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MELBOURNE, Australia – Canagliflozin (Invokana, Janssen) Decreases by 30% the risk of progression to end-stage renal failure in patients with type 2 diabetes and chronic renal failure, according to preliminary results from a global phase trial 3 that the investigators have described as a "landmark".
The CREDENCE multicenter, randomized, double-blind, placebo-controlled study (NCT02065791) of 4401 patients also showed that canagliflozin significantly reduces the risk of major cardiovascular events, including death and death. hospitalization for heart failure.
"This is something that will be really beneficial to our patients," said Vlado Perkovic, MBBS, PhD, of the George Institute for Global Health and University of New South Wales in Sydney, Australia.
"Many still end up progressing, have cardiovascular problems or die complications of kidney failure, but we now have a proven treatment to help patients with diabetes and kidney disease to live perhaps even longer, "said Perkovic. Medscape Medical News. "It's the home run we were hoping for but we do not count on."
Perkovic and his colleagues presented the findings in front of an audience of about 800 people during a session of last – minute clinical trials organized here at the International Society of Nephrology (ISN): Congress The study was published online in the New England Journal of Medicine to coincide with his presentation, with an accompanying editorial.
Canagliflozin is the first new treatment for nearly 20 years to reduce the risk of kidney failure, in addition to the current standard treatment for patients with chronic kidney disease and type 2 diabetes, the leading cause of insufficiency renal disease in the world. The latest approved treatments for this indication were ACE inhibitors and angiotensin receptor antagonists, which are now considered the gold standard in this patient population.
Janssen alluded to the strength of the CREDENCE test results two weeks ago by announcing that she had submitted an additional 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.
Accelerated regulatory examination
The sNDA has been subject to a priority review, which, if successful, would be approved in 6 months, said Norman Rosenthal, MD, vice president and leader of clinical development and compound development in metabolism at Janssen.
The drug, a cotransporter-sodium-glucose-2 (SGLT2) inhibitor, was approved in 2013 by the FDA and the European Agency for Drugs for the Treatment of Type 2 Diabetes. This indication was extended in 2018 for patients with established cardiovascular disease, canagliflozin may reduce the risk of heart attack, stroke and death.
The CREDENCE trial, launched in 2014, was stopped nearly a year earlier than planned because it met the predefined efficiency criteria, as previously reported by Medscape Medical News.
"This is changing the game, it's a whole new strategy that we can use," said Meg Jardine, co-author of the study, MBBS, PhD, also of the George Institute for Global Health.
"Patients participating in the CREDENCE trial got the standard treatment and the investigators were encouraged to optimize the control of their blood glucose and blood pressure, but even beyond that, we found these powerful effects," he said. declared Jardine Medscape Medical News.
CREDENCE was the first trial of an SGLT2 inhibitor to be added to standard treatment in order to examine renal outcomes in patients with type 2 diabetes and chronic renal failure, if any .
All participants had albuminuria and an estimated glomerular filtration rate of 30 to 89 ml / min for 1.73 m². All had been taking for at least 4 weeks the maximum tolerated dose of an ACE inhibitor or an angiotensin canagliflozin receptor antagonist once a day, 100 mg or placebo.
The risk for the composite primary endpoint of the study – progression to a doubling of serum creatinine, end-stage renal failure requiring kidney dialysis or transplantation, and renal or cardiovascular mortality – was 30%. % lower with canagliflozin than with placebo (P = .00001).
For the secondary endpoints, the composite risk associated with non-fatal myocardial infarction, nonfatal stroke and cardiovascular death was reduced by 20% (P = 0.0121); a 31% reduction in risk for composite cardiovascular death and hospitalization for heart failure (P = 0.0001); and a 39% reduction in the risk of hospitalization for heart failure alone (P = 0.003).
Cardiologists "are still trying to understand the benefit of SGLT2 inhibitors on heart failure outcomes in cardiac failure," said co-author of the study, Kenneth Mahaffey, MD, a cardiologist at Stanford University in Palo Alto, California.
"We did not necessarily anticipate the magnitude of the effect of the observed treatment," he said. Medscape Medical News. "People are trying to understand the mechanism by which canagliflozin in particular and SGLT inhibitors in general ameliorate heart failure.There are many assumptions around this, but no definitive understanding at the moment. "
Lower limb amputation, risk of fracture
Although serious side effects associated with canagliflozin included a higher risk of amputation or lower limb fracture, there was no difference 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," said Perkovic.
According to Rosenthal, the burden of type 2 diabetes and chronic kidney failure is generally underestimated.
"I think practitioners, patients, and families tend not to understand that when a patient has end stage renal failure, which means that she needs to have a good night's sleep." a dialysis or a transplant, its 5-year survival is more than 36% to 40% equivalent or worse than many cancers, "he said. Medscape Medical News.
Canagliflozin offers "another treatment option that could have a real impact on the evolution of diabetic kidney failure and save lives by preventing people from reaching the terminal stage of insufficiency. kidney, "said Shilpanjali Jesudason, MD, PhD, of Kidney Health Australia in Melbourne, who one of the many audience members who expressed their enthusiasm for the results.
"As the clinical director of a patient organization, I know that patients, their caregivers and the community are looking for breakthroughs in clinical care," Jesudason said. Medscape Medical News.
Adeera Levin, MD, of the University of British Columbia in Vancouver, Canada, has already echoed this sentiment. He was president of the ISN.
"We have not had anything that changes the course of kidney disease in a large group of people with diabetes for a very long time," Levin said. Medscape Medical News. "Certainly, people with diabetes and kidney disease are a vulnerable population, which gives hope."
The study was funded by Janssen. Perkovic has been a member of the pilot steering committees funded by the Australian Council of Health and Medical Research, Janssen, AbbVie, GSK, Boehringer Ingelheim, Eli Lilly, Gilead, Novartis, Novo Nordisk, Retrophin, Tricida and Pfizer; and has received honoraria for presentations or advisory committees for AbbVie, Amgen, AstraZeneca, Bayer, Baxter, Boehringer Ingelheim, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Novartis, Novo Nordisk, Pharmaling, Pizer , Reata, Relypsa, Roche, Sanofi and Servier. Jardine has received support from Gambro, Baxter, CSL, Amgen, Eli Lilly and MSD; and has served on advisory committees for Akebia, Baxter, Boehringer Ingelheim, CSL and Vifor; sits on a steering committee for an essay sponsored by Janssen; and spoke at scientific meetings sponsored by Janssen, Amgen and Roche. Mahaffey has received support from related researchers, Amgen, Apple, AstraZeneca, Cardiva Medical, Daiichi, Ferring, Google (in truth), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude and Tenax; and has received honoraria from speakers from Abbott, Ablynx, AstraZeneca, The Baim Institute, Boehringer Ingelheim, Bristol Myers Squibb, Elsevier, GlaxoSmithKline, Johnson & Johnson Johnson, MedErgy, Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nord, Springer Publishing and UCSF. Jesudason has not revealed any relevant financial relationship. Levin is Janssen's advisor.
International Society of Nephrology (ISN): World Congress 2019: Abstract O-358. Presented on April 15, 2019.
Follow Medscape on Twitter @Medscape and Maureen Salamon @maureensalamon
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