Metformine as a Protective Factor of Mortality in Type 2 Diabetic Patients Admitted to the ICU for Septic Shock. (SEPSMET)

Metformine as a Protective Factor of Mortality in Type 2 Diabetic Patients Admitted to the ICU for Septic Shock: a Multicentre Retrospective Cohort Study.

Septic shock is a major complication of sepsis and is one of the leading causes of admission to intensive care unit (ICU) as well as a major contributor to global mortality, accounting for one in five deaths worldwide and approximately 11 million deaths annually. There is around 530 millions of people living with diabetes, with type 2 diabetes accounting for 96% of these population. Among these patients, septic shock is a major concern, as they are more susceptible to developing infections and have more associated comorbidities. Metformin is the first line oral treatment for type 2 diabete. Beyond its metabolic effects, metformin has pleitropic effects exerting actions on mitochondrial metabolism and immune-inflammatory pathway that could potentially be benefit in septic shock. Several observational studies, converge on a reduction in mortality among patients treated with long-term metformin prior to their admission to the ICU for sepsis or septic shock as well as a reduction in renal dysfunction. Despite these results, the current literature remains highly heterogeneous in its methodology. Most studies focused on patients with sepsis rather than targetting specifically most severe patients with septic shock. Study designs vary widely, most of them are monocentric, some included patients in the emergency departments and others compared type 2 diabetic patients to patients without any history of diabetes making comparisons and generalisation of findings difficult. The main objective of this study was to evaluate the effect of pre-admission metformin exposure in type 2 diabetic patients admitted to the ICU for septic shock on 30-day mortality and on organ failures.

Study Overview

• Status: Completed
• Conditions: D012139; D003924

Detailed Description

Septic shock is one of the leading causes of admission to intensive care units (ICU), with an incidence of approximately 19 million patients per year worldwide. Despite progress made in the management of patients suffering from this condition, mortality and morbidity remain high and show little improvement. Indeed, according to studies, the mortality rate of septic shock ranges from 25 to 30%. Diabetic patients, due to their susceptibility to infections and greater vulnerability, represent a significant proportion of patient cohorts in septic shock. Moreover, diabetes is a factor of poor prognosis during septic shock.

Metformin, an oral anti-diabetic treatment, is currently considered the first-line therapy for type 2 diabetes. It modifies glucose metabolism by inhibiting, notably at the mitochondrial level, the electron transport chain through the inhibition of complex I. This inhibition of complex I decreases mitochondrial production of Adenosine Triphosphate (ATP) and induces activation of AMPK, a key enzyme in energy metabolism. Thus, metformin is responsible for an increase in glycolysis and an inhibition of gluconeogenesis in the liver.

During septic shock, mitochondrial ATP production is limited due to decreased arterial oxygen transport, leading to tissue hypoxia and mitochondrial dysfunction. This results in increased anaerobic energy production through activation of glycolysis, and consequently, increased lactate production responsible for metabolic acidosis. Several studies focusing on septic shock have observed that hyperlactatemia during the initial hours of management is a factor of poor prognosis.

Given the alterations in mitochondrial metabolism caused by metformin, which may exacerbate hyperlactatemia, its potential accumulation in cases of acute renal failure, the hepatic metabolism of lactate, and the deleterious consequences of lactic metabolic acidosis, it is recommended to discontinue metformin during septic shock. However, despite these recommendations, some studies suggest a lower mortality rate in septic shock patients treated with metformin, despite older age, higher rates of cardiovascular disease, and renal failure.

The first hypothesis is that patients on metformin may have better adaptation of their energy metabolism during a significant drop in oxygen supply (a mitochondrial adaptive mechanism reducing energy needs), which limits oxidative stress and its harmful effects. The second hypothesis is that metformin has an immunomodulatory role, resulting in a more moderate inflammatory response in case of infection, and thus less endothelial and visceral dysfunction. Thus, metformin, through modification of mitochondrial metabolism, appears to have pleiotropic, anti-inflammatory, antithrombotic, and vasoactive effects that could be beneficial in septic shock. The benefit of metformin in patients with septic shock therefore needs to be clarified through well-conducted large cohort studies.

• Study Type: Observational
• Enrollment (Actual): 2740

Contacts and Locations

Study Locations

• France
  • Paris, France, 75010
    • Unité de Recherche Clinique Paris Saclay

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adults patients with type 2 diabete admitted for septic shock to one of the 30 ICU across18 parisians hospitals (APHP) , from July 2017 to September 2022

Description

Inclusion Criteria:

• Patients with type 2 diabete
• admitted for septic shock to ICU (APHP) , from July 2017 to September 2022.

Exclusion Criteria:

• Patients under the age of 18,
• without electronical medical record,
• whithout any information about their antidiabetic treatment and those with multiple ICU hospitalization.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Patients who receiving metformin before the inclusion; Patients with type 2 diabete admitted to ICU for septic shock who receiving metformin before the inclusion
Patients who receiving other antidiabetic drugs before the inclusion; Patients with type 2 diabete admitted to ICU for septic shock who receiving other antidiabetic drugs before the inclusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
30-day mortality	The primary objective of this study is to evaluate the effect of metformin treatment on mortality in septic shock among type II diabetics patients. The primary endpoint is mortality within a 30-day time frame following admission to the intensive care unit.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
90-day mortality	Evaluate the effect of metformin treatment on mortality at 90 days after ICU admission.	90 days after ICU admission.
Multiorgan failures	Number of patients with at least one organ failure, defined by the presence of ≥1 ICD-10 diagnosis code for renal, hemodynamic, cardiac, respiratory, or hepatic failure.	From ICU admission to ICU discharge (up to 30 days)
Duration of vasopressor use	Duration of vasopressor use, defined as the cumulative number of days with administration of vasopressors based on repeated CCAM code EQLF003 (each code corresponding to 24 hours of therapy)	From ICU admission to ICU discharge (up to 30 days)
Mechanical ventilation	Number of patients with mechanical ventilation, defined by the presence of ≥1 CCAM procedure code for mechanical ventilation	From hospital admission to hospital discharge (up to 30 days)
Acute Kidney Injury (AKI)	Number of participants with acute kidney injury (AKI), defined according to the Kidney Disease Improving Global Outcomes (KDIGO)	From ICU admission to ICU discharge (up to 30 days)

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Marie Werner, MD, Service d'Anesthésie Réanimation Chirurgicale, DMU 12 Anesthésie Réanimation Chirurgicale Médecine Péri-opératoire et Douleur, Hôpital Bicêtre, AP-HP, Université Paris-Saclay, Le Kremlin-Bicêtre, France

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2019
• Primary Completion (Actual): December 1, 2022
• Study Completion (Actual): December 15, 2024

Study Registration Dates

• First Submitted: November 19, 2025
• First Submitted That Met QC Criteria: May 11, 2026
• First Posted (Actual): May 15, 2026

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 11, 2026
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: septic shock; type 2 diabete
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Pathological Conditions, Signs and Symptoms; Shock, Septic
• Other Study ID Numbers: APHP240993; CSE 19-0019 (Other Identifier: CSE)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Study Data/Documents

1. Clinical Data warehouse of Greater Paris University hospitals (Entrepôt de Données de Santé - EDS AP-HP )

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No