Effects of sotagliflozin on markers of volume status and sodium handling in patients with type 1 diabetes: A biomarker analysis of the inTandem3 clinical trial

Abstract Aims Sotagliflozin, an inhibitor of sodium‐glucose co‐transporter (SGLT)‐1 and 2, reduces albuminuria, slows GFR decline, and may have diuretic and osmoregulatory effects. The effect of sotagliflozin added to insulin was assessed on markers of neurohormone activation and volume homeostasis in patients with type 1 diabetes (T1D). Materials and Methods This is a post‐hoc analysis of the randomised, double‐blinded, placebo‐controlled inTandem3 trial, which assessed efficacy of sotagliflozin 400 mg/d versus placebo as an adjunct to insulin. The present biomarker analysis included 362 participants (26%) who had biological samples collected at baseline and week 24. Plasma renin, copeptin, serum N‐terminal pro b‐type natriuretic peptide (NT‐proBNP), and markers of tubular injury, inflammation, haematopoiesis, and iron homeostasis were measured at baseline and following week 24 treatment; fractional excretion of lithium (FE Li ) and glucose (FE Glucose ) were calculated. Results Participants were 46 years of age (60% female) with a mean eGFR and median UACR of 88.4 mL/min/1.73 m 2 and 7.5 mg/g, respectively. Sotagliflozin increased copeptin, FE Li , and FE Glucose by 33%, 14%, and 60‐fold, respectively (all p < 0.01), but did not change renin or NT‐proBNP (both p ≥ 0.11) compared to placebo. Further, urinary kidney injury molecule‐1 decreased by 19% ( p = 0.03). Haemoglobin and haematocrit increased (both p < 0.01), without altering inflammatory, erythropoietic, or iron biomarkers (all p ≥ 0.11). Conclusions In this T1D population, sotagliflozin increased copeptin levels, FE Li , and FE Glucose without altering renin, reflecting adaptive mechanisms that preserve sodium and fluid balance and protect against volume depletion. Sotagliflozin also decreased markers of kidney injury and increased haematocrit.