Aims/hypothesis
The sodium–glucose cotransporter 2 (SGLT2) inhibitor canagliflozin slows progression of kidney function decline in type 2 diabetes. The aim of this study was to assess the effect of ...the SGLT2 inhibitor canagliflozin on biomarkers for progression of diabetic kidney disease (DKD).
Methods
A canagliflozin mechanism of action (MoA) network model was constructed based on an in vitro transcriptomics experiment in human proximal tubular cells and molecular features linked to SGLT2 inhibitors from scientific literature. This model was mapped onto an established DKD network model that describes molecular processes associated with DKD. Overlapping areas in both networks were subsequently used to select candidate biomarkers that change with canagliflozin therapy. These biomarkers were measured in 296 stored plasma samples from a previously reported 2 year clinical trial comparing canagliflozin with glimepiride.
Results
Forty-four proteins present in the canagliflozin MoA molecular model overlapped with proteins in the DKD network model. These proteins were considered candidates for monitoring impact of canagliflozin on DKD pathophysiology. For ten of these proteins, scientific evidence was available suggesting that they are involved in DKD progression. Of these, compared with glimepiride, canagliflozin 300 mg/day decreased plasma levels of TNF receptor 1 (TNFR1; 9.2%;
p
< 0.001), IL-6 (26.6%;
p
= 0.010), matrix metalloproteinase 7 (MMP7; 24.9%;
p
= 0.011) and fibronectin 1 (FN1; 14.9%;
p
= 0.055) during 2 years of follow-up.
Conclusions/interpretation
The observed reduction in TNFR1, IL-6, MMP7 and FN1 suggests that canagliflozin contributes to reversing molecular processes related to inflammation, extracellular matrix turnover and fibrosis.
Trial registration ClinicalTrials.gov NCT00968812
The mechanisms by which SGLT‐2 inhibitors lower albuminuria are incompletely understood. We assessed in a post‐hoc analysis of a cross‐over trial the effects of the SGLT2 inhibitor dapagliflozin on ...glomerular markers (IgG to IgG4 and IgG to albumin), tubular markers (urinary KIM‐1, NGAL and LFABP) and inflammatory markers (urinary MCP‐1 and IL‐6) to provide more insight into kidney protective effects. Dapagliflozin decreased albuminuria by 43.9% (95% CI, 30.3%‐54.8%) and eGFR by 5.1 (2.0‐8.1) mL/min/1.73m2 compared to placebo. Dapagliflozin did not change glomerular charge or size selectivity index compared to placebo. Dapagliflozin decreased urinary KIM‐1 excretion by 22.6% (0.3%‐39.8%; P = .05) and IL‐6 excretion by 23.5% (1.4%‐40.6%; P = .04) compared to placebo, whereas no changes in NGAL, LFABP and MCP‐1 were observed. During dapagliflozin treatment, changes in albuminuria correlated with changes in eGFR (r = 0.36; P = .05) and KIM‐1 (r = 0.39; P = .05). In conclusion, the albuminuria‐lowering effect of 6 weeks of dapagliflozin therapy may be the result of decreased intraglomerular pressure or reduced tubular cell injury.
SGLT2 inhibitors and GLP-1 receptor agonists are used in patients with type 2 diabetes as glucose lowering therapies, with additional benefits of weight loss and blood pressure reduction. Data from ...cardiovascular outcome trials have highlighted that these drugs confer protection against major cardiovascular disease in those with established atherosclerotic cardiovascular disease, reduce the risk of admission to hospital for heart failure, and reduce cardiovascular and all-cause mortality. Ongoing research using hard renal endpoints such as end stage kidney disease rather than surrogate markers might clarify the renoprotective benefits of both agents. When used for glucose lowering, SGLT2 inhibitors are most effective if the estimated glomerular filtration rate is more than 60 ml per min per 1·73m2 at initiation and should be avoided where there is a risk of diabetic ketoacidosis. GLP-1 receptor agonists are contraindicated in those with a history of medullary thyroid cancer and used with caution in patients with a history of pancreatitis of a known cause. These drugs are now second-line, or even arguably first-line, glucose lowering therapies in patients with cardiorenal disease, irrespective of glycaemic control. If an SGLT2 inhibitor or GLP-1 receptor agonist is considered suitable in patients with type 2 diabetes, treatment should be prioritised according to existing evidence: GLP-1 receptor agonists should be considered in patients at a high risk of, or with established, cardiovascular disease and SGLT2 inhibitors considered for patients with heart failure (with reduced ejection fraction) or chronic kidney disease (with or without established cardiovascular disease). There is now compelling data on the benefits of these drugs for a range of other clinical indications even without type 2 diabetes, including for GLP-1 receptor agonists in patients with obesity and overweight with weight-related comorbidities.
Sodium-glucose cotransporter 2 inhibition with canagliflozin decreases HbA1c, body weight, BP, and albuminuria, implying that canagliflozin confers renoprotection. We determined whether canagliflozin ...decreases albuminuria and reduces renal function decline independently of its glycemic effects in a secondary analysis of a clinical trial in 1450 patients with type 2 diabetes receiving metformin and randomly assigned to either once-daily canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride uptitrated to 6-8 mg. End points were annual change in eGFR and albuminuria over 2 years of follow-up. Glimepiride, canagliflozin 100 mg, and canagliflozin 300 mg groups had eGFR declines of 3.3 ml/min per 1.73 m
per year (95% confidence interval 95% CI, 2.8 to 3.8), 0.5 ml/min per 1.73 m
per year (95% CI, 0.0 to 1.0), and 0.9 ml/min per 1.73 m
per year (95% CI, 0.4 to 1.4), respectively (P<0.01 for each canagliflozin group versus glimepiride). In the subgroup of patients with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, urinary albumin-to-creatinine ratio decreased more with canagliflozin 100 mg (31.7%; 95% CI, 8.6% to 48.9%; P=0.01) or canagliflozin 300 mg (49.3%; 95% CI, 31.9% to 62.2%; P<0.001) than with glimepiride. Patients receiving glimepiride, canagliflozin 100 mg, or canagliflozin 300 mg had reductions in HbA1c of 0.81%, 0.82%, and 0.93%, respectively, at 1 year and 0.55%, 0.65%, and 0.74%, respectively, at 2 years. In conclusion, canagliflozin 100 or 300 mg/d, compared with glimepiride, slowed the progression of renal disease over 2 years in patients with type 2 diabetes, and canagliflozin may confer renoprotective effects independently of its glycemic effects.
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
Abstract
Background
Recent cardiovascular outcome trials have shown that sodium–glucose co-transporter 2 (SGLT2) inhibitors slow the progression of chronic kidney disease (CKD) in patients with type ...2 diabetes at high cardiovascular risk. Whether these benefits extend to CKD patients without type 2 diabetes or cardiovascular disease is unknown. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) will assess the effect of the SGLT2 inhibitor dapagliflozin on renal and cardiovascular events in a broad range of patients with CKD with and without diabetes.
Methods
DAPA-CKD is a randomized, double-blind, placebo-controlled, trial in which ∼4300 patients with CKD Stages 2–4 and elevated urinary albumin excretion will be enrolled. The vast majority will be receiving a maximum tolerated dose of a renin–angiotensin system inhibitor at enrolment.
Results
After a screening assessment, eligible patients with a urinary albumin:creatinine ratio ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 are randomly assigned to placebo or dapagliflozin 10 mg/day. Enrolment is monitored to ensure that at least 30% of patients do not have diabetes and that no more than 10% have an eGFR >60 mL/min/1.73 m2. The primary endpoint is a composite of a sustained decline in eGFR of ≥50%, end-stage renal disease, renal death or cardiovascular death. The trial will conclude when 681 primary renal events have occurred, providing 90% power to detect a 22% relative risk reduction (α level of 0.05).
Conclusion
DAPA-CKD will determine whether the SGLT2 inhibitor dapagliflozin, added to guideline-recommended therapies, safely reduces the rate of renal and cardiovascular events in patients across multiple CKD stages with and without diabetes.
Graphical Abstract
Graphical Abstract
Surrogate end points are needed to assess whether treatments are effective in the early stages of CKD. GFR decline leads to kidney failure, but regulators have not approved using differences in the ...change in GFR from the beginning to the end of a randomized, controlled trial as an end point in CKD because it is not clear whether small changes in the GFR slope will translate to clinical benefits.
To assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects. We estimated treatment effects on GFR slope (mean difference in GFR slope between the randomized groups), for the total slope starting at baseline, chronic slope starting at 3 months after randomization, and on the clinical end point (doubling of serum creatinine, GFR<15 ml/min per 1.73 m
, or ESKD) for each study. We used Bayesian mixed-effects analyses to describe the association of treatment effects on GFR slope with the clinical end point and to test how well the GFR slope predicts a treatment's effect on the clinical end point.
Across all studies, the treatment effect on 3-year total GFR slope (median
=0.97; 95% Bayesian credible interval BCI, 0.78 to 1.00) and on the chronic slope (
0.96; 95% BCI, 0.63 to 1.00) accurately predicted treatment effects on the clinical end point. With a sufficient sample size, a treatment effect of 0.75 ml/min per 1.73 m
/yr or greater on total slope over 3 years or chronic slope predicts a clinical benefit on CKD progress with at least 96% probability.
With large enough sample sizes, GFR slope may be a viable surrogate for clinical end points in CKD RCTs.
Patients with chronic kidney disease and severely decreased glomerular filtration rate (GFR) are at high risk for kidney failure, cardiovascular disease (CVD) and death. Accurate estimates of risk ...and timing of these clinical outcomes could guide patient counseling and therapy. Therefore, we developed models using data of 264,296 individuals in 30 countries participating in the international Chronic Kidney Disease Prognosis Consortium with estimated GFR (eGFR)s under 30 ml/min/1.73m2. Median participant eGFR and urine albumin-to-creatinine ratio were 24 ml/min/1.73m2 and 168 mg/g, respectively. Using competing-risk regression, random-effect meta-analysis, and Markov processes with Monte Carlo simulations, we developed two- and four-year models of the probability and timing of kidney failure requiring kidney replacement therapy (KRT), a non-fatal CVD event, and death according to age, sex, race, eGFR, albumin-to-creatinine ratio, systolic blood pressure, smoking status, diabetes mellitus, and history of CVD. Hypothetically applied to a 60-year-old white male with a history of CVD, a systolic blood pressure of 140 mmHg, an eGFR of 25 ml/min/1.73m2 and a urine albumin-to-creatinine ratio of 1000 mg/g, the four-year model predicted a 17% chance of survival after KRT, a 17% chance of survival after a CVD event, a 4% chance of survival after both, and a 28% chance of death (9% as a first event, and 19% after another CVD event or KRT). Risk predictions for KRT showed good overall agreement with the published kidney failure risk equation, and both models were well calibrated with observed risk. Thus, commonly-measured clinical characteristics can predict the timing and occurrence of clinical outcomes in patients with severely decreased GFR.
The past decade has resulted in multiple new findings of potential proteomic biomarkers of diabetic kidney disease (DKD). Many of these biomarkers reflect an important role in the (patho)physiology ...and biological processes of DKD. Situations in which proteomics could be applied in clinical practice include the identification of individuals at risk of progressive kidney disease and those who would respond well to treatment, in order to tailor therapy for those at highest risk. However, while many proteomic biomarkers have been discovered, and even found to be predictive, most lack rigorous external validation in sufficiently powered studies with renal endpoints. Moreover, studies assessing short-term changes in the proteome for therapy-monitoring purposes are lacking. Collaborations between academia and industry and enhanced interactions with regulatory agencies are needed to design new, sufficiently powered studies to implement proteomics in clinical practice.
Chronic kidney disease (CKD) and heart failure affect many people worldwide. Despite the availability of pharmacological treatments, both diseases remain associated with considerable morbidity and ...mortality. After observations that sodium-glucose co-transporter 2 (SGLT2) inhibitors - originally developed as glucose-lowering agents - improved cardiovascular and renal outcomes in patients with type 2 diabetes, dedicated trials were initiated to evaluate the cardiovascular and kidney protective effects in patients with CKD or heart failure. The results of these clinical trials and subsequent detailed analyses have shown that the benefits of SGLT2 inhibitors are consistent across many patient subgroups, including those with and without type 2 diabetes, at different stages of CKD, and in patients with heart failure with preserved or reduced ejection fraction. In addition, post-hoc analyses revealed that SGLT2 inhibitors reduce the risk of anaemia and hyperkalaemia in patients with CKD. With respect to their safety, SGLT2 inhibitors are generally well tolerated. More specifically, no increased risk of hypoglycaemia has been observed in patients with CKD or heart failure without diabetes and they do not increase the risk of acute kidney injury. SGLT2 inhibitors therefore provide clinicians with an exciting new treatment option for patients with CKD and heart failure.
PDF
