In high-risk T2DM, canagliflozin reduced CV events regardless of baseline renal function

A secondary analysis of the CANVAS trial stratified patients according to their baseline kidney function (estimated glomerular filtration rate [eGFR] <45, 45 to <60, 60 to <90, and ≥90 mL/min/1.73 m²) and found that the beneficial effects of canagliflozin on cardiovascular (CV) outcomes were not modified by level of kidney function. The original CANVAS trial randomized 10,142 participants with type 2 diabetes to canagliflozin or placebo, with a primary outcome of a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke.

The study was published by Circulation on July 24, 2018. The following commentary by William G. Herrington, MD, Doreen Zhu, MBChB, and Richard Haynes, DM, was published in the ACP Journal Club section of the Feb. 19 Annals of Internal Medicine.

Three large placebo-controlled trials (EMPA-REG OUTCOME, CANVAS, and DECLARE) of sodium–glucose cotransporter-2 (SGLT-2) inhibitors have shown CV benefits in patients with T2DM at high CV risk. However, few patients with eGFR <45 mL/min/1.73m² were included in these trials. As the glycosuric effect of SGLT-2 inhibition is substantially attenuated at low eGFR, the relative effects on CV outcomes might be predicted to be attenuated in chronic kidney disease (CKD). However, Neuen and colleagues found no such trend with canagliflozin for the primary CV outcome or a renal composite outcome in the CANVAS trials. There may be two explanations for this. First, benefits of SGLT-2 inhibition may not be due to glycosuria (and conversely sodium effects may be enhanced in CKD). Second, too few patients with low eGFR were studied to adequately test for trend by eGFR.

CREDENCE, a placebo-controlled trial of canagliflozin in 4401 patients with albuminuric diabetic kidney disease, was recently stopped early for efficacy on its cardiorenal outcome. With a mean eGFR of 56 (standard deviation 18) mL/min/1.73m², CREDENCE may not fully address efficacy and safety questions in patients with eGFR <45 mL/min/1.73m² and provides no information for those with eGFR <30 mL/min/1.73m² or without albuminuria. Data for these patients, and for people without diabetes, are not yet available. EMPA-KIDNEY and Dapa-CKD are large, ongoing trials testing SGLT-2 inhibition in patients with CKD, with and without diabetes. EMPA-KIDNEY is recruiting patients with or without albuminuria and an eGFR as low as 20 mL/min/1.73m². The findings presented by Neuen and colleagues are promising for patients with diabetes and early CKD, but evidence on broader applications of SGLT-2 inhibition are awaited.