In an interview with Pharmacy Times, Lance Sloan, MD, MSE, FACE, FASN, FACP, FEAA, FASPC, medical director at the Texas Institute for Kidney and Endocrine Disorders, discussed findings from the CATALYST trial and what they mean for pharmacists and clinicians managing patients with difficult-to-control type 2 diabetes (T2D). The trial evaluated mifepristone in patients with T2D and hypercortisolism, including a subgroup receiving GLP-1 receptor agonists (GLP-1 RAs) or tirzepatide (Mounjaro, Tirzepatide; Eli Lilly), and found that mifepristone produced significant reductions in A1C, weight, and waist circumference—with the greatest improvements seen in patients already on GLP-1 RA or tirzepatide therapy.
Sloan explained that hypercortisolism is far more prevalent than previously recognized and should not be ruled out based on physical appearance alone. Instead, clinicians should focus on a patient's response to medications. When patients remain above goal despite multiple glucose-lowering agents or require excessive insulin, hypercortisolism should be considered as a contributing cause.
He noted that approximately 25% of patients with difficult-to-treat T2D may have underlying hypercortisolism—a figure that rises to roughly one-third when patients are also on multiple blood pressure medications. Sloan urged pharmacists and clinicians to screen appropriate patients, emphasizing that identifying and treating hypercortisolism could improve not only glycemic control but also long-term cardiovascular and renal outcomes.
Pharmacy Times: The CATALYST data suggest mifepristone added meaningful glycemic and weight benefit on top of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and tirzepatide. What does that tell us about why some patients simply don't respond to those therapies the way we expect?
Key Takeaways
- Hypercortisolism is more prevalent than clinical appearance suggests. The CATALYST trial found that approximately 25% of patients with difficult-to-control T2D had underlying hypercortisolism, rising to roughly one-third among those also on multiple antihypertensive agents.
- GLP-1 RA or tirzepatide use should not preclude screening for hypercortisolism. The CATALYST subanalysis showed that mifepristone produced the greatest A1c, weight, and waist circumference reductions in patients already on these therapies, underscoring that uncontrolled cortisol may be blunting their efficacy.
- Medication burden and response are key screening triggers. Clinicians and pharmacists should consider hypercortisolism when a patient remains above the A1c goal despite multiple glucose-lowering agents, requires large insulin doses, or continues to develop microvascular or cardiovascular complications.
Lance Sloan, MD, MSE, FACE, FASN, FACP, FEAA, FASPC: What it tells us is that hypercortisolism is more common than we thought. I think part of the problem is that we have been taught in medical school, or during our training, that we should look at a patient, and if a patient looks a particular way, then we should consider screening them. But it turns out that you can't always look at people and tell if they have hypercortisolism—and I think that is the problem here.
We need to look at something else, and that's their response to medications. If we're putting them on medications—particularly the newer medications that are so much more effective than what we've had in the past—and people aren't getting to the A1c goals that we want, then we should be asking, “Why are we seeing this resistance to medications?” If they're on multiple medications and you're not getting to goal, or even if you are getting to goal but it's taking a lot of insulin and a lot of different medications to get there—to the point where you're thinking, "I'm using so much insulin on this individual; maybe I'm causing other problems"—then you need to look and see if they have another underlying issue. One of the main things to consider is checking for hypercortisolism.
And don't think, "He doesn't have it—he doesn't look like the traditional Harvey Cushing's type of patient." You should be focusing on the response the person is having to medications, because the studies are showing that about 25% of those individuals will turn out to have hypercortisolism that you can treat. Of course, that's only 25%, so we have another 75% that won't, but it's certainly very important to pick up that 25% where you can really make a difference, because more specific treatment is going to have a greater impact. Not just in lower blood sugars and blood pressure, but hopefully in cutting down on cardiovascular and renal outcomes down the road.
It's really important to determine the underlying cause and to treat it. We're looking for other things now to help explain why patients sometimes don't respond the way we would like them to respond to certain medications, but certainly hypercortisolism is one of those things we should be thinking about.
Pharmacy Times: Given these findings, how should pharmacists and clinicians be thinking about screening for hypercortisolism in patients with type 2 diabetes (T2D) who aren't hitting their goals despite being on multiple agents?
Sloan: The number one easiest thing is that you just need to look at the number of medications and the response. We've got these great incretin drugs now—whether they’re GLP-1 agonists or GLP-1/GIP drugs—that have a tremendous impact on lowering blood sugars and helping people lose weight. If you have a patient on one of these medications, and they're also on a sodium-glucose cotransporter 2 (SGLT-2) inhibitor and metformin, and you're still sitting above 7.5%—you haven't gotten to goal, which is what we used in the CATALYST trial—then you ought to be thinking about why they're not responding to medicines the way most patients are. You should be thinking about hypercortisolism.
The other thing we found in the trial was that people who were on multiple medications for blood sugar lowering and multiple medications for blood pressure lowering were even more likely to have hypercortisolism. Now we're not looking at just a quarter of individuals—we’re moving up to a third of individuals who are having trouble controlling both their blood sugars and their blood pressure.
And of course, if someone is on multiple medications and is still developing microvascular complications—retinopathy—or they're having heart attacks or strokes, that's a very high-risk individual. You don't want to miss hypercortisolism in that person, because finding it and treating the true cause, or one of the major contributing causes, is really going to make a difference in their life. You want to go ahead and consider screening that individual too.
