Faculty Bibliography

Traditional management of diabetes mellitus has focused on glycemic control, beginning with lifestyle changes, followed by metformin, and then other classes of antiglycemic agents.¹ Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular (CV) events, including CV death, myocardial infarction (MI) and heart failure, and slow progression of renal dysfunction, including prevention of end-stage kidney disease (ESKD).^2-3 Because initial clinical trials included mostly patients with baseline HbA1c >7%, current guidelines have recommended this class as add-on therapy for patients whose HbA1c is not at goal, typically ≥7%.¹ We hypothesized that there would be similar benefits on CV and renal endpoints regardless of baseline HbA1c, including those with HbA1c <7%.

Background: Cardiac dysfunction and cardiovascular (CV) events are prevalent among patients with chronic kidney disease (CKD) without overt obstructive coronary artery disease (CAD) but the mechanisms remain poorly understood. Coronary microvascular dysfunction (CMD) has been proposed as a link between abnormal renal function and impairment of cardiac function and CV events. We sought to investigate the relationships between CKD, CMD, cardiac dysfunction and adverse CV outcomes. Methods: Patients undergoing cardiac stress positron emission tomography (PET), echocardiogram and renal function ascertainment at Brigham and Women's Hospital were studied longitudinally. Patients free of overt coronary (summed stress score < 3 & without history of ischemic heart disease), valvular and end-organ disease were followed for adverse composite outcome of death, hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was determined from PET. Echocardiograms were used to measure cardiac mechanics: diastolic (lateral and septal E/e') and systolic [global longitudinal (GLS), radial (GRS) and circumferential strain (GCS)]. Image analyses and event adjudication were blinded. The associations between estimated glomerular filtration rate (eGFR), CFR, diastolic, systolic indices and adverse CV outcomes were assessed in adjusted models and mediation analyses. Results: 352 patients (median age 65 years, 63% women and 22% black) were studied. 35% of patients had eGFR<60 ml/min/1.73 m², median LVEF of 62% and median CFR of 1.8. eGFR and CFR were associated with diastolic and systolic indices, as well as future CV events (all p<0.05). In multivariable models, CFR but not eGFR was independently associated with cardiac mechanics and CV events. The associations between eGFR, cardiac mechanics and CV events were partly mediated via CFR. Conclusions: CMD but not eGFR was independently associated with abnormal cardiac mechanics and an increased risk of CV events. CMD may mediate the effect of CKD on abnormal cardiac function and CV events in those without overt CAD.

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: 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: 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