Faculty Bibliography

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

We aimed to assess the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy according to prior history of heart failure in the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial. We found that participants with a prior history of heart failure at baseline (15%) were more likely to be older, female, white, have a history of atherosclerotic cardiovascular disease, and use diuretics and beta blockers (all P < .001), and that, compared with placebo, canagliflozin safely reduced renal and cardiovascular events with consistent effects in patients with and without a prior history of heart failure (all efficacy P interaction >.150). These results support the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy regardless of prior history of heart failure.

Background: The skin's hypertonic microenvironment has a protective antimicrobial function that may be disrupted by sodium glucose cotransporter 2 inhibitors (SGLT2i). We aimed to describe skin and soft tissue infections (SSTI) in the CREDENCE trial and determine whether canagliflozin affects the risk of SSTIs.
Method(s): We performed a post-hoc analysis of the CREDENCE trial that randomised people with type 2 diabetes and albuminuric stage 2 and 3 chronic kidney disease to either canagliflozin 100mg daily or placebo. Adverse events were assessed by two blinded authors following predetermined criteria for SSTI with discrepancies resolved by consensus. We analysed the risks of SSTIs in the on-treatment population as the more conservative approach, with sensitivity analyses conducted in the intentionto- treat population, for serious events only and for participant subgroups. Univariable time-to first-event regression models were assessed.
Result(s): Overall 373/4397 (8.5%) participants experienced 478 events comprising 252 bacterial skin infections (including 2 episodes of necrotising fasciitis), 94 fungal skin infections, 109 other skin infections and 23 soft tissue infections. Of these, 136/478 (28%) were serious. Canagliflozin did not increase the risk of SSTI (HR 0.85 [95% Confidence Interval (CI) 0.69-1.04] p=0.11), with similar results in the intention-to-treat population (HR 0.88 [95% CI 0.73-1.07] p=0.20), in analyses confined to serious SSTI (HR 0.83 [95% CI 0.58-1.21] p=0.33) and participant subgroups (all p interaction>=0.10). Both cases of necrotising fasciitis were in patients assigned to canagliflozin and the participants recovered after drug was withdrawn.
Conclusion(s): Canagliflozin did not increase the risk of skin and soft tissue infections overall or in any subgroup, in CREDENCE trial participants with type 2 diabetes mellitus and albuminuric chronic kidney disease

Background: Genital mycotic infections (GMI) and urinary tract infections (UTI) are common in patients with diabetes. We assessed the effects of canagliflozin on the risk of these infections in the CREDENCE trial population.
Method(s): The CREDENCE trial randomised people with type 2 diabetes and albuminuric stage 2 and 3 chronic kidney disease to canagliflozin 100mg daily or placebo. We analysed the risk of GMI and UTI with canagliflozin compared to placebo overall and in subgroups. The primary analysis was conducted in the on-treatment population. When canagliflozin increased risk, we determined patient risk factors for GMIs using multivariable Cox regression models.
Result(s): Overall 31/2905 (1.1%) men and 32/1492 (2.1%) women experienced 91 GMIs and 166/2905 (5.7%) men and 300/1492 (20.1%) women experienced 669 UTIs. 58/669 (8.7%) UTIs but no GMIs were reported as serious. Most participants continued treatment following their first infection with similar recurrence rates in the canagliflozin and placebo groups. Canagliflozin increased the risk of GMI (HR 3.83 [95% CI 2.08-7.06] p<0.0001). The hazard ratio (HR) for canagliflozin compared to placebo was consistent across most subgroups, though canagliflozin led to a greater increase in risk in those with a BMI>30 kg/ m² compared to those with a BMI<30 kg/ m² (HR 5.91 vs 1.36, p interaction=0.03) and in men compared to women (HR 9.30 vs HR 2.10, p interaction=0.04). In those who were randomised to canagliflozin, independent risk factors for GMI were higher BMI (HR 1.53 [95% CI 1.29-1.83] per 5 units p<0.0001) and longer diabetes duration (HR 1.18 [95% CI 1.01-1.40] per 5 years p=0.04). Canagliflozin did not affect the risk of UTI (HR 1.08 [95% CI 0.90-1.29] p=0.42) overall or in any subgroup.
Conclusion(s): Canagliflozin increased risk of GMI but not UTI. The proportional increase in GMI with canagliflozin was greater in men and people with higher BMI

Background: Iron Deficiency (ID), defined by a TSAT index <20 %, is present in approximately half of ND-CKD patients, varying little by CKD stage. Distinct from approaches in conditions such as heart failure, the importance of iron reserves and the basis for iron therapy in CKD has focused primarily on supporting effective erythropoiesis. A comprehensive approach and design to estimate the impact of ID, independently from hemoglobin (Hb) levels, on mortality risk has not been explored in ND-CKD until the present.
Method(s): 5144 patients from Brazil (N=294), France (N=2227), the US (N=494), and Germany (N=2129) enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) from 2013-2019 with available TSAT were included in the analysis. We categorized patients by first available TSAT at enrollment. Hb measurements at same time as TSAT were used. Cox models were used to estimate hazard ratios (HR) of TSAT on mortality, censored at start of dialysis or kidney transplantation. Models were progressively adjusted for confounders, including demographics, comorbidities, inflammation surrogates, treatment with erythropoietin stimulating-agents and Hb.
Result(s): Sample characteristics were: 59% male; 45% diabetes; and mean (SD) age 69 (13) years, eGFR 28 (11) mL/min, Hb 12 (2) g/dL, TSAT 24 (2) %, ferritin 196 (214) ng/dL. TSAT levels below 25% were progressively associated with higher mortality risk, while patients with TSAT greater than 45% tended to have higher risks for mortality (Figure).
Conclusion(s): ID, as measured by the TSAT index, is associated with higher risk of all-cause mortality in ND-CKD patients, even after extensive adjustments for clinical, demographic and biochemical confounders, including Hb levels. Interventional studies evaluating the impact of iron supplementation and alternative targets on clinical outcomes in ND-CKD patients are needed to better inform ID management strategies

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: There is a paucity of data examining electrolyte concentrations during and immediately after hemodialysis (HD) sessions. We describe these changes and provide predictive nomograms based on HD prescriptions and pre-HD electrolytes.
Method(s): We leveraged patient (n=66) and HD session-level pre- and post-HD laboratory data (n=1,713) from the Monitoring in Dialysis study and fit mixed effects regression models to analyze differences between pre-, 15-minutes post-, and 30-minutes post-HD levels (compared with immediately post-HD) of electrolytes, blood urea nitrogen, creatinine, and albumin as well as the association of post-HD values with dialysate prescriptions.
Result(s): Serum bicarbonate, calcium, and albumin increased (mean increase 4.9mEq/ L+/-0.3, 0.7mEq/L+/-0.1, and 0.4g/dL+/-0.03, respectively), and potassium, magnesium, and phosphorus decreased immediately post-HD (mean -1.2mEq/L+/-0.1, -0.3mEq/L+/-0.03, and -3.0mg/dL+/-0.2, respectively). Hypokalemia and hypophosphatemia were present in 34% and 67% of immediately post-HD samples, respectively. Changes were observed in electrolyte concentrations at 15- and 30-minutes post-HD compared to immediately post- HD (Fig. A: observed changes; Fig. B: predictive nomograms of post-HD electrolytes).
Conclusion(s): Contemporary HD results in marked changes in electrolyte concentrations during and after the treatment. We report a high frequency of post-HD hypokalemia and hypophosphatemia and present predictive nomograms relating post- HD changes to dialysate prescriptions. Whether the abnormalities observed in potassium and phosphorus post-HD predispose to adverse symptoms and arrhythmia is unclear and requires further research. (Figure Presented)

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: 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: People with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) are at very high risk of cardiovascular events and kidney failure. While canagliflozin reduces the risk of these outcomes, the consistency of this effect across all levels of estimated glomerular filtration rate (eGFR) and urinary albumin:creatinine ratio (UACR) remains uncertain.
Method(s): We pooled individual participant data from the CANVAS Program (n=10,142) and CREDENCE trial (n=4,401) to assess the effect of canagliflozin on a primary composite outcome of myocardial infarction, stroke, heart failure, doubling of serum creatinine, kidney failure, cardiovascular or kidney death. The effect of canagliflozin was assessed using Cox regression models with treatment by subgroup interaction terms stratified by trial.
Result(s): 2,051/14,543 (14%) participants experienced the primary outcome over a median follow-up of 2.5 years. Overall, canagliflozin reduced the risk of the primary outcome (HR 0.77, 95% 0.70-0.84; Figure). The magnitude of relative benefit increased as eGFR declined (P-trend=0.0067; Figure) with some evidence of greater relative benefit at higher UACR (P-trend=0.057; Figure). Lower eGFR and higher UACR levels were independently associated with cardio-renal risk. Consequently, absolute risk reductions increased more than 5-fold across lower eGFR categories and more than 9-fold across higher UACR categories (Figure).
Conclusion(s): Canagliflozin reduces the risk of cardio-renal outcomes in people with T2DM; the magnitude of relative and absolute protection varies by severity of CKD