Mifepristone in Resistant Type 2 Diabetes with Hypercortisolism

Kimmy Nguyen
17 hours ago
4 min read

Written by Thomas Henry, PharmD, BCPS and Stephanie Yager, PharmD, BCACP

Background: Endogenous hypercortisolism increases insulin resistance, impairs beta-cell function, inhibits glucagon like peptide-1 (GLP-1), increases hepatic glucose output, and is associated with cardiovascular disease. Hypercortisolism is increasingly recognized as heterogeneous as not all patients present with Cushing Syndrome. Mifepristone is a glucocorticoid receptor antagonist approved for treating hyperglycemia secondary to endogenous hypercortisolism in adults with type 2 diabetes (T2DM). The recent CATALYST trials offer updated prevalence estimates and evidence on the benefits of treatment targeting hypercortisolism to manage T2DM.(1,2)

The CATALYST Trials had 2 phases. The prevalence phase assessed the prevalence of hypercortisolism in difficult-to-control T2DM(1), and the treatment phase treated the broader hypercortisolism in persons found to have hypercortisolism in the prevalence phase.(2)

CATALYST Prevalence Phase (1)

Adult patients with resistant T2DM were recruited from general medicine and endocrinology clinics. Resistant T2DM included A1c ≥7.5% and at least 2-3 anti-hyperglycemic medications with varying degrees of antihypertensive use or micro/macrovascular outcomes. Exclusion criteria were in place to avoid false positive dexamethasone suppression tests (DST) (see Table 1).

Table 1. Key Catalyst Trial Inclusion and Exclusion Criteria (1,2)

Screening with an overnight 1 mg DST took place in 1057 patients. Patients ingested 1 mg of dexamethasone at 11 pm and serum cortisol was measured the next morning at 8:00 am. Hypercortisolism was defined as post-DST serum cortisol >1.8 µg/dL with dexamethasone level >140 ng/dL. These patients then underwent non-contrast abdominal CT to assess adrenal glands, as well as further fasting bloodwork including ACTH. Hypercortisolism was present in 23.8% of patients, the majority of which (65.3%) did not have adrenal imaging abnormalities. Patients with hypercortisolism were more likely to have a BMI <30, be on max dose of incretin therapy, have SGLT2 inhibitor use, or be prescribed fibrates.

Treatment Phase (2)

From the prevalence phase, 136 patients with hypercortisolism were randomized 2:1 to mifepristone or placebo over 24 weeks. Inclusion and exclusion criteria were extensive (see Table 1). Patients with or without adrenal abnormalities were eligible as long as ACTH was not elevated. Patients in the mifepristone arm (N=91) were started on 300 mg once daily, and if tolerated could be increased to 600 mg after 4 weeks, with an optional 900 mg dose at week 8. Mean dosing at the end of trial was not reported. Blood pressure and BMP were taken 2 weeks after initiation or dose titration of mifepristone. Patients treated with mifepristone had significantly greater reductions in A1c, body weight, and insulin therapy (see Table 2). Patients treated with mifepristone were more likely to have hypokalemia (30%), fatigue, GI symptoms, and peripheral edema. Nearly half of the mifepristone group discontinued therapy (46% vs 18% placebo).

Table 2. Treatment Phase Results (2)

Discussion and Clinical Practice Implications

The Catalyst studies showed that hypercortisolism is more prevalent than previously thought and treatment with medication can be very effective for patients despite previously having difficult-to-control diabetes. Surgery is still the first line treatment for hypercortisolism, when possible, but many patients are not surgical candidates or prefer oral therapy.

Mifepristone (brand Korlym) was FDA approved in 2012. Prior to this study, it was not commonly used in clinical practice for patients with diabetes and will require a learning curve as prescribers begin to use it more often. It is only available through the SPARK specialty pharmacy. Prescribers would need to monitor closely for hypokalemia, hypertension, and signs of cortisol withdrawal. Preemptive potassium correction or treatment with potassium sparing diuretic may help prevent hypokalemia. Education on the side effects of cortisol withdrawal and the metabolic benefits of the medication may help prevent premature discontinuation of the medication.

Treatment with Mifepristone: Overview of Approach

Identify candidates at risk of hypercortisolism: Patients with difficult-to-manage uncontrolled T2DM on multiple medications. Exclude patients with factors that put them at high risk of a false positive DST (Table 1).
Complete 1 mg DST. If positive:
1. Measure ACTH, DHEAS, cortisol
2. Complete CT of adrenal glands
Exclude and prevent pregnancy (with non-hormonal contraception due to the CYP3A4 inhibition from mifepristone).
1. Prior to and during treatment, and
2. Through 1 month after stopping treatment
Screen for drug interactions, correct potassium, consider addition of potassium sparing diuretic.
Start mifepristone 300 mg by mouth once daily via SPARK patient enrollment form.
Monitor potassium, blood pressure, weight, blood glucose, and symptoms of adrenal insufficiency 1-2 weeks after starting and periodically thereafter.
Titrate mifepristone after 4 weeks if tolerated. Deescalate glucose lowering medications as needed.

1. Buse JB, Kahn SE, Aroda VR, et al. Prevalence of hypercortisolism in difficult-to-control type 2 diabetes. Diabetes Care. 2025;48(12):2012-20. doi:10.2337/dc24-2841.

2. DeFronzo RA, Fonseca V, Aroda VR, et al. Inadequately controlled type 2 diabetes and hypercortisolism: improved glycemia with mifepristone treatment—a randomized controlled trial. Diabetes Care. 2025;48(12):2036-2044. doi:10.2337/dc25-1055.

3. Fleseriu M, Biller BM, Findling JW, et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits, in patients with Cushing’s Syndrome. J Clin Endocrinol Metab. 2012;97(6):2039-2049. doi:10.1210/jc.2011-3350.