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Diabetes Core Update
Special Edition: What's Next—Cortisol, Metabolism & Future Innovation, Part 4
00:27:06
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- [00:03]
A
Welcome to this special edition of Diabetes Core Update, where we will discuss hypercortisolism and its effect on both diabetes and on hypertension. If you missed our podcast series last year, you may be asking yourself, why are we discussing hypercortisilism? It is vanishingly rare. Well, if you listen to that series, then you may remember that we discussed the Catalyst study, which showed that it is anything but rare, and that in people with uncontrolled diabetes, the prevalence of hypercortisolism was approximately 24%. And now you're saying, okay, I remember that, but I don't remember you discussing hypertension. What is this with cortisol and hypertension? While science never sleeps, we blink. There's new information. And today we're going to review new evidence that suggests that hypercortisolism may be the hidden culprit in a significant proportion of both difficult to treat diabetes as well as resistant hypertension. I'm your host, Dr. Neal Skolnick, professor of Family and Community Medicine at the Sidney Kimmel Medical College of Thomas Jefferson University University. This special series of Diabetes Core Update is sponsored by Corcept. And joining us again, returning for Today's episode is Dr. John Buesse. Dr. Buse is the Vern S. Cavanis Distinguished professor at the University of North Carolina, Chapel Hill School of Medicine. He has been President for Medicine and Science at the American Diabetes Association. He is a recipient of the ADA Outstanding Achievement in Clinical Diabetes Research Award. He's authored more than 600 publications. He's participated in and led numerous clinical trials. And in fact, if you read the diabetes literature, you see his name so often, you feel like he's a friend. John, welcome back to our podcast.
- [02:16]
B
It's great to be here. And I am indeed a friend.
- [02:20]
A
John, let's start with the basics. Tell us, what is hypercortisilism and how do you tell us how to understand it? Being distinguished from Cushing's syndrome.
- [02:33]
B
Yeah, so hypercortisolism is like the pathophysiology, an increased level of cortisol associated with a variety of features. And in medical school or nursing school or pharmacy school or whichever medical health professional school you go to, we often hear about Cushing's syndrome, which refers to the presence of hypercortisolism along with certain distinctive features. Moon facies, dorsal cervical fat pad, purplish stria across the abdomen, particularly in younger patients, central obesity. But in fact, the majority of people with hypercortisolism, or elevations of cortisol that aren't suppressed in a dexamethasone suppression test. The majority of people with hypercortisolism have very few of those syndromic features.
- [03:33]
A
That's fascinating. And so as such, if we weren't looking for it, it would be hard or impossible to know it's there. Had it you all think to even look for this in and we'll talk in a couple of minutes about the effect of cortisol on glucose and blood pressure. But how did you think to look for it in these two areas?
- [03:58]
B
We know that cortisol affects glucose control. We know that cortisol affects blood pressure levels. And there had been prior studies not done in the United States, and the various studies had different inclusion criteria and different kinds of analyses that were done. But we knew that there was likely more hypercortisolism in people with difficult to control type 2 diabetes as well as in people with resistant hypertension.
- [04:31]
A
That's fascinating. And so like taking those one at a time. How does cortisol affect glucose control? And then we'll take talk about how it affects blood pressure.
- [04:42]
B
All of us have had the experience of putting a patient on a steroid taper and noting hyperglycemia, and that results from a variety of pathophysiologic mechanisms. In fact, Dr. Ralph DeFronzo has an outstanding paper published recently in Diabetes Care that goes through it in detail. But cortisol induces insulin resistance in muscle and fat, and it also decreases insulin secretion. So the two primary defects in diabetes are both negatively impacted by excess cortisol. And beyond there, some of the effects on fat cells result in increased lipolysis. The extra lipid that's being delivered to the liver results in what we call de novo lipogenesis. These elevated levels of lipids can drive hepatic glucose production and they also affect the mechanisms of incretin secretion as well as other features. So it does. It affects negatively virtually every mechanism we know of in diabetes management.
- [05:52]
A
So that makes a lot of sense. So this really fits. And then how about for blood pressure?
- [05:57]
B
Well, it's more complicated with blood pressure, but it has broad effects on the renin aldosterone angiotensin system that we know is so important in. In blood pressure control. There's an increase in angiotensinogen production, the substrate for the creation of angiotensin ii. It increases the levels of the angiotensin II receptor. It has effects to increase vasoconstriction and downregulate vasodilator tone. It, independently of those mechanisms, also increases renal sodium reabsorption and it has direct effects on mineralocorticoid receptor activation. So it has, again, very broad effects to increase blood pressure.
- [06:46]
A
Interesting. When you're saying broad effects like decreasing vasodilation, increasing vasoconstriction, effect on renal sodium excretion, there then are probably other effects as well on the cardiovascular system.
- [07:04]
B
Yeah. So through the mechanisms that we just discussed, hyperglycemia and hypertension, it has effects on cardiovascular events, but there are also a number of indirect mechanisms that contribute to excess cardiovascular risk. Also major contributor to metabolic bone disease. And it has neuropsychiatric effects that are quite broad as well. So people are often more anxious, more depressed, and they just have a lot of neuropsychiatric overlay to them.
- [07:36]
A
So let's go on now and talk about the prevalence of hypercortisilism as a hidden cause of two things. First, difficult to control diabetes and then resistant hypertension. Let's tackle uncontrolled diabetes first. You were the first author, if I remember correctly, in the Catalyst trial that was published about a year ago. Can you tell us about that study?
- [08:02]
B
Yeah. In the Catalyst study, we recruited patients with what we call difficult to control diabetes, which we broadly defined as people with an A1C above 7.5, so higher than the target for the vast majority of people. We excluded people with an A1C above 10.5 because we wanted. Didn't want people that were so uncontrolled that the, the dehydration associated with uncontrolled diabetes could drive hypercortisolism as sort of a false positive kind of result. And we defined sort of the effort to control diabetes as people who had that A1C above 7.5 and less than 10.5, who were on at least three diabetes medications or were on at least two diabetes medications, and they had a complication of diabetes as well, or at least two blood sugar medications as well as at least two antihypertensive medications. Those were the main inclusion criteria. But with that as a definition of uncontrolled diabetes, what we ended up finding is that about 24% of people had hypercortisolism, as defined as a post dexamethasone suppression test result greater than 1.8, and that's the standard cutoff from the Endocrine Society and guidelines. Interestingly, those that were on three or more blood pressure medications in the Catalyst study, again recruited specifically because they had diabetes and not hypertension. One in three, not one in four, one in three had hypercortisolism. And particularly when you Looked at people that were on the most potent glucose lowering drugs like tirzepatide or high dose GLP1 receptor agonists, the incidence was even higher. So the people that were really pounding on their, on their glycemic control and still didn't get to the A1C of less than 7.5, they had a higher incidence of hypercortisolism.
- [10:14]
A
And it's interesting, correct me if I'm wrong here, but while it's hard, at least for us in primary care and general endocrinology to remember all the specific criteria, the general criteria, you know, more than three medicines and still not under control is not that unusual. Is that right?
- [10:35]
B
Yeah. So the estimate is that maybe something on the order of 20% or so of people with diabetes might fit these criteria. And basically the way I've translated the complicated details of the protocol into something easily actionable in clinic is if you've really done a good job as a provider in trying to push the therapeutic process in a patient and they just aren't responding well with the lowering of a 1C that you would expect, you might think to yourself that the patient is non compliant and it's certainly worth talking to them about, can they afford their medications, do they have problems getting their medications filled or taking them? But you know, if the bottom line is that the patient seems to be communicating to you that they're doing the best they can, they certainly are likely to be imperfect in their diabetes management. Hypercortisolism might in fact be the underlying cause, which is a tremendous relief to patients and to providers. When you discover that I'm not being a bad doctor, I'm not being a bad patient. In fact, there's another problem I haven't accounted for.
- [11:51]
A
You know, it's interesting as you say, that it reminds me a little bit of our treatment of obesity and how that's changed. When we talk to people that it's not their fault. People tell us they try their hardest and for years we were saying, well, you could do more. Well, we could always do more. But in fact, it's biology that is driving a lot of what we see, certainly in obesity and now in difficult to control diabetes, that person is being honest that, you know, I'm trying my best and things are not working. And I like the way you just described operationalizing it. It's interesting. The 2026 ACE consensus statement on the management of type 2 diabetes just this year added a new section on classification of diabetes, encouraging us to think, think about secondary causes. Can you Say a few words about this. I'm not sure most of our listeners are aware of that.
- [12:48]
B
Yeah, you know, I think it was a great innovation on the, on the part of ACE to do that. They point out that, in fact, you need to think that they might have type 1 diabetes and they really need insulin in their management. Remember that 5% of new onset diabetes, even in patients in their 40s, 50s, 60s, 70s, even in their 80s, can have type 1 diabetes. And you just need to keep that in mind. If people aren't responding well to type 2 diabetes medications, or also if they present with weight loss, for instance, that's much more common in lada or latent autoimmune diabetes in adults. And then the second thing that they go into is this whole hypercortisolism problem. There's also monogenic forms of diabetes, other pancreatic kind of disease causes, cystic fibrosis or chronic pancreatitis, that sort of thing. So they have a nice listing of half a dozen things that we should keep in mind.
- [13:51]
A
Yeah, it's really helpful to have that called out. Let's now shift to discuss hypercortisalism in resistant hypertension, a concept which is we now have some information about. Can you tell us about the Momentum study? And you were also, I believe, one of the investigators in that study.
- [14:11]
B
Yes, I was. And this data hasn't been published, but it was presented at the American College of Cardiology meeting in March. And the overarching design was similar in that we were looking at resistant hypertension kind of conceptually aligned with difficult to control diabetes. The way we define resistant hypertension is using the standard definitions. That would be people who have a systolic blood pressure greater than 130 on at least three drugs, including a diuretic, each at either maximally tolerated or maximally effective dose, or at any level of blood pressure, people that were on four or more drugs. And in that study, what we discovered is that 27% of people with, quote, resistant hypertension had hypercortisolism as defined by the post Dex cortisol greater than 1.8. And very interestingly, in both the Catalyst study and in Momentum, among the patients with hypercortisolism, 25% of them had adrenal nodules that, at least theoretically, surgical removal of those adrenal nodules would have a good shot at reversing the hypercortisolism and improving glycemic control.
- [15:34]
A
And then similarly, in the people with resistant hypertension, were there certain groups that had a higher prevalence of high Cortisol
- [15:42]
B
levels in general, people on more blood pressure medications had a higher prevalence. I'm sure there'll be additional analyses that come out in the main publication, but that was the major feature.
- [15:56]
A
Okay. You know, it's fascinating to me because we've heard a lot over the last couple of years about hyperaldosteronism and hyperin hypertension, particularly in people with difficult to control or resistant hypertension. ACE earlier this year, last year had a guideline suggesting that we routinely screen for hyperaldosteronism in people with hypertension. The new 2025American Heart association guidelines also talk about checking for aldosterone. Any thoughts? Because this is pretty phenomenal. I have to imagine as an endocrinologist to now watch and see these underlying endocrine causes as kind of the secret culprits behind some of the most common things we struggle with.
- [16:47]
B
Yeah. Another interesting finding. In momentum. We also screen patients for hyperaldosteronism. So 25% of patients with resistant hypertension had hypercortisolism, but another or 21% had hyperaldosteronism and 6% had both. So there are patients where the pathophysiology seems to involve excess secretion of both aldosterone and cortisol, and that certainly hadn't been well described before.
- [17:24]
A
Yeah, that is fascinating. So, putting this all together, when we think about hypercortisolism, who should we think about screening? And I know you mentioned it as part of the study, but remind us how to do that screening. Who do we screen and how do we screen?
- [17:40]
B
Yeah, I think that, you know, again, the way I've kind of formulated it is if you're doing your best with regards to the lifestyle counseling and the medication management to control someone's diabetes or their hypertension or both, and they just aren't getting the response that you would expect based on your assessment of their ability to comply with the regimen, et cetera, et cetera. It's definitely worth screening patients for hypercortisolism because if you find it, it's such a bonus to be able to intervene on the cortisol as a method of helping you achieve the goals that you haven't been able to achieve doing what you've been doing so far. The dexamethasone suppression test is relatively easy to perform. It involves writing a prescription for 1 milligram of dexamethasone. The patient goes and gets a single tablet from the pharmacy. They take it at 11pm and then they present to have their blood drawn for cortisol. The next morning around 8am, ideally before 9am and that single test, the cortisol level, if it's greater than 1.8, that makes the criteria for hypercortisolism, with one important caveat. And you can do it as a reflex order where you don't order a dexamethasone level on everyone you know, if they pass, if they pass the test, it's not such a problem. But if they flunk the test, you need to make sure that the dexamethasone level was elevated, that they took the tablet, and they're not one of these unusual, very fast metabolizers of dexamethasone. And that cut point varies from lab to lab, but generally greater than 140.
- [19:39]
A
Okay, so that's helpful. It's really a very straightforward test. As long as you. Now as we know what to do, it only matters if we find something when there's something we can actually do about it. Can you briefly tell us what you do when you do the dexamethasone suppression test? It's greater than 1.8. It's positive. Then what?
- [20:05]
B
In the Catalyst study, there was a second phase of that study where we took the patients who screened for positively for hypercortisolism with the overnight dexamethasone suppression test. We did additional testing to identify that it seemed to be adrenal hypercortisolism. So we looked for a morning ACTH and DHEA sulfate that were at or near the lower limits of normal for the assay. And that kind of pegs it as being an adrenal cause. And in that study, we randomized patients to mifepristone, a cortisol receptor antagonist or placebo. And we showed that the patients with hypercortisolism, they on average drop their A1C from 8.5% to about 7.1%. They had a very small response to placebo. So clear indication that cortisol directed therapy is associated with clinically very meaningful benefits with regards to glucose reduction. And that's despite the fact that about half the patients had to back off or discontinue some of their diabetes medications, particularly insulin and sulfonylurea. And despite the fact that nearly a quarter of the nearly half the patients didn't actually tolerate the drug well enough to continue with the mifepristone therapy throughout the protocol. We can talk about that tolerability issue in a moment. But the point really is this is a proof of concept that if you identify hypercortisolism, there's very likely going to be benefit from cortisol directed therapy.
- [22:02]
A
I think that's important. And if you want to briefly talk about side effects, the medicine you mentioned, I don't want to take a deep dive on that now, but just so people have some sense. Yeah.
- [22:13]
B
There are two main issues with mifepristone. One is hypokalemia. And in a real adrenal practice, as opposed to a bunch of diabetes docs like me in the clinical trial where we didn't know whether the patient was taking the drug or not. But in clinical practice, what you would normally do is use some kind of mineralocorticoid receptor antagonist in advance of using mifepristone like spironolactone to prevent hypokalemia. The hypokalemia results from the fact that as you block the action of cortisol, actually cortisol levels go up and cortisol can act on the mineralocorticoid receptor. So this is almost an expected side effect, but it needs to be prevented with a priori treatment with something like spironolactone. It often takes relatively high doses. The second issue is that whether you do surgery on an adrenal module in the setting of hypercortisolism or surgery on a pituitary source for ACTH that drives excess cortisol production, the classic Cushing's disease, anything you do that lowers cortisol exposure relatively abruptly, you can get this glucocorticoid withdrawal syndrome, which is basically associated with feeling poorly, nausea, headache, that sort of thing. Again, because we were kind of rookies in this process, we probably didn't do as good a job at teeing up patients for that expectation and managing, you know, managing the side effects by encouraging people that they could, you know, if they tough it out, those side effects will generally go over, go away over a couple of weeks or even starting more slowly in the therapy than we did in the study. So with expectant management, this can be a tolerable approach.
- [24:15]
A
That makes sense. We're nearing the end of our podcast. If I remember correctly, last year you mentioned there was a new drug in development. Any updated info with that?
- [24:27]
B
Yeah. So there's a drug called relicorulant that seems to be better tolerated, is more specific in its mineralocorticoid receptor blocking activity. We were expecting, or we got a, a decision from the FDA with regards to approvability of relicorilant, but unfortunately they decided that the data wasn't adequate and additional trials would be necessary. There are other agents that are being studied as well. Obviously now that this isn't a rare disease, you know, this is a substantial portion of two very common disorders, diabetes and hypertension. There's a lot of interest in the pharmaceutical industry now in developing new approaches for cortisol directed therapy.
- [25:19]
A
That makes a lot of sense. John, we're almost out of time. Any final thoughts for our listeners?
- [25:25]
B
Yeah, I think the most important thing is to not get hung up on that picture of the patient with Cushing's syndrome is the phenotype. The phenotype is really people that are on multiple drugs and not responding well to drug therapy, often with sort of anxiety, depression, overlaid. And in those kinds of patients, screening for hypercortisolism is really important. Obesity is not a great predictor of hypercortisolism. In fact, in the Catalyst study, the patients with a BMI less than 30 were more likely to have hypercortisalism than the people with a BMI over 30.
- [26:06]
A
Such important information. Dr. John Bush, thank you so much for joining us.
- [26:11]
B
It's been a pleasure. I'll talk to you any day.
- [26:15]
A
And most of all, of course, thanks to our listeners. Thanks for joining us on this first of a multi part series on hypercortisolism and in people with diabetes and in people with hypertension. We covered a lot of ground today. I think we've all learned a lot. This special series of Diabetes Core Update is sponsored by Corset. We thank you for listening. For the American diabetes association, I'm Dr. Neal Skolnick. Till next time, stay safe and keep learning.
- [26:50]
B
Sam.