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Cited by 30Adrenal Hormones and DisordersDiabetes Treatment and ManagementAdipokines, Inflammation, and Metabolic Diseases

Safety profile and metabolic effects of 14 days of treatment with DIO-902: results of a phase IIa multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in patients with type 2 diabetes mellitus

SCHWARTZ, S, RENDELL, M, AHMANN, A, THOMAS, A, ARAUZPACHECO, C, WELLES, B·2008·Clinical Therapeutics
DOI 10.1016/j.clinthera.2008.05.021
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Abstract

Background Elevated levels of cortisol have been implicated in the development of type 2 diabetes mellitus and the metabolic syndrome. Modulation of cortisol levels and activity may be useful in the treatment of type 2 diabetes and its comorbidities.Objective The purpose of this study was to evaluate the safety profile and pharmacodynamic effects of DIO-902 (2S,4R-ketoconazole), an inhibitor of cortisol synthesis.Methods Subjects with type 2 diabetes who were between the ages of 18 and 70 years and were drug naive or receiving metformin at a stable dose were randomized to receive one of the following once daily at bedtime for 14 days: ketoconazole 400 mg; DIO-902 200, 400, or 600 mg; or placebo. Tolerability was assessed based on adverse events reported by subjects and the results of physical examinations and standard hematology, chemistry, and urinalysis tests performed on days 8 and 15. Glycosylated hemoglobin (HbA1c) and levels of fructosamine, fasting glucose, lipoproteins, and C-reactive protein were measured at baseline and the end of treatment. The Jonckheere-Terpstra test was used to test for an ordinal dose-response trend between the DIO-902 doses and placebo. Morning (7:30 am) salivary cortisol levels were measured and overnight plasma cortisol levels were analyzed as a 12-hour AUC at baseline and the end of treatment. Adrenocorticotropic hormone (ACTH) levels were measured and an ACTH stimulation test was used to assess adrenal reserve at baseline and the end of treatment.Results The study enrolled 21 women (58.3%) and 15 (41.7%) men. Their mean (SD) age was 55.4 (8.5) years; mean HbA1c, 8.1% (1.3%); and mean duration of diabetes, 4.8 (3.7) years. White subjects were in the majority (86.1%), with black subjects constituting 11.1% of the population and those of other racial backgrounds constituting 2.8%; 47.2% of subjects were of Hispanic ethnicity. The proportions of subjects experiencing any adverse event were 62.5% in the ketoconazole group; 60.0%, 83.3%, and 100% in the DIO-902 200-, 400-, and 600-mg groups, respectively; and 50.0% in the placebo group. Gastrointestinal disorders were the most common adverse event, reported in 12.5% of the ketoconazole group, 35.0% of the combined DIO-902 treatment group, and 16.7% of the placebo group. Headache, the second most commonly reported adverse event, was reported in 12.5% of the ketoconazole group, 30.0% of the overall DIO-902 group, and none of the placebo group. DIO-902 treatment was not associated with any significant differences in measures of glycemic control relative to placebo or any significant decreases in mean morning salivary cortisol levels or mean overnight cortisol exposure. Dose-dependent reductions from baseline were seen in mean levels of low-density lipoprotein cholesterol (mean percent reductions: -11.39, -23.38, and -42.10 with DIO-902 200, 400, and 600 mg, respectively; P<0.001), as well as in total cholesterol (P<0.001) and high-density lipoprotein cholesterol (P=0.034). Mean levels of C-reactive protein were significantly reduced relative to placebo at all doses of DIO-902 (P=0.027); no reductions in either of these parameters were seen in the placebo group.Conclusion In this small, short-term study in subjects with type 2 diabetes, DIO-902 was generally well tolerated, although it was associated with an increased incidence of gastrointestinal disorders and headache. Levels of low-density lipoprotein cholesterol were significantly decreased in subjects treated with DIO-902.

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Crossref · 10.1016/j.clinthera.2008.05.021

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  • At doses of 200 to 1200 mg daily, ketoconazole has been shown to improve glucose metabolism in patients with Cushing syndrome and in those with type 2 diabetes.

    “At doses of  to  mg daily, this steroidogenesis inhibitor has been shown to improve glucose metabolism in patients with CS and in those with type  DM (-).”

    From Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management (2017) · cites this paper as [278]

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Authors
SCHWARTZ, S., RENDELL, M., AHMANN, A., THOMAS, A., ARAUZPACHECO, C., & WELLES, B.
Affiliations
  • Diabetes & Glandular Disease Clinic (US)
  • Radiant Research (United States) (US)
ORCID
RENDELL, M
Venue
Clinical Therapeutics
Publisher
Elsevier BV
Published
2008-06
Volume
30
Issue
6
Pages
1081-1088
ISSN
0149-2918 (ISSN-L)
DOI
10.1016/j.clinthera.2008.05.021
OpenAlex
W2114001870
Cited by
29
References
28
Citations by year
2026: 1 · 2023: 1 · 2021: 6 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 2 · 2013: 2
FWCI
1.21
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Clinical Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
type 2 diabetes, cortisol synthesis inhibition, glucocorticoid receptor antagonist, salivary cortisol, ACTH stimulation test, adrenal reserve, HbA1c, fructosamine, lipoproteins, C-reactive protein, safety profile, dose-response relationship, pharmacodynamics
MeSH terms
Adolescent, Adrenocorticotropic Hormone, Adult, Aged, Antifungal Agents, Blood Glucose, Diabetes Mellitus, Type 2, Dose-Response Relationship, Drug, Double-Blind Method, Female, Follow-Up Studies, Glycated Hemoglobin, Humans, Ketoconazole, Lipids, Male, Middle Aged, Treatment Outcome, Young Adult

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