CREDENCE Shifts Our Thinking About SGLT2 Inhibitors

Today I'm going to discuss the CREDENCE trial: "Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy."^[1] This is a very important trial because it starts shifting us to think about SGLT2 inhibitors as drugs that work to preserve renal function independently of things like glucose lowering or weight reduction. It's also a new way to start thinking about how to treat patients with diabetes and nephropathy.

This was a randomized controlled trial of 4401 patients who had type 2 diabetes and albuminuric chronic kidney disease (CKD). Their albumin-to-creatinine ratios ranged from 300 to 5000, so they were quite albuminuric. All of these individuals were on renin-angiotensin system blockade coming into the trial.

The study participants were randomized to either canagliflozin 100 mg per day or placebo. This is a lower dose of canagliflozin, and it wasn't uptitrated but kept at 100 mg throughout the trial.

To enter the trial, patients had to have an estimated glomerular filtration rate (eGFR) between 30 and 90 mL/min/1.73 m², but the trial was designed to include 60% of the patients having an eGFR of 30-60. As I mentioned, they all had a significantly elevated albumin-to-creatinine ratio.

The primary outcome was a composite of end-stage renal disease (which was defined as dialysis, transplantation, or a sustained eGFR of less than 15) or a doubling of serum creatinine or death from renal or cardiovascular disease causes. So there were renal outcomes and cardiovascular or renal death.

Positive Results

The trial was stopped after a planned interim analysis because it was positive. They showed benefit of canagliflozin, so they stopped it at 2.6 years. It's not a very long trial, but they demonstrated a 34% risk reduction in the canagliflozin group compared with those on placebo.

You should read the paper to look at all of the different subanalyses, but the bottom line is that the canagliflozin group did better in basically all of the renal outcomes and in terms of hospitalizations for congestive heart failure.

One third of trial participants were women and two thirds were men. The initial A1c was 8.3%, the average eGFR was 56 mL/min/1.73 m², and blood pressure was 140/78 mm Hg.

When they started the trial, patients on canagliflozin exhibited what we're used to seeing, which is a slight worsening of eGFR when patients are started on an SGLT2 inhibitor. But then it improved. The patients in the placebo group had a worsening in their renal function.

Because this was a low dose of canagliflozin, there was not much difference in terms of glucose levels. There was some reduction in the patients with canagliflozin but not much change in weight or blood pressure. These parameters were not as affected as they were in other trials, where higher doses of SGLT2 inhibitors were used in patients with more normal renal function.

What About the Side Effects?

Now, what was quite significant, at least in terms of side effects, was that most of them were as expected. However, unlike the CANVAS trial,^[2] there was no increase in lower-extremity amputation or in the proportion of patients who developed fractures.

I'm not sure why there was an increase in amputation in CANVAS but not in CREDENCE. The two trials had different patient populations. In CREDENCE, they were actually a somewhat higher-risk population initially. Partway through the trial, however, the researchers changed who they enrolled because they were concerned about the finding of increased amputations reported in the CANVAS trial. But in the CREDENCE trial, with these higher-risk patients with known renal dysfunction, there was not an increase in amputation or fracture.

This trial is important because it shows us another aspect of SGLT2 inhibitors. It's not that these drugs only lower glucose, or only lower blood pressure, and have other cardiovascular benefits. They also reduce the risk of developing end-stage renal disease and other negative renal outcomes in patients with significant CKD and albuminuria—independent of lowering glucose.

In the future, we may see a reduction in the eGFR cutpoint for the use of SGLT2 inhibitors. Currently, they're not recommended for use in patients with an eGFR of less than 45. However, in this trial, the patients with the lowest eGFRs experienced the most benefit.

I suggest that we consider this when we treat our patients with type 2 diabetes and CKD, while being careful to follow the guidelines of the FDA and various societies. I think that we'll see more and more discussion about the use of SGLT2 inhibitors in patients with CKD.

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.