Microcirculatory dysfunction is a key driver of organ failure and mortality in septic shock, characterized by endothelial injury and impaired vasoregulation. Despite its strong prognostic value, it remains unaddressed by current therapies. SGLT-2 inhibitors (SGLT-2i) have shown promising vasculoprotective, anti-inflammatory, and glucose-lowering effects that may help restore endothelial function, reduce vascular leakage, and manage stress-induced hyperglycemia-factors central to septic shock pathophysiology. Preclinical and clinical observational studies suggest potential benefits, but clinical research in this specific context is lacking. This trial aims to evaluate the efficacy and safety of SGLT-2i in septic shock patients with clinical signs of microcirculatory failure, addressing a critical unmet medical need.
Septic shock management relies on rapid infection control, hemodynamic stabilization with fluids and vasopressors, and supportive care, with corticosteroids used in select cases. However, this standardized approach faces major limitations due to patient heterogeneity, treatment-related complications (e.g., fluid overload, vasopressor side effects), and rising antimicrobial resistance. Adjunctive therapies have largely failed to improve outcomes, reflecting the complex pathophysiology of septic shock. These challenges highlight a pressing need for novel, targeted interventions and a shift toward personalized treatment strategies.
The investigators hypothesize that early administration of SGLT-2 inhibitors within 14 hours of septic shock onset in patients showing signs of microcirculatory dysfunction will improve 28-day outcomes mainly by targeting endothelial and microvascular injury. Expected benefits include reduced mortality and organ dysfunction, faster recovery with lower resource use, a favorable safety profile, and potential for global implementation as a cost-effective adjunctive therapy.
This study will be a multicenter, prospective, randomized, and comparative double-blind trial. All patients admitted with septic shock in the ICU will be screened for trial eligibility criteria.
After verifying the eligibility criteria and obtaining patient or family consent, or after an emergency inclusion procedure, eligible patients will be randomized in a 1:1 ratio to receive either Dapagliflozin (10 mg once daily) or matching placebo in addition to standard-of-care.
Patients will be followed up for 1 year or until death, whichever occurs first.
Patient aged ≥ 18 years
Hospitalized in ICU for septic shock according to Sepsis-3 definition (PMID: 26903338). Septic shock should be the primary reason for admission.
Septic shock diagnosed for less than 12 hours prior to randomization
Skin mottling (mottling score ≥ 2) according to Ait-Oufella and/or prolonged capillary refill time > 3 seconds
Patient in whom oral administration is not possible at the initial stage (e.g., emergency digestive surgery, acute mesenteric ischemia, etc.).
Patient treated with SGLT2 inhibitor before ICU admission
Hypoglycemia < 0.5 g/L (2.75 mmol/L)
End-stage kidney disease undergoing maintenance dialysis
Parallel
Dapaglifozin
DrugOral Dapaglifozin 10mg once-daily administration, for 7 days
Placebo
DrugOral Placebo once-daily administration, for 7 days
Composite endpoint including all-cause mortality, weaning of vasopressor, and initiation of renal replacement therapy.
These outcomes will be observed up to 28 days post-randomization, with events censored at the point of hospital discharge
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