Sodium-glucose cotransporter 2 inhibitors are the most promising of a number of diabetes medications that have shown potential in renoprotection through a mechanism other than glucose homeostasis.
The study suggests canagliflozin’s effects are felt both in the renal system and systemically. The initial decrease in glomerular filtration rate in the first few weeks of treatment could be the result of decreases in glomerular perfusion and intraglomerular pressure, but this effect does stabilize. Levels of angiotensin II and atrial natriuretic peptide decrease, and there is also a decrease in inflammation and an increase in intrarenal oxygenation.
These findings are good news for patients with diabetes and chronic kidney disease, and their importance cannot be overstated.
Julie R. Ingelfinger, MD, is from the Tufts University in Boston, and Clifford J. Rosen, MD, is from the Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough. These comments are adapted from an accompanying editorial (N Engl J Med. 2019 Apr 14. doi: 10.1056/NEJMe1904740).
Patients with type 2 diabetes and chronic kidney disease (CKD) show significantly lower incidence of kidney failure and cardiovascular events after treatment with the sodium-glucose cotransporter 2 inhibitor canagliflozin, in the CREDENCE trial.
CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) is a double-blind, placebo-controlled trial involving 4,401 patients with type 2 diabetes and albuminuric CKD, who were randomized to either 100 mg of canagliflozin daily or placebo.
After a median follow-up of 2.62 years, there was a significant 30% lower risk of the primary outcome, which was a composite of end-stage kidney disease, a doubling of serum creatinine, or death from renal or cardiovascular causes, a highly significant difference at P = .00001.
Separately, there was a 32% lower risk of end-stage kidney disease, a 20% lower risk of cardiovascular death, MI, or stroke, and a 39% lower risk of hospitalization for heart failure, both significant differences. Patients treated with canagliflozin also had a 40% lower risk of a doubling of serum creatinine, and a 28% lower risk of dialysis, kidney transplantation, or renal death.
“These findings were observed despite very modest between-group differences in blood glucose level, weight, and blood pressure, and in contrast to previous concern about the initial acute reduction in the estimated GFR [glomerular filtration rate] observed with SGLT2 inhibitors,” wrote Vlado Perkovic, MD, from the George Institute for Global Health, University of New South Wales Sydney, and his coauthors. “This suggests that the mechanism of benefit is likely to be independent of glucose levels and may possibly stem from a reduction in intraglomerular pressure, with other possible mechanisms presently being studied.”
The trial was stopped early after reaching the prespecified efficacy criteria for early cessation. The authors estimated that 21.2 patients would need to be treated with canagliflozin to prevent one primary outcome.
There were no significant differences between the two groups in the rate of adverse and serious adverse events, including the risk of lower limb amputation and fracture.
The study was supported by Janssen Research and Development. Eighteen authors declared steering committee, support and consultancies with Janssen, and thirteen also declared personal fees from other pharmaceutical and private industry. Five authors were employees of Janssen.
SOURCE: Perkovic V et al. N Engl J Med. 2019 Apr 14. doi: 10.1056/NEJMoa1811744.