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13 May 2014
New potential for non-alcoholic fatty liver disease?

The prevalence of non-alcoholic fatty liver disease (NAFLD) is escalating in line with the global epidemic of obesity and diabetes. This study evaluated the potential of a novel agent inhibiting 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1, also known as HSD11B1) in decreasing liver-fat in NAFLD.

Stefan N, Ramsauer M, Jordan P, Nowotny B, Kantartzis K, Machann J, Hwang J-H, Nowotny P, Kahl S, Harreiter J, Hornemann S, Sanyal AJ, Stewart PM, Pfeiffer AF, Kautzky-Willer A, Roden M, Häring H U, Fürst-Recktenwald S. Inhibition of 11ß-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2014; Epub ahead of print: http://dx.doi.org/10.1016/S2213-8587(13)70170-0
Summary
Comments & References
STUDY SUMMARY
Objective To investigate whether the novel agent RO5093151, which inhibits 11β-HSD1, and hence conversion of inactive cortisone to active cortisol, could safely and effectively decrease liver-fat content in patients with NAFLD.
Study design Multicentre, randomised, double-blind, placebo-controlled trial conducted at 4 centres in Germany and Austria. The study consisted of a screening visit (up to 4 weeks before randomisation), a 12-week double-blind drug treatment period, and a 2-week follow-up period. After screening, eligible patients were stratified for fasting triglycerides (<1.7 mmol/L or ≥1.7 mmol/L) and randomly allocated to oral RO5093151 (200 mg twice daily) or matching placebo for 12 weeks.
Study population

82 patients aged 35-65 years with NAFLD, defined as ¹H magnetic resonance spectroscopy liver-fat content >5.56%, and with insulin resistance (homoeostatic model assessment of insulin resistance [HOMA-IR] of at least 2.0 mmol/L∙mU/L), and body mass index (BMI) > 27 kg/m². Patients with other liver diseases, aspartate aminotransferase or alanine aminotransferase levels > 2.5 x upper limit of normal (ULN), with a history of diabetes or bariatric surgery, or who were using weight lowering drugs were excluded. Overall, 41 patients were randomly assigned to RO5093151 and 41 to placebo. Efficacy analysis was based on 74 patients, 35 in the RO5093151 group and 39 in the placebo group.

Primary variable • Percent change in liver-fat content, measured by ¹H magnetic resonance spectroscopy, from baseline to 12 weeks.
• Secondary endpoints: changes in insulin resistance and endogenous glucose production (assessed by hyperinsulinaemic-euglycaemic clamp with stable-labelled glucose) from baseline to 12 weeks.
Methods Efficacy analysis included all patients who received at least one dose of study drug and had a baseline and follow-up measurement of liver-fat content. Safety analyses included all patients who received at least one dose of study drug.
Main results

Baseline demographic and metabolic characteristics were well balanced between the two groups; overall, 71% of patients were male, ~80% had a BMI >30 kg/m2, 73% had normal glucose tolerance and ~50% had fasting triglycerides ≥1∙7 mmol/L.  Liver fat content at baseline, mean (SD) was 18.25 (10.03) in the placebo group and 16.90 (8.44) in the RO5093151 group; this difference was not statistically significant.

After 12 weeks, mean liver fat decreased significantly in the RO5093151 group but not in the placebo group (Table 1). NAFLD resolved in 20% (7/35) patients in the RO5093151 group versus 3% (1/39) in the placebo group (p=0·02). Treatment with RO5093151 also resulted in decreases in total body-fat (p<0.0001) and visceral-fat (p=0.01). These changes were associated with a decrease in liver enzyme concentrations. There were no significant differences between the two groups with respect to changes in insulin resistance or endogenous glucose production.

Table 1. Liver fat at baseline and 12 weeks.                                                                           
Data are given as mean (SD) except where indicated

 

Placebo (n=39)

RO5093151 (n=35)

Treatment difference*

Baseline

18.53 (10.00)

16.75 (8.67)

 

Week 12

18.46 (10.78)

14.28 (8.89)

 

Change*

−0·02 (−1·52 to 1·48)

−2·59 (−4·19 to −0·98)

−2·57                          (−4·64 to −0·49)
p=0.02

* Least square mean with 95% confidence interval

Adverse events were reported by 26 patients (65%) in the RO5093151 group (64 events) versus 21 patients (53%) in the placebo group (41 events). The most common adverse events were gastrointestinal disorders (12 patients [30%] in the RO5093151 group versus 7 [18%] in the placebo group), and infections and infestations (8 [20%] versus 9 [23%]).

Author's conclusion Inhibition of 11β-HSD1 by RO5093151 was effective and safe in reducing liver-fat content, suggesting that targeting of 11β-HSD1 might be a promising approach for the treatment of NAFLD.
 

COMMENT

This month the focus has been on NAFLD, which is within the spectrum of cardiometabolic abnormalities associated with metabolic syndrome, insulin resistance and atherogenic dyslipidaemia. Obesity is a key driver of the condition.(1) The liver is the site of production of two of the key components of the metabolic syndrome, fasting plasma glucose and very low-density lipoproteins (VLDL), which contain most of the triglycerides present in the serum. In NAFLD, however, the ability of insulin to normally suppress production of glucose and VLDL is impaired. In addition, there is overproduction of inflammatory factors, such as C-reactive protein, as well as thrombogenic and coagulation markers. Assessment of liver-fat provides a marker of the metabolic abnormalities that characterise NAFLD.

The optimal management of patients with NAFLD remains a clinical challenge. Lifestyle changes are currently the mainstay of treatment. While thiazolidinediones have been shown to decrease liver-fat content and hepatic inflammation, and improve insulin sensitivity, safety issues preclude their use for most patients.(2) Thus, there is an unmet need for new therapeutic approaches for the management of NAFLD.

The current study investigated the potential of inhibiting 11β-HSD1 to reduce liver-fat in NAFLD. The rationale for selection of this target is based on current understanding of the control of systemic glucocorticoid levels, which in turn regulate energy metabolism, cardiovascular homoeostasis, and the body’s response to stress. In metabolic tissues such as the liver and adipose tissue, 11β-HSD1 converts inactive cortisone into active cortisol which in turn influences glucocorticoid levels. In addition, 11β-HSD1 has been shown to regulate hepatic glucose output and has been linked to intrahepatic fat accumulation.(3,4) Supported by studies in animal models of diabetes and obesity (5,6) these insights suggest that inhibition of 11β-HSD1 may offer promise in the setting of NAFLD.

The results from this proof of concept study are interesting. Treatment with RO5093151 for 12 weeks significantly reduced liver-fat, and more patients had resolution of NAFLD compared with the placebo group (20% versus 3%, p=0.02). Treatment with RO5093151 was also associated with significant reductions in total body fat and visceral fat, although it should be borne in mind that these were considered exploratory variables.

However, while these findings are promising, there are also important limitations. First, while the study captured data relating to diet and changes in diet and exercise during the study, a possible indirect effect on food intake cannot be discounted. Second, although lifestyle intervention is regarded as the current mainstay of treatment for NAFLD, a control lifestyle intervention arm was not included in the study design. Thus, it is not possible to judge whether the magnitude of the effect with RO5093151 was greater than that achieved by lifestyle alone. Third, the duration of treatment was limited to 12 weeks, and therefore further studies of longer duration are clearly warranted.

In conclusion, this proof of concept study suggests that RO5093151 may have potential as a treatment for NAFLD. However, further studies involving longer duration of treatment are clearly needed.

References

1. Lazo M, Hernaez R, Eberhardt MS et al. Prevalence of non-alcoholic fatty liver disease in the United States: the third national health and nutrition examination survey, 1988-1994. Am J Epidemiol 2013; 178: 38–45.
2. Chalasani N, Younossi Z, Lavine JE et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012; 142: 1592–609.
3. Paterson JM, Morton NM, Fievet C et al. Metabolic syndrome without obesity: hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in transgenic mice. Proc Natl Acad Sci USA 2004; 101: 7088–93.
4. Gathercole LL, Lavery GG, Morgan SA et al. 11β-Hydroxysteroid dehydrogenase 1: translational and therapeutic aspects. Endocr Rev 2013; 34: 525–55.
5. Morton NM, Holmes MC, Fiévet C, et al. Improved lipid and lipoprotein profi le, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice. J Biol Chem 2001; 276: 41293–300.
6. Kotelevtsev Y, Holmes MC, Burchell A et al. 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. Proc Natl Acad Sci USA 1997; 94: 14924–929