Faculty Bibliography

Background: The association between early changes in albuminuria and kidney and CV events is primarily based on trials of renin-angiotensin system blockade. It is unclear whether this association is similar with sodium-glucose cotransporter 2 inhibitors.
Method(s): In this post-hoc analysis of the CREDENCE trial in patients with type 2 diabetes and chronic kidney disease, we assessed the effect of CANA versus placebo on albuminuria at week 26, and the association of early changes in urinary albumin:creatinine ratio (UACR) for the first 26 weeks with kidney and CV outcomes using multivariable Cox regression. Kidney and CV outcomes were defined as (1) endstage kidney disease, doubling of serum creatinine or death due to kidney disease, (2) major adverse cardiovascular events (MACE) and (3) hospitalization for heart failure (HHF) or CV death.
Result(s): This analysis included 3836 participants (87.2%) with complete data for early changes in UACR. CANA lowered UACR by 31% (95%CI 27-36%) at week 26 and increased the likelihood of achieving a 30% UACR reduction (OR 2.69, 95%CI 2.35- 3.07). We observed log-linear associations of early changes in UACR during 26 weeks with kidney and CV outcomes (all p trend <0.001; Table). Each 30% UACR reduction was independently associated with a lower hazard for clinical outcomes, overall and in each treatment arm (all p <0.001).
Conclusion(s): In people with type 2 diabetes and CKD, canagliflozin results in early and sustained reductions in albuminuria, which was independently associated with longterm kidney and cardiovascular outcomes. (Table Presented)

Background: CANA slows progression of chronic kidney disease (CKD) in people with type 2 diabetes. CANA also induces a reversible acute decline in estimated glomerular filtration rate (eGFR), which is believed to be a hemodynamic effect. Predictors of the initial decline and its association with long-term eGFR trajectories and safety outcomes are unknown.
Method(s): This post hoc study of CREDENCE included 4289 patients with type 2 diabetes and CKD who had eGFR measured at both baseline and week 3. Participants were categorized by percentage decline in eGFR at week 3: greater than 10% decline; between 0 and 10% decline; and no decline. Baseline characteristics associated with acute eGFR drop >10% were evaluated using logistic regression. Long-term eGFR decline and safety outcomes were estimated in each eGFR decline category by linear mixed effects models and Cox regression after adjustment for laboratory measures and medication use.
Result(s): More participants in the CANA (956 [45%]) versus placebo (PBO) group (450 [21%]) had an acute eGFR decline >10% (p<0.001). A >30% decline occurred infrequently (89 [4%] with CANA and 39 [2%] with PBO; p<0.001). In the CANA but not in the PBO group, older age (OR CANA 1.17, 95% CI 1.05-1.31; per 10 years) and history of heart failure (OR CANA 0.77, 0.59-0.99) were associated with a higher and lower likelihood of an acute eGFR decline >10%, respectively (both p interaction<0.05). Following the initial eGFR change, long-term eGFR trajectories were similar across eGFR decline categories (all p>0.05). Safety profiles were also similar except when the drop unusually exceeded 30%, in which case adverse events and renal related adverse events occurred more frequently. Results were consistent in subgroup analysis by baseline eGFR (30-<45, 45-<60, and 60-<90 mL/min/1.73m²).
Conclusion(s): Although acute eGFR declines >10% occurred in nearly half of all patients following initiation of CANA, the benefit of CANA compared with PBO was observed regardless of the acute eGFR decline and safety profiles were similar

Background: Canagliflozin (CANA) reduces the risk of cardiovascular (CV) events and kidney failure in people with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Inherent in its mechanism of action is enhanced natriuresis and osmotic diuresis. It is unclear if the efficacy or safety of CANA is modified by concomitant diuretic use.
Method(s): CREDENCE randomized participants with T2DM and CKD to CANA or matching placebo. The primary outcome was a composite of end-stage kidney disease, doubling of serum creatinine, CV or renal death. We estimated effects on key efficacy and safety outcomes by baseline use of loop diuretics.
Result(s): Of 4401 CREDENCE participants, 955 (21.7%) received loop diuretics at baseline. These participants were older (mean age 63.5 vs 62.7 y; P=0.01), with a longer diabetes duration (17.0 vs 15.5 y), lower eGFR (49.7 vs 58.0 mL/min/1.73m²), and were more like to have a history of heart failure (27.6 vs 11.3%; all P<0.0001). Unadjusted event rates were higher in those using loop diuretics (Figure). Effects of CANA on the primary outcome and other CV and renal outcomes were consistent irrespective of loop diuretic use. The risk of renal-related adverse events, acute kidney injury, and volume depletion was not elevated by loop diuretic use (data not shown; all Pinteraction>0.05).
Conclusion(s): CANA reduces the risk of CV and renal outcomes in people with T2DM and CKD irrespective of baseline use of loop diuretics, without additional adverse effects. (Table Presented)

Background and aims: Individuals with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) are at high risk for hospitalized heart failure (HHF) and these events are reduced by canagliflozin (CANA). We investigated whether the effect of CANA on HHF or cardiovascular (CV) death differs by key participant characteristics.
Material(s) and Method(s): CREDENCE randomized participants with T2DM and CKD to CANA or matching placebo. In this analysis, we assessed the effect of CANA on the prespecified secondary outcome of HHF/CV death by baseline characteristics. Hazard ratios (HRs) and 95% CIs were estimated with Cox regression models, with subgroup by treatment interaction terms added to test for heterogeneity.
Result(s): Of 4401 trial participants, 432 experienced a HHF/CV death event over a median follow-up of 2.6 years. Participants at higher risk included those with a history of CV disease or HF, lower eGFR, higher UACR and baseline use of loop diuretics. CANA reduced the risk of HHF/CV death by 31% in the overall population (HR 0.69, 95% CI 0.57, 0.83), with consistent effect across a broad range of participant subgroups including those at high risk (all Pinteraction>0.246; Figure). The effect of CANA on HHF alone (HR 0.61, 95% CI 0.47-0.80) was also similar across most key participant subgroups (all Pinteraction>0.10).
Conclusion(s): CANA consistently reduces the risk of HHF/CV death and of HHF in T2DM and CKD across a broad range of participant subgroups, including those with and without prior HF

Background and aims: Canagliflozin (CANA) slows progression of chronic kidney disease (CKD) in people with type 2 diabetes. CANA also induces a reversible acute decline in estimated glomerular filtration rate (eGFR), which is believed to be a hemodynamic effect. Predictors of the initial decline and its associationwith long-term eGFRtrajectories and safety outcomes are unknown.
Material(s) and Method(s): This post hoc study of the CREDENCE trial included 4289 patientswith type 2 diabetes andCKDwho had eGFRmeasured at both baseline andweek 3. Participants were categorized by percentage decline in eGFR at week 3: >10%, <=10% to >0%, and <=0%. Baseline characteristics associatedwith acute eGFRdeclines >10%were evaluated using logistic regression. Long-term eGFR decline and safety outcomes were estimated in each eGFR decline category by linear mixed effects models and Cox regression after adjustment for laboratory measures and medication use.
Result(s): More participants in the CANA (956 [45%]) versus placebo (PBO) group (450 [21%]) had an acute eGFR decline >10% (p <0.001). A >30% decline occurred infrequently (89 [4%] with CANA and 39 [2%] with PBO; p <0.001). In the CANA but not in the PBO group, older age (OR CANA 1.17, 95% CI 1.05-1.31; per 10 years) and history of heart failure (OR CANA 0.77, 0.59-0.99) were associated with a higher and lower likelihood of an acute eGFR decline >10%, respectively (both p for interaction <0.05). Following the initial eGFR change, long-term eGFR trajectories as well as overall safety profiles were similar across eGFR decline categories (all p values >0.05). Results were consistent when other decline thresholds (>20%) were used and in subgroup analysis by baseline eGFR (30-<45, 45-<60, and 60-<90 mL/min/1.73 m2).
Conclusion(s): Although acute eGFR declines >10% occurred in nearly half of all patients following initiation of CANA, the benefit of CANA compared with placebo was observed regardless of the acute eGFR decline and safety profiles were similar