Canagliflozin cuts ESRD risk by nearly one third in type 2 diabetics


By Gene Emery

(Reuters Health) - The type 2 diabetes drug canagliflozin lowers the combined risk of end-stage kidney disease and death from kidney or cardiovascular problems by 30% compared to placebo, according to test of 4,401 patients that was terminated prematurely because the benefits were so dramatic.

"This is the biggest protection against kidney failure we've ever seen from any drug," chief author Vlado Perkovic told Reuters Health in a telephone interview.

"When it was approved, it was done based on its glucose-lowering effects. We now know the effects go well beyond glucose lowering, with a one-third reduction in kidney failure, a 40% reduction in heart failure and, for cardiovascular events like myocardial infarction and stroke, we found a 20% reduction," he said.

The results were released April 14 at the International Society of Nephrology's World Congress of Nephrology in Melbourne, Australia, and online by the New England Journal of Medicine.

The study, known as CREDENCE, was financed by Janssen Research and Development, a subsidiary of New Jersey-based Johnson & Johnson, which sells the oral sodium-glucose cotransporter 2 inhibitor under the brand name Invokana. It works by removing blood sugar through the urine. It also lowers pressure within the kidney, which may be responsible for its protective renal effects.

"With diabetes, this means it should become the standard of care," said Dr. Perkovic, executive director of the George Institute for Global Health at the University of New South Wales in Sydney, Australia. In a disclosure form he reported receiving financial support from Janssen and other pharmaceutical companies.

He noted that other drugs in the same class may prove to have similar renal benefits and be useful to treat kidney disease in non-diabetics. Those studies are underway.

"We should find that out over the next few years," said Dr. Perkovic. "These result offer to transform the management of kidney disease in diabetics now, and perhaps in the future, in other patients."

Only a small percentage of type diabetics currently have kidney problems. But people who develop diabetes have a 40% risk of developing renal disease at some point in their lives.

The diabetics in the new study all had albuminuric chronic kidney disease. They were treated with renin-angiotensin-aldosterone blockade and baseline diabetic therapy and were followed for a median of 2.62 years before the test was halted prematurely because the benefit was so clear.

In most countries, canagliflozin is not approved for people with substantially reduced kidney function, although such drugs are widely used to lower the cardiovascular risk.

Invokana carries a black box warning advising doctors that it can increase the risk of amputation.

"Another important finding is we didn't find an increased risk of amputation," said Dr. Perkovic. "In this population treated with this drug with this protocol, we're comfortable there isn't a major increased risk of amputation."

Invokana typically costs more than $500 per month for the daily 100 milligram dose used in the study, according to the website

A formal cost-benefit analysis of the drug has not been done, the researcher said. But "just one person requiring kidney failure treatment in the United States means treatment costing well over $100,000 a year. So you don't need to prevent too many people from reaching kidney failure to be saving very substantial amounts of money."

In 2017, Dr. Perkovic and others reported that the CANVAS and CANVAS-R studies of 10,142 type 2 diabetics with a high risk of cardiovascular disease saw the combined odds of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke drop by 14% with canagliflozin.

They also saw a reduction in renal outcomes but reported that "on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant." That prompted the CREDENCE study.

But the team also found that the incidence of amputation doubled with Invokana use, rising to 6.3 per 1000 patient-years versus 3.4 per 1000 patient-years with placebo. Most amputations involved toes or metatarsals.


N Engl J Med 2019

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