Julie Silverstein, MD, is the medical director of the pituitary center and of the clinical trials unit and professor of medicine and neurological surgery at WashU Medicine.

Julie Silverstein, MD

Relacorilant Reduces HbA1c in Cushing’s Despite GLP-1 Treatment, With Julie Silverstein, MD

Relacorilant reduced hemoglobin A1c (HbA1c) by nearly 1% in patients with 

 and hyperglycemia despite ongoing GLP-1 treatment, according to a secondary analysis of the GRACE phase 3 clinical trial.

American Association of Clinical Endocrinology (AACE) Annual Meeting 2026

 in Las Vegas, Nevada, by Julie Silverstein, MD, medical director of the pituitary center and of the clinical trials unit and professor of medicine and neurological surgery at WashU Medicine. In an interview with 

, Silverstein discusses the complex pathway between excess cortisol and a plethora of long-term health detriments.

“There are multiple parts at play,” Silverstein told 

. “When you have excess cortisol, you have increased glyconeogenesis in the liver. This increased fasting glucose impairs interferon signaling, including GLP-1 receptor signaling. It leads to increased insulin resistance in the adipose tissue, decreasing uptake of glucose in the skeletal tissue.”

The original GRACE trial was a phase 3, double-blind, placebo-controlled, randomized-withdrawal study assessing the safety, efficacy, and pharmacokinetics of relacorilant in patients with endogenous Cushing syndrome and concurrent type 2 diabetes mellitus/impaired glucose intolerance (DM/IGT) and/or uncontrolled hypertension. Patients were excluded from the trial if they had non-endogenous hypercortisolism, uncontrolled, clinically significant hypo- or hyperthyroidism, poorly controlled hypertension, severe renal insufficiency, or poorly controlled diabetes mellitus.

In the open-label phase, patients were assigned to receive relacorilant in 100 mg capsules, increased sequentially to a maximum dose of 400 mg once daily; after 22 weeks, patients were then evaluated for inclusion in the randomized-withdrawal phase based on predefined hyperglycemia and hypertension response criteria. Eligible patients were then randomly assigned in a 1:1 ratio to either relacorilant or placebo for 12 weeks.

GRACE ultimately achieved its primary endpoint, as substantially more participants who were switched to placebo lost hypertension control versus those who stayed on relacorilant (odds ratio [OR], 0.17; 

 = 0.02). However, a subgroup of participants had hyperglycemia despite using GLP-1s or dual GIP/GLP-1s.

To that end, Silverstein and colleagues undertook this analysis to examine this subgroup. Patients taking GLP-1s or GIP/GLP-1s prior to and for ≥80% of the open-label phase were included in the trial. The team utilized a mixed model for repeated measures to analyze least squares mean change from baseline to the open-label period week 22 in HbA1c, weight, waist circumference, and body composition.

A total of 152 patients were enrolled in the open-label phase; of these, 28 had hyperglycemia despite using GLP-1s or GIP/GLP-1s. Baseline mean HbA1c, weight, and waist circumference were 8.5%, 108.4 kg, and 124.8 cm, respectively. Investigators recorded baseline tissue lean mass percentage at 53.2%. Among this group, relacorilant treatment led to substantial reductions in HbA1c from baseline (-0.9%; 95% CI, -1.6 to -0.3; 

“There are glucose receptor modulators being studied in other diseases,” Silverstein said. “Relacorilant, in fact, in combination with a chemotherapeutic agent, is FDA approved for the treatment of platinum resistant ovarian cancer; there’s a glucose receptor modulator being investigated for patients with MASH; I think there’s also a modulator being studied in patients with ALS. There seems to be lots of different areas where these could be used clinically.”

Editors’ Note: Silverstein reports disclosures with Xeris, Chiesi, Camurus, Ascendis Pharma, Bayer, Recordati, and others.

Silverstein J, Dobri G, Elenkova A, et al. Relacorilant Treatment Improves Glycemic Control Among Individuals With Cushing Syndrome (Endogenous Hypercortisolism) and Hyperglycemia on Glucagon-Like Peptide-1 Receptor Agonists: Insights From a Phase 3 Study. Abstract presented at the American Association of Clinical Endocrinology Annual Meeting 2026, Las Vegas, NV. April 22-24, 2026.

Corcept Therapeutics. A Study of the Efficacy and Safety of Relacorilant in Patients With Endogenous Cushing Syndrome (GRACE). ClinicalTrials.gov Identifier: NCT03697109. Updated July 16, 2025. Accessed April 29, 2026. 

https://clinicaltrials.gov/study/NCT03697109

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Silverstein addresses a secondary analysis of the GRACE trial, highlighting relacorilant’s efficacy in reducing cortisol in patients taking GLP-1 RAs.

Julie Silverstein, MD

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