The 11-β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor INCB13739 Improves Hyperglycemia in Patients With Type 2 Diabetes Inadequately Controlled by Metformin Monotherapy

Abstract

OBJECTIVE11-β-hydroxysteroid dehydrogenase type 1 (11βHSD1) converts inactive cortisone into active cortisol, thereby amplifying intracellular glucocorticoid action. The efficacy and safety of the 11βHSD1 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 METHODSThis 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.RESULTSAfter 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.CONCLUSIONSINCB13739 added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone. 11βHSD1 inhibition offers a new potential approach to control glucose and cardiovascular risk factors in type 2 diabetes.

Acute Inhibition of 11β-Hydroxysteroid Dehydrogenase Type-1 Improves Memory in Rodent Models of Cognition

“…In mice with genetic or diet-induced obesity, selective HSD1 inhibitors normalized glucose levels (Lloyd et al, 2009;Wan et al, 2009). Similar effects of HSD1 inhibition have also been noted in humans (Rosenstock et al, 2010). Recent studies have shown that HSD1 is not strictly limited to metabolic processes.…”

Mechanisms in endocrinology: Non-alcoholic fatty liver disease in common endocrine disorders

“…An additional study has also demonstrated increased 5bR activity with increasing hepatic fat (78). Although selective 11b-HSD1 inhibitors have not been studied in the context of hepatic steatosis, in patients with diabetes, they caused modest improvement in glycaemic control and weight loss and improved lipid profiles (79,80).…”

Relationship of 11.BETA.-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase gene polymorphisms with metabolic syndrome and type 2 diabetes

“…Recently, HSD11B1 has emerged as a promising therapeutic target for diabetes and obesity [28][29][30][31]. HSD11B1, which amplifies intracellular glucocorticoid activity, plays a critical role in the pathogenesis of visceral obesity, metabolic syndrome, and diabetes [1, 4-8].…”