Diabetes Drug 'Home Run' Curtailing Kidney Failure Risk

Maureen Salamon

April 15, 2019

MELBOURNE, Australia — Canagliflozin (Invokana, Janssen) lowers the risk for progression to end-stage kidney disease by 30% in patients with type 2 diabetes and chronic kidney disease, according to first results from a global phase 3 trial that investigators called "landmark".

The multicenter, randomized, double-blind, placebo-controlled CREDENCE trial (NCT02065791) of 4401 patients also showed that canagliflozin significantly lowers risks for major cardiovascular events, including death and hospitalization for heart failure.

"This is something that will be truly beneficial for our patients," said Vlado Perkovic, MBBS, PhD, from the George Institute for Global Health and the University of New South Wales in Sydney, Australia.

"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," Perkovic told Medscape Medical News. "This is the home run we were hoping for but not banking on."

Perkovic and his colleagues presented the findings in front of an audience of about 800 during a late-breaking clinical trials session here at the International Society of Nephrology (ISN): 2019 World Congress. The study was published online in the New England Journal of Medicine to coincide with its presentation, along with an accompanying editorial.

Canagliflozin is the first new therapy in nearly 20 years to reduce the risk for kidney failure when added to the current standard of care in patients with chronic kidney disease and type 2 diabetes, the leading cause of end-stage kidney disease around the world. The last therapies approved for this indication were ACE inhibitors and angiotensin-receptor blockers, which are now considered the standard of care in this patient population.

Janssen hinted at the strength of the CREDENCE trial results 2 weeks ago by announcing that it has submitted a supplemental New Drug Application (sNDA) to the US Food and Drug Administration (FDA) for the treatment of patients with chronic kidney disease and type 2 diabetes.

Fast-Tracking Through Regulatory Review

The sNDA has been submitted for priority review, which, if successful, would be approved in 6 months, said Norman Rosenthal, MD, vice president and clinical and compound development leader in metabolism for Janssen.

The drug, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, was approved for the treatment of type 2 diabetes by the FDA and the European Medicines Agency in 2013. That indication was expanded in 2018 to include patients with established cardiovascular disease, a population in which canagliflozin can lower the risk for heart attack, stroke, and death.

The CREDENCE trial, launched in 2014, was stopped nearly a year earlier than planned because it met its prespecified efficacy end points, as previously reported by Medscape Medical News.

"This is a game-changer, a whole new strategy we can use," said study coauthor Meg Jardine, MBBS, PhD, also from the George Institute for Global Health.

"Patients in the CREDENCE trial got the standard of care and investigators were encouraged to optimize their blood sugar and blood pressure control, but even beyond that we saw these powerful effects," Jardine told Medscape Medical News.

CREDENCE was the first trial of any SGLT2 inhibitor added to the standard of care to examine renal outcomes in patients with type 2 diabetes and chronic kidney disease when.

All participants had albuminuria and an estimated glomerular filtration rate from 30 to 89 mL/min per 1.73 m², and all had been taking the maximum tolerated daily dose of an ACE inhibitor or an angiotensin-receptor blocker for at least 4 weeks before randomization to either once-daily canagliflozin 100 mg or placebo.

Risk for the study's primary composite end point — progression to a doubling of serum creatinine, end-stage kidney disease requiring dialysis or kidney transplantation, and renal or cardiovascular death — was 30% lower with canagliflozin than with placebo (= .00001).

For secondary end points, there was a 20% reduction in risk for the composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (= .0121); a 31% reduction in risk for the composite of cardiovascular death and hospitalization for heart failure (= .0001); and a 39% reduction in risk for hospitalization for heart failure alone (= .003).

Cardiologists are "still trying to understand the benefit of the SGLT2 inhibitors on outcomes in the cardiology of heart failure," said study coauthor Kenneth Mahaffey, MD, a cardiologist from Stanford University in Palo Alto, California.

"We didn't necessarily anticipate the magnitude of the treatment effect we're seeing," he told Medscape Medical News. "People are trying to understand the mechanism by which canagliflozin in particular and SGLT inhibitors in general improve heart failure. There are a lot of hypotheses around that but no definitive understandings yet."

Lower-Limb Amputation, Fracture Risk

Although serious adverse effects related to canagliflozin include a higher risk for lower-limb amputation or fracture, there were no differences in the rates of these events between the canagliflozin and placebo groups. In fact, all adverse events were less common in the canagliflozin group than in the placebo group.

"Patients can get the benefits without worrying about the risks," Perkovic said.

There is a general lack of awareness about the burden of having both type 2 diabetes and chronic kidney disease, said Rosenthal.

"I think practitioners, patients, and families tend not to appreciate that, by the time a patient gets to end-stage renal disease, meaning they need dialysis or a transplant, their 5-year survival is only 36% to 40%. That's equivalent to or worse than a lot of cancers," he told Medscape Medical News.

Canagliflozin offers "another treatment option that could have a real impact on diabetic kidney disease progression and save lives by preventing people from getting to end-stage kidney failure," said Shilpanjali Jesudason, MD, PhD, from Kidney Health Australia in Melbourne, who was one of many audience members who expressed enthusiasm for the findings.

"As clinical director of a patient organization, I know patients, their care-givers, and the community are looking for lifesaving breakthroughs in clinical care," Jesudason told Medscape Medical News.

This sentiment was echoed by Adeera Levin, MD, from the University of British Columbia in Vancouver, Canada, who is a past president of ISN.

"We haven't had anything that changes the course of kidney disease in a large group of people with diabetes in a very long time," Levin told Medscape Medical News. "Certainly, people with diabetes and kidney disease are a vulnerable population, and this gives hope."

The study was funded by Janssen. Perkovic has been a member of steering committees of trials funded by National Health and Medical Research Council of Australia, Janssen, AbbVie, GSK, Boehringer Ingelheim, Eli Lilly, Gilead, Novartis, Novo Nordisk, Retrophin, Tricida and Pfizer; and has received honoraria for presentations or advisory boards for AbbVie, Amgen, AstraZeneca, Bayer, Baxter, Boehringer Ingelheim, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Novartis, Novo Nordisk, Pharmaling, Pfizer, Reata, Relypsa, Roche, Sanofi and Servier. Jardine has received research support from Gambro, Baxter, CSL, Amgen, Eli Lilly, and MSD; and has served on advisory boards for Akebia, Baxter, Boehringer Ingelheim, CSL, and Vifor; serves on a steering committee for a trial sponsored by Janssen; and has spoken at scientific meetings sponsored by Janssen, Amgen, and Roche. Mahaffey has received research support from Afferent, Amgen, Apple, AstraZeneca, Cardiva Medical, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, and Tenax; and has received speaker fees from Abbott, Ablynx, AstraZeneca, Baim Institute, Boehringer Ingelheim, Bristol Myers Squibb, Elsevier, GlaxoSmithKline, Johnson & Johnson, MedErgy, Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, Springer Publishing, and UCSF. Jesudason has disclosed no relevant financial relationships. Levin is an advisor to Janssen.

International Society of Nephrology (ISN): 2019 World Congress: Abstract O-358. Presented April 15, 2019.

Follow Medscape on Twitter @Medscape and Maureen Salamon @maureensalamon

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