An industry-funded study found improved outcomes among patients with diabetes and chronic kidney disease (CKD) who were randomized to canagliflozin versus placebo. After a median follow-up of 2.62 years, rates of the primary outcome—a composite of end-stage kidney disease, doubling of serum creatinine level, or death from renal or cardiovascular (CV) causes—were significantly lower in patients taking the drug. The trial was discontinued based on the results of this planned interim analysis.
The study was published on April 14 by the New England Journal of Medicine and summarized in the May ACP Diabetes Monthly. The following commentary by Tejas Patel, MD, FACP, was published in the ACP Journal Club section of the Aug. 20 Annals of Internal Medicine.
The CREDENCE trial compared canagliflozin with placebo in patients who had diabetes and albuminuric (median urinary albumin-to-creatinine ratio 927 mg/g) CKD and were already receiving ACE [angiotensin-converting enzyme] inhibitors or ARBs [angiotensin receptor blockers]. Canagliflozin reduced risk for kidney failure and CV events. These findings are consistent with the CANVAS program and EMPA-REG trials, which enrolled patients who had CV disease or were at high risk for CV events; the latter trials did not specifically enroll patients with CKD.
The principal mechanism for the effect of canagliflozin has a sound physiologic basis of activating tubuloglomerular feedback, an adaptive mechanism that links change in GFR [glomerular filtration rate] to the concentration of sodium in the tubules at the macula densa. CREDENCE showed that canagliflozin only reduced HbA1c by 0.25% and blood pressure by 3.3 (systolic) and 0.95 (diastolic) mm Hg, compared with placebo. Thus, reductions in these intermediate outcomes probably do not account for the impressive results seen in the primary outcome in the relatively short period of 2.6 years.
The evidence for the benefits of sodium–glucose cotransporter 2 (SGLT-2) inhibitors in patients with diabetes is robust. Moreover, ongoing randomized trials—EMPA-KIDNEY (NCT03594110) and Dapa-CKD (NCT03036150)—are assessing the effect of SGLT-2 inhibitors in patients with CKD, with and without diabetes; EMPA-KIDNEY is recruiting patients with and without albuminuria and with [estimated GFR] as low as 20 mL/min/1.73 m2. The future holds promise for SGLT-2 inhibitors. This is an exciting time for clinicians who care for patients with diabetes-related CKD.