Persistently Elevated Glucagon-Like Peptide-1 Levels among Critically Ill Surgical Patients after Sepsis and Development of Chronic Critical Illness and Dismal Long-Term Outcomes

Abstract

Background: Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin secretion, cellular glucose uptake, and has immune-regulatory functions. Glucagon-like peptide-1 is markedly altered after trauma and sepsis, but the implications remain unclear.

Study design: We performed an analysis of a prospective, longitudinal cohort study of critically ill surgical patients with sepsis. Patient characteristics and clinical data were collected, as well as peripheral blood sampling for biomarker analysis, out to 28 days after sepsis onset. We prospectively adjudicated sepsis diagnosis, severity, clinical outcomes, and 6-month follow-up.

Results: The cohort included 157 septic surgical patients with significant physiologic derangement (Maximum Sequential Organ Failure Assessment [SOFA] score 8, interquartile range [IQR] 4 to 11), a high rate of multiple organ failure (50.3%), and septic shock (24.2%). Despite high disease severity, both early death (<14 days; n = 4, 2.9%) and overall inpatient mortality were low (n = 12, 7.6%). However, post-discharge 6-month mortality was nearly 3-fold higher (19.7%). Both GLP-1 and interleukin [IL]-6 levels were significantly elevated for 21 days (p ≤ 0.01) in patients who developed chronic critical illness (CCI) compared with patients with a rapid recovery. Elevated GLP-1 at 24 hours was a significant independent predictor for the development of CCI after controlling for IL-6 and glucose levels (p = 0.027), and at day 14 for death or severe functional disability at 6 months (WHO/Zubrod score 4-5, p = 0.014).

Conclusions: Elevated GLP-1 within 24 hours of sepsis is a predictor of early death or persistent organ dysfunction. Among early survivors, persistently elevated GLP-1 levels at day 14 are strongly predictive of death or severe functional disability at 6 months. Persistently elevated GLP-1 levels may be a marker of a nonresolving catabolic state that is associated with muscle wasting and dismal outcomes after sepsis and chronic critical illness.

Trial registration: ClinicalTrials.gov NCT02276417.

Figure 1.

Post-sepsis biomarker trajectories. Select biomarker levels measured from peripheral blood samples collected at 0.5, 1, 4, 7, 14 and 28 days after sepsis onset, while hospitalized. (A) Interleukin-6 (IL-6, (B) Glucagon-like peptide-1 (GLP-1), (C) Maximum measured daily glucose. Grey-shaded areas represent standard reported normal ranges.

Figure 2.

Correlation analysis of GLP-1, organ dysfunction and comorbidity burden. (A) Correlation plot of GLP-1 level and total Sequential Organ Failure Assessment (SOFA) score at 24 hours. (B) Correlation plot of GLP-1 level and total SOFA score at 14 days. (C) Corrleation plot of GLP-1 level at 24 hours and Charlson comorbidity score. (D) Correlation plot of Total SOFA score and Charlson comorbidity score. Blue oval represents 95% prediction ellipse.