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Canagliflozin Study Stopped Early Due to Positive Results in Reducing CKD, Death and ESRD

Apr 20, 2019
 

Author: Steve Freed, R.PH., CDE


Featuring exclusive comments from Dr. George Bakris

Studies are rarely stopped early; when it happens, we should take notice of the results.

Randomized clinical trials are designed with stopping boundaries to guide data monitoring committees with their decision making concerning ongoing trials. In rare cases, when extremely positive results are seen, and a boundary is crossed, the data monitoring committee may recommend releasing the results earlier to the public than at the definitive final analysis time specified in the protocol. That is exactly what happened with the CREDENCE trial of 4,401 patients which showed that canagliflozin significantly lowers risks for major cardiovascular events, including death and hospitalization for heart failure.

The Janssen Pharmaceutical Companies of Johnson & Johnson has ended the phase 3 Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation, also known as CREDENCE, based on the achievement of pre-specified efficacy criteria, the company reported. The goal of the study is to assess whether Invokana (canagliflozin, Janssen Pharmaceuticals Inc.) has a renal and vascular protective effect in reducing the progression of renal impairment relative to placebo in patients with type 2 diabetes mellitus, stage 2 or 3 CKD and macroalbuminuria.

The increasing prevalence of type 2 diabetes during recent decades is the primary factor accounting for the substantial global increase in end-stage kidney disease. Currently, more than 3 million people worldwide are estimated to be receiving treatment for kidney failure, with predictions that the number will increase to more than 5 million by 2035. The only currently approved treatment for renoprotection in patients with type 2 diabetes is renin–angiotensin system blockade, which was first shown to be effective 18 years ago.

Nearly half of all people with type 2 diabetes will develop chronic kidney disease, causing a high risk of kidney failure and cardiovascular disease, and impacting their quality and length of life, even with the current best available care.

Inhibitors of sodium–glucose cotransporter 2 (SGLT2) were developed to lower blood glucose levels in patients with type 2 diabetes. In several trials designed to meet regulatory requirements for cardiovascular safety, investigators found reductions in cardiovascular events with SGLT2 inhibitors. Secondary and exploratory analyses of these trials suggested that SGLT2 inhibition might improve renal outcomes; however, some uncertainty persisted, since relatively few patients reached end-stage kidney disease and the trial patients were at low risk for kidney failure. So, the CREDENCE Trial was designed to assess the effects of the SGLT2 inhibitor canagliflozin on renal outcomes in patients with type 2 diabetes and albuminuric chronic kidney disease.

The trial enrolled approximately 4,400 patients with type 2 diabetes mellitus and an eGFR of at least 30 mL/min/1.73 m2 to less than 90 mL/min/1.73 m2, and albuminuria (urinary albumin: creatinine ratio >300 mg/g to 5,000 mg/g), Janssen said. All patients were required to be on the maximum labeled or tolerated dose of an angiotensin-converting enzyme inhibitor or angiotensin 2 receptor blocker for more than 4 weeks prior to randomization.

Currently, Invokana is contraindicated for patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), ESRD or patients on dialysis. In addition, Invokana is not recommended when eGFR is persistently less than 45 mL/min/1.73 m2.

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.

What makes the results of this study unique is that, those who took Invokana had a 30% lower risk of developing kidney failure, a 30% lower risk of dying from kidney failure or heart disease, a 20% lower risk of major heart events such as heart attack, stroke, or heart-related death, and a 39% lower risk of hospitalization for heart failure, the researchers reported.  There was no higher risk of major side effects among those who took Invokana, according to the study

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.

Study coauthor Kenneth Mahaffey, MD, a cardiologist from Stanford University in Palo Alto, California, stated that cardiologists are “still trying to understand the benefit of the SGLT2 inhibitors on outcomes in the cardiology of heart failure…. We are trying to understand the mechanism by which canagliflozin in particular and SGLT inhibitors as a class in general improve heart failure. There are a lot of hypotheses around that but no definitive understandings yet.”

For patients, you have 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.

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.

Practice Pearls

The results of the study showed:

  • A 30% lower risk of developing kidney failure.
  • A 30% lower risk of dying from kidney failure or heart disease
  • A 20% lower risk of major heart events such as heart attack, stroke, or heart-related death, and a 39% lower risk of hospitalization for heart failure

The findings were published April 15 in the New England Journal of Medicine.

Exclusive Commentary: Dr. George L. Bakris

To truly understand the importance of the CREDENCE trial we asked Dr. George L. Bakris, our advisory board member, to explain the importance of this groundbreaking study.

CREDENCE is the first positive renal outcome trial in almost 20 years showing a robust, statistically significant 30% reduction in the primary outcome ESKD, doubling of creatinine, or renal/cardiovascular death. We now have a class of medications, i.e. the SGLT2 inhibitors, that slows progression of kidney disease event at glomerular filtration rates that do NOT lower glucose.

Additionally, canagliflozin reduced the risk of ESKD alone by 32% as well as renal and cardiovascular death, and reduced major cardiovascular events. Moreover, it reduced the risk of the renal outcomes in a broad range of patient subgroups, including in patients with eGFR  well below 45 ml/min. In CREDENCE, we enrolled participants with a screening eGFR down to 30 ml/min and showed renal benefit down to this level. Of note, the protocol instructed continued treatment until the initiation dialysis or renal transplantation; those people have much lower eGFR, generally <15 ml/min.

Also, there was no difference in amputation risk between canagliflozin and placebo. This was despite a much higher risk of amputation in the CREDENCE population, i.e. 5% of patients had a history of amputation at baseline. When compared to the CANVAS trial, there were 133 patients in CREDENCE that had an amputation post-randomization compared with 187 patients in the CANVAS Program. Whether the increased risk of lower limb amputation in the CANVAS Program was due to differing trial populations or protocols, or to chance remains unclear. Additionally, in CREDENCE, there was no difference in the risk of fracture between canagliflozin and placebo and all fractures were adjudicate.

George L. Bakris (Advisory Board Member-Diabetes in Control), is a member of the National Kidney Foundation’s Board of Directors. He is Professor of Medicine and Director of the American Society of Hypertension’s Comprehensive Hypertension Center at the University of Chicago Medicine. Dr. Bakris has published more than 700 articles and book chapters in the areas of kidney disease, hypertension, and progression of nephropathy.