Inadequately Controlled Type 2 Diabetes and Hypercortisolism: Improved Glycemia With Mifepristone Treatment
Ralph A. DeFronzo, Vivian Fonseca, Vanita R. Aroda, Richard J. Auchus, Timothy Bailey, Irina Bancos, Robert S. Busch, John B. Buse, Elena A. Christofides, Bradley Eilerman, James W. Findling, Yehuda Handelsman, Steven E. Kahn, Harold J. Miller, Jonathan G. Ownby, John C. Parker, Athena Philis-Tsimikas, Richard Pratley, Julio Rosenstock, Michael H. Shanik, Lance A. Sloan, Guillermo Umpierrez, Samir Shambharkar, Iulia Cristina Tudor, Tina K. Schlafly, Daniel Einhorn, , John C. Parker, Lauren Kruszon, Robert S. Busch, Abbey Fruiterman, Yehuda Handelsman, Narges Heidarpour, Jonathan G. Ownby, Nashia Stephens, Vanita R. Aroda, Rita Gyurko, Pratibha Rao, Kelly Paulus, Mark Kipnes, Terri Ryan, Michael H. Shanik, Lisa Iannuzzi, Guillermo Umpierrez, Gloria Centeno, Iris Castro-Revoredo, Timothy Bailey, Andrew Eskeland, Ronald S. Swerdloff, Elizabeth Ruiz, Jean Park, Maria Hurtado, Adline Ghazi, Mia Hamm, Harold J. Miller, Rosina Ducote, Lawrence Blonde, Shannon Williams, Kathleen Wyne, Lindsey Aldrich, Andrew Ahmann, Deborah Branigan, Samer Nakhle, Sasha Sandry, Elena A. Christofides, Jennifer Botte, Athena Philis-Tsimikas, Rosario Rosal, Bradley Eilerman, Cashmere Hardy, Lance Alan Sloan, Katia Sloan, Sam Lerman, Maria Martin, Dragana Lovre, Mary Simmons, Richard J. Auchus, Rodica Pop-Busui, Thaira Blanco Varela, John B. Buse, Franziska Gassaway, Ralph A. DeFronzo, Curtiss Puckett, Steven E. Kahn, Karen Atkinson, Michael Zimmerman, Colleen Jacobsen, Matthew Wenker, Austin Schultz, Dan Lender, Julio Rosenstock, Allison Camacho, Mark Leibowitz, Rosario Sanchez, John Delgado, Kari Jaasko, Stanley Hsia, Cecilia Rodriguez, David Guzman, Lourdes Garibay, Margaret Chang, Tatyana NixonOBJECTIVE
In many individuals, type 2 diabetes (T2D) remains poorly controlled despite taking multiple glucose-lowering therapies. Several studies have demonstrated that endogenous hypercortisolism is prevalent among these individuals. We tested whether cortisol-directed therapy improves their glycemic control.
RESEARCH DESIGN AND METHODS
In this prospective, multicenter, double-blind study, 136 individuals with T2D (hemoglobin A1c [HbA1c] 7.5%–11.5% [58–102 mmol/mol] on multiple medications) and hypercortisolism (by dexamethasone suppression test) were randomized 2:1 to the glucocorticoid receptor antagonist mifepristone (300–900 mg once daily; n = 91) or placebo (n = 45) for 24 weeks, with stratification by presence/absence of an adrenal imaging abnormality. The primary end point was the change in HbA1c. Secondary end points included changes in glucose-lowering medications, weight, and waist circumference and safety.
RESULTS
Mean baseline HbA1c in the study cohort was 8.55% (69.9 mmol/mol). At 24 weeks, the least squares mean (LSM) difference from placebo in HbA1c was −1.32% (95% CI −1.81 to −0.83; P < 0.001). Participants receiving mifepristone experienced reductions in body weight and waist circumference (placebo-adjusted LSM differences of −5.12 kg [95% CI −8.20 to −2.03] and −5.1 cm [−8.23 to −1.99], respectively). Of participants on mifepristone, 46% discontinued therapy, compared with 18% on placebo. Adverse events with mifepristone (>10% of participants) included hypokalemia, fatigue, nausea, vomiting, headache, peripheral edema, diarrhea, and dizziness, consistent with mifepristone’s known tolerability profile. Increases in blood pressure also occurred.
CONCLUSIONS
In individuals with inadequately controlled T2D and hypercortisolism, cortisol-directed medical therapy with mifepristone reduced HbA1c, with a manageable tolerability profile.