Modelling Cardiorenal Protection with SGLT2 Inhibition in Type 1 Diabetes - An Analysis of DEPICT-1 and DEPICT-2.

Abstract

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve glycemia and reduce insulin requirements in type 1 (T1D) and type 2 (T2D) diabetes. While SGLT2 inhibitors lower cardiovascular disease (CVD) and end-stage kidney disease (ESKD) risk in T2D, no dedicated cardiorenal outcome trials in T1D have been done 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 1,473 participants with T1D enrolled in the Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes (DEPICT)-1 and -2 trials. Data at baseline, 24-, 52- and 56-weeks (four weeks post-drug cessation) were used to estimate 10-year CVD and five-year ESKD risk using the Steno T1 Risk Engine (SRE) and Scottish Diabetes Research Network (SDRN) risk prediction models. Risk reduction was determined based on relative change in risk from baseline between participants receiving dapagliflozin (pooled 5 and 10 mg) vs. placebo. Subgroup analyses were conducted by age, sex, diabetes duration, CVD risk and chronic kidney disease (CKD) status at baseline.

Results: The relative change in 10-year estimated CVD risk (SRE: -6.50% [-8.04, -4.95%] & SDRN: -6.77% [-8.40, -5.13%]; all P<0.001) and five-year ESKD risk (SRE: -4.48% [-7.68, -1.28%]; P=0.006) were lower at the end of 24 weeks of dapagliflozin treatment compared to placebo. Further, the greatest relative change in 5-year ESKD risk was observed at week 56 (SRE: -12.84% [-16.65, -9.03%]; P<0.001), in conjunction with an expected rise in estimated glomerular filtration rate post-drug washout. Subgroup analysis revealed larger relative lowering in 10-year CVD risk in those with CKD compared to those without (SRE: -11.3% vs -5.9%, & SDRN: -11.9% vs -6.1%, respectively; all Pinteraction<0.02).

Conclusion: Dapagliflozin improves estimated CVD and ESKD risk in T1D participants, emphasizing the need for cardiorenal outcome trials in people living with T1D.