The substantial reduction in risk of renal disease and major cardiovascular events seen with canagliflozin in patients with type 2 diabetes is likely to be a class effect of SGLT2 inhibitors, Australian study investigators say.
A randomised controlled trial involving more than 4400 patients with type 2 diabetes and albuminuric chronic kidney disease found that canagliflozin treatment was associated with a 30% lower risk of the primary outcome of end-stage kidney disease, doubling of the serum creatinine level, or death from renal or cardiovascular causes compared to placebo.
Published in the NEJM, the CREDENCE trial led by Professor Vlado Perkovic of the George Institute for Global Health, Sydney, also showed that patients in the canagliflozin group had a lower risk of end-stage kidney disease, hospitalisation for heart failure, and the composite of cardiovascular death, myocardial infarction, or stroke.
The study investigators estimated that among 1000 patients treated for 2.5 years, 22 would need to be treated with canagliflozin to prevent one case of end stage renal failure.
“These results indicate that canagliflozin may be an effective treatment option for renal and cardiovascular protection in patients with type 2 diabetes with chronic kidney disease,” they concluded.
With canagliflozin withdrawn from the PBS in 2015 and no longer marketed in Australia, Professor Perkovic said Australian patients could likely gain similar benefits from other SGLT2 inhibitors such as empagliflozin and dapagliflozin
“They’re doing trials at the moment to prove that [these SGLT2 inhibitors] also reduce kidney failure but I think at this stage we can be reasonably confident that this is likely to be a class effect,” he said.
In the study, 4401 patients with T2D and an estimated GFR of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria were randomised to treatment with canagliflozin 100mg or placebo in addition to renin–angiotensin system blockade.
After a median follow-up of 2.62 years event rates for the primary outcome of end-stage kidney disease, a doubling of the serum creatinine level, or death from renal or cardiovascular causes were 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70).
Canagliflozin treatment was also associated with a 20-39% reduction in the risk of the secondary cardiovascular endpoints such as cardiovascular death and hospitalisation for heart failure. Rates of amputations and fractures were not significantly different in the two groups, but diabetic ketoacidosis was more frequent in the canagliflozin group than in the placebo group, despite the overall low rates (2.2 vs. 0.2 per 1000 patient-years).
An accompanying editorial said the mechanism of action of SGLT2 inhibitors was probably both renal and systemic.
“SGLT2 inhibition increases glucose and sodium delivery to the distal renal tubule, which is sensed by the juxtaglomerular apparatus as increased glomerular perfusion. This leads to increased vasoconstriction of the afferent arteriole, which decreases glomerular perfusion and intraglomerular pressure,” it noted.
“Although these effects decrease the estimated GFR in the short term, as was seen during the first weeks of the CREDENCE trial, over time that effect stabilizes. The level of angiotensin II in the circulation decreases, as does the level of atrial natriuretic peptide, with a subsequent decrease in inflammation and an increase in intrarenal oxygenation. Decreased body weight and sympathetic output, decreased uric acid, and perhaps an increase in glucagon may also contribute.”