Modeling Cardiorenal Protection with Sodium-Glucose Cotransporter 2 Inhibition in Type 1 Diabetes: An Analysis of DEPICT-1 and DEPICT-2

Key Points Risk modelling analysis of DEPICT trials show that dapagliflozin reduced estimated cardiovascular and kidney disease risk in T1D persons. Greatest reduction in estimated ESKD risk was accompanied by an expected rise in eGFR, after 4 weeks post drug discontinuation. Dedicated outcome trials with SGLT2 inhibitors are warranted in T1D persons with CKD or CVD for best determination of efficacy and risks. Background Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve glycemia and reduce insulin requirements in type 1 diabetes (T1D) and type 2 diabetes. Although SGLT2 inhibitors lower cardiovascular disease (CVD) and ESKD risk in type 2 diabetes, no dedicated cardiorenal outcome trials in T1D have been conducted to date. Using validated risk prediction models, this study evaluated the effect of SGLT2 inhibition on estimated CVD and ESKD risk in a T1D cohort. Methods Demographics, medical history, and biomarkers were extracted from 1473 participants with T1D enrolled in the Dapagliflozin Evaluation in Patients with Inadequately Controlled Type -1 and -2 trials. Data at baseline, 24, 52, and 56 weeks (4 weeks after drug cessation) were used to estimate 10-year CVD and 5-year ESKD risk using the Steno T1 Risk Engine (SRE) and Scottish Diabetes Research Network (SDRN) risk prediction models. Risk reduction was determined on the basis of relative change in risk from baseline between participants receiving dapagliflozin (pooled 5 and 10 mg) versus placebo. Subgroup analyses were conducted by age, sex, diabetes duration, CVD risk, and CKD status at baseline. Results The relative change in 10-year estimated CVD risk (SRE: –6.50% [–8.04% to –4.95%] and SDRN: –6.77% [–8.40% to –5.13%]; all P < 0.001) and 5-year ESKD risk (SRE: –4.48% [–7.68% to –1.28%]; P = 0.006) were lower at the end of 24 weeks of dapagliflozin treatment compared with placebo. Furthermore, the greatest relative change in 5-year ESKD risk was observed at week 56 (SRE: –12.84% [–16.65% to –9.03%]; P < 0.001), in conjunction with an expected rise in eGFR after drug washout. Subgroup analysis revealed larger relative lowering in 10-year CVD risk in those with CKD compared with those without (SRE: –11.3% versus –5.9%, and SDRN: –11.9% versus –6.1%, respectively; all P interaction < 0.02). Conclusions Dapagliflozin improves estimated CVD and ESKD risk in participants with T1D, emphasizing the need for cardiorenal outcome trials in people living with T1D.