ORCID Profile
0000-0001-9276-8380
Current Organisations
George Institute for Global Health
,
UNSW Sydney
,
James Cook University
,
University of Oxford
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Publisher: Oxford University Press (OUP)
Date: 23-08-2021
DOI: 10.1093/EURHEARTJ/EHAB497
Abstract: Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin–angiotensin–aldosterone system, particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium‒glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain. The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium ≥6.0 and & .5 mmol/L, respectively) and change in serum potassium. At baseline, the mean serum potassium in canagliflozin and placebo arms was 4.5 mmol/L 4395 (99.9%) participants were receiving renin–angiotensin system blockade. The incidence of investigator-reported hyperkalaemia or initiation of potassium binders was lower with canagliflozin than with placebo [occurring in 32.7 vs. 41.9 participants per 1000 patient-years hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.64–0.95, P = 0.014]. Canagliflozin similarly reduced the incidence of laboratory-determined hyperkalaemia (HR 0.77, 95% CI 0.61–0.98, P = 0.031), with no effect on the risk of hypokalaemia (HR 0.92, 95% CI 0.71–1.20, P = 0.53). The mean serum potassium over time with canagliflozin was similar to that of placebo. Among patients treated with renin–angiotensin–aldosterone system inhibitors, SGLT2 inhibition with canagliflozin may reduce the risk of hyperkalaemia in people with T2DM and CKD without increasing the risk of hypokalaemia.
Publisher: Springer Science and Business Media LLC
Date: 20-08-2021
DOI: 10.1007/S00125-021-05512-5
Abstract: Higher plasma concentrations of tumour necrosis factor receptor (TNFR)-1, TNFR-2 and kidney injury molecule-1 (KIM-1) have been found to be associated with higher risk of kidney failure in in iduals with type 2 diabetes in previous studies. Whether drugs can reduce these biomarkers is not well established. We measured these biomarkers in s les of the CANVAS study and examined the effect of the sodium–glucose cotransporter 2 inhibitor canagliflozin on these biomarkers and assessed whether the early change in these biomarkers predict cardiovascular and kidney outcomes in in iduals with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS). Biomarkers were measured with immunoassays (proprietary multiplex assay performed by RenalytixAI, New York, NY, USA) at baseline and years 1, 3 and 6. Mixed-effects models for repeated measures assessed the effect of canagliflozin vs placebo on the biomarkers. Associations of baseline levels and the early change (baseline to year 1) for each biomarker with the kidney outcome were assessed using multivariable-adjusted Cox regression. In total, 3523/4330 (81.4%) of the CANVAS participants had available s les at baseline. Each doubling in baseline TNFR-1, TNFR-2 and KIM-1 was associated with a higher risk of kidney outcomes, with corresponding HRs of 3.7 (95% CI 2.3, 6.1 p 0.01), 2.7 (95% CI 2.0, 3.6 p 0.01) and 1.5 (95% CI 1.2, 1.8 p 0.01), respectively. Canagliflozin reduced the level of the plasma biomarkers with differences in TNFR-1, TNFR-2 and KIM-1 between canagliflozin and placebo during follow-up of 2.8% (95% CI 3.4%, 1.3% p 0.01), 1.9% (95% CI 3.5%, 0.2% p = 0.03) and 26.7% (95% CI 30.7%, 22.7% p 0.01), respectively. Within the canagliflozin treatment group, each 10% reduction in TNFR-1 and TNFR-2 at year 1 was associated with a lower risk of the kidney outcome (HR 0.8 [95% CI 0.7, 1.0 p = 0.02] and 0.9 [95% CI 0.9, 1.0 p 0.01] respectively), independent of other patient characteristics. The baseline and 1 year change in biomarkers did not associate with cardiovascular or heart failure outcomes. Canagliflozin decreased KIM-1 and modestly reduced TNFR-1 and TNFR-2 compared with placebo in in iduals with type 2 diabetes in CANVAS. Early decreases in TNFR-1 and TNFR-2 during canagliflozin treatment were independently associated with a lower risk of kidney disease progression, suggesting that TNFR-1 and TNFR-2 have the potential to be pharmacodynamic markers of response to canagliflozin.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-09-2020
Abstract: Studies of renin-angiotensin system inhibitors have consistently shown that the magnitude of albuminuria reduction during the first months of treatment is associated with risk reduction for kidney and cardiovascular outcomes. Whether or not the association between early changes in albuminuria and these outcomes also occurs with sodium-glucose cotransporter 2 (SGLT2) inhibition is unclear. This post hoc analysis of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that, in people with type 2 diabetes and CKD, treatment with the SGLT2 inhibitor canagliflozin results in an early and sustained reduction in albuminuria. It also shows that early changes in albuminuria were independently associated with long-term kidney and cardiovascular outcomes. These findings highlight the importance of monitoring albuminuria during canagliflozin treatment to assess kidney and cardiovascular prognosis. The association between early changes in albuminuria and kidney and cardiovascular events is primarily based on trials of renin-angiotensin system blockade. It is unclear whether this association occurs with sodium-glucose cotransporter 2 inhibition. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial enrolled 4401 patients with type 2 diabetes and CKD (urinary albumin-creatinine ratio [UACR] mg/g). This post hoc analysis assessed canagliflozin’s effect on albuminuria and how early change in albuminuria (baseline to week 26) is associated with the primary kidney outcome (ESKD, doubling of serum creatinine, or kidney death), major adverse cardiovascular events, and hospitalization for heart failure or cardiovascular death. Complete data for early change in albuminuria and other covariates were available for 3836 (87.2%) participants in the CREDENCE trial. Compared with placebo, canagliflozin lowered UACR by 31% (95% confidence interval [95% CI], 27% to 36%) at week 26, and significantly increased the likelihood of achieving a 30% reduction in UACR (odds ratio, 2.69 95% CI, 2.35 to 3.07). Each 30% decrease in UACR over the first 26 weeks was independently associated with a lower hazard for the primary kidney outcome (hazard ratio [HR], 0.71 95% CI, 0.67 to 0.76 P .001), major adverse cardiovascular events (HR, 0.92 95% CI, 0.88 to 0.96 P .001), and hospitalization for heart failure or cardiovascular death (HR, 0.86 95% CI, 0.81 to 0.90 P .001). Residual albuminuria levels at week 26 remained a strong independent risk factor for kidney and cardiovascular events, overall and in each treatment arm. In people with type 2 diabetes and CKD, use of canagliflozin results in early, sustained reductions in albuminuria, which were independently associated with long-term kidney and cardiovascular outcomes.
Publisher: Wiley
Date: 14-08-2023
DOI: 10.1111/DOM.15232
Abstract: To estimate the lifetime benefit of a combination treatment of sodium‐glucose co‐transporter 2 (SGLT2) inhibitors and mineralocorticoid‐receptor antagonists (MRA) in patients with type 2 diabetes and chronic kidney disease (CKD). The cumulative effect of combination treatment was derived from trial‐level estimates of the effect of an SGLT2 inhibitor (canagliflozin) and MRA (finerenone) from the CREDENCE (N = 4401) and FIDELIO (N = 5734) trials, respectively. The cumulative effect was applied to the control group of patients with type 2 diabetes in the DAPA‐CKD trial (N = 1451) to estimate long‐term gains in event‐free and overall survival. The analysis was repeated in an observational study. The primary outcome was a composite endpoint of doubling of serum creatinine, end‐stage kidney disease or death because of kidney failure. The hazard ratio of combination treatment for the primary outcome was 0.50 [95% confidence interval (CI): 0.44, 0.57]. At age 50 years, the estimated event‐free survival from the primary outcome was 16.7 years (95% CI: 18.1, 21.0) with combination treatment versus 10.0 years (95% CI: 6.8, 12.3) with angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers resulting in an incremental gain of 6.7 years (95% CI: 5.5, 7.9). In an observational study, the estimated gain in event‐free survival regarding primary outcome was 6.3 years (95% CI: 5.2, 7.3). In a conservative scenario, assuming low adherence (70% of the observed adherence) and less pronounced efficacy (70% of the observed efficacy with 2% yearly decline) of combination therapy, gain in event‐free survival regarding primary outcome was 2.5 years (95% CI: 2.0, 2.9). Combined disease‐modifying treatment with an SGLT2 inhibitor and MRA in patients with type 2 diabetes and CKD may substantially increase the number of years free from kidney failure and mortality.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 03-2021
Publisher: Wiley
Date: 16-04-2021
DOI: 10.1111/DOM.14386
Abstract: Heart failure is prevalent in those with type 2 diabetes and chronic kidney disease, and is associated with significant mortality and morbidity. In the CREDENCE trial, canagliflozin reduced the risk of hospitalization for heart failure (HHF) or cardiovascular (CV) death by 31%. In the current analysis we sought to determine whether the effect of canagliflozin on HHF/CV death differed in subgroups defined by key baseline participant characteristics. Cox regression models were used to estimate hazard ratios and 95% confidence intervals. Canagliflozin was associated with a reduction in the relative risk of HHF/CV death regardless of age, sex, history of heart failure or CV disease, and the use of loop diuretics or glucagon‐like peptide‐1 receptor agonists (all p interaction .114). The absolute benefit of canagliflozin was greater in those at highest baseline risk, such as those with CV disease (50 fewer events/1000 patients treated over 2.5 years vs. 20 fewer events in those without CV disease) or advanced kidney disease (estimated glomerular filtration rate [eGFR] 30–45 mL/min/1.73m 2 : 61 events prevented/1000 patients treated over 2.5 years vs. 23 events in eGFR 60–90 mL/min/1.73m 2 ). Canagliflozin consistently reduces the proportional risk of HHF/CV death across a broad range of subgroups with greater absolute benefits in those at highest baseline risk.
Publisher: Wiley
Date: 15-05-2023
DOI: 10.1111/DOM.15112
Abstract: In the CANVAS Program and CREDENCE trials, the sodium glucose co‐transporter 2 inhibitor canagliflozin reduced the risk of cardiovascular and kidney events in patients with type 2 diabetes. The current study analysed a pooled population to ascertain the kidney protection provided by canagliflozin across the full spectrum of kidney parameters. This post‐hoc pooled analysis of the CANVAS Program (N = 10 142) and CREDENCE trial (N = 4401), assessed the risk of the primary kidney composite (doubling of serum creatinine, end‐stage kidney disease, renal death), in all patients and subgroups defined by baseline estimated glomerular filtration rate ( , 30 to , 45 to and ≥60 ml/min/1.73 m 2 ), albuminuria [ , 30‐300, mg/g ( .39, 3.39‐33.9, .9 mg/mmol)] and 2012 Kidney Disease: Improving Global Outcomes (KDIGO) classification of chronic kidney disease (low/moderate, high and very high risk). In the overall population, the risk for the primary kidney composite outcome was 37% lower in the canagliflozin group versus placebo (HR: 0.63 95% CI: 0.53, 0.77 p .001). There was no evidence of heterogeneity in the kidney protective effects of canagliflozin across a range of kidney risks when stratified by baseline estimated glomerular filtration rate, albuminuria or KDIGO risk category (all p interaction .05). A statistically significant risk reduction of the primary kidney composite outcome was sustained by approximately 18 months after randomization. These results emphasize a critical role of canagliflozin in kidney protection across a broad spectrum of participants with type 2 diabetes with varying levels of kidney function.
Publisher: Elsevier BV
Date: 10-2013
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.JVIR.2014.05.020
Abstract: Patency after percutaneous transluminal angioplasty of native hemodialysis arteriovenous fistulae (AVFs) is highly variable. This study aimed to identify predictors of patency following angioplasty in native AVFs. All endovascular procedures performed in native AVFs between 2005 and 2013 at two institutions were retrospectively reviewed. Clinical, anatomic, biochemical, and medication variables were subjected to univariate and multivariate Cox regression analysis to identify predictors of postintervention primary and secondary patency. During the study period, 207 patients underwent first angioplasty of their AVF. Follow-up ranged from 14 days to 8 years, during which another 247 endovascular interventions were performed to maintain patency. Postintervention primary patency rates at 6, 12, and 24 months were 66%, 49%, and 29%, respectively. Postintervention secondary patency rates at 6, 12, and 24 months were 94%, 84%, and 79%, respectively. On multivariate adjusted Cox regression analysis, upper-arm AVFs (P = .00072), AVFs less than 6 months of age (P = .0014), presence of multiple stenoses (P = .019), and degree of initial stenosis (P = .016) were significantly associated with shorter postintervention primary patency. A previously failed AVF was the only significant predictor of postintervention secondary patency loss (P = .0053). Anatomic factors related to the AVF location, AVF age, and the extent of the lesion are important predictors of restenosis after balloon angioplasty. Traditional cardiovascular risk factors, metabolic and inflammatory markers, and medications were not associated with postintervention patency.
Publisher: Wiley
Date: 29-10-2021
DOI: 10.1111/DOM.14226
Publisher: Oxford University Press (OUP)
Date: 2020
DOI: 10.1093/NDT/GFZ252
Abstract: The advent of sodium-glucose cotransporter 2 (SGLT2) inhibitors represents a major advance for people with type 2 diabetes (T2DM) and chronic kidney disease (CKD). The results of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial have clearly demonstrated that canagliflozin prevents kidney failure and cardiovascular events. The results from three other large-scale randomized trials, collectively enrolling & 000 participants, have provided further evidence that the effects of SGLT2 inhibition on major kidney outcomes in people with T2DM may be present across the class, although this will only be known for certain when Dapagliflozin and Renal Outcomes and Cardiovascular Mortality in Patients with CKD (DAPA-CKD) (NCT03036150) and The Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY) (NCT03594110) are reported over coming years. Importantly, the benefits of SGLT2 inhibition have been achieved in addition to the current standard of care. This review summarizes evidence for SGLT2 inhibition in people with T2DM and CKD, evaluates key patient characteristics and concomitant drug use that may influence the use of these drugs in people with CKD, discusses current guideline recommendations and explores how these drugs may be used in people with CKD in the future, including in combination with other treatments.
Publisher: Elsevier BV
Date: 07-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2022
DOI: 10.2215/CJN.08780621
Abstract: Clinical trials in nephrology are enriched for patients with micro- or macroalbuminuria to enroll patients at risk of kidney failure. However, patients with normoalbuminuria can also progress to kidney failure. TNF receptor-1, TNF receptor-2, and kidney injury marker-1 (KIM-1) are known to be associated with kidney disease progression in patients with micro- or macroalbuminuria. We assessed the value of TNF receptor-1, TNF receptor-2, and KIM-1 as prognostic biomarkers for CKD progression in patients with type 2 diabetes and normoalbuminuria. TNF receptor-1, TNF receptor-2, and KIM-1 were measured using immunoassays in plasma s les from patients with type 2 diabetes at high cardiovascular risk participating in the Canagliflozin Cardiovascular Assessment Study trial. We used multivariable adjusted Cox proportional hazards analyses to estimate hazard ratios per doubling of each biomarker for the kidney outcome, stratified the population by the fourth quartile of each biomarker distribution, and assessed the number of events and event rates. In patients with normoalbuminuria ( n =2553), 51 kidney outcomes were recorded during a median follow-up of 6.1 (interquartile range, 5.8–6.4) years (event rate, 3.5 95% confidence interval, 2.6 to 4.6 per 1000 patient-years). Each doubling of baseline TNF receptor-1 (hazard ratio, 4.2 95% confidence interval, 1.8 to 9.6) and TNF receptor-2 (hazard ratio, 2.3 95% confidence interval, 1.5 to 3.6) was associated with a higher risk for the kidney outcome. Baseline KIM-1, urinary albumin-creatinine ratio, and eGFR were not associated with kidney outcomes. The event rates in the highest quartile of TNF receptor-1 (≥2992 ng/ml) and TNF receptor-2 (≥11,394 ng/ml) were 5.6 and 7.0 events per 1000 patient-years, respectively, compared with 2.8 and 2.3, respectively, in the lower three quartiles. TNF receptor-1 and TNF receptor-2 are associated with kidney outcomes in patients with type 2 diabetes and normoalbuminuria. CANagliflozin cardioVascular Assessment Study (CANVAS), NCT01032629
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-12-2020
Publisher: Springer Science and Business Media LLC
Date: 11-2019
DOI: 10.1186/S12909-019-1832-3
Abstract: Recent trends in faculty development demonstrate a shift from short term to long-term programs formal to informal learning in the workplace in idual to group settings and from in idual support to institutional support. The purpose of this study was to develop and evaluate a one-year Clinical Teaching Fellowship (CTF) program designed to equip early career medical practitioners and basic scientists with necessary skills to facilitate Team-based learning (TBL). The CTF program provided formal training, a choice of informal professional development activities, and practical co-teaching opportunities in TBL. Of the 40 registrants, 31 (78%) completed the program. Data were collected via questionnaire and focus group. Data were analysed using descriptive statistics and framework analysis. Participants considered the CTF program as relevant to their needs and useful to their career. Learning was enriched through the combination of training, practical teaching experience alongside senior clinical teachers, the multi-disciplinary context of training and co-teaching in TBLs and the sense of community. Competing clinical responsibilities made it difficult to attend training and TBL teaching. The CTF program provided a longitudinal faculty development framework promoting preparation, practice and development of teaching skills. Securing institutional support to invest in the growth and development of early career teachers is essential to sustained innovation and excellence in teaching.
Publisher: Wiley
Date: 17-02-2021
DOI: 10.1002/EHF2.13236
Abstract: The CANVAS Program identified the effect of canagliflozin on major adverse cardiovascular events (MACE) differed according to whether participants were using diuretics at study commencement. We sought to further evaluate this finding related to baseline differences, treatment effects, safety, and risk factor changes. The CANVAS Program enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomized to canagliflozin or placebo and followed for a mean of 188 weeks. The primary outcome was major cardiovascular events, a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included multiple cardiovascular, renal, and safety events. In this post hoc subgroup analysis, participants were categorized according to baseline use of any diuretic. The effect on outcomes was compared using Cox proportional hazards models, while risk factor changes were compared using mixed‐effect models. At baseline, 4490 (44.3%) participants were using a diuretic. Compared with those not using a diuretic, participants using a diuretic were more likely to be older (mean age ± standard deviation, 64.3 ± 8.0 vs. 62.5 ± 8.3), be female (38.9% vs. 33.4%), and have heart failure (19.6% vs. 10.3%) (all P difference 0.0001). The effect of canagliflozin on major cardiovascular events was greater for those using diuretic at baseline than for those who were not [adjusted hazard ratio 0.65 (95% confidence interval 0.54–0.78) vs. adjusted hazard ratio 1.13 (95% confidence interval 0.93–1.36), P heterogeneity 0.0001]. Changes in most risk factors, including blood pressure, body weight, and urine albumin‐to‐creatinine ratio, were similar between groups (all P difference 0.11), although the effect of canagliflozin on haemoglobin A1c reduction was slightly weaker in participants using compared with not using diuretics at baseline (−0.52% vs. −0.64%, P heterogeneity = 0.0007). Overall serious adverse events and key safety outcomes, including adverse renal events, were also similar (all P heterogeneity 0.07). Participants on baseline diuretics derived a greater benefit for major cardiovascular events from canagliflozin, which was not fully explained by differences in participant characteristics nor risk factor changes.
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.JVIR.2014.02.010
Abstract: Percutaneous transluminal angioplasty (PTA) is an established treatment for dysfunctional hemodialysis fistulas. This article systematically reviews evidence for predictors of patency after PTA. Outcomes assessed were primary, assisted primary, and secondary patency after intervention, and findings were summarized descriptively. This review included 11 nonrandomized observational studies of 965 fistulas in 939 patients. Follow-up ranged from 0 days to 10 years. Study quality was overall suboptimal. Newer fistulas and longer lesion length may be associated with primary patency loss after PTA. Further studies are needed to confirm these findings, to identify potentially modifiable factors, and to guide the testing of new endovascular devices.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2021
DOI: 10.1161/STROKEAHA.120.031623
Abstract: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis. In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo hazard ratio [HR], 0.77 [95% CI, 0.55–1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61–1.28] n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19–1.32] n=18), and undetermined (HR, 0.54 [95% CI, 0.20–1.46] n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53–1.10] n=115). The overall effects in the 4 CVOTs combined were: total stroke (HR pooled , 0.96 [95% CI, 0.82–1.12]), ischemic stroke (HR pooled , 1.01 [95% CI, 0.89–1.14]), hemorrhagic stroke (HR pooled , 0.50 [95% CI, 0.30–0.83]), undetermined stroke (HR pooled , 0.86 [95% CI, 0.49–1.51]), and AF/AFL (HR pooled , 0.81 [95% CI, 0.71–0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate ( P =0.01), with protection in the lowest estimated glomerular filtration rate ( mL/min/1.73 m 2 ]) subgroup (HR pooled , 0.50 [95% CI, 0.31–0.79]). Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. URL: www.clinicaltrials.gov Unique identifier: NCT02065791.
Publisher: Elsevier BV
Date: 07-2021
DOI: 10.1053/J.ACKD.2021.02.006
Abstract: Large-scale randomized trials have demonstrated the remarkable capacity of sodium-glucose cotransporter 2 inhibitors to reduce the risk of cardiovascular outcomes and kidney disease progression, irrespective of the presence or absence of type 2 diabetes mellitus. Although the results of these trials have transformed clinical practice guidelines, the mechanisms underpinning the wide-ranging benefits of this class of agents remain incompletely understood and subject to ongoing investigation. Improvements in cardiometabolic risk factors such as glucose, blood pressure, body weight, and albuminuria likely contribute. However, other direct effects on physiological and cellular function, such as restoration of tubuloglomerular feedback, improvements in kidney and cardiac oxygenation and energy efficiency, as well as restoration of normal autophagy are also likely to be important. This review summarizes the rationale and potential mechanisms for cardiorenal protection with sodium-glucose cotransporter 2 inhibitors in people with and without diabetes, their relative importance, and the experimental and clinical lines of evidence supporting these hypotheses.
Publisher: BMJ
Date: 14-09-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-09-2019
Abstract: Albuminuria commonly occurs in people with type 2 diabetes and is an independent risk factor for progression of kidney disease and cardiovascular events. SGLT2 inhibitors are thought to protect the kidneys by lowering albuminuria. If this is true, it suggests people with type 2 diabetes with higher levels of albuminuria would reap greater renoprotective benefits. The authors conducted a post-hoc analysis of data from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program to assess renal, cardiovascular, and safety outcomes with canagliflozin by baseline albuminuria subgroups (urinary albumin/creatinine ratio , 30–300, and mg/g). The data suggest that the relative effects of canagliflozin on renal and cardiovascular outcomes are mostly consistent across different levels of baseline albuminuria, but participants with severely increased albuminuria saw the largest absolute benefits. If SGLT2 inhibitors protect the kidneys by reducing albuminuria as hypothesized, people with type 2 diabetes mellitus (T2DM) with higher albuminuria should benefit more. We conducted a post-hoc analysis of data from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, which randomized 10,142 participants with T2DM and high cardiovascular risk to canagliflozin or placebo. We assessed effects of canagliflozin on renal, cardiovascular, and safety outcomes by baseline albuminuria. The trial included 2266 participants (22.3%) with moderately increased albuminuria (urinary albumin/creatinine ratio [UACR] 30–300 mg/g) and 760 (7.5%) with severely increased albuminuria (UACR mg/g) at baseline. Canagliflozin lowered albuminuria with greater proportional reductions in those with moderately and severely increased albuminuria ( P heterogeneity .001). After week 13, canagliflozin slowed the annual loss of kidney function across albuminuria subgroups, with greater absolute reductions in participants with severely increased albuminuria (placebo-subtracted difference 3.01 ml/min per 1.73 m 2 per year P heterogeneity .001). Heterogeneity for the renal composite outcome of 40% reduction in eGFR, ESKD, or renal-related death was driven by lesser effects in participants with moderately increased albuminuria ( P heterogeneity=0.03), but no effect modification was observed when albuminuria was fitted as a continuous variable ( P heterogeneity=0.94). Cardiovascular and safety outcomes were mostly consistent across albuminuria levels including increased risks for utation across albuminuria subgroups ( P heterogeneity=0.66). Greater absolute risk reductions in the renal composite outcome were observed in participants with severely increased albuminuria ( P heterogeneity=0.004). The proportional effects of canagliflozin on renal and cardiovascular outcomes are mostly consistent across patients with different levels of albuminuria, but absolute benefits are greatest among those with severely increased albuminuria.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-10-2018
DOI: 10.1161/CIRCULATIONAHA.118.035901
Abstract: Canagliflozin is approved for glucose lowering in type 2 diabetes and confers cardiovascular and renal benefits. We sought to assess whether it had benefits in people with chronic kidney disease, including those with an estimated glomerular filtration rate (eGFR) between 30 and 45 mL/min/1.73 m 2 in whom the drug is not currently approved for use. The CANVAS Program randomized 10 142 participants with type 2 diabetes and eGFR mL/min/1.73 m 2 to canagliflozin or placebo. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with other cardiovascular, renal, and safety outcomes. This secondary analysis describes outcomes in participants with and without chronic kidney disease, defined as eGFR and ≥60 mL/min/1.73 m 2 , and according to baseline kidney function (eGFR , 45 to , 60 to , and ≥90 mL/min/1.73 m 2 ). At baseline, 2039 (20.1%) participants had an eGFR mL/min/1.73 m 2 , 71.6% of whom had a history of cardiovascular disease. The effect of canagliflozin on the primary outcome was similar in people with chronic kidney disease (hazard ratio, 0.70 95% CI, 0.55–0.90) and those with preserved kidney function (hazard ratio, 0.92 95% CI, 0.79–1.07 P heterogeneity = 0.08). Relative effects on most cardiovascular and renal outcomes were similar across eGFR subgroups, with possible heterogeneity suggested only for the outcome of fatal/nonfatal stroke ( P heterogeneity = 0.01), as were results for almost all safety outcomes. The effects of canagliflozin on cardiovascular and renal outcomes were not modified by baseline level of kidney function in people with type 2 diabetes and a history or high risk of cardiovascular disease down to eGFR levels of 30 mL/min/1.73 m 2 . Reassessing current limitations on the use of canagliflozin in chronic kidney disease may allow additional in iduals to benefit from this therapy. URL: www.clinicaltrials.gov . Unique identifiers: NCT01032629, NCT01989754.
Publisher: Wiley
Date: 13-10-2020
DOI: 10.1111/DOM.14197
Abstract: Sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors are effective for the treatment of macrovascular complications and nephropathy in type 2 diabetes, but effects on microvascular eye outcomes are unclear. We conducted a systematic review and meta‐analysis of randomized placebo‐controlled trials to evaluate the effect of SGLT2 inhibition on total ocular events and retinopathy in patients with type 2 diabetes. We searched MEDLINE and Embase for the period from database inception date to October 11, 2019. Two reviewers working independently extracted relevant data. Random‐effects models with inverse variance weighting were selected to estimate summary risk ratios (RRs) and 95% confidence intervals (CIs). We included nine studies, involving 39 982 patients with a mean follow‐up of 2.8 years. There were 1414 total ocular events, of which 624 were retinopathy events. SGLT2 inhibition was not associated with a change in the risk of total ocular events (RR 0.97, 95% CI 0.85, 1.11) or retinopathy (RR 0.98, 95% CI 0.84, 1.16), with consistent effects across studies ( P for heterogeneity = 0.35 and 0.45, respectively). The effects of SGLT2 inhibition on eye disease in in iduals with type 2 diabetes are probably null, although the available data cannot exclude small to moderate benefits or harms.
Publisher: Wiley
Date: 07-03-2022
DOI: 10.1111/DOM.14671
Abstract: To define the proportional and absolute benefits of the sodium‐glucose co‐transporter‐2 inhibitor canagliflozin in patients with type 2 diabetes (T2D) with and without peripheral arterial disease (PAD). We pooled in idual participant data from the CANVAS Program (n = 10 142) and CREDENCE trial (n = 4401). In this post hoc analysis, the main outcomes of interest were major adverse cardiovascular events (MACE: non‐fatal myocardial infarction, non‐fatal stroke or cardiovascular death), kidney outcomes, and extended major adverse limb events (MALE). Cox proportional hazards models were used to assess canagliflozin treatment effects in those with and without PAD. Absolute risk reductions per 1000 patients treated for 2.5 years were estimated using Poisson regression. Of 14 543 participants, 3159 (21.7%) had PAD at baseline. In patients with PAD, canagliflozin reduced MACE (hazard ratio, 0.76 95% confidence interval, 0.62‐0.92), with similar relative benefits for other cardiovascular and kidney outcomes in participants with or without PAD at baseline (all P interaction .268). There was no increase in the relative risk of extended MALE with canagliflozin, irrespective of baseline PAD history ( P interaction .864). The absolute benefits of canagliflozin were greater in those with PAD. Patients with T2D and PAD derived similar relative cardiorenal benefits from canagliflozin treatment but higher absolute benefits compared with those without PAD, with no increase in extended MALE.
Publisher: Springer Science and Business Media LLC
Date: 26-08-2021
DOI: 10.1007/S00125-021-05524-1
Abstract: Type 2 diabetes mellitus can manifest over a broad clinical range, although there is no clear consensus on the categorisation of disease complexity. We assessed the effects of canagliflozin, compared with placebo, on cardiovascular and kidney outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program over a range of type 2 diabetes mellitus complexity, defined separately by baseline intensity of treatment, duration of diabetes and glycaemic control. We performed a post hoc analysis of the effects of canagliflozin on major adverse cardiovascular events (MACE) according to baseline glucose-lowering treatments (0 or 1, 2 or 3+ non-insulin glucose-lowering treatments, or insulin-based treatment), duration of diabetes ( , 10 to 16, years) and HbA 1c (≤53.0 mmol/mol [ .0%], .0 to 58.5 mmol/mol [ .0% to 7.5%], .5 to 63.9 mmol/mol [ .5 to 8.0%], .9 to 69.4 mmol/mol [8.0% to 8.5%], .4 to 74.9 mmol/mol [ .5 to 9.0%] or .9 mmol/mol [ .0%]). We analysed additional secondary endpoints for cardiovascular and kidney outcomes, including a combined kidney outcome of sustained 40% decline in eGFR, end-stage kidney disease or death due to kidney disease. We used Cox regression analyses and compared the constancy of HRs across subgroups by fitting an interaction term ( p value for significance .05). At study initiation, 5095 (50%) CANVAS Program participants were treated with insulin, 2100 (21%) had an HbA 1c 74.9 mmol/mol (9.0%) and the median duration of diabetes was 12.6 years (interquartile interval 8.0–18 years). Canagliflozin reduced MACE (HR 0.86 [95% CI 0.75, 0.97]) with no evidence that the benefit differed between subgroups defined by the number of glucose-lowering treatments, the duration of diabetes or baseline HbA 1c (all p-heterogeneity .17). Canagliflozin reduced MACE in participants receiving insulin with no evidence that the benefit differed from other participants in the trial (HR 0.85 [95% CI 0.72, 1.00]). Similar results were observed for other cardiovascular outcomes and for the combined kidney outcome (HR for combined kidney outcome 0.60 [95% CI 0.47, 0.77]), with all p-heterogeneity .37. In people with type 2 diabetes mellitus at high cardiovascular risk, there was no evidence that cardiovascular and renal protection with canagliflozin differed across subgroups defined by baseline treatment intensity, duration of diabetes or HbA 1c .
Publisher: Wiley
Date: 20-08-2014
DOI: 10.1111/HDI.12208
Publisher: Elsevier BV
Date: 11-2020
Publisher: CMA Impact Inc.
Date: 14-10-2019
DOI: 10.1503/CMAJ.190047
Publisher: Massachusetts Medical Society
Date: 15-06-2023
DOI: 10.1056/NEJMC2301923
Publisher: American Diabetes Association
Date: 11-03-2020
DOI: 10.2337/DC19-1803
Abstract: To determine the incidence of and factors associated with an estimated glomerular filtration rate (eGFR) & mL/min/1.73 m2 in people with diabetes. We identified people with diabetes in the EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45), a population-based cohort study (2006–2014) that linked the Sax Institute’s 45 and Up Study cohort to community laboratory and administrative data in New South Wales, Australia. The study outcome was the first eGFR measurement & mL/min/1.73 m2 recorded during the follow-up period. Participants with eGFR & 60 mL/min/1.73 m2 at baseline were excluded. We used Poisson regression to estimate the incidence of eGFR & mL/min/1.73 m2 and multivariable Cox regression to examine factors associated with the study outcome. Of 9,313 participants with diabetes, 2,106 (22.6%) developed incident eGFR & mL/min/1.73 m2 over a median follow-up time of 5.7 years (interquartile range, 3.0–5.9 years). The eGFR & mL/min/1.73 m2 incidence rate per 100 person-years was 6.0 (95% CI 5.7–6.3) overall, 1.5 (1.3–1.9) in participants aged 45–54 years, 3.7 (3.4–4.0) for 55–64 year olds, 7.6 (7.1–8.1) for 65–74 year olds, 15.0 (13.0–16.0) for 75–84 year olds, and 26.0 (22.0–32.0) for those aged 85 years and over. In a fully adjusted multivariable model incidence was independently associated with age (hazard ratio 1.23 per 5-year increase 95% CI 1.19–1.26), geography (outer regional and remote versus major city: 1.36 1.17–1.58), obesity (obese class III versus normal: 1.44 1.16–1.80), and the presence of hypertension (1.52 1.33–1.73), coronary heart disease (1.13 1.02–1.24), cancer (1.30 1.14–1.50), and depression/anxiety (1.14 1.01–1.27). In participants with diabetes, the incidence of an eGFR & mL/min/1.73 m2 was high. Older age, remoteness of residence, and the presence of various comorbid conditions were associated with higher incidence.
Publisher: Wiley
Date: 10-05-2023
DOI: 10.1111/DOM.15091
Abstract: To assess whether the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor canagliflozin affects risk of non‐genital skin and soft tissue infections (SSTIs). We performed a post hoc pooled in idual participant analysis of the CANVAS Program and CREDENCE trials that randomized people with type 2 diabetes at high cardiovascular risk and/or with chronic kidney disease to either canagliflozin or placebo. Investigator‐reported adverse events were assessed by two blinded authors following predetermined criteria for non‐genital SSTIs. Risks of non‐genital SSTIs, overall and within prespecified subgroups, and risk of non‐genital fungal SSTIs, were analysed using Cox regression models. Factors associated with non‐genital SSTIs were assessed using multivariable Cox regression models. Overall, 903 of 14 531 participants (6%) experienced non‐genital SSTIs over a median follow‐up of 26 months. No difference was observed in non‐genital SSTI rates between canagliflozin and placebo (24.0 events/1000 person‐years vs. 23.9 events/1000 person‐years, respectively hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.85‐1.11 P = 0.70), with consistent results across subgroups (all P interaction 0.05). The risk of recurrent events and non‐genital fungal infection also did not differ significantly between canagliflozin and placebo (HR 1.06, 95% CI 0.94‐1.19 [ P = 0.32] and HR 1.18, 95% CI 0.88‐1.60 [ P = 0.27], respectively). Baseline factors independently associated with non‐genital SSTIs were younger age, male sex, higher body mass index, higher glycated haemoglobin, lower estimated glomerular filtration rate (eGFR), established peripheral vascular disease, and history of neuropathy. Canagliflozin did not affect risk of non‐genital SSTIs or non‐genital fungal SSTIs compared with placebo. These findings suggest that any SGLT2 inhibitor‐mediated change in skin microenvironment is unlikely to have meaningful clinical consequences.
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/971202
Abstract: This study aims to report the outcomes of nitinol and polytetrafluoroethylene covered stent placement to treat hemodialysis arteriovenous access stenosis at a single center over a five-year period. Clinical and radiological information was reviewed retrospectively. Poststent primary and secondary patency rates were determined using Kaplan-Meier analysis. Ten clinical variables were subjected to multivariate Cox regression analysis to determine predictors of patency after stent placement. During the study period 60 stents were deployed in 45 patients, with a mean follow-up of 24.5 months. The clinical and anatomical success rate was 98.3% (59/60). Poststent primary patency rates at 6, 12, and 24 months were 64%, 46%, and 35%, respectively. Poststent secondary patency rates at 6, 12, and 24 months were 95%, 89%, and 85%, respectively. Stent placement for upper arm lesions and in access less than 12 months of age was associated with reduced primary patency (adjusted hazards ratio [HR] 5.1, p = 0.0084 , and HR 3.5, p = 0.0029 , resp.). Resistant or recurrent stenosis can be successfully treated by endovascular stent placement with durable long-term patency, although multiple procedures are often required. Stent placement for upper arm lesions and in arteriovenous access less than 12 months of age was associated with increased risk of patency loss.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-07-2023
Abstract: Sodium glucose cotransporter‐2 inhibitors reduce systolic blood pressure (SBP), but whether they affect SBP variability is unknown. There also remains uncertainty regarding the prognostic value of SBP variability for different clinical outcomes. Using in idual participant data from the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program and CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial, we assessed the effect of canagliflozin on SBP variability in people with type 2 diabetes across 4 study visits over 1.5 years as measured by standard deviation, coefficient of variation, and variability independent of the mean. We used multivariable Cox regression models to estimate associations of SBP variability with cardiovascular, kidney, and mortality outcomes. In 11 551 trial participants, canagliflozin modestly lowered the standard deviation of SBP variability (−0.25 mm Hg [95% CI, –0.44 to −0.06]), but there was no effect on coefficient of variation (0.02% [95% CI, –0.12 to 0.16]) or variability independent of the mean (0.08 U [95% CI, –0.11 to 0.26]) when adjusting for correlation with mean SBP. Each 1 standard deviation increase in standard deviation of SBP variability was independently associated with higher risk of hospitalization for heart failure (hazard ratio [HR], 1.19 [95% CI, 1.02–1.38]) and all‐cause mortality (HR, 1.12 [95% CI, 1.01–1.25]), with consistent results observed for coefficient of variation and variability independent of the mean. Increases in SBP variability were not associated with kidney outcomes. In people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease, higher visit‐to‐visit SBP variability is independently associated with risks of hospitalization for heart failure and all‐cause mortality. Canagliflozin has little to no effect on SBP variability, independent of its established SBP‐lowering effect. URL: www.clinicaltrials.gov Unique identifiers: NCT01032629, NCT01989754, NCT02065791.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 31-03-2023
DOI: 10.2215/CJN.0000000000000161
Abstract: In the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin improved kidney and cardiovascular outcomes and reduced the rate of estimated glomerular filtration decline (eGFR slope) in patients with type 2 diabetes and CKD. In other clinical trials of patients with CKD or heart failure, the protective effects of SGLT2 inhibitors on eGFR slope were greater in participants with versus participants without type 2 diabetes. This post hoc analysis of the CREDENCE trial assessed whether the effects of canagliflozin on eGFR slope varied according to patient subgroups by baseline glycated hemoglobin A1c (HbA1c). CREDENCE (ClinicalTrials.gov [NCT02065791]) was a randomized controlled trial in adults with type 2 diabetes with an HbA1c of 6.5%–12.0%, an eGFR of 30–90 ml/min per 1.73 m 2 , and a urinary albumin-to-creatinine ratio of 300–5000 mg/g. Participants were randomly assigned to canagliflozin 100 mg once daily or placebo. We studied the effect of canagliflozin on eGFR slope using linear mixed-effects models. The annual difference in total eGFR slope was 1.52 ml/min per 1.73 m 2 (95% confidence interval [CI], 1.11 to 1.93) slower in participants randomized to canagliflozin compared with placebo. The rate of eGFR decline was faster in those with poorer baseline glycemic control. The mean difference in total eGFR slope between canagliflozin and placebo was greater in participants with poorer baseline glycemic control (difference in eGFR slope of 0.39, 1.36, 2.60, 1.63 ml/min per 1.73 m 2 for HbA1c subgroups 6.5%–7.0%, 7.0%–8.0%, 8.0%–10.0%, 10.0%–12.0%, respectively P interaction = 0.010). The mean difference in change from baseline in urinary albumin-to-creatinine ratio between participants randomized to canagliflozin and placebo was smaller in patients with baseline HbA1c 6.5%–7.0% (−17% [95% CI, −28 to −5]) compared with those with an HbA1c of 7.0%–12% (−32% [95% CI, −40 to −28] P interaction = 0.03). The effect of canagliflozin on eGFR slope in patients with type 2 diabetes and CKD was more pronounced in patients with higher baseline HbA1c, partly because of the more rapid decline in kidney function in these in iduals. Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791 This article contains a podcast at edirect.mp3/edia odcast/CJASN/2023_06_08_CJN0000000000000161.mp3
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-05-2021
DOI: 10.1161/CIRCULATIONAHA.120.048740
Abstract: People with type 2 diabetes and chronic kidney disease experience a high burden of hypertension, but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population are uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP-lowering therapy is also unknown. The CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) randomized people with type 2 diabetes and chronic kidney disease to canagliflozin or placebo. In a post hoc analysis, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP-lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mm Hg while receiving ≥3 classes of BP-lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. The trial included 4401 participants, of whom 3361 (76.4%) had baseline systolic BP ≥130 mm Hg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50 mm Hg (95% CI, –4.27 to –2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP-lowering therapy subgroups (all P interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP-lowering agents during the trial (hazard ratio, 0.68 [95% CI, 0.61–0.75]). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death caused by kidney or cardiovascular disease (hazard ratio, 0.70 [95% CI, 0.59–0.82]) was consistent across BP and BP-lowering therapy subgroups (all P interaction ≥0.35), as were effects on other key kidney, cardiovascular, and safety outcomes. In people with type 2 diabetes and chronic kidney disease, canagliflozin lowers systolic BP across all BP-defined subgroups and reduces the need for additional BP-lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP-lowering therapy in people with chronic kidney disease. URL: www.clinicaltrials.gov Unique identifier: NCT02065791.
Publisher: Springer Science and Business Media LLC
Date: 28-07-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2022
Abstract: GFR slope has been proposed as a surrogate endpoint for progression to kidney failure in clinical trials studying patients with CKD. Acute or immediate effects on GFR after treatment initiation may complicate the interpretation of long-term treatment effects. In this large meta-analysis of 53 randomized clinical studies of CKD progression, the authors found the magnitude and nature of acute effects are variable across different interventions and may be larger at a higher baseline GFR. Negative acute effects (such as an acute reduction in GFR) were observed in trials of renin-angiotensin system blockade and BP lowering, whereas positive acute effects were more common in trials of immunosuppressive therapies. Such information can inform the optimal design and analysis plan for randomized clinical trials in CKD. Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects. To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. The mean acute effect across all studies was −0.21 ml/min per 1.73 m 2 (95% confidence interval, −0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, −2.50 to +2.08 ml/min per 1.73 m 2 ). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-12-2021
Abstract: Studies have suggested that sodium glucose co‐transporter 2 inhibitors exert anti‐inflammatory effects. We examined the association of baseline growth differentiation factor‐15 (GDF‐15), a marker of inflammation and cellular injury, with cardiovascular events, hospitalization for heart failure (HF), and kidney outcomes in patients with type 2 diabetes in the CANVAS (Canagliflozin Cardiovascular Assessment Study) and determined the effect of the sodium glucose co‐transporter 2 inhibitor canagliflozin on circulating GDF‐15. The CANVAS trial randomized 4330 people with type 2 diabetes at high cardiovascular risk to canagliflozin or placebo. The association between baseline GDF‐15 and cardiovascular (non‐fatal myocardial infarction, non‐fatal stroke, cardiovascular death), HF, and kidney (40% estimated glomerular filtration rate decline, end‐stage kidney disease, renal death) outcomes was assessed using multivariable adjusted Cox regression models. During median follow‐up of 6.1 years (N=3549 participants with available s les), 555 cardiovascular, 129 HF, and 137 kidney outcomes occurred. Each doubling in baseline GDF‐15 was significantly associated with a higher risk of cardiovascular (hazard ratio [HR], 1.2 95% CI, 1.0‒1.3), HF (HR, 1.5 95% CI, 1.2‒2.0) and kidney (HR, 1.5 95% CI, 1.2‒2.0) outcomes. Baseline GDF‐15 did not modify canagliflozin’s effect on cardiovascular, HF, and kidney outcomes. Canaglifozin treatment modestly lowered GDF‐15 compared with placebo however, GDF‐15 did not mediate the protective effect of canagliflozin on cardiovascular, HF, or kidney outcomes. In patients with type 2 diabetes at high cardiovascular risk, higher GDF‐15 levels were associated with a higher risk of cardiovascular, HF, and kidney outcomes. Canagliflozin modestly lowered GDF‐15, but GDF‐15 reduction did not mediate the protective effect of canagliflozin.
Publisher: Elsevier BV
Date: 02-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-02-2021
DOI: 10.2215/CJN.15260920
Abstract: The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial. The study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to ml/min per 1.73 m 2 , and UACR of to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g ( n =2348), to mg/g ( n =1547), and ≥3000 mg/g ( n =506). In addition, we examined the effects of canagliflozin on UACR itself, eGFR slope, and the intermediate outcomes of glycated hemoglobin, body weight, and systolic BP. Overall, higher UACR was associated with higher rates of kidney and cardiovascular events. Canagliflozin reduced efficacy outcomes for all UACR levels, with no evidence that relative benefits varied between levels. For ex le, canagliflozin reduced the primary composite outcome by 24% (hazard ratio [HR], 0.76 95% confidence interval [95% CI], 0.56 to 1.04) in the lowest UACR subgroup, 28% (HR, 0.72 95% CI, 0.56 to 0.93) in the UACR subgroup to mg/g, and 37% (HR, 0.63 95% CI, 0.47 to 0.84) in the highest subgroup ( P heterogeneity =0.55). Absolute risk reductions for kidney outcomes were greater in participants with higher baseline albuminuria the number of primary composite events prevented across ascending UACR categories were 17 (95% CI, 3 to 38), 45 (95% CI, 9 to 81), and 119 (95% CI, 35 to 202) per 1000 treated participants over 2.6 years ( P heterogeneity =0.02). Rates of kidney-related adverse events were lower with canagliflozin, with a greater relative reduction in higher UACR categories. Canagliflozin safely reduces kidney and cardiovascular events in people with type 2 diabetes and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥3000 mg/g. ClinicalTrials.gov: CREDENCE, NCT02065791. This article contains a podcast at edia odcast/CJASN/2021_02_22_CJN15260920_final.mp3
Publisher: Wiley
Date: 07-2020
DOI: 10.1111/IMJ.14710
Abstract: The incidence, presentation and outcomes of lupus nephritis (LN) vary with geography, ethnicity, socioeconomic status and gender. There are relatively few data on LN in the non-Caucasian populations in Australia. To describe the clinical presentation, histological features, natural history, and outcomes of a historical cohort of Aboriginal and Torres Strait Islanders people in Far North Queensland with biopsy-proven LN. This is a retrospective observational study, and the study was conducted in Cairns and Hinterland Hospital and Health Service, Queensland, Australia. The study included Aboriginal and Torres Strait Islander patients with biopsy-proven LN treated between 1990 and 2013. The main outcome measures were renal replacement therapy and overall patient survival. Aboriginal and Torres Strait Islander people represented a substantial proportion (n = 16/40, 40%) of all patients diagnosed with LN during the observation period. The frequency of nephrotic range proteinuria (n = 11/14, 78.5%), estimated glomerular filtration rate <60 mL/min/1.73 m The clinical presentation of LN in Aboriginal and Torres Strait Islanders in Far North Queensland is severe and the response to standard immunosuppressive therapy is unsatisfactory. Larger prospective multi-centre studies are required to better understand ethnic disparities in prognosis and response to immunosuppressive therapy in this specific population.
Publisher: S. Karger AG
Date: 19-11-2021
DOI: 10.1159/000520909
Abstract: b i Background: /i /b Heart failure (HF), diabetes mellitus (DM), and chronic kidney disease (CKD) are commonly occurring and interlinked conditions. Approximately 25%–40% of patients with HF have DM, and approximately 40%–50% of patients with HF have CKD. Both DM and CKD are associated with increased risk of incident HF. Furthermore, 40% of people with DM develop CKD, making DM the leading cause of kidney failure globally. Importantly, 16% of patients with HF have both comorbid DM and CKD, and the combination of these 3 comorbidities is associated with substantially increased risk for hospitalization and mortality. Mechanisms that underlie the relationships between HF, DM, and CKD are complex but likely relate to shared cardiovascular and metabolic risk factors, as well as downstream effects on inflammation, oxidative stress, and neurohormonal pathways. b i Summary: /i /b This review outlines the epidemiology and links between HF, DM, and CKD, as well as current clinical evidence for the treatment of in iduals with a combination of these comorbidities. A case study of a patient with concomitant HF, DM, and CKD is discussed to explore potential treatment approaches for patients in whom all 3 comorbidities exist. b i Key Messages: /i /b Treatment plans for patients with a combination of these 3 comorbidities should consider the available clinical evidence.
Publisher: Bioscientifica
Date: 09-05-2023
DOI: 10.1530/EC-23-0005
Abstract: Sodium‐glucose co-transporter 2 (SGLT2) inhibitors have recently emerged as an effective means to protect kidney function in people with type 2 diabetes and chronic kidney disease (CKD). In this review, we explore the role of SGLT2 inhibition in these in iduals. SGLT2 inhibitors specifically act to inhibit sodium and glucose reabsorption in the early proximal tubule of the renal nephron. Although originally developed as glucose-lowering agents through their ability to induce glycosuria, it became apparent in cardiovascular outcome trials that the trajectory of kidney function decline was significantly slowed and the incidence of serious falls in kidney function was reduced in participants receiving an SGLT2 inhibitor. These observations have recently led to specific outcome trials in participants with CKD, including DAPA-CKD, CREDENCE and EMPA-KIDNEY, and real-world studies, like CVD-REAL-3, that have confirmed the observation of kidney benefits in this setting. In response, recent KDIGO Guidelines have recommended the use of SGLT2 inhibitors as first-line therapy in patients with CKD, alongside statins, renin–angiotensin–aldosterone system inhibitors and multifactorial risk factor management as indicated. However, SGLT2 inhibitors remain significantly underutilized in the setting of CKD. Indeed, an inertia paradox exists, with patients with more severe disease less likely to receive an SGLT2 inhibitor. Concerns regarding safety appear unfounded, as acute kidney injury, hyperkalaemia, major acute cardiovascular events and cardiac death in patients with CKD appear to be lower following SGLT2 inhibition. The first-in-class indication of dapagliflozin for CKD may begin a new approach to managing kidney disease in type 2 diabetes.
Publisher: Elsevier BV
Date: 10-2014
Publisher: Wiley
Date: 04-04-2023
DOI: 10.1111/DOM.15057
Publisher: Springer Science and Business Media LLC
Date: 17-06-2023
Publisher: Elsevier BV
Date: 11-2019
Publisher: Wiley
Date: 07-03-2023
DOI: 10.1111/DOM.15018
Abstract: To investigate the extent to which improvements in multiple cardiovascular risk markers are associated with a lower risk of cardiovascular and kidney outcomes in patients with type 2 diabetes and high cardiovascular risk participating in the CANVAS programme. Clinically relevant improvements in cardiovascular risk factors were defined as a reduction in glycated haemoglobin ≥1.0%, systolic blood pressure ≥10 mmHg, body weight ≥3 kg, urinary‐albumin‐creatinine ratio ≥30%, uric acid ≥0.5 mg/dl, and an increase in haemoglobin of ≥1.0 g/dl from baseline to week 26. Participants were categorized according to the number of improvements in cardiovascular risk markers: zero, one, two, three, or four or more risk marker improvements. The Cox proportional hazard regression adjusted for treatment assignment, demographic variables and laboratory measurements was performed to determine the association between the number of risk marker improvements and risk of a composite cardiovascular, heart failure or kidney outcomes. We included 9487 (93.5%) participants with available data at baseline and week 26. After week 26, 566 composite cardiovascular, 370 heart failure/cardiovascular death and 153 composite kidney outcomes occurred. The multivariable adjusted hazard ratios associated with four or more improvements in risk markers versus no risk marker improvement were 0.67 (95% CI 0.48, 0.92), 0.58 (95% CI 0.39, 0.87) and 0.49 (95% CI 0.25, 0.96) for the three outcomes respectively. We observed a trend of decreased hazard ratios across subgroups of increasing number of risk marker improvements ( p for trend = .008, .02 and .047, respectively). In patients with type 2 diabetes, improvements in multiple risk markers were associated with a reduced risk of cardiovascular and kidney outcomes as compared with no risk marker improvement.
Publisher: Elsevier BV
Date: 11-2017
Publisher: Wiley
Date: 24-06-2020
DOI: 10.1111/DOM.14091
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-01-2023
DOI: 10.2215/CJN.0000000000000050
Abstract: The GFR slope has been evaluated as a surrogate end point for kidney failure in meta-analyses on a broad collection of randomized controlled trials (RCTs) in CKD. These analyses evaluate how accurately a treatment effect on GFR slope predicts a treatment effect on kidney failure. We sought to determine whether severity of CKD in the patient population modifies the performance of GFR slope. We performed Bayesian meta-regression analyses on 66 CKD RCTs to evaluate associations between effects on GFR slope (the chronic slope and the total slope over 3 years, expressed as mean differences in ml/min per 1.73 m 2 /yr) and those of the clinical end point (doubling of serum creatinine, GFR ml/min per 1.73 m 2 , or kidney failure, expressed as a log-hazard ratio), where models allow interaction with variables defining disease severity. We evaluated three measures (baseline GFR in 10 ml/min per 1.73 m 2 , baseline urine albumin-to-creatinine ratio [UACR] per doubling in mg/g, and CKD progression rate defined as the control arm chronic slope, in ml/min per 1.73 m 2 /yr) and defined strong evidence for modification when 95% posterior credible intervals for interaction terms excluded zero. There was no evidence for modification by disease severity when evaluating 3-year total slope (95% credible intervals for the interaction slope: baseline GFR [−0.05 to 0.03] baseline UACR [−0.02 to 0.04] CKD progression rate [−0.07 to 0.02]). There was strong evidence for modification in evaluations of chronic slope (95% credible intervals: baseline GFR [0.02 to 0.11] baseline UACR [−0.11 to −0.02] CKD progression rate [0.01 to 0.15]). These analyses indicate consistency of the performance of total slope over 3 years, which provides further evidence for its validity as a surrogate end point in RCTs representing varied CKD populations.
Publisher: Wiley
Date: 26-10-2023
DOI: 10.1111/DOM.15340
Publisher: Wiley
Date: 24-04-2023
DOI: 10.1111/DOM.15065
Publisher: Oxford University Press (OUP)
Date: 22-12-2020
DOI: 10.1093/NDT/GFAA343
Abstract: Health information systems (HIS) are fundamental tools for the surveillance of health services, estimation of disease burden and prioritization of health resources. Several gaps in the availability of HIS for kidney disease were highlighted by the first iteration of the Global Kidney Health Atlas. As part of its second iteration, the International Society of Nephrology conducted a cross-sectional global survey between July and October 2018 to explore the coverage and scope of HIS for kidney disease, with a focus on kidney replacement therapy (KRT). Out of a total of 182 invited countries, 154 countries responded to questions on HIS (85% response rate). KRT registries were available in almost all high-income countries, but few low-income countries, while registries for non-dialysis chronic kidney disease (CKD) or acute kidney injury (AKI) were rare. Registries in high-income countries tended to be national, in contrast to registries in low-income countries, which often operated at local or regional levels. Although cause of end-stage kidney disease, modality of KRT and source of kidney transplant donors were frequently reported, few countries collected data on patient-reported outcome measures and only half of low-income countries recorded process-based measures. Almost no countries had programs to detect AKI and practices to identify CKD-targeted in iduals with diabetes, hypertension and cardiovascular disease, rather than members of high-risk ethnic groups. These findings confirm significant heterogeneity in the global availability of HIS for kidney disease and highlight important gaps in their coverage and scope, especially in low-income countries and across the domains of AKI, non-dialysis CKD, patient-reported outcomes, process-based measures and quality indicators for KRT service delivery.
Publisher: American College of Physicians
Date: 16-07-2019
DOI: 10.7326/M19-0087
Publisher: Oxford University Press (OUP)
Date: 25-02-2022
DOI: 10.1093/NDT/GFAC046
Publisher: Cold Spring Harbor Laboratory
Date: 22-06-2023
DOI: 10.1101/2023.06.18.23290762
Abstract: There remains substantial variation in the reported prevalence of CKD in Australia. Using a large, nationally-representative general practice data source in Australia, we determined the contemporary prevalence and staging of CKD in Australian primary care. We performed a retrospective, community-based observational study using healthcare data from MedicineInsight, a national general practice data source in Australia. The study included all adults with ≥1 visit to a general practice participating in the MedicineInsight program and ≥1 serum creatinine measurement (with or without a urine albumin-to-creatinine ratio [UACR] measurement) between 1 January 2011 and 31 December 2020 n=2,720,529 patients). The prevalence of CKD was estimated using three definitions: (1): an estimated glomerular filtration rate (eGFR) mL/min/1.73m 2 or an eGFR ≥60 mL/min/1.73m 2 with a UACR ≥2.5 mg/mmol for males and ≥3.5 mg/mmol for females (definition 1), (2) two consecutive eGFR measures mL/min/1.73m 2 at least 90 days apart or an eGFR ≥60 mL/min/1.73m 2 with a UACR ≥2.5 mg/mmol for males and ≥3.5 mg/mmol for females (definition 2), and (3) two consecutive eGFR measures mL/min/1.73m 2 at least 90 days part and/or two consecutive UACR measures ≥2.5 mg/mmol for males and ≥3.5 mg/mmol for females at least 90 days apart (definition 3). Patient sociodemographic characteristics including comorbid conditions were assessed across the three definitions. The prevalence of CKD in the study cohort progressively increased over the 10-year study period, irrespective of the method used to define CKD. The annual prevalence of CKD varied across the three CKD definitions, with definition 1 resulting in the highest estimates. In 2020, the prevalence of CKD in the study cohort was 8.4% (n=123,988), 4.7% (n=69,110) and 3.1% (n=45,360) using definitions 1, 2 and 3, respectively. The number of patients with UACR measurements was low such that, among those identified as having CKD in 2020, only 3.8%, 3.2% and 1.5% respectively, had both eGFR and UACR measurements available in the corresponding year. Patients in whom both eGFR and UACR measurements were available mostly had moderate or high risk of CKD progression by local and international CKD guidelines (83.6%, 80.6% and 76.2%, respectively). Comorbid burden in patients with CKD was also frequently observed (coronary heart disease: 28.9%, type 2 diabetes: 38.5%, heart failure: 17.9% using CKD definition 3). In this large, nationally representative study, we observed an increasing trend in CKD prevalence in primary care settings in Australia. Most patients with CKD were at moderate to high risk of CKD progression with a significant comorbid burden including coronary heart disease and diabetes. These findings highlight the need for early detection and effective management to slow progression of CKD.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-02-2020
Abstract: Several trials have demonstrated protective effects from inhibition of sodium‐glucose cotransporter 2 among patients with type 2 diabetes mellitus. There is uncertainty about the consistency of the cardiovascular benefits achieved across patient subsets. We included 4 large‐scale trials of sodium‐glucose cotransporter 2 inhibition compared with placebo in patients with diabetes mellitus that reported effects on cardiovascular outcomes overall and for participant subgroups defined at baseline by cardiovascular disease, reduced kidney function, and heart failure. Fixed effects models with inverse variance weighting were used to estimate summary hazard ratios and 95% CIs . There were 38 723 patients from 4 trials, with a mean 2.9 years of follow‐up. Of the patients, 22 870 (59%) had cardiovascular disease, 7754 (20%) had reduced kidney function, and 4543 (12%) had heart failure. There were 3828 major adverse cardiac events. There was overall benefit for major adverse cardiac events (0.88 95% CI , 0.82–0.94 P .001) and no evidence that the effects of sodium‐glucose cotransporter 2 inhibition varied across patient subgroups, defined by the presence of cardiovascular disease or heart failure at baseline (all P interaction .252 I 2 %). All patient subgroups benefited with respect to hospitalization for heart failure (all P interaction .302 I 2 %), cardiovascular death (all P interaction .167 I 2 %), and death from any cause (all P interaction .354 I 2 =0%). The only difference in effects across subgroups was for stroke, with protection observed among those with reduced kidney function but not those with preserved kidney function ( P interaction=0.020 I 2 =81%). Sodium‐glucose cotransporter 2 inhibitors protect against cardiovascular disease and death in erse subsets of patients with type 2 diabetes mellitus regardless of cardiovascular disease history.
Publisher: Wiley
Date: 06-02-2023
DOI: 10.1111/DOM.14978
Publisher: Elsevier BV
Date: 08-2021
Publisher: Elsevier BV
Date: 09-2020
Publisher: BMJ
Date: 07-2017
Publisher: Wiley
Date: 04-03-2019
DOI: 10.1111/DOM.13648
Abstract: The use of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has been limited, primarily because glycaemic efficacy is dependent on kidney function. We performed a systematic review and meta-analysis to assess the efficacy and safety of SGLT2 inhibitors in patients with T2DM and CKD, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m We searched MEDLINE, EMBASE and the Cochrane Library until 7 August 2018 and websites of the US, European and Japanese regulatory authorities until 27 July 2018 for data from randomized controlled trials of SGLT2 inhibitors that included reporting of effects on biomarkers, cardiovascular, renal or safety outcomes in in iduals with T2DM and CKD. Random effects models and inverse variance weighting were used to calculate relative risks with 95% confidence intervals. Data were obtained from 27 studies with up to 7363 participants involved. In patients with T2DM and CKD, SGLT2 inhibitors lowered glycated haemoglobin (-0.29% 95% CI, -0.39 to -0.19) as well as blood pressure, body weight and albuminuria. SGLT2 inhibition reduced the risk of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (RR, 0.81 95% CI, 0.70-0.94) and heart failure (RR, 0.61 95% CI, 0.48-0.78), without a clear effect on all-cause mortality (HR, 0.86 95% CI, 0.73-1.01). These agents also attenuated the annual decline in eGFR slope (placebo-subtracted difference of 1.35 mL/1.73 m Currently available data suggest that, despite only modest reductions in glycated haemoglobin, SGLT2 inhibitors reduce the risk of cardiovascular and renal outcomes in patients with T2DM and CKD, without clear evidence of additional safety concerns.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Wiley
Date: 06-09-2023
DOI: 10.1111/DOM.15267
Publisher: Wiley
Date: 05-2022
DOI: 10.1111/IMJ.15074
Abstract: To determine risk factors for incident chronic kidney disease (CKD) in a large population-based cohort. This prospective opt-in population-based cohort study is based on the 45 and Up Study, where New South Wales residents aged ≥45 years were randomly s led from the Services Australia database and agreed to complete the 45 and Up Study baseline questionnaire and have their responses linked to their health data in routinely collected databases. The primary outcome was the development of incident CKD, defined as eGFR < 60 mL/min/1.73 m In 39 574 participants who did not have CKD at enrolment, independent factors associated with developing CKD included: older age, regional residence (HR 1.38 (1.27-1.50) for outer regional vs major city), smoking (1.13 (1.00-1.27) for current smoker vs non-smoker), obesity (1.25 (1.16-1.35) for obese vs normal body mass index), diabetes mellitus (1.41 (1.33-1.50)), hypertension (1.53 (1.44-1.62)), coronary heart disease (1.13 (1.07-1.20)), depression/anxiety (1.16 (1.09-1.24)) and cancer (1.29 (1.20-1.39)). Migrants were less likely to develop CKD compared with people born in Australia (0.88 (0.83-0.94)). Gender, partner status and socioeconomic factors were not independently associated with developing CKD. This large population-based study found multiple modifiable and non-modifiable factors were independently associated with developing CKD. In the Australian setting, the risk of CKD was higher with regional residence. Differences according to socioeconomic status were predominantly explained by age, comorbidities and harmful health-related behaviours.
Publisher: Wiley
Date: 09-06-2022
DOI: 10.1111/DOM.14772
Abstract: To assess the effects of canagliflozin on the incidence of atrial fibrillation/atrial flutter (AF/AFL) and other key cardiorenal outcomes in a pooled analysis of the CANVAS and CREDENCE trials. Participants with type 2 diabetes and high risk of cardiovascular disease or chronic kidney disease were included and randomly assigned to canagliflozin or placebo. We explored the effects of canagliflozin on the incidence of first AF/AFL events and AF/AFL‐related complications (ischaemic stroke/transient ischaemic attack/hospitalization for heart failure). Major adverse cardiovascular events and a renal‐specific outcome by baseline AF/AFL status were analysed using Cox regression models. Overall, 354 participants experienced a first AF/AFL event. Canagliflozin had no detectable effect on AF/AFL (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.67‐1.02) compared with placebo. Subgroup analysis, however, suggested a possible reduction in AF/AFL in those with no AF/AFL history (HR 0.78, 95% CI 0.62‐0.99). Canagliflozin was also associated with a reduction in AF/AFL‐related complications (HR 0.74, 95% CI 0.65‐0.86). There was no evidence of treatment heterogeneity by baseline AF/AFL history for other key cardiorenal outcomes (all P interaction 0.14). Meta‐analysis of five sodium‐glucose cotransporter‐2 (SGLT2) inhibitor trials demonstrated a 19% reduction in AF/AFL events with active treatment (HR 0.81, 95% CI 0.72‐0.92). Overall, a significant effect of canagliflozin on the incidence of AF/AFL events could not be shown, however, a possible reduction in AF/AFL events in those with no prior history requires further investigation. Meta‐analysis suggests SGLT2 inhibition reduces AF/AFL incidence.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-05-2022
DOI: 10.1161/CIRCULATIONAHA.121.057736
Abstract: Hyperkalemia increases risk of cardiac arrhythmias and death and limits the use of renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, which improve clinical outcomes in people with chronic kidney disease or systolic heart failure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiorenal events in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease. However, their effect on hyperkalemia has not been systematically evaluated. A meta-analysis was conducted using in idual participant data from randomized, double-blind, placebo-controlled clinical outcome trials with SGLT2 inhibitors in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease in whom serum potassium levels were routinely measured. The primary outcome was time to serious hyperkalemia, defined as central laboratory–determined serum potassium ≥6.0 mmol/L, with other outcomes including investigator-reported hyperkalemia events and hypokalemia (serum potassium ≤3.5 mmol/L). Cox regression analyses were performed to estimate treatment effects from each trial with hazards ratios and corresponding 95% CIs pooled with random-effects models to obtain summary treatment effects, overall and across key subgroups. Results from 6 trials were included comprising 49 875 participants assessing 4 SGLT2 inhibitors. Of these, 1754 participants developed serious hyperkalemia, and an additional 1119 investigator-reported hyperkalemia events were recorded. SGLT2 inhibitors reduced the risk of serious hyperkalemia (hazard ratio, 0.84 [95% CI, 0.76–0.93]), an effect consistent across studies ( P heterogeneity =0.71). The incidence of investigator-reported hyperkalemia was also lower with SGLT2 inhibitors (hazard ratio, 0.80 [95% CI, 0.68–0.93] P heterogeneity =0.21). Reductions in serious hyperkalemia were observed across a range of subgroups, including baseline kidney function, history of heart failure, and use of renin-angiotensin-aldosterone system inhibitor, diuretic, and mineralocorticoid receptor antagonist. SGLT2 inhibitors did not increase the risk of hypokalemia (hazard ratio, 1.04 [95% CI, 0.94–1.15] P heterogeneity =0.42). SGLT2 inhibitors reduce the risk of serious hyperkalemia in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease without increasing the risk of hypokalemia.
Publisher: Cold Spring Harbor Laboratory
Date: 28-06-2023
DOI: 10.1101/2023.06.26.23291881
Abstract: Although sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of kidney failure and death in patients with chronic kidney disease (CKD), they are underused in routine clinical practice. We evaluated the number of patients with CKD in Australia that would be eligible for treatment with an SGLT2 inhibitor and estimated the number of cardiorenal and kidney failure events that could be averted with improved uptake of SGLT2 inhibitors. Using nationally-representative Australian primary care data (MedicineInsight), we identified patients that would have met inclusion criteria of the CREDENCE, DAPA-CKD, and EMPA-KIDNEY trials between 1 January 2020 and 31 December 2021. We applied these data to age and sex-stratified estimates of CKD prevalence from the broader Australian population (using national census data) to generate population-level estimates for: (1) the number of CKD patients eligible for treatment with SGLT2 inhibitors and (2) the annual number of potentially preventable cardiorenal (CKD progression, kidney failure, or death due to cardiovascular disease or kidney failure), and kidney failure events with SGLT2 inhibitors based on trial event rates. In MedicineInsight, 44.2% of adults with CKD would have met CKD eligibility criteria for an SGLT2 inhibitor baseline use was 4.1%. Applying these data to the broader Australian population, we estimated 230,246 patients with CKD in Australia would have been eligible for treatment with any SGLT2 inhibitor. Optimal implementation of SGLT2 inhibitors (75% uptake in eligible patients) could reduce cardiorenal and kidney failure events annually in Australia by 3,644 (95% CI 3,526-3,764) and 1,312 (95% CI 1,242-1,385), respectively. Improved uptake of SGLT2 inhibitors for patients with CKD in Australian primary care has the potential to prevent large numbers of patients experiencing CKD progression or dying due to cardiovascular or kidney disease. Identifying strategies to increase the uptake of SGLT2 inhibitors is critical to realising the population-level benefits of this drug class.
Publisher: Elsevier BV
Date: 07-2023
Publisher: BMJ
Date: 07-2021
DOI: 10.1136/BMJOPEN-2020-047245
Abstract: The Global Kidney Health Atlas (GKHA) is a multinational, cross-sectional survey designed to assess the current capacity for kidney care across all world regions. The 2017 GKHA involved 125 countries and identified significant gaps in oversight, funding and infrastructure to support care for patients with kidney disease, especially in lower-middle-income countries. Here, we report results from the survey for the second iteration of the GKHA conducted in 2018, which included specific questions about health financing and oversight of end-stage kidney disease (ESKD) care worldwide. A cross-sectional global survey. Key stakeholders from 182 countries were invited to participate. Of those, stakeholders from 160 countries participated and were included. Primary outcomes included cost of kidney replacement therapy (KRT), funding for dialysis and transplantation, funding for conservative kidney management, extent of universal health coverage, out-of-pocket costs for KRT, within-country variability in ESKD care delivery and oversight systems for ESKD care. Outcomes were determined from a combination of desk research and input from key stakeholders in participating countries. 160 countries (covering 98% of the world’s population) responded to the survey. Economic factors were identified as the top barrier to optimal ESKD care in 99 countries (64%). Full public funding for KRT was more common than for conservative kidney management (43% vs 28%). Among countries that provided at least some public coverage for KRT, 75% covered all citizens. Within-country variation in ESKD care delivery was reported in 40% of countries. Oversight of ESKD care was present in all high-income countries but was absent in 13% of low-income, 3% of lower-middle-income, and 10% of upper-middle-income countries. Significant gaps and variability exist in the public funding and oversight of ESKD care in many countries, particularly for those in low-income and lower-middle-income countries.
Publisher: AMPCo
Date: 11-2018
DOI: 10.5694/MJA18.00929
Publisher: Elsevier BV
Date: 11-2022
Publisher: Elsevier BV
Date: 06-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-10-2023
Publisher: Elsevier BV
Date: 2020
Publisher: BMJ
Date: 31-10-2019
DOI: 10.1136/BMJ.L5873
Abstract: To determine the global capacity (availability, accessibility, quality, and affordability) to deliver kidney replacement therapy (dialysis and transplantation) and conservative kidney management. International cross sectional survey. International Society of Nephrology (ISN) survey of 182 countries from July to September 2018. Key stakeholders identified by ISN’s national and regional leaders. Markers of national capacity to deliver core components of kidney replacement therapy and conservative kidney management. Responses were received from 160 (87.9%) of 182 countries, comprising 97.8% (7338.5 million of 7501.3 million) of the world’s population. A wide variation was found in capacity and structures for kidney replacement therapy and conservative kidney management—namely, funding mechanisms, health workforce, service delivery, and available technologies. Information on the prevalence of treated end stage kidney disease was available in 91 (42%) of 218 countries worldwide. Estimates varied more than 800-fold from 4 to 3392 per million population. Rwanda was the only low income country to report data on the prevalence of treated disease 5 ( %) of 53 African countries reported these data. Of 159 countries, 102 (64%) provided public funding for kidney replacement therapy. Sixty eight (43%) of 159 countries charged no fees at the point of care delivery and 34 (21%) made some charge. Haemodialysis was reported as available in 156 (100%) of 156 countries, peritoneal dialysis in 119 (76%) of 156 countries, and kidney transplantation in 114 (74%) of 155 countries. Dialysis and kidney transplantation were available to more than 50% of patients in only 108 (70%) and 45 (29%) of 154 countries that offered these services, respectively. Conservative kidney management was available in 124 (81%) of 154 countries. Worldwide, the median number of nephrologists was 9.96 per million population, which varied with income level. These comprehensive data show the capacity of countries (including low income countries) to provide optimal care for patients with end stage kidney disease. They demonstrate substantial variability in the burden of such disease and capacity for kidney replacement therapy and conservative kidney management, which have implications for policy.
Publisher: Public Library of Science (PLoS)
Date: 02-2023
DOI: 10.1371/JOURNAL.PGPH.0001467
Abstract: National strategies for addressing chronic kidney disease (CKD) are crucial to improving kidney health. We sought to describe country-level variations in non-communicable disease (NCD) strategies and CKD-specific policies across different regions and income levels worldwide. The International Society of Nephrology Global Kidney Health Atlas (GKHA) was a multinational cross-sectional survey conducted between July and October 2018. Responses from key opinion leaders in each country regarding national NCD strategies, the presence and scope of CKD-specific policies, and government recognition of CKD as a health priority were described overall and according to region and income level. 160 countries participated in the GKHA survey, comprising 97.8% of the world’s population. Seventy-four (47%) countries had an established national NCD strategy, and 53 (34%) countries reported the existence of CKD-specific policies, with substantial variation across regions and income levels. Where CKD-specific policies existed, non-dialysis CKD care was variably addressed. 79 (51%) countries identified government recognition of CKD as a health priority. Low- and low-middle income countries were less likely to have strategies and policies for addressing CKD and have governments which recognise it as a health priority. The existence of CKD-specific policies, and a national NCD strategy more broadly, varied substantially across different regions around the world but was overall suboptimal, with major discrepancies between the burden of CKD in many countries and governmental recognition of CKD as a health priority. Greater recognition of CKD within national health policy is critical to improving kidney healthcare globally.
Publisher: Elsevier BV
Date: 12-2011
DOI: 10.1053/J.AJKD.2011.06.019
Abstract: Diagnostic errors represent an important cause of preventable harm in health care that may be reduced through evidence-based choice, use, and interpretation of diagnostic tests. We hypothesized that diagnostic errors are reduced through evidence-based choice, use, and interpretation of diagnostic tests. Retrospective cohort study. Diagnostic test studies. Publications from 1966-2008 retrieved from MEDLINE. The Quality of Diagnostic Accuracy Studies (QUADAS) tool. Number and coverage of diagnostic studies in nephrology and methodological quality of the test accuracy subset. Fewer diagnostic studies were published in nephrology than other areas of internal medicine, although the proportion of total citations that were diagnostic studies (4.9% ± 2.8% [SD]) was not statistically different from other specialties (P = 0.2). Within nephrology, some topic areas (eg, urinary tract infections) were over-represented, whereas others (eg, acute kidney injury) had relatively few diagnostic studies (range, 2.7%-12.5%). Examining the randomly selected subset of studies that were diagnostic test accuracy studies (120) showed variable quality. Ninety-seven percent (116 of 120) of studies adequately described index test procedure, but only 27% (32 of 120) adequately blinded investigators to results of index tests, and 36% (43 of 120), to results of reference tests. The quality of nephrology diagnostic test accuracy studies has not improved substantially during the past 30 years. Comparing nephrology with other specialties, some potential inequalities of scale could not be addressed, which may influence research output results across specialties. Diagnostic research in nephrology is published less frequently than most other medical specialties. The quality of diagnostic test accuracy studies that are published is variable and leaves room for improvement.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Brendon Neuen.