| Description: |
Background/Introduction The impact of insulin on cardiorenal outcomes in type 2 diabetes (T2D) remains unclear among anti-diabetic treatments, while the proposed cardiovascular (CV) benefits of metformin are not well established. Additionally, although canagliflozin is known to lower cardiorenal risk, its specific effects in insulin-treated patients are not yet fully understood. Purpose This study aimed to evaluate the impact of background insulin and metformin monotherapy on major CV and renal outcomes in individuals with T2D and high CV risk, and to assess whether canagliflozin can offset the cardio-renal risk associated with different anti-diabetic therapies. Methods We merged data from the CANVAS and CREDENCE trials, totalling 14,530 participants aged 30–90 years, randomised to placebo or canagliflozin (100-300 mg) treatment and followed up for a median of 2.6 years. Among them, 2,766 (19%) were on insulin monotherapy and 2,127 (14.6%) on metformin monotherapy. Outcomes included a composite of hospitalisation for heart failure (hHF) and CV death (cvDeath), major adverse cardiovascular events (MACE), all-cause death (acDeath), non-fatal myocardial infarction (nfMI), and a composite of renal outcomes. Multivariable Cox proportional hazards models were used to assess risk, with extensive adjustments for confounders. Results Patients on insulin monotherapy were older, with longer diabetes duration and poorer glycaemic control. In univariate analysis, insulin was associated with an increased risk of hHF/cvDeath (HR=1.80 [95% CI:1.57-2.05]), MACE (HR=1.61 [95% CI:1.43-1.81]), acDeath (HR=1.66 [95% CI:1.45-1.90]), nfMI (HR=1.42 [95% CI:1.16-1.73]) and renal outcomes (HR=1.85 [95% CI:1.56-2.20]). After adjusting for confounders, insulin remained a risk factor only for hHF/cvDeath (HR=1.18 [95% CI:1.02-1.36]) and MACE (HR=1.22 [95% CI:1.02-1.45]). In contrast, metformin monotherapy was associated with a reduction in risk of hHF/cvDeath (HR=0.73 [95% CI:0.60-0.89]) MACE (HR=0.77 [95% CI:0.66-0.90]), acDeath ... |