CATALYST Trial Shows Hypercortisolism in 24% of Poorly Controlled Diabetes Patients, Opening New Treatment Avenues

The CATALYST trial has revealed a significant finding in diabetes management, showing that excess cortisol contributes to insulin resistance, liver glucose production, and impaired beta cell function, making diabetes control difficult. Ralph A DeFronzo, MD, professor of medicine at UT Health San Antonio, suggests that addressing hypercortisolism, either through surgical removal of adrenal adenomas or medication like mifepristone (Korlym; Corcept Therapeutics), a glucocorticoid receptor antagonist, could potentially improve glucose tolerance and blood pressure control in these patients. Ongoing research, including the second part of the CATALYST study and the GRAY study with relacorilant (Corcept Therapeutics), aims to further explore the effectiveness of these treatments while addressing potential adverse events.

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Q: What were the key findings from the prevalence phase of the CATALYST trial?

Ralph DeFronzo: The CATALYST trial is actually, to me, the most important, most exciting of the presentations here at the American Diabetes Association. So to kind of put this into perspective, in the United States, we have about 40 million people with type 2 diabetes. Of those 40 million people, 25% of them have a hemoglobin A1c see above eight, which is really bad control. So that's 10 million people. Of those 10 million people. Half of them are on multiple oral agents plus/minus insulin. So that takes us down to about 5 million. What the CATALYST has shown is that 24% of that group of people actually have hypercortisolism as a pathophysiologic abnormality that's causing the diabetes. We're looking at about 1.2-1.3 million people who are poorly controlled on multiple drugs for the treatment of their diabetes. We've been looking at them saying, "Mrs. Hernandez, you're not taking your medicines right?" "No, I take my medicines everyday." "You sure?", and there's a reason why they've been taking their medicines and it not well controlled. There are a large number of these people, and it's because they have adrenal hypersecretion of cortisol. We can talk a little bit about what are the bad actors that cortisol does, and so this is a huge population. We actually can do something because we have some potential therapies that could help these people.

Q: The CATALYST trial is evaluating the use of mifepristone for treating hypercortisolism in this population. Can you explain how this medication works and the potential benefits for patients with diabetes?

Ralph DeFronzo: So now that we've identified this large group of people who are poorly controlled, on multiple medications, and it looks like cortisol or excess cortisol is playing a role here. First question is, why is cortisol bad? So if you go through the literature at it, there actually been very, very good studies that have been carried out that cortisol causes insulin resistance and muscle. Of course, this is very bad for diabetic patients, because part of the genetic problem is insulin resistance. Cortisol causes insulin resistance in the liver, in too much glucose production by your liver is an a problem, and cortisol also interferes with beta cell function, the ability to secrete insulin. So these are 3 huge defects that are present in people with diabetes, and cortisol, independent of the genetic contribution, aggravates these defects. So we have a good understanding of why your glucose tolerance should be poor, and why it's so difficult to control these people.

So now, if we can, and we have, established in these people hypercortisolism as an important player, can we do anything about it? Well, most importantly, you need to do an imaging study of the abdomen and look at the adrenal gland. So if there is an adenoma, that is hypersecreting cortisol, of course, the way you want to go to take care of this is to remove the adenoma, and we found in the CATALYST study, that about one quarter of the people with hypercortisolism have an adenoma, that's seems to be hyperfunctioning. The other 3 quarters have just adrenal hyperplasia, their adrenals are hypersecreting. So how could you attack this? Well, one way would be, you could add more diabetes medicines, you could add more blood pressure medicines, you can add more lipid lower medications, but wouldn't it be easier if we add something that really got rid of the hypercortisolism.

So the second part of the catalyst is take these people who have been identified, who have hypercortisolism, and the treatment with a drug that is already approved, again very important, already approved by the Food and Drug Administration for treating hyperglycemia associated with Cushing disease, and that's [mifepristone (Korlym; Corcept Therapeutics)] and [mifepristone] is a glucocorticoid receptor antagonists. So in high cortisol levels, the cortisol has to interact with its receptor do its all these bad things we talked about. So we're going to block the ability of cortisol to interact with the receptor, and in doing so, we can ameliorate the antagonistic effects of cortisol. Now, as I said, part 2 of the CATALYST study is to look and see how effective is Korlym, mifepristone. I like to say Korlym because it's a lot easier to pronounce. So part 2 is ongoing. So we'll have to see now that we've identified this defect hypercortisolism, can locking the glucocorticoid receptor improve your glucose tolerance? We also know that this high incidence of hypertension. Many of these people are on 2-3 anti-hypertensive drugs, can we get their blood pressure controlled now with fewer medications? There are some side effects that occur with [mifepristone]. One is important is that [mifepristone] is also interferes [and blocks] the progesterone receptor. So in females, it can cause endometrial thickening and vaginal bleeding. So that is a potential sort of downside. As I said, that doesn't happen in most women, but it can be a problem in some women. There is in development, a sort of stepchild of colon. It's a relacorilant [(Corcept Therapeutics)], which is highly specific for the glucocorticoid receptor that does not block the progesterone receptor. So again, these are trials that are going on. This is with relacorilant is the GRAY study. The results of that had just been announced. They look pretty impressive. So there may be even another sort of generation which we'll get around this problem with intermedio endometrial thickening that we see in hand ladies in vaginal bleeding.