11β-HSD1 inhibitors for the treatment of type 2 diabetes and cardiovascular disease

Drugs. 2013 Sep;73(13):1385-93. doi: 10.1007/s40265-013-0112-5.

Abstract

Inhibition of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been proposed as a novel therapeutic target for the treatment of type 2 diabetes mellitus. Over 170 new compounds targeting 11β-HSD1 have been developed. This article reviews the current published literature on compounds that have reached phase II clinical trials in patients with type 2 diabetes, and summarises the preclinical evidence that such agents may be useful for associated conditions, including peripheral vascular disease, coronary artery disease and cognitive decline. In clinical trials, 11β-HSD1 inhibitors have been well tolerated and have improved glycaemic control, lipid profile and blood pressure, and induced modest weight loss. The magnitude of the effects are small relative to other agents, so that further development of 11β-HSD1 inhibitors for the primary therapeutic indication of type 2 diabetes has stalled. Ongoing programmes are focused on additional benefits for cognitive function and other cardiovascular risk factors.

Publication types

  • Review

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Animals
  • Antihypertensive Agents / adverse effects
  • Antihypertensive Agents / pharmacology
  • Antihypertensive Agents / therapeutic use
  • Cardiovascular Diseases / drug therapy*
  • Cardiovascular Diseases / enzymology
  • Cardiovascular Diseases / immunology
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / enzymology
  • Diabetes Mellitus, Type 2 / immunology
  • Drugs, Investigational / adverse effects
  • Drugs, Investigational / pharmacology
  • Drugs, Investigational / therapeutic use*
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use
  • Hypolipidemic Agents / adverse effects
  • Hypolipidemic Agents / pharmacology
  • Hypolipidemic Agents / therapeutic use
  • Immunity, Innate / drug effects
  • Metabolic Syndrome / drug therapy
  • Metabolic Syndrome / enzymology
  • Metabolic Syndrome / immunology
  • Molecular Targeted Therapy* / adverse effects

Substances

  • Antihypertensive Agents
  • Drugs, Investigational
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Hypolipidemic Agents
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • HSD11B1 protein, human