BACKGROUNDType 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODSIn this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m 2 of bodysurface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2 ), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTSThe trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of endstage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONSIn patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.) a bs tr ac t

Background In patients with type 2 diabetes, the effects of intensive glucose control on vascular outcomes remain uncertain.

anzctr.org.au Identifier: ACTRN12611000161921.

This review summarises data from four studies including 38,723 participants across six continents.There was clear evidence that SGLT2 inhibitors reduce the risk dialysis, transplantation or death due to kidney disease, as well as a range of other major kidney outcomes, and that these agents also provide protection against acute kidney injury. Additionally, there were definitive, separate benefits at all levels of kidney function, including an approximate 30% proportional risk reduction in the composite kidney outcome in participants with baseline eGFR less than 45 mL/min/1•73m 2 in whom these drugs are mostly not permitted for use. Implications of all the available evidenceThese results provide the strongest evidence yet that SGLT2 inhibitors should be routinely offered to individuals with type 2 diabetes at risk of progressive kidney disease. The clear evidence of renoprotection across the spectrum of kidney function studied to date call into question current restrictions on the use of SGLT2 inhibitors in people with reduced kidney function, and suggest that many more individuals with type 2 diabetes at high risk of kidney failure are likely to benefit from treatment.