Authors' Reply: Further Considerations on the Clinical Evaluation of Sotagliflozin in Type 1 Diabetes with CKD

We appreciate the opportunity to respond to the Letter to the Editor by Wang et al.1 on our article published in JASN on the efficacy and safety of sotagliflozin in patients with type 1 diabetes and CKD.2 People with type 1 diabetes continue to have high burden of CKD and kidney failure, with a conspicuous absence of new therapies beyond glycemic control and renin-angiotensin system blockade. We therefore evaluated the safety and efficacy of the sodium-glucose cotransporter 1 (SGLT1) and 2 inhibitor sotagliflozin in a post hoc analysis using participant-level data from the inTandem 1, 2, and 3 trials of sotagliflozin in people with type 1 diabetes. While we agree with Wang et al. that factors such as smoking history, diet, and exercise are predictors of cardiorenal outcomes in patients with type 1 diabetes, as reflected by their incorporation into type 1 diabetes specific risk prediction models,3 these variables were unavailable in the inTandem 1, 2, and 3 trials and, therefore, unable to be incorporated into our analyses. Our colleagues' points on the importance of prospective and longitudinal analyses of kidney function when evaluating the efficacy of therapeutics on kidney outcomes are well taken. We would like to re-emphasize that inTandem 1, 2, and 3 were trials with glycemic end points without enrichment for cardiovascular and kidney end points and with relatively short periods of follow-up. Therefore, we did not focus on more traditional kidney end points including longitudinal changes in eGFR modeled as defined percentage changes over follow-up or as annualized eGFR slope. However, acute effects of SGLT inhibition on eGFR, as observed in our analyses, have been highly associated with longer-term kidney protection, possibly through activation of glomerular hemodynamic mechanisms.4,5 Dedicated clinical trials in patients at high risk of cardiorenal complications are clearly warranted to better understand both clinical benefits and safety of SGLT inhibition in patients with type 1 diabetes and CKD. The ongoing SodiUm Glucose co-trAnspoRt inhibitioN diabeteS And kidney function Loss in Type 1 diabetes trial (SUGARNSALT, NCT06217302) will evaluate the efficacy and safety of sotagliflozin versus placebo in patients with type 1 diabetes, eGFR 20–60 ml/min per 1.73 m2, and albuminuria. As a multicenter trial with well-defined participant selection criteria, collection of granular longitudinal data on kidney function, cardiovascular outcomes, the implementation and assessment of a robust diabetic ketoacidosis mitigation protocol, as well as a predefined economic analysis, we are confident that SUGARNSALT will be a definitive evaluation of SGLT inhibition in patients with type 1 diabetes and moderate-to-severe diabetic kidney disease, particularly with respect to slowing kidney disease progression.