25-07-2025
CATALYST: A Novel Approach to Treating Diabetes
This transcript has been edited for clarity.
Akshay B. Jain, MD:Welcome, from the ADA 85th Annual Sessions in Chicago. I'm endocrinologist Akshay Jain, from University of British Columbia in Vancouver. With us today is Dr Vivian Fonseca, professor of medicine at Tulane. Welcome, Dr Fonseca.
Vivian Fonseca, MD: Hi there. Thank you for asking me to join you.
Jain: Dr Fonseca, you're presenting the results of the CATALYST study. Tell us a little bit more about the study.
Fonseca: The CATALYST study is a very novel approach to treating diabetes. We took people with uncontrolled diabetes despite taking many medications, including insulin, GLP-1 receptor agonists, dual agonists, SGLT2 inhibitors, and metformin. They also had many medications for hypertension.
We asked the question as to whether cortisol was elevated and nonsuppressed in this population. We did a very simple overnight, 1-mg dexamethasone suppression test in a little over 1000 people. We were very surprised to find that 24% of them had a cortisol that did not fully suppress. They met the criteria for hypercortisolism as recommended by the European and the US endocrine societies today, at more than 1.8.
Jain: That's a staggering number.
Fonseca: That is a staggering number. It was quite a surprise to me and my colleagues.
Jain: Once you identify these individuals, what's the next step for them?
Fonseca: For the next steps, there is a range of things to do. If you identify hypercortisolism, you want to see whether there's an adrenal tumor or something like that. We did CT scans of the abdomen in that population, and one third of them had some abnormality. Not all of them had a tumor that was surgically resectable. Some had bilateral disease, and some just had thickening, which you would just wait and watch.
Here, you have a population with hypercortisolemia at a higher rate than expected, with or without an abnormality on imaging. Some of them were surgically treatable, but for this particular study, we chose to take that group of people and treat them medically.
There is a wide variety of medicines available for treating elevated cortisol, which have mainly been tested in Cushing syndrome. Mifepristone is a nonspecific steroid hormone receptor blocker that's known to block cortisol action and is approved for treating hyperglycemia in people with hypercortisolism.
It was okay to actually test it in this population, so we did a randomized trial, randomizing those people with hypercortisolemia in a 2:1 ratio to mifepristone or placebo and following them for 24 weeks.
Jain: What were the results?
Fonseca: Again, another very surprising result. The A1c fell by 1.47%, almost 1.5% from the baseline of 8.5%. That is a very, very robust response. What I like about it is that this is not giving it to everybody with diabetes. You're using what I would call precision medicine. You find an abnormality, you treat that abnormality, and you get a very good result.
There were a few other spinoff things. The weight fell significantly. The waist circumference declined significantly. There were also side effects that are consistent with the mifepristone side effect profile. The potassium fell. You get hypokalemia because the cortisol levels don't fall. They rise because you're blocking the receptor and you stimulate the mineralocorticoid receptor. The blood pressure went up a little bit, but it was still mostly at goal in most of the patients. You can treat that hypokalemia, so I won't go into that.
We also had what we call glucocorticoid withdrawal syndrome. People on steroids who just stop, when you treat Cushing syndrome, or any of the medications for hypercortisolemia will give you a feeling of withdrawal of the steroid that you're used to. Those are to be expected.
The side effect profile shows expected side effects in many people. But still, we can get around it and get a very good result on diabetes treatment.
Jain: This is fascinating. We are unmasking hypercortisolemia as an underlying reason for insulin resistance.
Fonseca: I wouldn't say unmasking. We are recognizing it in a novel way for the first time, and are able to treat people who we were throwing many drugs at [the problem] — wasting those drugs, if you ask me — when we were not treating the fundamental problem.
Jain: When should clinicians think about this as an underlying issue?
Fonseca: The way I translate every clinical trial, you do it for what the trial was done for. You have people who are uncontrolled, or you may say difficult to control, uncontrolled or on many medications. Often, you find comorbidities. They have had this problem for a while. Many of them have complications of diabetes, and a significant number had heart disease. You treat them with a very specific treatment, and you get a good result.
Now, in some people the treatment may be surgical. You could use this drug or other drugs, and there are some new ones. This has become an important target for therapy, so we will see this approach.
That also leaves the question as to [the fact that] there were 24% with this abnormality. What's happening in the other 75%? Maybe there are other abnormalities that we haven't recognized. I think you and I still have a large amount of work to do.
Jain: We do indeed. Your target population was individuals with type 2 diabetes.
Fonseca: Type 2 diabetes that was not controlled.
Jain: Do you think this could be an underlying problem in type 1 diabetes as well?
Fonseca: Hypercortisolism can occur in anybody. If you're finding many challenges in type 1 diabetes, you could do it. Obviously, people who are not doing well in their general health without diabetes could have hypercortisolism. This is not what we recognize as the textbook Cushing syndrome.
These people did not have those features. The obesity was mild and low central. They had little features, but not the full-blown textbook description, which comes after many years of having very severe hypercortisolism.
Jain: For those individuals who, say, are on birth control, would you then recommend doing a urine test?
Fonseca: That's a very important question. We excluded those people from the study because you get a false elevation due to raising cortisol-binding globulin with estrogen. We did it in people who had a probability based on some anecdotal things and studies in Europe that were done before, and also excluding people who would have a false positive or a false negative, such as [those with] estrogen use. We don't know how to really identify those people well, without stopping the therapy.
Jain: Any final key pearls of wisdom from this trial?
Fonseca: I think, like anything that's new, it's exciting. Many of these people were very glad that we found an abnormality. I mean, it sounds bad, but they were blaming themselves, they were being labeled as noncompliant, and they were very frustrated with this.
Jain: And the medication burden that they were facing.
Fonseca: We actually withdrew a number of medications on several people.
Jain: Great. Those are the results of the CATALYST trial. Thank you so much, Dr Fonseca, for joining.
Fonseca: Thank you. It's a pleasure to be here.
