Aims/hypothesis: Sodium–glucose cotransporter 2 (SGLT2) inhibitors provide cardiovascular and renal protection in type 2 diabetes and chronic kidney disease (CKD). Although both excess and restricted sodium intake are linked to adverse outcomes, the interaction of sodium intake with SGLT2 inhibitors has not been explored. This study aimed to examine how dietary sodium intake affects cardiorenal outcomes and whether canagliflozin modifies these effects. Methods: A post hoc analysis of the CREDENCE trial (median follow-up 2.6 years) was conducted in individuals with type 2 diabetes and CKD randomised to canagliflozin 100 mg or placebo. Using a validated formula, we estimated daily sodium intake from urine in 2573 participants, divided into low–normal sodium (LNS; n=1286) and high sodium (HS; n=1287) groups. Outcomes included the following: cardiovascular death or hospitalisation for heart failure; heart failure alone; a composite renal outcome; and all-cause death. Cox models were adjusted for confounders. Sodium intake was additionally analysed as a continuous variable to assess non-linearity. Results: In the placebo group, LNS intake increased the risk of heart failure/cardiovascular death vs HS (adjusted HR [adjHR] 1.56 [95% CI 1.10, 2.23]). Canagliflozin significantly reduced this risk in the LNS group (adjHR 0.48 [95% CI 0.33, 0.70]) but not in the HS group (adjHR 1.05 [95% CI 0.73, 1.53]). Similar patterns were seen for heart failure alone. Sodium intake had no effect on renal outcomes, while canagliflozin reduced renal risk in both the LNS group and the HS group. Neither sodium intake nor canagliflozin influenced all-cause mortality. Continuous modelling revealed a near-linear rise in heart failure/cardiovascular death risk as sodium intake decreased in placebo recipients, while this gradient was flattened with canagliflozin. Conclusions/interpretation: In individuals with type 2 diabetes and CKD, LNS intake increases the risk of heart failure and cardiovascular death, while renal outcomes are unaffected by sodium intake. Canagliflozin mitigates the increased cardiovascular risk in individuals with LNS intake, while offering renal protection irrespective of dietary sodium. Trial registration: Clinicaltrial.gov NCT02065791
Impact of canagliflozin on the cardiorenal effects of dietary sodium intake in type 2 diabetes: a post hoc analysis of the CREDENCE trial
Chiriaco M.
Primo
;Trico D.;Sacchetta L.;Baldi S.;Scozzaro T.;Natali A.;Ferrannini E.Ultimo
2026-01-01
Abstract
Aims/hypothesis: Sodium–glucose cotransporter 2 (SGLT2) inhibitors provide cardiovascular and renal protection in type 2 diabetes and chronic kidney disease (CKD). Although both excess and restricted sodium intake are linked to adverse outcomes, the interaction of sodium intake with SGLT2 inhibitors has not been explored. This study aimed to examine how dietary sodium intake affects cardiorenal outcomes and whether canagliflozin modifies these effects. Methods: A post hoc analysis of the CREDENCE trial (median follow-up 2.6 years) was conducted in individuals with type 2 diabetes and CKD randomised to canagliflozin 100 mg or placebo. Using a validated formula, we estimated daily sodium intake from urine in 2573 participants, divided into low–normal sodium (LNS; n=1286) and high sodium (HS; n=1287) groups. Outcomes included the following: cardiovascular death or hospitalisation for heart failure; heart failure alone; a composite renal outcome; and all-cause death. Cox models were adjusted for confounders. Sodium intake was additionally analysed as a continuous variable to assess non-linearity. Results: In the placebo group, LNS intake increased the risk of heart failure/cardiovascular death vs HS (adjusted HR [adjHR] 1.56 [95% CI 1.10, 2.23]). Canagliflozin significantly reduced this risk in the LNS group (adjHR 0.48 [95% CI 0.33, 0.70]) but not in the HS group (adjHR 1.05 [95% CI 0.73, 1.53]). Similar patterns were seen for heart failure alone. Sodium intake had no effect on renal outcomes, while canagliflozin reduced renal risk in both the LNS group and the HS group. Neither sodium intake nor canagliflozin influenced all-cause mortality. Continuous modelling revealed a near-linear rise in heart failure/cardiovascular death risk as sodium intake decreased in placebo recipients, while this gradient was flattened with canagliflozin. Conclusions/interpretation: In individuals with type 2 diabetes and CKD, LNS intake increases the risk of heart failure and cardiovascular death, while renal outcomes are unaffected by sodium intake. Canagliflozin mitigates the increased cardiovascular risk in individuals with LNS intake, while offering renal protection irrespective of dietary sodium. Trial registration: Clinicaltrial.gov NCT02065791I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
