American Diabetes Association 2024 Conference Summary featuring Robert Gabbay, MD and John Buse, MD, PhD

ADA KOL Interview with Robert Gabbay, MD — Chief Scientific and Medical Officer of the ADA and John Buse, MD, PhD — Director, UNC Diabetes Care Center, UNC School of Medicine

I'm Doctor Robert Gabbay, the Chief Scientific and Medical Officer for the American Diabetes Association.

This year's ADA Scientific Sessions really had a number of themes. I would say one very big one was around obesity and the explosion of new knowledge, treatments, clinical trials. There were a number of really interesting presentations around type 1 diabetes and that's always a perennial important part of the meeting. Technology continues to play an important role. And health disparities, another important theme. The last is the overall spirit of innovation best captured by our innovation challenge. We brought in a competition of startup companies with solutions for diabetes. They presented, they pitched the audience, and a group of judges identified the best and brightest and most promising of them all.

So, I think one of the important studies that came out was around the Flow Trial and it's looking at the GLP 1s. We know that they have significant cardiovascular benefits, but the data on kidney outcomes have been less clear. Because diabetes is leading cause of kidney failure, it's important to understand what its impact would be.

It was a randomized controlled trial with semaglutide and identified that, in fact, there is a 24% reduction in adverse kidney outcomes. And so clearly protective, and this was the case whether individuals were on T2 inhibitors, which we know are of course beneficial and have a long history of that…but even in those without. So, either way, and so I think this is an opportunity for us to rethink what are the medications, in a sense, cocktails that we can use for people with chronic kidney disease to prevent progression.

I would say another really exciting study was the Surmount OSA. And this is sort of a theme throughout the meeting -- of the GLP-1 medications and do they have impacts beyond the areas that we know like weight loss and cardiovascular disease. But what other outcomes.

And this was an interesting one looking at obstructive sleep apnea, an area that we typically don't think about so much in the world of diabetes. But there are 80 million Americans with sleep apnea. Most of them, in fact, are undiagnosed. And although CPAP is effective, many people don't tolerate it.

And so, the idea was, in a randomized controlled trial could terzepatide have an impact on sleep apnea measured by episodes of apnea and sort of the usual kinds of indices that are used to assess sleep apnea?

And in fact, it turned out that there was a pretty significant improvement whether people were on CPAP or not – a reduction of about 50% in terms of episodes.

Given that there are so many people undiagnosed, and many don't tolerate standard therapy, this could present a new option to be able to manage this very common disease.

There are some really exciting areas happening in the world of diabetes. One continues to be around technology as we understand the value, for example, of continuous glucose monitors in a wider population of individuals. ADA standards of care recommend continuous glucose monitors for anyone on insulin, regardless of age, type of diabetes. But now we're starting to see data around individuals not on insulin and how it can influence behavior and be really effective. And could there be value in prediabetes? So, I think that's one theme that we'll see a lot more, over the next year. 

HyperCortisolism in PATients with Difficult-to-Control Type 2 DiAbetes Despite Receiving Standard-of-Care Therapies (CATALYST Study)

John B. Buse, MD, PhD

Director, Diabetes Center; Co-Director, Translational and Clinical Sciences Institute, University of North Carolina

I'm John Buse, a professor of medicine at the University of North Carolina in Chapel Hill, where I also direct the Diabetes Center and the Translational and Clinical Sciences Institute.

Hypercortisolism is something that we all learn about in medical school, nursing school, whatever school we went to. But we usually think of it in its most extreme form - often referred to as Cushing's syndrome. So, someone that would be morbidly obese with hypertension, diabetes, perhaps, some hirsutism, facial plethora, dorsal cervical fat pad. Often quite ill. But that's just the tip of the iceberg. In fact, hypercortisolism exists as an entire spectrum. And the form of hypercortisolism we look for in the Catalyst study is much milder in presentation. So, in fact, most people with hypercortisolism have essentially none of those features but may have difficult to control diabetes, difficult to control hypertension, problems with weight, depression, anxiety, more subtle signs and symptoms than what we think of is Cushing's syndrome.

The CATALYST study is a two-part, phase 4 study which was conducted at 36 sites in the United States. Initially, the plan was to screen at least a thousand patients for the presence of hypercortisolism. And what we looked for in this first prevalence phase of the study was people with type two diabetes who were inadequately controlled despite substantial efforts. And I mean specifically, at least, two medications for their diabetes with a hemoglobin A1C greater than 7.5%, or A1C greater than 7.5%, with hypertension difficult to control or microvascular complications.

And then these patients underwent the one milligram overnight dexamethasone suppression test -- taking one milligram at 11 p.m. and then reporting to have their blood drawn at 8 a.m. the next morning.

The criteria we use for hypercortisolism was the post dexamethasone level of greater than 1.8, with a simultaneously measured dexamethasone level greater than 140. And people who met that criteria of hypercortisolism had further evaluation, ACTH and adrenal CT to establish whether or not there was an adrenal tumor.

Part 2 of the study involves taking those patients with hypercortisolism that seem to have an adrenal origin of their hypercortisolism and randomizing them to a Mifepristone or placebo, if appropriate.

Mifepristone has a fair number of contraindications related to drug interactions and sometimes that couldn't be resolved. But that second part of the study is fully enrolled and ongoing. The last patient, last visit should be in December.

And the aim there is to see in these patients with hypercortisolism, treated with a cortisol receptor antagonist mifepristone versus placebo, what happens with regards to important metabolic outcomes like hemoglobin A1C, blood pressure, lipids and how aggressively patients have to be treated to maintain, or achieve those targets.

So, the phase 1 study results were pretty shocking. Before we conducted the study, the steering committee discussed what proportion of patients we thought might have hypercortisolism. And I think the range of, responses was from about 1%, to about, 8%.

And in fact, what we found is it was 24% of the population screened had evidence of hypercortisolism as defined by the one milligram dexamethasone suppression test. This was more common in older patients, in whites, in patients that were treated with the most modern medications, like the GLP-1 receptor agonists.

Further analyses are going to be ongoing to try and understand if we can better predict who really should be screened for hydrocortisone. But with 24% of these patients with difficult to control diabetes having hypercortisolism this is a potentially paradigm shifting study.

If part 2 is positive and shows us that treatment of these patients with hypercortisolism results in better outcomes, then I do think that guidelines in the future will change to recommend screening for people with difficult to control type two diabetes.

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