Research Square · Mar 13, 2026
SGLT2 inhibition attenuates γδ T cell–mediated meta-inflammation associated with cardiometabolic risk in type 2 diabetes
By Cuculić MT, Sergo D, Kavazović I et al.
Background Cardiovascular and renal protection conferred by sodium–glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) extends beyond glucose lowering. Chronic low-grade meta-inflammation is a key driver of cardiometabolic risk in type 2 diabetes (T2D), yet the cellular mediators modified by modern antidiabetic therapy remain poorly defined. We investigated whether SGLT2i alone or combined with GLP-1RA attenuate γδ T cell mediated meta-inflammation in T2D. Methods Twenty-five patients with poorly controlled T2D initiating SGLT2i therapy (n = 15) or SGLT2i plus GLP-1RA (n = 10) were prospectively followed for 12 months. Age- and sex-matched non-diabetic controls (n = 30) were included at baseline. Peripheral blood γδ T cell phenotype and cytokine production were assessed by multiparametric flow cytometry. Metabolic, hepatic, and renal parameters were evaluated longitudinally. Results At baseline, T2D was associated with increased interferon-γ (IFN-γ) production by both Vδ1⁺ and Vδ2⁺ γδ T cells without changes in subset frequency. Antidiabetic treatment induced a sustained reduction in IFN-γ production of up to 40% at 12 months (p < 0.01), independent of glycemic improvement. Decreases in IFN-γ correlated with improved insulin sensitivity (HOMA-IR) and reduced fat mass, but not with HbA1c reduction. The anti-inflammatory effect was most pronounced in patients with mild hepatic or renal impairment and correlated with liver fibrosis indices and renal function markers. Conclusions Modern antidiabetic therapy attenuates γδ T cell-mediated meta-inflammation independently of glucose lowering. Reduction of IFN-γ production associates with improved insulin resistance and early organ involvement, identifying γδ T cells as a potential immuno-metabolic biomarker linking metabolic therapy to cardiovascular and renal protection.