Type 2 diabetes is the most common cause of kidney failure in many countries,1 and the number of people who receive renal replacement therapy for kidney failure worldwide is projected to increase from 2·6 million in 2010, to more than 5 million in 2030.2 Control of risk factors, including blood glucose concentration,3, 4, 5 blood pressure,6, 7, 8 and albuminuria,9 is the main focus of efforts to protect kidney function, alongside renin–angiotensin system (RAS) blockade.10, 11 Nonetheless, residual risk remains high and several novel interventions targeting kidney disease have proved unsuccessful.12, 13, 14, 15
Research in context
Evidence before this study
We searched PubMed for papers published until the end of December, 2017, using the search terms “SGLT2 inhibitors”, “sodium glucose co-transporter-2 inhibitors” and the names of individual agents in this class, without language restriction. Randomised trials reporting the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors in participants with baseline chronic kidney disease were selected. SGLT2 inhibitors such as canagliflozin reduce blood glucose concentration, blood pressure, bodyweight, and albuminuria in patients with type 2 diabetes, which suggests that these drugs might have protective effects on the kidney. Analyses of the effects of the SGLT2 inhibitor empagliflozin on exploratory renal outcomes in the EMPA-REG OUTCOME trial suggested that empagliflozin-treated participants with established cardiovascular disease had a slower decline in kidney function and a reduced risk of a composite outcome that consisted of end-stage kidney disease and doubling of creatinine concentrations compared with patients treated with placebo, although these outcomes were not adjudicated in that trial. Findings from the CANVAS Program showed that canagliflozin prevents major cardiovascular events, and exploratory analyses on adjudicated renal outcomes suggested that, compared with placebo, canagliflozin reduced risk of adverse kidney outcomes, as determined from a composite endpoint of a sustained 40% reduction in estimated glomerular filtration rate, end-stage kidney disease, or death from renal causes. The effects of canagliflozin on a comprehensive range of kidney outcomes are therefore of interest in better defining the effects of canagliflozin and SGLT2 inhibitors on kidney function in patients with type 2 diabetes.
Added value of this study
This prespecified exploratory analysis of the CANVAS Program showed that canagliflozin reduced the risk of sustained and adjudicated major kidney outcomes (doubling of creatinine, end-stage kidney disease, or death from renal causes) in participants with type 2 diabetes at high risk of cardiovascular events (including patients with and those without established cardiovascular disease). This analysis also showed that kidney function declined progressively in participants treated with placebo, but was stabilised in participants who were treated with canagliflozin, and that albumin loss in the urine of canagliflozin-treated participants was reduced relative to those treated with placebo. The results were consistent across subgroups of participants, and renal adverse event rates were not increased with canagliflozin compared with placebo.
Implications of all the available evidence
These data suggest substantial kidney protection associated with canagliflozin treatment in participants with type 2 diabetes at high cardiovascular risk. These results, although consistent with those reported for empagliflozin, provide additional support for the growing evidence that SGLT2 inhibitors could have an important role in slowing the progression of diabetic kidney disease, given that renal outcomes were both confirmed and adjudicated in the CANVAS Program. Further studies are required to assess whether canagliflozin can delay time to kidney failure in patients with established kidney disease.
Sodium-glucose co-transporter-2 (SGLT2) inhibitors lower glucose, blood pressure, and bodyweight in people with type 2 diabetes and alter intrarenal haemodynamics in hyperfiltering individuals with type 1 diabetes,16 although the effects of these drugs on glycaemia and bodyweight are attenuated in people with reduced kidney function.17 The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program18 consists of two parallel trials (CANVAS and CANVAS-R [renal]). The primary data from the CANVAS Program18 demonstrated the cardiovascular safety of canagliflozin and showed a 14% reduction in rates of major adverse cardiovascular events in participants assigned to canagliflozin compared with placebo-treated participants. In prespecified, exploratory analyses outside the formal hypothesis testing sequence (appendix), canagliflozin was also associated with a 27% reduction in the likelihood of progression of albuminuria and a 70% higher likelihood of regression of albuminuria. Additionally, there was a 40% reduction in rates of a composite renal outcome that consisted of sustained and adjudicated reductions of 40% in estimated glomerular filtration rate (eGFR), end-stage kidney disease, or death from renal causes.18 Exploratory analyses of the EMPA-REG OUTCOME study19 have shown that the SGLT2 inhibitor empagliflozin also has potential benefits on renal outcomes, although these outcomes were not adjudicated in that trial.
Collectively, these data suggest that SGLT2 inhibitors might have renoprotective efficacy, but regulatory decisions and guidelines have previously required benefits to be shown for harder endpoints based on doubling in creatinine, with central adjudication. Although a sustained doubling of serum creatinine is undoubtedly an important endpoint, given that it reflects a loss of 57% of kidney function (as measured by eGFR), the rate of decline in kidney function in conditions such as type 2 diabetes is often moderate. Clinical trials therefore require very long follow-up duration, large numbers of participants, or both, to accumulate an adequate number of events in broad populations of participants, which can affect the feasibility of trials. There is therefore an increasing interest in the use of smaller changes in eGFR as an alternative outcome.
To address this challenge, a workshop convened by the US National Kidney Foundation and the US Food and Drug Administration, in collaboration with academic researchers, proposed that a sustained 40% reduction in eGFR could be a reasonable replacement for doubling of serum creatinine, but trials that use this outcome have not yet led to treatment indications by regulatory authorities. As such, there is great interest in the extent and consistency of effects of canagliflozin on a range of renal outcomes from the CANVAS Program.
Here we report the results of prespecified analyses that assessed the effects of canagliflozin on a range of adjudicated, exploratory renal outcomes from the CANVAS Program.20