Risk of dialysis, transplantation, or death due to kidney disease was significantly lower among patients with type 2 diabetes who took a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, according to a systematic review and meta-analysis. It included four randomized trials, which assessed three SGLT-2 inhibitors: empagliflozin (EMPA-REG OUTCOME), canagliflozin (CANVAS Program and CREDENCE), and dapagliflozin (DECLARE–TIMI 58).
The meta-analysis was published Sept. 5, 2019, by The Lancet Diabetes & Endocrinology. The following commentary by Sarah Yoon Ai Ng, MBChB, Doreen Zhu, BMBCh, and William G. Herrington, MD, was published in the ACP Journal Club section of the Feb. 18 Annals of Internal Medicine.
The CREDENCE trial of canagliflozin confirmed a hypothesis raised by 3 other large placebo-controlled trials that SGLT-2 inhibition substantially slows kidney disease progression in patients with type 2 diabetes and diabetic kidney disease with overt albuminuria.
The meta-analysis of all 4 trials by Neuen and colleagues suggests that the relative benefits of SGLT-2 inhibitors on kidney disease progression outcomes are similar across the full range of kidney function tested (as low as an estimated glomerular filtration rate [eGFR] of 30 mL/min/1.73 m2). This was perhaps unexpected, given the substantial attenuation of the glycosuric effect of SGLT-2 inhibition at lower eGFRs.
Since CREDENCE, the US Food and Drug Administration indicates use of canagliflozin for renoprotection among “adults with type 2 diabetes and diabetic nephropathy with albuminuria of > 300 mg/day” but not for glycemic control at an eGFR < 30 mL/min/1.73 m2. CREDENCE excluded patients without albuminuria, but meta-analysis of the other 3 trials of patients with generally preserved kidney function suggests that renal benefits of SGLT-2 inhibitors in type 2 diabetes may not be dependent on the presence of albuminuria. Further, despite an initial dip in eGFR, SGLT-2 inhibition appears to lower the risk for acute kidney injury by about 25%.
The data from randomized controlled trials raise the hypothesis that renoprotection with SGLT-2 inhibition may not require the presence of diabetes nor albuminuria and may be effective even in patients with lower eGFRs. Placebo-controlled trials are currently assessing empagliflozin and dapagliflozin in patients with nondiabetic causes of kidney disease, and the ongoing EMPA-KIDNEY includes nonproteinuric diseases. This will not be the last meta-analysis of SGLT-2 inhibitor trials.