Improvements in diabetes and hypertension were sustained over long-term osilodrostat treatment in patients with Cushing

Rosario Pivonello; Maria Fleseriu; John Newell-Price; Monica Gadelha; Richard Auchus; Richard Feelders; Andre Lacroix; Shimatsu Akira; Przemysław Witek; Marie Bex; Andrea Piacentini; Alberto Pedroncelli; Biller Beverly M.K.

doi:10.1530/endoabs.99.P340

P340

Prev Next

Section Contents Cite

Endocrine Abstracts (2024) 99 P340 | DOI: 10.1530/endoabs.99.P340

ECE2024 Poster Presentations Pituitary and Neuroendocrinology (120 abstracts)

Improvements in diabetes and hypertension were sustained over long-term osilodrostat treatment in patients with Cushing’s disease: A pooled analysis of LINC 3 and LINC 4

Rosario Pivonello ¹ , Maria Fleseriu ² , John Newell-Price ³ , Monica Gadelha ⁴ , Richard Auchus ⁵ , Richard Feelders ⁶ , Andre Lacroix ⁷ , Shimatsu Akira ⁸ , Przemysław Witek ⁹ , Marie Bex ¹⁰ , Andrea Piacentini ¹¹ , Alberto Pedroncelli ^12,13 & Beverly M.K. Biller ¹⁴

Err

Author affiliations

¹Università Federico II di Napoli, Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Naples, Italy; ²Oregon Health & Science University, Pituitary Center, Departments of Medicine and Neurological Surgery, Portland, OR, United States; ³University of Sheffield, School of Medicine and Population Health, Sheffield, United Kingdom; ⁴Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Neuroendocrinology Research Center, Endocrinology Section, Rio de Janeiro, Brazil; ⁵University of Michigan, Department of Pharmacology and Division of Metabolism, Endocrinology and Diabetes, Ann Arbor, MI, United States; ⁶Erasmus Medical Center, Department of Internal Medicine, Endocrine Section, Rotterdam, Netherlands; ⁷Centre hospitalier de l’Université de Montréal, Montreal, Canada; ⁸Omi Medical Center, Kusatsu, Japan; ⁹Medical University of Warsaw, Department of Internal Medicine, Endocrinology and Diabetes, Warsaw, Poland; ¹⁰University Hospitals Leuven, Department of Endocrinology, Leuven, Belgium; ¹¹Recordati SpA, Milan, Italy; ¹²Recordati AG, Basel, Switzerland; ¹³Camurus AB, Lund, Sweden; ¹⁴Massachusetts General Hospital, Neuroendocrine and Pituitary Tumor Clinical Center, Boston, MA, United States

Introduction: Diabetes mellitus (DM) and hypertension are common comorbidities that pose significant clinical burden in Cushing’s syndrome patients and may be improved by normalising cortisol. In two Phase III trials (LINC3 [NCT02180217]; LINC4 [NCT02697734]), osilodrostat, a potent oral 11β-hydroxylase inhibitor, provided reductions in cortisol and improved clinical manifestations of hypercortisolism in most Cushing’s disease (CD) patients. Here, we describe changes in glycaemic parameters and blood pressure (BP) in a pooled patient population, according to baseline hypertensive and diabetic status.

Methods: LINC3 comprised a 48-week (W) core phase, including an 8W randomised-withdrawal phase for eligible patients. LINC4 included an initial 12W, double-blind, randomised, placebo-controlled period, then 36W of open-label osilodrostat. Both studies included an optional extension. Baseline DM was defined as prior diagnosis, taking antidiabetic medication, HbA_1c ≥6.5%, and/or fasting plasma glucose (FPG) ≥126 mg/dl. Baseline hypertension was defined as prior diagnosis, taking antihypertensive medication, and/or systolic/diastolic BP (SBP/DBP) >130/>90mmHg. Data were pooled in a secondary exploratory analysis for all patients with data at baseline and W72; periods whereby patients received placebo are excluded. No formal statistical testing was performed; all analyses are descriptive.

Results: Of patients with baseline DM (n=84/210; 40.0%), mean (SD) FPG and HbA_1c, respectively, decreased from 90.9 (17.3) mg/dl and 5.8 (0.8)% at baseline to 87.1 (9.9) mg/dl and 5.4 (0.6)% at W72 for those not receiving antidiabetic treatment during the study, and decreased from 118.1 (33.5) mg/dl and 6.9 (1.0)% at baseline to 102.7 (27.6) mg/dl and 6.1 (0.8)% at W72 in those receiving antidiabetic medication. Higher baseline FPG and HbA_1c was associated with greater improvements at W72, demonstrated by a negative correlation between change in FPG and HbA_1c from baseline to W72 and baseline FPG and HbA_1c (r=−0.60 and −0.68, respectively; P<0.0001). Most patients (n=174/210; 82.9%) had baseline hypertension. ~50% of patients with baseline SBP >130mmHg had SBP ≤130mmHg at W72, and ~60% with baseline DBP >90mmHg had DBP ≤90mmHg at W72. Higher baseline SBP/DBP was associated with greater improvements at W72, demonstrated by a negative correlation between change in SBP/DBP from baseline to W72 and baseline SBP/DBP (r=−0.69/−0.64; P<0.0001).

Conclusion: DM severity and prevalence of hypertension reduced over long-term osilodrostat treatment. Patients with higher baseline FPG, HbA_1c, SBP and DBP experienced the greatest reductions in these parameters at W72. These findings highlight the importance of treating hypercortisolism to improve comorbidities in CD patients.