First SGLT2 inhibitor approved to treat diabetic kidney disease

Canagliflozin (Invokana) can now be prescribed to slow the progression of kidney disease in patients with type II diabetes.

SGLT2 inhibitors reduce reabsorption of filtered glucose by the kidneys, increasIng urinary glucose excretion and thereby lowering elevated plasma glucose levels. | GETTY IMAGES
SGLT2 inhibitors reduce reabsorption of filtered glucose by the kidneys, increasIng urinary glucose excretion and thereby lowering elevated plasma glucose levels. | GETTY IMAGES

A 100mg daily dose of canagliflozin is indicated to treat diabetic kidney disease as an add-on to standard care such as ACE inhibitors or angiotensin II antagonists.

Patients can be initiated on canagliflozin, and maintained on treatment until dialysis or renal transplantation, if they have:

  • an estimated glomerular filtration rate (eGFR) of 45 to <60ml/min/1.73m2, or
  • an eGFR of 30ml/min/1.73m2 to <45ml/min/1.73m2 and albuminuria (urinary albumin: creatinine ratio >30mg/mmol [>300mg/g]). 

The glucose-lowering effect of canagliflozin is reduced in patients with moderate renal impairment and likely to be absent in patients with severe renal impairment, so prescribers should consider adding other anti-hyperglycaemic agents if glycaemic control is insufficient on the 100mg dose.

Renal outcomes study

The new indication is based on data from the CREDENCE trial, a randomised, double-blind renal outcomes study in patients with type II diabetes and albuminuric chronic kidney disease.

The study enrolled 4401 patients with an eGFR of 30 to <90ml/min/1.73m2 and albuminuria (urinary albumin: creatinine ratio >300 to 5000mg/g). All participants received standard therapy for diabetic kidney disease in the form of a maximum tolerated dose of an ACE inhibitor or angiotensin II antagonist, in addition to canagliflozin 100mg daily or placebo.

Compared with patients who received placebo, those treated with canagliflozin experienced a 30% reduction in the risk of the primary composite endpoint, comprising end-stage renal disease, doubling of serum creatinine and renal or cardiovascular death, with event rates of 43.2 versus 61.2 per 1000 patient-years (hazard ratio [HR] 0.70; 95% CI 0.59–0.82; p=0.00001).

Diabetic ketoacidosis

Overall rates of adverse events and serious adverse events were comparable in the canagliflozin group and the placebo group. There was no significant differences between the groups in the incidence of lower limb amputations or bone fractures. Rates of diabetic ketoacidosis were low but higher in the canagliflozin group than in the placebo group (2.2 vs 0.2 events per 1,000 patient-years).

Professor Vlado Perkovic, study author and professorial fellow at the George Institute, Australia, and dean of medicine at UNSW Sydney, said: 'Canagliflozin is the first medical breakthrough in nearly 20 years proven to slow the progression of chronic kidney disease in patients with diabetes at high risk of developing kidney failure. These impressive results from the CREDENCE study have significant clinical implications for preventing kidney failure and have now been incorporated in major kidney, diabetes and cardiovascular guidelines globally. They provide an opportunity to significantly improve the health of millions of people living with chronic kidney disease and type 2 diabetes.'

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