Predictors of cardio-kidney complications and treatment failure in patients with chronic kidney disease and type 2 diabetes treated with SGLT2 inhibitors

Background: Clinical practice guidelines recommend sodium-glucose co-transporter 2 inhibitors (SGLT2is) to mitigate adverse kidney and cardiovascular outcomes in patients with type 2 diabetes (T2D), including patients with comorbid chronic kidney disease (CKD), also referred to as diabetic kidney disease (DKD), who are at even higher risk. In this study, we sought to identify predictors of cardio-kidney events, cardio-kidney complications, and treatment failure (i.e., addition/initiation of a new T2D class, insulin, or discontinuation of SGLT2is) after new initiation of SGLT2is in patients with CKD and T2D (DKD).

Methods: In this retrospective cohort study, we identified adult patients with DKD who initiated SGLT2is between April 1, 2012, and June 30, 2019, in Optum claims data. Outcome rates per 1000 person-years (PY) are reported with 95% confidence intervals (CIs). Cox proportional hazards regression identified patient characteristics associated with each outcome.

Results: The study population consisted of 6389 initiators of SGLT2is. The rate of CV hospitalization was 26.0 (95% CI 21.6, 30.4) per 1000 PY. Baseline characteristics associated with higher risk of CV hospitalization included age, atrial fibrillation, peripheral vascular disease (PVD), and cancer. The rate of kidney hospitalization was 12.0 (95% CI 9.0, 15.0) per 1000 PY. The risk increased significantly with baseline evidence of heart failure, hyperkalemia, respiratory failure, depression, and use of loop diuretics. In total, 55.0% of all SGLT2i initiators discontinued treatment during the follow-up period. The rate of treatment failure was 510.5 (95% CI 492.9, 528.1) per 1000 PY. Analysis of key time-dependent SGLT2i-associated adverse events showed that experiencing diabetic ketoacidosis and volume depletion were associated with risk of treatment failure.

Conclusions: Our study demonstrated high rates of residual cardio-kidney outcomes and treatment failure in patients with DKD treated with SGLT2is. Patients with high baseline CV risk and the presence of certain conditions, such as atrial fibrillation, PVD, and heart failure, were at higher risk for cardio-kidney events. Further research is needed to assess the potential relationship between adverse events and SGLT2i treatment failure.