Canagliflozin reduces oral loop diuretic intensification in patients with type 2 diabetes: a participant level pooled analysis of CREDENCE and CANVAS

Abstract Background Patients with type 2 diabetes often have coexistent heart failure or chronic kidney disease (CKD) that require treatment with loop diuretics; however, the prognostic implications of oral loop diuretic intensification are not well characterized. The sodium glucose cotransporter-2 inhibitor canagliflozin reduces the risk of hospitalization for heart failure or cardiovascular death and CKD progression among patients with type 2 diabetes at high cardiovascular risk or with concomitant CKD. Purpose To assess the prognostic implications of oral loop diuretic intensification and the treatment effects of canagliflozin versus placebo on loop diuretic use in high-risk patients with type 2 diabetes. Methods This was a post-hoc participant-level pooled analysis of the CANVAS Program and CREDENCE trial which enrolled patients with type 2 diabetes at high cardiovascular risk or with CKD. Oral loop diuretic intensification was defined as a composite of new loop diuretic initiation (among patients not receiving loop diuretics at baseline) or loop diuretic dose increase (among patients receiving loop diuretics at baseline). We assessed the association between the requirement for loop diuretic intensification and the incidence of subsequent all-cause death. The effect of canagliflozin versus placebo on the composite of loop diuretic intensification as well as its components were evaluated. We further examined the effect of canagliflozin on an expanded post hoc composite of cardiovascular death, hospitalization for heart failure or loop diuretic intensification. Results 2,263 (15.6%) of 14,543 patients were treated with loop diuretics at baseline. Over a median follow-up of 2.2 years, 1,264 patients (9.4%) required oral loop diuretic intensification, of which 981 (77.6%) patients required initiation of oral loop diuretics and 283 (22.4%) required oral loop diuretic dose increase. Patients requiring oral loop diuretic intensification experienced rates of subsequent mortality that were 3.5-fold higher (5.9[5.4-6.5] per 100 patient-years) than those not requiring oral loop diuretic intensification (1.7[1.6-1.9] per 100 patient-years). Treatment with canagliflozin reduced the need for oral loop diuretic intensification by 41% (HR 0.59; 95%CI: 0.53-0.66) including both new diuretic initiation (HR 0.65; 95%CI: 0.57-0.74) and diuretic dose increase (HR 0.42; 95%CI: 0.33-0.54); Figure 1. Treatment with canagliflozin similarly reduced an expanded composite of worsening heart failure inclusive of cardiovascular death, heart failure hospitalization or diuretic intensification (HR 0.64; 95%CI: 0.58-0.70). Conclusion Among high-risk patients with T2D, new oral loop diuretic intensification was frequent and associated with an increased risk of subsequent mortality. Treatment with canagliflozin significantly reduced the need for loop diuretic intensification.