entitled “Is HBP a mechanism of albumin’s efficacy in human septic shock?”) that was provided to and administered by UBC.
Ethics Approval Statement: UK Biobank Cohort 1 was approved by the UK Biobank (ID: 42857) and by the Clinical Research Ethics Board of the University of British Columbia. Single Centre Cohort 2 was approved by the Institutional Review Board of St. Paul’s Hospital and the University of British Columbia. The Inflammation Mechanism Cohort 3 was approved by each participating hospital. Lipid Mechanism Cohort 4 was approved by the Institutional Review Board of St. Paul’s Hospital and the University of British Columbia. For each study written informed consent was obtained from patients, next of kin or surrogate decision maker.
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