Chronic kidney disease is a progressive disease with no cure and high morbidity and mortality that occurs commonly in the general adult population, especially in people with diabetes and ...hypertension. Preservation of kidney function can improve outcomes and can be achieved through non-pharmacological strategies (eg, dietary and lifestyle adjustments) and chronic kidney disease-targeted and kidney disease-specific pharmacological interventions. A plant-dominant, low-protein, and low-salt diet might help to mitigate glomerular hyperfiltration and preserve renal function for longer, possibly while also leading to favourable alterations in acid-base homoeostasis and in the gut microbiome. Pharmacotherapies that alter intrarenal haemodynamics (eg, renin–angiotensin–aldosterone pathway modulators and SGLT2 SLC5A2 inhibitors) can preserve kidney function by reducing intraglomerular pressure independently of blood pressure and glucose control, whereas other novel agents (eg, non-steroidal mineralocorticoid receptor antagonists) might protect the kidney through anti-inflammatory or antifibrotic mechanisms. Some glomerular and cystic kidney diseases might benefit from disease-specific therapies. Managing chronic kidney disease-associated cardiovascular risk, minimising the risk of infection, and preventing acute kidney injury are crucial interventions for these patients, given the high burden of complications, associated morbidity and mortality, and the role of non-conventional risk factors in chronic kidney disease. When renal replacement therapy becomes inevitable, an incremental transition to dialysis can be considered and has been proposed to possibly preserve residual kidney function longer. There are similarities and distinctions between kidney-preserving care and supportive care. Additional studies of dietary and pharmacological interventions and development of innovative strategies are necessary to ensure optimal kidney-preserving care and to achieve greater longevity and better health-related quality of life for these patients.
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
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 >300 mg/g) at baseline.
Canagliflozin lowered albuminuria with greater proportional reductions in those with moderately and severely increased albuminuria (
heterogeneity<0.001). 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
per year;
heterogeneity<0.001). 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 (
heterogeneity=0.03), but no effect modification was observed when albuminuria was fitted as a continuous variable (
heterogeneity=0.94). Cardiovascular and safety outcomes were mostly consistent across albuminuria levels including increased risks for amputation across albuminuria subgroups (
heterogeneity=0.66). Greater absolute risk reductions in the renal composite outcome were observed in participants with severely increased albuminuria (
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.
The effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on kidney failure, particularly the need for dialysis or transplantation or death due to kidney disease, is uncertain. Additionally, ...previous studies have been underpowered to robustly assess heterogeneity of effects on kidney outcomes by different levels of estimated glomerular filtration rate (eGFR) and albuminuria. We aimed to do a systematic review and meta-analysis to assess the effects of SGLT2 inhibitors on major kidney outcomes in patients with type 2 diabetes and to determine the consistency of effect size across trials and different levels of eGFR and albuminuria.
We did a systematic review and meta-analysis of randomised, controlled, cardiovascular or kidney outcome trials of SGLT2 inhibitors that reported effects on major kidney outcomes in people with type 2 diabetes. We searched MEDLINE and Embase from database inception to June 14, 2019, to identify eligible trials. The primary outcome was a composite of dialysis, transplantation, or death due to kidney disease. We used random-effects models to obtain summary relative risks (RRs) with 95% CIs and random-effects meta-regression to explore effect modification by subgroups of baseline eGFR, albuminuria, and use of renin-angiotensin system (RAS) blockade. This review is registered with PROSPERO (CRD42019131774).
From 2085 records identified, four studies met our inclusion criteria, assessing three SGLT2 inhibitors: empagliflozin (EMPA-REG OUTCOME), canagliflozin (CANVAS Program and CREDENCE), and dapagliflozin (DECLARE-TIMI 58). From a total of 38 723 participants, 252 required dialysis or transplantation or died of kidney disease, 335 developed end-stage kidney disease, and 943 had acute kidney injury. SGLT2 inhibitors substantially reduced the risk of dialysis, transplantation, or death due to kidney disease (RR 0·67, 95% CI 0·52-0·86, p=0·0019), an effect consistent across studies (I
=0%, p
=0·53). SGLT2 inhibitors also reduced end-stage kidney disease (0·65, 0·53-0·81, p<0·0001), and acute kidney injury (0·75, 0·66-0·85, p<0·0001), with consistent benefits across studies. Although we identified some evidence that the proportional effect of SGLT2 inhibitors might attenuate with declining kidney function (p
=0·073), there was clear, separate evidence of benefit for all eGFR subgroups, including for participants with a baseline eGFR 30-45 mL/min per 1·73 m
(RR 0·70, 95% CI 0·54-0·91, p=0·0080). Renoprotection was also consistent across studies irrespective of baseline albuminuria (p
=0·66) and use of RAS blockade (p
=0·31).
SGLT2 inhibitors reduced the risk of dialysis, transplantation, or death due to kidney disease in individuals with type 2 diabetes and provided protection against acute kidney injury. These data provide substantive evidence supporting the use of SGLT2 inhibitors to prevent major kidney outcomes in people with type 2 diabetes.
None.
Aim
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 m2.
Materials and methods
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 individuals with T2DM and CKD. Random effects models and inverse variance weighting were used to calculate relative risks with 95% confidence intervals.
Results
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 m2/y; 95% CI, 0.78‐1.93) and reduced the risk of the composite renal outcome (HR, 0.71; 95% CI, 0.53‐0.95). There was no evidence of additional risks with SGLT2 inhibition in CKD beyond those already known for the class, although heterogeneity was observed across individual agents for some safety outcomes.
Conclusion
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.
Background 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. Methods and Results 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;
<0.001) 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
interaction >0.252; I
<25%). All patient subgroups benefited with respect to hospitalization for heart failure (all
interaction>0.302; I
<10%), cardiovascular death (all
interaction>0.167; I
<50%), and death from any cause (all
interaction>0.354; I
=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 (
interaction=0.020; I
=81%). Conclusions Sodium-glucose cotransporter 2 inhibitors protect against cardiovascular disease and death in diverse subsets of patients with type 2 diabetes mellitus regardless of cardiovascular disease history.
Aims/hypothesis
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 individuals with type 2 diabetes in previous studies. Whether drugs can reduce these biomarkers is not well established. We measured these biomarkers in samples 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 individuals with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS).
Methods
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.
Results
In total, 3523/4330 (81.4%) of the CANVAS participants had available samples 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.
Conclusions/interpretation
Canagliflozin decreased KIM-1 and modestly reduced TNFR-1 and TNFR-2 compared with placebo in individuals 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.
Graphical abstract
Changes in urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) have been used separately as alternative kidney disease outcomes in randomized trials. We tested the ...hypothesis that combined changes in UACR and eGFR predict advanced kidney disease better than either alone.
Observational cohort study.
91,319 primary care patients assembled from the Clinical Practice Research Datalink in the United Kingdom between 2000 and 2015.
Changes in UACR and eGFR (categorized as ≥30% increase, stable, or ≥30% decrease), alone and in combination, over a 3-year period.
The primary outcome was advanced CKD (sustained eGFR <30 mL/min/1.73 m2); secondary outcomes included kidney failure, cardiovascular disease, and all-cause mortality.
Multivariable Cox regression with bias from missing values assessed using multiple imputation; discrimination statistics compared across exposure groups.
91,319 individuals were studied, with a mean eGFR of 72.6 mL/min/1.73 m2 and median UACR of 9.7 mg/g; 70,957 (77.7%) had diabetes. During a median follow-up of 2.9 years, 2,541 people progressed to advanced CKD. Compared with stable values, hazard ratios for a ≥30% increase in UACR and ≥30% decrease in eGFR were 1.78 (95% CI, 1.59-1.98) and 7.53 (95% CI, 6.70-8.45), respectively, for the outcome of advanced CKD. Compared with stable values of both, the hazard ratio for the combination of an increase in UACR and a decrease in eGFR was 15.15 (95% CI, 12.43-18.46) for the outcome of advanced CKD. The combination of changes in UACR and eGFR predicted kidney outcomes better than either alone.
Selection bias, relatively small proportion of individuals without diabetes, and very few kidney failure events.
In a large-scale general population, the combination of an increase in UACR and a decrease in eGFR was strongly associated with the risk of advanced CKD. Further assessment of combined changes in UACR and eGFR as an alternative outcome for kidney failure in trials of CKD progression is warranted.
Display omitted
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 individual 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 (
=0.71). The incidence of investigator-reported hyperkalemia was also lower with SGLT2 inhibitors (hazard ratio, 0.80 95% CI, 0.68-0.93;
=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;
=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.
PDF
