Ajay K. Singh, MBBS, FRPC, MBA
Brigham and Women’s Hospital and Harvard Medical School
Diabetic nephropathy is the most common cause of end-stage renal disease. With the rates of type 2 diabetes reaching epidemic proportions worldwide, it is likely that diabetes as a cause of kidney failure will continue to increase. The current treatment of diabetic nephropathy focuses on tight control of blood sugar, control of blood pressure, and the use of renin-angiotensin blockade with either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB).
The emergence of sodium-glucose linked transporter type 2 (SGLT2) inhibitors, which are sodium-glucose cotransporter 2 inhibitors, has presented a unique opportunity to further slow kidney progression. Medicines in the SGLT2 inhibitor class include canagliflozin, dapagliflozin, and empagliflozin.
Zinman and colleagues in 20151 reported that empagliflozin was superior to placebo in reducing the risk of major cardiovascular events. In a follow-up secondary analysis of renal outcomes from this randomized trial, published in 2016, Wanner and colleagues2 reported that empagliflozin administration was also associated with significant renoprotection, including slowing the rate of decline in estimated glomerular filtration rate, progression of albuminuria, and initiation of renal replacement therapy. These results strongly suggested but didn’t prove that SGLT2 inhibitors might have an important role in slowing progression of diabetic nephropathy. Another randomized trial was needed to do this.
Therefore, the news that the CREDENCE (Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation) trial3,4—a double blind placebo controlled RCT evaluating the role of the SGLT2 inhibitor canagliflozin in renoprotection—was stopped early by the data monitoring committee due to positive efficacy results is striking.5
CREDENCE assessed whether treatment with the SGLT2 inhibitor canagliflozin in patients with type 2 diabetes and stage 2 or 3 chronic kidney disease and macroalbuminuria provided kidney and vascular protection effect compared with placebo. The trial enrolled approximately 4400 patients. All patients were required to be treated with either an ACE inhibitor or an ARB 4 weeks prior to randomization.
This news about CREDENCE comes following data presented recently at the American Diabetes Association from the CANVAS (Canagliflozin Cardiovascular Assessment Study) in which patients with type 2 diabetes at high risk for cardiovascular disease treated with canagliflozin demonstrated slowing in kidney progression compared with those treated with placebo.6
What’s the bottom-line? The emerging data now strongly point to benefit in using SGLT2 inhibitors in the treatment of diabetic nephropathy. We are at the dawn of a new era where tight glucose control, blood pressure reduction, and renin angiotensin blockade will not be enough. The use of an SGLT2 inhibitor to both better manage blood sugar and reduce blood pressure will become an essential and key component to managing diabetic nephropathy and slowing progression of kidney disease.
- Zinman B, Wanner C, Lachin JM, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.
- Wanner C, Inzucchi SE, Lachin JM, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016 Jul 28;375(4):323-34. doi: 10.1056/NEJMoa1515920. Epub 2016 Jun 14.
- Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE)https://clinicaltrials.gov/ct2/show/NCT02065791
- Jardine MJ, Mahaffey KW, Neal B, et al.; CREDENCE study investigators. The canagliflozin and renal endpoints in diabetes with established nephropathy clinical evaluation (CREDENCE) study Rationale, design, and baseline characteristics. Am J Nephrol. 2017 Dec 13;46(6):462-472. doi:10.1159/000484633.
- www.prnewswire.com/news-releases/phase-3-credence-renal-outcomes-trial-of-invokana-canagliflozin-is-being-stopped-early-for-positive-efficacy-findings-300681634.html. Accessed August 8, 2018
- https://www.mdmag.com/conference-coverage/ada-2018/canagliflozin-continues-showing-of-positive-renal-outcomes-in-canvas-data. Accessed August 8, 2018