The increased prevalence of type 2 diabetes mellitus (T2DM) may cause an increase in chronic kidney disease burden.1 Sodium-glucose cotransporter 2 (SGLT2) inhibitors are used to lower blood glucose levels in patients with T2DM, and have been suggested to improve renal outcomes. The CREDENCE trial, a randomized, double-blind and placebo-controlled trial, reported a decrease in relative risk of kidney failure, as well as a lower risk of cardiovascular events in patients with T2DM and kidney disease receiving canagliflozin, an SGLT2 inhibitor.2 Based on the results of this landmark trial, a new indication for canagliflozin is being sought.3 The results were presented at the World Congress of Nephrology (WCN) 2918, an International Society of Nephrology (ISN) event that was held in Melbourne, Australia, and the study simultaneously published in The New England Journal of Medicine.2,4
Accompanying the growing prevalence of T2DM worldwide is an increase in end-stage kidney disease, due to the impact of hyperglycemia and hypertension on kidney hemodynamics.1 In Hong Kong, the number of cases of renal replacement therapy due to diabetes mellitus has increased from 26.2% in 1996 to 49.6% in 2013.5 SGLT2 inhibitors were developed to lower blood glucose levels in patients with T2DM, and exploratory analyses have suggested that SGLT inhibition may improve renal outcomes.2 The CREDENCE trial was designed to assess the effects of the SGLT2 inhibitor, canagliflozin, on the renal outcomes in patients with T2DM and albuminuric chronic kidney disease.2
The CREDENCE trial was a randomized, double-blind, placebo-controlled, and multicentre clinical trial conducted in 4,401 patients aged 30 years or older with T2DM, a glycated haemoglobin level between 6.5% and 12%, albuminuria, and an estimated glomerular filtration rate (eGFR) of 30 to <90mL/min/1.73m2.2 Patients were randomly assigned to receive canagliflozin 100mg or matching placebo added to renin-angiotensin-aldosterone blockade, and the primary outcome of the study was a composite of end stage kidney disease (ESKD), doubling of serum creatinine level from baseline, or death from renal or cardiovascular disease.2 The trial was stopped earlier than planned after meeting prespecified efficacy endpoints.2
Canagliflozin was found to reduce the risk of the primary outcome by 30% (HR=0.70; 95% CI: 0.59-0.82; p=0.00001).2 These effects were consistent over subgroups of patients stratified according to screening eGFR and baseline albuminuria.2 Canagliflozin was also shown to reduce the risk of cardiovascular death or hospitalization for heart failure by 31% (HR=0.69; 95% CI: 0.57-0.93; p<0.001).2 These results indicate that canagliflozin could be an effective renoprotective and cardioprotective treatment option for patients with T2DM and chronic kidney disease.2
Currently, the only renoprotective medications approved for the treatment of T2DM are ACE inhibitors and angiotensin-receptor blockers, highlighting the clinical significance of these results.2,6 The CREDENCE trial population included patients at high risk of kidney failure, in contrast to other completed cardiovascular outcome trials of SGLT2 inhibitors.2 The trial population was also at high risk for cardiovascular outcomes, with cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure occurring in 13.8% of the population over a median time of 2.62 years of follow-up.2 “Many still end up progressing, having cardiovascular events, or dying from complications of kidney failure, but we now have a proven treatment to help patients with diabetes and kidney disease lead perhaps an even longer life”, said Vlado Perkovic, the lead study investigator, about the results.4
Canagliflozin was approved for the treatment of T2DM by the US Food and Drug Administration (FDA) and European Medicines Agency in 2013.7,8 The indication was expanded in 2018 to include patients with established cardiovascular disease.9 Janssen has recently submitted a supplemental New Drug Application to the US FDA, seeking a new indication for canagliflozin for the treatment of patients with chronic kidney disease and T2DM on the basis of the positive results seen in the CREDENCE trial.3
1. Alicic RZ, Rooney MT, Tuttle KR. Diabetic Kidney Disease. Clin J Am Soc Nephrol. 2017;12(12):2032-45.
2. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. New England Journal of Medicine. 2019;0(0):null.
3. Janssen Submits Supplemental New Drug Application to U.S. FDA for INVOKANA® (canagliflozin) for the Treatment of Chronic Kidney Disease in Patients with Type 2 Diabetes. Content Lab – U.S. (Accessed May 22, 2019, at https://www.jnj.com/janssen-submits-supplemental-new-drug-application-to-u-s-fda-for-invokana-canagliflozin-for-the-treatment-of-chronic-kidney-disease-in-patients-with-type-2-diabetes.)
4. Diabetes Drug ‘Home Run’ Curtailing Kidney Failure Risk. Medscape (Accessed May 22, 2019, at http://www.medscape.com/viewarticle/911789.)
5. Leung CB, Cheung WL, Li PKT. Renal registry in Hong Kong—the first 20 years. Kidney Int Suppl (2011). 2015;5(1):33-8.
6. Lozano-Maneiro L, Puente-García A. Renin-Angiotensin-Aldosterone System Blockade in Diabetic Nephropathy. Present Evidences. J Clin Med. 2015;4(11):1908-37.
7. U.S. FDA Approves INVOKANATM (Canagliflozin) for the Treatment of Adults with Type 2 Diabetes. Content Lab – U.S. (Accessed May 22, 2019, at https://www.jnj.com/media-center/press-releases/us-fda-approves-invokana-canagliflozin-for-the-treatment-of-adults-with-type-2-diabetes.)
8. INVOKANATM (canagliflozin) Approved In The European Union For Treatment Of Adults With Type 2 Diabetes. Content Lab – U.S. (Accessed May 22, 2019, at https://www.jnj.com/media-center/press-releases/invokana-canagliflozin-approved-in-the-european-union-for-treatment-of-adults-with-type-2-diabetes-1.)
9. U.S. FDA Approves INVOKANA® (canagliflozin) to Reduce the Risk of Heart Attack, Stroke or Cardiovascular Death in Adults with Type 2 Diabetes and Established Cardiovascular Disease. Janssen (Accessed May 22, 2019, at https://www.janssen.com/us-fda-approves-invokanar-canagliflozin-reduce-risk-heart-attack-stroke-or-cardiovascular-death.)