Efficacy and Safety of Dapagliflozin by Baseline Insulin Regimen and Dose: Post Hoc Analyses from DECLARE-TIMI 58

Objective: The cardiorenal benefits of adding SGLT2 inhibitors to patients on insulin, particularly those on intensive regimens which include short acting (SA) insulin have not been explored.

Research design and methods: The DECLARE-TIMI 58 trial randomized 17,160 patients with type 2 diabetes to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular, renal, metabolic and safety outcomes with dapagliflozin vs. placebo by insulin dose and regimen were studied by Cox regression models.

Results: The study included 7,013 insulin users at baseline, with 4,650 (66.3%) patients on regimens including SA insulin. Insulin doses varied with 2,443 (34.8%) patients receiving <0.5 IU/kg, 2,795 (39.9%) 0.5-≤1 IU/kg and 1,339 (19.1%) >1 IU/kg. Dapagliflozin reduced cardiovascular death/hospitalization for heart failure among overall insulin users (HR [95% CI] 0.82[0.69-0.97]), and consistently in patients on insulin regimens with or without SA insulin (HR 0.83[0.67-1.03] and 0.78[0.57-1.07] respectively, Pinteraction= 0.75). No heterogeneity was observed by insulin dose (Pinteraction = 0.43). The HR for major adverse cardiovascular events with dapagliflozin among insulin users (HR 0.84[0.74-0.97]) was similar irrespective of regimen or dose (Pinteraction 0.75 and 0.07, respectively). Dapagliflozin reduced the rate of adverse renal outcomes overall, and consistently across subgroups of insulin users. Decreases in HbA1c, weight and systolic blood pressure with dapagliflozin were seen regardless of insulin dose or regimen. The known safety profile of dapagliflozin was unchanged in patients on intensive insulin regimens.

Conclusions: The benefits and safety of dapagliflozin were maintained in high-risk patients receiving high-dose or intensive insulin regimens including SA insulin.