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: The efficacy of an aggressive multiple risk factor intervention approach - optimal medical therapy (OMT) - to reduce major adverse cardiovascular events in patients with CKD has not been tested.
Objective(s): to examine OMT goal attainment in patients with CKD on dialysis (CKD-D) and non-dialysis CKD (CKD-ND) in the ISCHEMIA-CKD trial.
Method(s): OMT was recommended to all participants in ISCHEMIA-CKD. Longitudinal trajectories of individual OMT components (smoking cessation, systolic blood pressure (SBP) <140 mmHg, low density lipoprotein (LDL) cholesterol <70 mg/dL, high-intensity statin use, and aspirin use) were modeled over study follow-up. Covariateadjusted percentage point difference in each OMT goal achieved at 24 months between CKD-D and CKD-ND groups (% difference [95% credible interval (CrI)]) was estimated.
Result(s): There were 415 CKD-D and 362 CKD-ND patients at baseline. CKD-D were younger (61 v 67 yrs, p<0.001) and less often diabetic (53% v 62%, p=0.023). CKD-D patients were 7.9 % (0.7%, 14.8%) more likely than CKD-ND to attain the SBP goal at 24 months (Figure). CKD-D patients were 22.7% (-33.3%, -11.4%) less likely to receive high-intensity statins. There was a steady and similar increase in proportional achievement of OMT during follow up.
Conclusion(s): OMT improved over time in advanced CKD-ND and CKD-D. CKD-D achieved the SBP goal more than CKD-ND, yet CKD-D were less likely to be treated with high-intensity statin. Future studies should explore systemic and patient-related barriers to attainment of OMT in this high-risk cohort.(Figure Presented)

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

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: Albuminuria is a risk factor for kidney disease progression and CV disease. We examined the relative and absolute effects of CANA by baseline albuminuria among CREDENCE participants.
Method(s): CREDENCE was a double-blind, randomized study of 4401 participants with eGFR 30-<90mL/min/1.73m2 and uACR >300-5000mg/g who demonstrated that CANA significantly reduced renal and CV outcomes, including the primary composite of end-stage kidney disease, doubling serum creatinine, or renal or CV death. We analyzed the effect of CANA on renal, CV, and safety outcomes by baseline uACR.
Result(s): At baseline, 2348 (53.4%), 1547 (35.2%), and 506 (11.5%) participants had uACR <=1000, >1000-<3000, >=3000mg/g. Higher uACR was associated with higher event rates (Figure). CANA reduced renal and CV endpoints, with no statistical variation by uACR (all p heterogeneity >0.17). CANA led to a greater absolute reduction in renal events in those with higher uACR (number needed to treat to prevent 1 episode of the primary composite: 22 and 8 for uACR >1000-<3000 and >=3000mg/g). Rates of renalrelated adverse events were lower with CANA, and the relative reduction was greater with higher uACR (p heterogeneity=0.003). CANA had no significant effect on acute kidney injury, volume depletion, hyperkalemia, urinary tract infections or hypoglycemia, with no differences by uACR (all p heterogeneity >0.12).
Conclusion(s): CANA safely reduces renal and CV events in people with type 2 diabetes and substantial albuminuria, with the greatest absolute renal benefit in those with uACR of 3000-5000mg/g

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)

Cardiovascular disease is one of the most common causes of death with social factors increasingly recognized as determinants of cardiovascular prognosis. Homelessness, transient or chronic, may be one of the factors which predict treatment access and eventual outcomes as socially and economically disadvantaged group has high prevalence of cardiovascular risk factors such as smoking, and delayed diagnosis and poor control of other risk factors such as diabetes and hypertension. This perspective article aims to discuss the issues associated with cardiovascular disease treatment, outcomes and future directions for homeless patients.

Background and Aims: The skin's hypertonic microenvironment has a hypothesized protective antimicrobial function that may be disrupted by SGLT2i. The association between sodiumglucose cotransporter inhibitors (SGLT2i) and genital mycotic infections is well established, but it is not known if these agents increase the risk of other skin and soft tissue infections (SSTI).We aimed to describe SSTI in the CREDENCE trial, and determine whether canagliflozin affects the risk of skin and soft tissue infections (SSTIs) overall and in subgroups.
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. Infections reported as 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 a sensitivity analysis conducted in the intention-to-treat population. 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. Drug was continued in 290/373 (78%) of first events, with similar frequency of subsequent events between groups (31/133 (23%) and 33/157 (21%) for those continuing canagliflozin and placebo respectively). In both cases of necrotising fasciitis, drug was withdrawn and the participants recovered.Canagliflozin did not increase the risk of SSTI (HR 0.85 [95% Confidence Interval (CI) 0.69-1.04] p=0.11) (Figure 1). Results were similar 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 in the predefined subgroups.
Conclusion(s): Although other studies suggest that SGLT2i may reduce the sodium content of the skin, we found that canagliflozin does not increase the risk of skin and soft tissue infections, overall or in any subgroup, in people with type 2 diabetes mellitus and albuminuric chronic kidney disease. (Figure Presented)

Background and Aims: To describe genital mycotic infections (GMI) and urinary tract infections (UTI) in the CREDENCE trial, determine whether canagliflozin increased the risk of these infections overall and in subgroups, and describe predictors of risk for genital mycotic infections.
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 patient subgroups. The primary analysis was conducted in the on-treatment population, as the more conservative approach with sensitivity analyses conducted using an intention-to-treat population. When canagliflozin increased risk, we determined patient risk factors for GMIs using multivariable Cox regression models adjusting for age, gender, race, markers of disease severity (body mass index (BMI), haemoglobin A1c, diabetes duration, other glucose lowering medications at baseline and kidney function).
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. Canagliflozin increased the risk of GMI (HR 3.83 [95% CI 2.08-7.06] p<0.0001). The hazard ratio for canagliflozin compared to placebo was consistent across most subgroups, though the risk with canagliflozin was greater in those with a higher BMI (HR 5.91 [95% CI 2.65-13.15] for BMI >=30 kg/m² vs HR 1.36 [95% CI 0.47-3.92] for BMI<30 kg/m², p interaction=0.03) and was higher in men (HR 9.30 [95% CI 2.83-30.60] vs HR 2.10 [95% CI 1.00-4.45] for men and women respectively, 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 over placebo (HR 1.08 [95% CI 0.90-1.29] p=0.42) overall or in any subgroup, however risk was higher in women (HR 1.23 [95% CI 0.98-1.54] vs HR 0.82 [0.60-1.11] for women and men respectively, p interaction=0.04).58/669 (8.7%) UTIs but no GMIs were reported as serious. Drug was continued in 56/63 (89%) of first GMIs, with similar frequency of subsequentGMI in those continuing on canagliflozin (13/43, 30.2%) or placebo (4/13, 30.8%). Drug was continued in 385/466 (82.6%) first UTIs, with similar frequency of subsequent UTIs in those continuing on cangliflozin (50/199 (25.1%) or placebo 49/186 (26.3%). All findings were similar when conducted using an intention-to-treat approach.
Conclusion(s): Canagliflozin increased the risk of genital mycotic infections but not urinary tract infections. The risk of genital mycotic infections from canagliflozin over placebo was higher in men and those with higher BMI. In those treated with canagliflozin, higher BMI and longer diabetes duration independently predicted infection. Most participants continued treatment following their first infection with similar recurrence rates in the canagliflozin and placebo groups.These findings will be useful in clinical care, and help identify those at greatest risk for genital infections with canagliflozin treatment