Meg Jardine, MBBS: Results and Impact of CREDENCE Results

A new subgroup analysis from the CREDENCE study found that canagliflozin (Invokana) use significantly reduced the risk of major cardiovascular events and kidney failure in patients with type 2 diabetes and chronic kidney disease (CKD).

Results of the analysis, which were recently added to the American Diabetes Association Standards of Medical Care in Diabetes, were presented at the American Diabetes Association (ADA) 2019 Scientific Session in San Francisco, CA.

In this subgroup analysis, investigators examined cardiovascular and renal outcomes in the primary prevention group (n=2,181; 49.6%) and secondary prevention group (n=2,220; 50.4%). Investigators found that both CV and renal results observed in the study population were consistent across primary and secondary prevention groups. I

Investigators noted that canagliflozin reduced the risk of end-stage renal disease by 31% and 33% in the primary and secondary groups, respectively. Use of canagliflozin reduced the risk of composite CV death, heart attack, and stroke by 32% in the primary prevention group and 15% in the secondary prevention group.

Study investigator Meg Jardine, MBBS, associate professor of medicine at University of New South Wales, sat down with MD Magazine® at ADA 2019 to discuss the results of the subgroup analyses and the impact of canagliflozin on primary care.

MD Mag: What were the results of the subgroup analysis of the CREDENCE study?

Jardine: What we were trying to do is find a way to prevent the progression of kidney disease. A lot of people with diabetes do progress on to get kidney disease, 30 to 40%, and it's now become the most common reason why people end up on dialysis and around the world we are overflowing in every dialysis unit. So, we were trying to put a step on that. There was some promising data from SGLT2s. From the early studies, we knew they reduce the albumin in the urine. Now, that's a good marker for kidney risk but in itself it's not an endpoint, it's not what patients care about.

So, we took that data and, with that, designed a study that was specifically designed to test whether these agents would help protect the kidney and so to do that we needed people at high risk of kidney disease — and so we specifically recruited people who already had evidence of kidney damage and we recruited from around the world. The other thing was we really wanted to know that this was an addition to current care not a replacement.

So, we mandated that everyone in the study was already on renin-angiotensin blockade. Now, they're agents that we found two decades ago and they do slow the progression of kidney disease, but there's still a lot left over — a lot of people still progress and so we mandated that everyone would be on those agents and then we tested whether SGLT2, in addition, would help protect the kidney. So, that's how we set the study up.

We started in 2014 before any of the cardiovascular outcome trials had reported. So, at that point we didn't know what the benefits would be for cardiovascular protection. We recruited these patients and followed them and then, after the cardiovascular outcomes studies showed benefit for the heart, we were coming up to our interim analysis and after that the data monitoring safety committee advised that we stopped the study for efficacy — because the agent worked. So then, we pulled everyone back took them off of study treatment and closed out the study and analyzed the results — and what we saw was that canagliflozin reduces progression of kidney disease by about 30 to 34% across the board. The exciting thing is that, in a post-hoc analysis, we saw that it reduced the need for dialysis and transplantation or renal death. Now, this is the first study ever, that I know of, that's been able to show that impact on that outcome.

The cardiovascular protection was there for people with kidney disease as well. This is an agent that has to be filtered by the kidney to get to its site of action. So, there was a plausibility that maybe they wouldn't work in people with reduced kidney impairment — we didn't find that. It works just as well in people with reduced kidney function and that's important because they have more cardiovascular events than other people. So, it's good for the kidney, good for the heart, and no real safety concerns.