Promising Approach to Treat Non-Alcoholic Fatty Liver Disease and Visceral Obesity

Norbert Stefan, MD Heisenberg Professorship for Clinical and Experimental Diabetology Department of Internal Medicine IV University Hospital Tübingen Tübingen, Interview with:
Norbert Stefan, MD
Heisenberg Professorship for Clinical and Experimental Diabetology
Department of Internal Medicine IV
University Hospital Tübingen
Tübingen, Germany What are the main findings of the study?

Dr. Stefan: Currently there is little evidence for an effective and safe pharmacological treatment of nonalcoholic fatty liver disease (NAFLD). Based on the fact that inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme, that converts inactive cortisone into active cortisol in metabolic tissues such as liver and adipose, was found to be effective to improve lipid metabolism in animals, we hypothesized that inhibition of 11β-HSD1 may also prove to be effective to decrease liver fat content in patients with NAFLD. In our 12 week trial in 82 patients with NAFLD, inhibition of 11β-HSD1 with RO5093151 resulted in a 14 % decrease of liver fat content and in a resolution of NAFLD in 20 % of the patients. This was accompanied by a decrease of liver enzymes. Furthermore, inhibition of 11β-HSD1 brought about a reduction of body weight and total body- and visceral adipose tissue mass, while insulin sensitivity did not change. In agreement with findings from other trials, also in our study 11β-HSD1 inhibition was well tolerated and safe. Were any of the findings unexpected?

Dr. Stefan: These findings were not unexpected. High 11β-HSD1 activity in metabolic tissues as the liver and adipose tissue is known to be closely related to features of the Cushing’s disease. Thus, the observed decrease in liver fat content and visceral adipose tissue mass was in agreement with the expected mode of action of a compound that specifically inhibits 11β-HSD1 activity. This supports the hypothesis that targeting 11β-HSD1 is a promising approach to treat NAFLD and visceral obesity. What should clinicians and patients take away from your report?

Dr. Stefan: Our trial was a phase 1b study. Currently there is no approved drug available that inhibits 11β-HSD1 activity. However, our findings are encouraging in that in more advanced phases such a pharmacological concept may prove to be effective in larger studies. What recommendations do you have for future research as a result of this study?

Dr. Stefan: Further clinical studies are now needed to evaluate whether longer term 11β-HSD1 inhibition might be more effective to reduce liver fat content in NAFLD, and whether it may have beneficial effects in non-alcoholic steatohepatitis. In addition, such trials should further explore whether 11β-HSD1 inhibition may qualify as a pharmacological treatment option for obesity.


Inhibition of 11β-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a multicentre, randomised, double-blind, placebo-controlled trial
Prof Norbert Stefan MD,Markus Ramsauer PhD,Paul Jordan PhD,Bettina Nowotny MD,Konstantinos Kantartzis MD,Jürgen Machann PhD,Jong-Hee Hwang PhD,Peter Nowotny PhD,Sabine Kahl MD,Jürgen Harreiter MD,Silke Hornemann MD,Prof Arun J Sanyal MD,Prof Paul M Stewart MD,Prof Andreas F Pfeiffer MD,Prof Alexandra Kautzky-Willer MD,Prof Michael Roden MD,Prof Hans-Ulrich Häring MD,Sabine Fürst-Recktenwald MD
The Lancet Diabetes & Endocrinology – 17 February 2014
DOI: 10.1016/S2213-8587(13)70170-0

Last Updated on November 26, 2014 by Marie Benz MD FAAD