The 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy.

Abstract

OBJECTIVE:

11-Beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) converts inactive cortisone into active cortisol, thereby amplifying intracellular glucocorticoid action. The efficacy and safety of the 11betaHSD1 inhibitor INCB13739 were assessed when added to ongoing metformin monotherapy in patients with type 2 diabetes exhibiting inadequate glycemic control (A1C 7-11%).

RESEARCH DESIGN AND METHODS:

This double-blind placebo-controlled paralleled study randomized 302 patients with type 2 diabetes (mean A1C 8.3%) on metformin monotherapy (mean 1.5 g/day) to receive one of five INCB13739 doses or placebo once daily for 12 weeks. The primary end point was the change in A1C at study end. Other end points included changes in fasting glucose, lipids, weight, adverse events, and safety.

RESULTS:

After 12 weeks, 200 mg of INCB13739 resulted in significant reductions in A1C (-0.6%), fasting plasma glucose (-24 mg/dl), and homeostasis model assessment-insulin resistance (HOMA-IR) (-24%) compared with placebo. Total cholesterol, LDL cholesterol, and triglycerides were all significantly decreased in hyperlipidemic patients. Body weight decreased relative to placebo after INCB13739 therapy. A reversible dose-dependent elevation in adrenocorticotrophic hormone, generally within the normal reference range, was observed. Basal cortisol homeostasis, testosterone in men, and free androgen index in women were unchanged by INCB13739. Adverse events were similar across all treatment groups.

CONCLUSIONS:

INCB13739 added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone. 11BetaHSD1 inhibition offers a new potential approach to control glucose and cardiovascular risk factors in type 2 diabetes.

• Authors: Julio Rosenstock, Salomon Banarer, Vivian A Fonseca, Silvio E Inzucchi, William Sun, Wenqing Yao, Gregory Hollis, Robert Flores, Richard Levy, William V Williams, Jonathan R Seckl, Reid Huber, INCB13739-202 Principal Investigators
• Journal: Diabetes care (Diabetes Care) Vol. 33 Issue 7 Pg. 1516-22 (Jul 2010) ISSN: 1935-5548 [Electronic] United States
• PMID: 20413513 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Hypoglycemic Agents
• INCB 13739
• Placebos
• Sulfonamides
• Metformin
• 11-beta-Hydroxysteroid Dehydrogenase Type 1

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (antagonists & inhibitors)
• Administration, Oral
• Adolescent
• Adult
• Aged
• Diabetes Mellitus, Type 2 (drug therapy)
• Dose-Response Relationship, Drug
• Drug Therapy, Combination
• Enzyme Inhibitors (administration & dosage, adverse effects)
• Humans
• Hyperglycemia (drug therapy)
• Hypoglycemic Agents (administration & dosage)
• Metformin (administration & dosage)
• Middle Aged
• Placebos
• Sulfonamides (administration & dosage, adverse effects)
• Treatment Outcome
• Young Adult