---
title: "Diabetes and ASCVD Alter the Link Between sTNFR1 Levels and Sepsis Mortality"
id: "pubmed-42813914"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42813914"
content_type: "clinical_feed_article"
specialty: "Critical Care"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42813914/"
doi: "10.1097/CCM.0000000000007374"
published_at: "2026-09-30T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Diabetes and ASCVD Alter the Link Between sTNFR1 Levels and Sepsis Mortality
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42813914
- **Specialty:** [Critical Care](https://medichelpline.com/clinical-feed/critical-care.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42813914/)
- **DOI:** [10.1097/CCM.0000000000007374](https://doi.org/10.1097%2FCCM.0000000000007374)
- **Published At:** 2026-09-30T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- This secondary cohort analysis evaluated whether **diabetes mellitus** or **atherosclerotic cardiovascular disease (ASCVD)** modify the association between baseline **soluble tumor necrosis factor receptor 1 (sTNFR1)** and 90-day mortality in sepsis. - The analysis used the Acetaminophen and Ascorbate in Sepsis research materials and included 466 adult patients with sepsis and either respiratory failure or vasopressor-dependent shock who had baseline sTNFR1 measured. - Of 466 patients, 243 (52.1%) had either diabetes or ASCVD as defined by Charlson comorbidity categories; illness severity and crude mortality were similar between groups. - Median sTNFR1 was higher in patients with diabetes or ASCVD (6547 pg/mL) than in those without (4883 pg/mL). - In patients without diabetes or ASCVD, higher sTNFR1 was associated with increased 90-day mortality (hazard ratio 2.25 per standard deviation; 95% CI 1.76–2.88). - Among patients with diabetes or ASCVD the association between sTNFR1 and mortality was attenuated, with a plateau in mortality risk above ~12,000 pg/mL (overall HR 1.04; 95% CI 0.83–1.30); the interaction p-value was < 0.001. - The modifying effect of diabetes/ASCVD was specific to **sTNFR1**; similar interactions were not observed for **interleukin-6 (IL-6)** or **angiopoietin-2**. - No effect modification was found for patients with obesity or hypertension in the absence of diabetes or ASCVD. - Analyses adjusted for illness severity, age (in tertiles), and sex using Cox regression with restricted cubic splines. - The authors conclude that preexisting comorbid conditions can alter the biological relationship between a biomarker and outcome, with implications for biomarker-guided risk stratification and sepsis pathophysiology.
## Clinical Analysis & Structured Key Points
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Online ahead of print. # Diabetes and Atherosclerotic Cardiovascular Disease Modify the Association Between Soluble Tumor Necrosis Factor Receptor 1 and Sepsis Mortality: A Secondary Cohort Analysis [Timothy G Gaulton](https://pubmed.ncbi.nlm.nih.gov/?term=Gaulton+TG&cauthor_id=42813914)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#full-view-affiliation-1 "Department of Anesthesiology, Mass General Brigham, Boston, MA.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#full-view-affiliation-2 "Harvard Medical School, Boston, MA."), [Rachel Rigsby](https://pubmed.ncbi.nlm.nih.gov/?term=Rigsby+R&cauthor_id=42813914)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#full-view-affiliation-3 "Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA."), [Nathan I Shapiro](https://pubmed.ncbi.nlm.nih.gov/?term=Shapiro+NI&cauthor_id=42813914)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#full-view-affiliation-2 "Harvard Medical School, Boston, MA.")[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#full-view-affiliation-4 "Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA."), [Eric P Schmidt](https://pubmed.ncbi.nlm.nih.gov/?term=Schmidt+EP&cauthor_id=42813914)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#full-view-affiliation-2 "Harvard Medical School, Boston, MA.")[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#full-view-affiliation-5 "Division of Pulmonary and Critical Care Medicine, Mass General Brigham, Boston, MA."), [Maurizio Cereda](https://pubmed.ncbi.nlm.nih.gov/?term=Cereda+M&cauthor_id=42813914)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#full-view-affiliation-1 "Department of Anesthesiology, Mass General Brigham, Boston, MA.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#full-view-affiliation-2 "Harvard Medical School, Boston, MA.") Affiliations Expand ### Affiliations * 1 Department of Anesthesiology, Mass General Brigham, Boston, MA. * 2 Harvard Medical School, Boston, MA. * 3 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. * 4 Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA. * 5 Division of Pulmonary and Critical Care Medicine, Mass General Brigham, Boston, MA. * PMID: **42813914** * DOI: [ 10.1097/CCM.0000000000007374 ](https://doi.org/10.1097/ccm.0000000000007374) Item in Clipboard # Diabetes and Atherosclerotic Cardiovascular Disease Modify the Association Between Soluble Tumor Necrosis Factor Receptor 1 and Sepsis Mortality: A Secondary Cohort Analysis Timothy G Gaulton et al. Crit Care Med. 2026. Show details Display options Display options Format Abstract PubMed PMID Crit Care Med Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Crit+Care+Med%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Crit+Care+Med%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42813914/) . 2026 Sep 30. doi: 10.1097/CCM.0000000000007374. Online ahead of print. ### Authors [Timothy G Gaulton](https://pubmed.ncbi.nlm.nih.gov/?term=Gaulton+TG&cauthor_id=42813914)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#short-view-affiliation-1 "Department of Anesthesiology, Mass General Brigham, Boston, MA.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#short-view-affiliation-2 "Harvard Medical School, Boston, MA."), [Rachel Rigsby](https://pubmed.ncbi.nlm.nih.gov/?term=Rigsby+R&cauthor_id=42813914)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#short-view-affiliation-3 "Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA."), [Nathan I Shapiro](https://pubmed.ncbi.nlm.nih.gov/?term=Shapiro+NI&cauthor_id=42813914)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#short-view-affiliation-2 "Harvard Medical School, Boston, MA.")[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#short-view-affiliation-4 "Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA."), [Eric P Schmidt](https://pubmed.ncbi.nlm.nih.gov/?term=Schmidt+EP&cauthor_id=42813914)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#short-view-affiliation-2 "Harvard Medical School, Boston, MA.")[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#short-view-affiliation-5 "Division of Pulmonary and Critical Care Medicine, Mass General Brigham, Boston, MA."), [Maurizio Cereda](https://pubmed.ncbi.nlm.nih.gov/?term=Cereda+M&cauthor_id=42813914)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#short-view-affiliation-1 "Department of Anesthesiology, Mass General Brigham, Boston, MA.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42813914/#short-view-affiliation-2 "Harvard Medical School, Boston, MA.") ### Affiliations * 1 Department of Anesthesiology, Mass General Brigham, Boston, MA. * 2 Harvard Medical School, Boston, MA. * 3 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. * 4 Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA. * 5 Division of Pulmonary and Critical Care Medicine, Mass General Brigham, Boston, MA. * PMID: **42813914** * DOI: [ 10.1097/CCM.0000000000007374 ](https://doi.org/10.1097/ccm.0000000000007374) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID Linked Discoveries ## Abstract **Objectives:** To determine whether diabetes mellitus or atherosclerotic cardiovascular disease (ASCVD) modify the association between soluble tumor necrosis factor receptor 1 (sTNFR1) and mortality in sepsis. **Design:** Secondary cohort analysis using the Acetaminophen and Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery Research Materials. **Setting:** Academic hospitals in the United States. **Patients:** A total of 466 adults with sepsis and respiratory failure or vasopressor-dependent shock with available baseline sTNFR1 measurements. **Interventions:** None. **Measurements and main results:** We tested the interaction between sTNFR1 and diabetes or ASCVD (defined by Charlson comorbidity categories) on 90-day mortality using Cox regression with restricted cubic splines, adjusted for illness severity, age (in tertiles), and sex. Of 466 patients, 243 patients (52.1%) had diabetes or ASCVD. Despite similar illness severity and mortality between groups, sTNFR1 was higher among patients with diabetes or ASCVD (median, 6547 vs. 4883 pg/mL). Among patients without diabetes or ASCVD, higher sTNFR1 was associated with 90-day mortality (hazard ratio [HR], 2.25 per sd; 95% CI, 1.76-2.88). The association was attenuated among those with diabetes or ASCVD, with a plateau in mortality risk above approximately 12,000 pg/mL (overall HR, 1.04; 95% CI, 0.83-1.30; interaction p < 0.001). This interaction was specific to sTNFR1 and was not observed for interleukin-6 or angiopoietin-2. No effect modification was present among patients with obesity or hypertension without diabetes or ASCVD. **Conclusions:** Diabetes or ASCVD attenuated the association between sTNFR1 and sepsis mortality. These findings suggest that comorbid conditions may alter the biological relationship between a biomarker and outcome, with implications for biomarker-guided risk stratification and disease mechanisms in sepsis. **Keywords:** atherosclerosis; diabetes mellitus; mortality; receptors; sepsis; tumor necrosis factor; type I. Copyright © 2026 by the Society of Critical Care Medicine and Wolters Kluwer Health, LLC. All Rights Reserved. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Dr. Gaulton is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K23HL175128-01A1. Dr. Gaulton’s institution received funding from the National Heart, Lung, and Blood Institute. Drs. Gaulton, Shapiro, and Cereda received support for article research from the National Institutes of Health. Dr. Schmidt received funding from Merck. Dr. Rigsby disclosed that she does not have any potential conflicts of interest. ## References 1. 1. Ware LB, Files DC, Fowler A, et al.; National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network: Acetaminophen for prevention and treatment of organ dysfunction in critically ill patients with sepsis: The ASTER randomized clinical trial. JAMA 2024; 332:390–400 2. 1. Angriman F, Saoraya J, Lawler PR, et al.; Sepsis Canada Network: Preexisting diabetes mellitus and all-cause mortality in adult patients with sepsis: A population-based cohort study. Crit Care Explor 2024; 6:e1085 3. 1. Schuetz P, Castro P, Shapiro NI: Diabetes and sepsis: Preclinical findings and clinical relevance. Diabetes Care 2011; 34:771–778 4. 1. Sethi JK, Hotamisligil GS: Metabolic messengers: Tumour necrosis factor. Nat Metab 2021; 3:1302–1312 5. 1. Libby P: Inflammation in atherosclerosis. 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