A (4:11)

So clearly important. And then in addition to its effect on glucose, are there other effects on other endpoints?

B (4:22)

But it basically affects all organ systems. We talked about some of the skin changes, some of the morphologic changes related to fat deposition, but it's associated with neuropsychiatric consequences. Depression, anxiety, irritability, tremulousness. It can cause sort of heat disturbance. People often complain of excessive sweating, skin changes, bone fractures, hypertension, dyslipidemia, early cardiovascular disease, you name it. And hypercortisolism caused it.

A (4:58)

Yeah. And again, in thinking about it, it's kind of scary to think that has been around for a while and we haven't even thought about it much except in the circumstance of someone with classic Cushing's syndrome.

B (5:13)

Of the 30 or so investigators in this study, of which I was just one, many of us very experienced clinical trialists who've been involved in diabetes research for a long time, none of us thought that what we found was remotely possible. And we're frankly embarrassed that we've been practicing for 30 years and have probably let hundreds of people with hypercortisolism slip by.

A (5:41)

Yeah. And that's interesting. And that brings us to the Catalyst trial, which just came out this past month in Diabetes Care. You were first author. How did you think to look at it? What's the background that led to the question?

B (5:55)

It's very interesting. A gentleman named Dan Einhorn, who was a practicing endocrinologist in San Diego for 30 plus years, as his last act, took a job with a company called Corcept that has a drug called mifepristone, as well as developing new agents, some of them currently under review at the fda, that block the action of cortisol that are used for the Treatment of hypercortisolism. And this one, mifepristone in particular, marketed in the trade name Quarlym, is specifically indicated for the management of hyperglycemia in the setting of hypercortisolism. But it had always been studied by finding people with Cushing's syndrome, the, the sort of more severe manifestation with the dorsal cervical fat pad and the central obesity, et cetera, et ceter, etc. So that was the studies that had been done in the past. You find these people with pretty flagrant hypercortisolism and there the drug has been used to control the hyposimin, specifically to reduce hyperglycemia. But he talked to a number of us about was there a possibility of doing a broader study where we started from people with poorly controlled diabetes to see what proportion of them had hypercortisolism. And there were about seven of us in the beginning that he talked to and all of us said yeah, love to do that study. I think the person who guessed the highest number thought it might be 2 or 3% of people. But there were some prior studies, much smaller, different definitions of what hypercortisolism were done in foreign countries, published in more obscure journals that most of us frankly weren't aware of, that suggested that the, the prevalence of hypercortisolism in difficult to control diabetes might be between 10 and 25%. So there was prior art that at some level was available.

A (8:02)

So his hypothesis was if we look for it, we will likely find a higher proportion of people in those with uncontrolled diabetes than we thought was there. Before we go on and talk about it, you mentioned mifera mifepristine and is that the same medicine that many of us in primary care are more familiar with in, in a different area?

B (8:25)

It is exactly the same. If marketed for pregnancy termination. It, it is a cortisol receptor antagonist and the primary effect is to reduce cortisol action. But it has a profound effect on, on sex steroid activity as well. And that's actually how it interferes with, with pregnancy.

A (8:48)

Interesting. Okay. And because I didn't want our listeners to be confused that there were different medicines that were sound alike, it's the.

B (8:56)

Same chemical entity and there are different manufacturers that have produced it in different ways and marketed in different ways. And Korlym is the medication indicated for the treatment of hypercortisolism and that comes in 300 milligram tablets that can't be crushed or chewed.

A (9:14)

That's very helpful. And so the hypothesis was that there would be a Higher than expected prevalence of hypercortisilism. Can you tell us more about methodology, how you selected patients, where the patients came from? Yeah.

B (9:33)

So the major things for the selection criteria was difficult to control type 2 diabetes, so they had to have type 2 diabetes, not type 1 diabetes or secondary causes of diabetes. The A1C had to be between 7.5 and 11%. So they didn't have to be horribly controlled, but they had to have some elevation in glucose despite a good faith effort on the part of their providers and the patients to get their diabetes control. So they had to be on three drugs for diabetes or they could be on two drugs for diabetes if one was insulin. Or they could be on two drugs for diabetes if they also had at least one microvascular or macrovascular complication. So kidney disease or a prior heart attack or something like that. Or they could be on two drugs for diabetes and two drugs for hypertension. So that was how we defined difficult to control diabetes. You could pick a lot of other definitions, but the one thing I would say is that the clinics where these people were found were generally pretty bright eyed, bushy tailed, diabetes oriented practices that are used to doing clinical trials. So they're early adopters of novel therapies. These were high end places. In the real world you may have a lower prevalence because people aren't poorly controlled on pretty aggressive care.

A (11:08)

Yeah. Although it's interesting, those are broad criteria. I'm just thinking of patients I take care of. There's a lot of people that meet that A1C above seven and a half on meds.

B (11:20)

And the estimate is it's probably pushing 10% or so of the diabetes population would be on that many meds with an A1C of, of 7.5 or greater. It may be even 25% of the diabetes population. So we're talking millions of people.

A (11:38)

Yeah. When I'm listening to that. And even just two, two diabetes medicine, two blood pressure medicines, would say most of my patients might even be on.

B (11:48)

That, but not all of them would have any one. So the average A1C in America is about 7.5. So already 50% in America won't qualify. And but when you look at people on insulin, it's already starting to be a substantial proportion that would be on insulin plus one drug.

A (12:08)

Yeah.

B (12:08)

And have an A1C over.

A (12:10)

Interesting. And then tell us about the results.

B (12:15)

So the quick and so the test we did something called an overnight dexamethasone suppression test and that involves taking a 1mg tablet of Dexamethasone or Decadron at 11pm and then coming in for a blood draw at 8am the next day. But certainly we like to do it before 9am and if that result was greater than 1.8, that was a, quote, positive test. For the dexamethasone suppression test, we tried to exclude people who might have false positive results. So people with sleep disorders or shift workers or people on estrogen containing medications, people with morbid obesity, severe depression, severe anxiety, severe sleep apnea, those sort of things. But people that were generally civilians with uncontrolled diabetes were the catchment audience. And what we found was that 25 or 24% of them actually flunked this dexamethasone suppression test and thus, by definition, according to guidelines, have, quote, hypercortisolism. Now that this was followed up with some additional studies. So the 24% had hypercortisolism. Most of them underwent an adrenal CT scan, a regular old abdominal CT scan. And about a third of them had an abnormality on their adrenal. On their abdominal CT, specifically in the adrenal, 23% of them had a solitary nodule. That's a pretty common condition that we know about is people with an adrenal adenoma that secretes cortisol. And those patients potentially could be surgically cured. The other 2/3 did not have any adrenal abnormalities.

A (14:19)

And then what is the currently, what do you do with those other 2/3 who have hypercortisolism identified? They don't have an adrenal identified. Now what?

B (14:35)

Yeah, that's a great question. And the truth of the matter is, in most practices, if people don't have a lot of manifestations of hypercortisolism or they don't have an additional test that's abnormal. So the other tests are late night salivary cortisol or 24 hour urinary free cortisol. Those tests are more specific, but they're less sensitive. They're extremely valuable for finding people with pituitary tumors that have much higher levels of cortisol. But I would say that many endocrinologists with isolated what's often called mild adrenal suspected hypercortisolism, many endocrinologists will not in fact, treat those people and kind of watch them. But that's the part two of this study that will be presented at the American Diabetes Association. We offered all the patients that had the 24% that had hypercortisolism the opportunity to be treated with mifepristone. The Korlym formulation or mashed placebo for 24 weeks to look to see what happened with hemoglobin A1C. Those results aren't available yet. The top line results were disclosed in December at the at the World Congress on Insulin Resistance and the top line result is that there was about a 1.4% reduction in hemoglobin A1C with mifepristone and with placebo there was none or essentially none. So the top line result is quite positive. And I do think that many endocrinologists will be rethinking their algorithms for care. It's a lot more straightforward. If someone has adrenal adenoma, it's an easy, easy, generally laparoscopic procedure to rewrite them. Mifepristone is a challenging drug to use. There are many contraindications, there are trouble that can develop related to hypokalemia, hypertension, symptoms of adrenal insufficiency. So generally we would recommend if people start screening for hypercortisolism in their practice in people with difficult to control diabetes. If they do detect it, probably the safest thing to do is refer the patients to an endocrinologist or other practitioner who's experienced in using these drugs that interfere with cortisol metabolism or cortisol action.

A (17:14)

That makes sense. And we'll talk more about treatments specifically in a future episode and we'll look forward to hearing the detailed results when they come out really in the near future, end of June. Let me make sure I'm understanding the pathophysiology correctly. So this is something that's not coming from an adenom, it's not coming from the pituitary being overactive. That leaves the adrenal glands that are hyperactive. Is that what is going on?

B (17:42)

Yeah, and we don't understand that, or at least I don't. But there is another syndrome that's very similar that we have been talking about for 50 years and that is hyperaldosteronism. So aldosterone is another steroid hormone like cortisol that's made in the adrenal gland like cortisol and is associated for quote, resistant hypertension or difficult to control hypertension in about a quarter of the cases like we found for cortisol in difficult to control diabetes. And about a third of those patients have a solitary adenoma that can be surgically resected. So it's remarkably parallel situation. The only thing I hope is we've known about these aldosterone producing hyperaldosteronism. We've known about it for more than 50 years and still we're not doing a great job of screening for hyperaldosteronism and treating people with hyperaldosteronism effectively.

A (18:44)

No, we not.

B (18:46)

We need to do a better job on both.

A (18:48)

Yeah. And that's an area where we've had a medicine, spironolactone, that is easy to use. Been around forever and we still don't look at it. Although my understanding is there's a couple of medicines now in development that are also going to be targeting hyperaldosteronism and we'll be learning a lot more about that area as well. It's amazing how these two areas seem to be moving ahead in parallel. We're almost out of time. Any other things that you think would be important for our listeners to know at this point?

B (19:26)

Yeah, I think I'd like to just tell you a quick story. So there was a patient who had an A1C of 7.3 who didn't qualify for the study because her A1C was 7.3. But I decided to work her up in the same way. So she was someone that I had known 20 years ago, delightful, charming, brilliant woman. She moved to Spain and worked there for 20 years, came back to the United States and reestablished care with me and said she was just a wreck and that she couldn't think, she couldn't sleep, that she was flush all the time and sweaty. And her blood, she'd never had diabetes before and now she had hyperglycemia and was even taking insulin. And it's like things had really gone amok in the last five or six years. And so we screened her for hypercortisolism. She had it, and we treated her with mifepristone. And she's done very well. But the amazing thing about it was she was just so relieved to find out what her problem was. And the benefit of the therapy went far beyond the glucose management. It was actually the sort of neuropsychiatric part of hypercortisolism that was really messing her up the worst. So if you find these cases of hypercortisolism, it's a real opportunity to make a huge difference in. In people's lives. And the screening test is pretty easy to do. The treatment is challenging, but there are people around who know how to do that very well.

A (20:56)

This is so helpful. It just occurs to me we talked about a lot. Can you go over just briefly as we're about to close? In the group, we identify who have uncontrolled diabetes. What is the approach again to screen.

B (21:13)

The 1mg overnight dexamethasone suppression test. So 1mg of dexamethasone at 11pm a serum sample for cortisol at 8am generally with a reflex that if it's greater than 1.8 that you would then also measure dexamethasone levels on that sample. And the reason is just to make sure the patient swallowed the tablet and actually absorbed the medication. There are occasional people who who failed at dexamethasone part.

A (21:43)

This is so helpful. Dr. John Buesse, thanks so much for joining us. It's been a pleasure and most of all, of course thanks to our listeners. Thanks for joining us in this first of a multi part series on hypercortisilism. This is an emerging and critically important concept as we've just heard about in the diagnosis and management of people with uncontrolled diabetes. This special series of diabetes core update is sponsored by corcept. We thank you for listening the American diabetes association. I'm Dr. Neal Skolnick. Till next time, stay safe and keep learning.