POORLY controlled Type 2 diabetes (T2D) remains a persistent challenge for many individuals, even when multiple glucose-lowering medications are used. Emerging evidence suggests that a subset of these patients may have underlying hypercortisolism, which contributes to their resistance to standard therapies. A recent study explored whether targeting cortisol pathways with a glucocorticoid receptor antagonist could improve glycaemic outcomes in this population. Notably, treatment with mifepristone led to a significant reduction in HbA1c levels over 24 weeks.
The prospective, multicentre, double-blind, placebo-controlled trial involved 136 adults with T2D and evidence of endogenous hypercortisolism, as determined by a dexamethasone suppression test. Participants had HbA1c levels between 7.5% and 11.5% (58–102 mmol/mol) despite being on multiple antihyperglycaemic medications. They were randomised in a 2:1 ratio to receive either mifepristone (300–900 mg daily) or placebo for 24 weeks. Randomisation was stratified based on the presence or absence of adrenal imaging abnormalities. The primary outcome was change in HbA1c, with secondary measures including changes in body weight, waist circumference, glucose-lowering therapy use, and safety outcomes.
At baseline, mean HbA1c was 8.55% (69.9 mmol/mol). After 24 weeks, the least squares mean difference in HbA1c between the mifepristone and placebo groups was −1.32% (95% CI: −1.81–−0.83; p<0.001). Mifepristone also led to placebo-adjusted reductions in weight (−5.12 kg; 95% CI: −8.20–−2.03) and waist circumference (−5.1 cm; 95% CI: −8.23–−1.99). However, 46% of participants in the mifepristone group discontinued treatment, compared to 18% in the placebo group. Common adverse events included hypokalaemia, fatigue, nausea, and dizziness, aligning with the drug’s known safety profile. Blood pressure elevations were also observed.
This study demonstrates that cortisol-directed therapy with mifepristone can significantly improve glycaemic control and reduce weight in patients with uncontrolled T2D and hypercortisolism. These findings highlight the importance of screening for hypercortisolism in individuals with treatment-resistant diabetes. While side effects were relatively common, most were consistent with established safety data. Limitations include a relatively high discontinuation rate and a short duration of follow-up. Nonetheless, the results support the potential for a more personalised approach in diabetes management, particularly when conventional treatments fall short.
Reference
DeFronzo RA et al. Inadequately Controlled Type 2 Diabetes and Hypercortisolism: Improved Glycemia With Mifepristone Treatment. Diabetes Care. 2025;DOI: 10.2337/dc25-1055.
