If your A1c is above eight, that means you’re poorly controlled. But you have to be poorly controlled on at least three oral hypoglycaemic agents or two oral hypoglycaemic agents plus insulin. But if you’re now screening these difficult-to-control diabetic patients, you can expect to find about 25 % of them have elevated cortisol levels as the aetiologic factor in the development of their type 2 diabetes. I’m Professor Ralph DeFranzo and I’m Chief of the Diabetes Division at the University of Texas Health Science Center in San Antonio, Texas. And I also run the Texas Diabetes Institute where we take care of about ten thousand unduplicated patients on a yearly basis. And I’ve been very much involved with a new story, a very interesting one that’s developing, and it has to do with the role of hypercortisolism in people with type 2 diabetes. This is really an old story. Usually, this was documented with pituitary tumours that overproduce ACTH, they have very high cortisol levels. This is described by Harvey Cushing many years ago. And people with Cushing’s Syndrome develop type 2 diabetes that looks like sort of typical type 2 diabetes that we take care of, that you see every day in your practice. But what we have come to learn is that there is what we call an adrenal aetiology of the hypercortisolism that’s been previously unrecognised. And these people who have hypercortisolism related to either adrenal adenomas or adrenal hyperplasia do not present as the typical patients that Harvey Cushing described many years ago. They don’t present with the buffalo humps and the puffy faces and the striae and visceral adiposity. They look like any other diabetic patient in your practice. And what we’ve learned, however, is that even though they don’t look like the typical Cushing’s patients, like the Cushing’s patients, they are extremely difficult to treat. We started a very large study to look first at the prevalence of hypercortisolism or Cushing’s Syndrome in difficult-to-control people with type 2 diabetes. So, what we did is, entry criteria, look at people who are on three oral hypoglycaemic agents or more, two oral agents with insulin, or two oral agents for hyperglycaemia control and two agents for blood pressure control, because cortisol also raises your blood pressure. There were, I think, 1,057 patients in the study. The prevalence of hypercortisol was about 25 %. Now, if you were to extrapolate from the United States, we have about 40 million people with type 2 diabetes, that would mean there are about a million to 1.2 million people who have hypercortisolism as the cause of their type 2 diabetes, which is very difficult to manage. So that was the first part of the CATALYST study to identify the prevalence. Now having identified the prevalence and identified these people, and I might say, the way we identify the people is to give them 1 mg of dexamethasone in the evening. And then they come in the morning, and we measure the plasma cortisol. And you and I, our plasma cortisol level should be really close to zero. So, the magical cut-point for plasma cortisol not suppressing is 1.8. In these people who did not suppress their cortisol and had hypercortisolism, we then went on to treat them with a glucocorticoid receptor antagonist called mifepristone. And what we saw was that in these difficult-to-control people the A1c dropped by about 1.5 % and the people lost about 5 kg of body weight. So, the beauty of mifepristone is that it was already approved by the FDA for treating people with severe Cushing’s disease who had hyperglycaemia related to that. So, the FDA has already approved this drug. In the old days, I think I’ve seen four patients with pituitary Cushing’s. So, it was a very rare disease. But now what we’re seeing is that there are probably about 1 to 1.2 million people who actually have this disease. And in particular, what we noted is that many of the people who actually turn out to have elevated cortisol levels as the cause of their diabetes were being treated by the newer GLP-1 receptor agonists. So, if you have people who are on some of these newer agents that really are very powerful and they’re not working very well, you should be thinking about hypercortisolism. So in conclusion, what i’d like to leave you with: Who are the people you should be screening for hypercortisolism? Well, I think I would use the same criteria that we use in the CATALYST study. So, if your A1c is above eight, that means you’re poorly controlled. But you have to be poorly controlled on at least three oral hypoglycaemic agents or two oral hypoglycaemic agents plus insulin. We’re not recommending you screen the entire diabetic population, because that would be a relatively small percentage of people. But if you’re now screening these difficult-to-control diabetic patients, you can expect to find about 25 % of them have elevated cortisol levels as the aetiologic factor in the development of their type 2 diabetes. Any of these people who have difficult-to-control diabetes are candidates for mifepristone therapy. But of course, as part of the work-up, these individuals who have hypercortisolism, meaning the dexamethasone suppression is abnormal, they should have a CT of the abdomen, because it turns out that about one third of these people will have an adrenal adenoma. And if you identify people who have an adrenal adenoma, the appropriate treatment, assuming that the patient is a surgical candidate, should be to remove the adrenal adenoma. But in the other two thirds of the people who don’t have an adrenal adenoma, they are candidates for medical therapy. There are some other drugs that are approved that are enzyme inhibitors that block enzymatic steps within the adrenal gland. But these other medications tend to have more side effects whereas the mifepristone is specifically a glucocorticoid receptor antagonist and therefore is associated with fewer side effects. You should recognise that hypercortisolism, in addition to promoting diabetes, also promotes accelerated cardiovascular disease and promotes hypertension. So, there’s a really important need to really block the effect of cortisol in order to slow the progression of cardiovascular disease and also to help with the treatment of the hypertension, which can be very difficult to treat.