Combination of acarbose and ezetimibe prevents non-alcoholic fatty liver disease: A break of intestinal insulin resistance?
Authors: Natalia N. Rudovich, Martin O. Weickert, Juergen Machann, Andreas F.H. Pfeiffer
Journal: Journal of Hepatology (2010)

Long-term combination therapy of ezetimibe and acarbose for non-alcoholic fatty liver diseaseJournal of HepatologyVol. 51Issue 3PreviewNon-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome that is closely associated with multiple factors such as obesity, hyperlipidemia, type 2 diabetes mellitus and hypertension, making it difficult to treat NAFLD effectively using any monotherapy available to date. In this study, we propose a novel combination therapy for NAFLD comprising ezetimibe (EZ), a cholesterol absorption inhibitor, and acarbose (AC), an α-glucosidase inhibitor. Full-Text PDF To the Editor: We read with great interest the study by Nozaki and colleagues [[1]Nozaki Y. Fujita K. Yoneda M. Wada K. Shinohara Y. Takahashi H. et al.Long-term combination therapy of ezetimibe and acarbose for non-alcoholic fatty liver disease.J Hepatol. 2009; 51: 548-556Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar] that evaluated the effect of combination therapy of ezetimibe, an intestinal cholesterol adsorption inhibitor, and acarbose, an alpha glucosidase inhibitor, on the prevention of the high-fat diet induced, non-alcoholic fatty liver disease (NAFLD) in mice. In their study, the authors concluded that the combination of both drugs for 24 weeks significantly reduced steatosis, inflammation, and fibrosis in the liver of animals, compared to long-term monotherapy with either drug. Insulin resistance and liver steatosis are interlinked metabolic abnormalities, whose prevalence is rapidly increasing worldwide [[2]Qureshi K. Abrams G.A. Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of non-alcoholic fatty liver disease.World J Gastroenterol. 2007; 14; 13: 3540-3553Crossref Scopus (206) Google Scholar]. We absolutely agree that the effective pharmacological therapy for prevention or treatment of NAFLD does not exist today, and we thus acknowledge that the recent study by Nozaki and colleagues has paved the way towards a new therapeutic approach for the prevention and treatment of NAFLD. However, we have some concerns regarding this study and its conclusions, which are outlined as follows: The authors use the high-fat diet which contains more than 57% of calories from fat and only 22.8% of carbohydrates to induce the NAFLD in animals. Despite the importance of impairment in the lipid metabolism and quantity of the dietary fat intake for the development of NAFLD [[2]Qureshi K. Abrams G.A. Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of non-alcoholic fatty liver disease.World J Gastroenterol. 2007; 14; 13: 3540-3553Crossref Scopus (206) Google Scholar], the high carbohydrate intake is also involved in the pathogens of NAFLD: first, the "soft drinks" without fat content were associated with hepatic steatosis independent of insulin resistance in humans [[3]Abid A. Taha O. Nseir W. Farah R. Grosovski M. Assy N. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome.J Hepatol. 2009; 51: 918-924Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar]; second, dietary habits with high glycemic index were associated with liver steatosis [[4]Valtuena S. Pellegrini N. Ardigo D. Del Rio D. Numeroso F. Scazzina F. et al.Dietary glycemic index and liver steatosis.Am J Clin Nutr. 2006; 84: 136-142Crossref PubMed Scopus (96) Google Scholar]. Thus, the additional model using the high glycemic load were of interest for such experimental design. Another point is the action of the acarbose in the studied dietary conditions: the strong reduction of carbohydrate intake led to the diminished action of acarbose and promising effects for ezetimibe. Interestingly and surprisingly, the reduction of fasting glycemia and insulinemia under ezetimibe treatment was as pronounced as the effects of the antidiabetic drug acarbose. Based on the principal postprandial actions of both drugs, the data from oral stimulation tests, such as oral glucose loading or meal test, could be of great interest regarding the mechanisms of NAFLD prevention. The major and very intriguing observation is the effect of the combination of acarbose and ezetimibe during the progression of NAFLD in the high-fat diet. The authors concluded two hypotheses in order to explain the observed effects: (i) the additive or multiplicative effects of both drugs on cholesterol reduction accompanying the inhibition of gut glucose absorption lead to the improvement of systemic insulin sensitivity and/or (ii) the promotion of lipid discharge from the liver and the β-oxidation of lipids in the liver. Regarding the first hypothesis, after a 12-week high-dose acarbose treatment (300 mg/d), our data in humans showed no effects on whole body insulin sensitivity, measured in the euglycemic clamp, and no changes in body weight [[5]Rudovich N. Ernst A. Pivovarova O. Traberth A. Bergmann A. Pfeiffer A.F.H. Acarbose increases atrial natriuretic peptide levels in subjects with metabolic syndrome: a novel mechanism of cardiovascular protection.J Diab. 2009; 1: A42Google Scholar]. Moreover, we observed a strong and significant decrease in the postprandial glucose and insulin concentration as an index for the improvement in the intestinal and hepatic insulin sensitivity. In the sub-group analysis of subjects with an elevated hepatic fat content, we observed 26% of the decrement under acarbose treatment [Rudovich et al., unpublished data], (Fig. 1). However, no definitive conclusion can be drawn from this first human data due to small observation sizes. No data exists on the effects of ezetimibe on insulin sensitivity in humans. Thus, the reduction in the body weight is primarily responsible for the observed improvement of insulin sensitivity under combination therapy in the study from Nozaki et al. [[1]Nozaki Y. Fujita K. Yoneda M. Wada K. Shinohara Y. Takahashi H. et al.Long-term combination therapy of ezetimibe and acarbose for non-alcoholic fatty liver disease.J Hepatol. 2009; 51: 548-556Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar]. The strongest effect of the combination therapy on the markers of the lipid metabolism in the liver was the upregulation of the SREBP-2 gene. The authors consider this effect as a secondary and compensative reaction of diminished hepatic cholesterol synthesis. The upregulation of SREBP-2 under ezetimibe application is not only a hepatic effect and was observed on the different types of enteroendocrine cells of the gut [[7]Jeon T.I. Zhu B. Larson J.L. Osborne T.F. SREBP-2 regulates gut peptide secretion through intestinal bitter taste receptor signaling in mice.J Clin Invest. 2008; 118: 3693-3700Crossref PubMed Scopus (127) Google Scholar]. Moreover, the secretion of some gastro-intestinal hormones such as cholecystokinine and glucagons-like peptide-1 are modulated by SREBP-2 via regulation of the sweet taste receptor expression [[7]Jeon T.I. Zhu B. Larson J.L. Osborne T.F. SREBP-2 regulates gut peptide secretion through intestinal bitter taste receptor signaling in mice.J Clin Invest. 2008; 118: 3693-3700Crossref PubMed Scopus (127) Google Scholar]. Thus, the upregulation of SREBP-2 under combination therapy of ezetimibe and acarbose can lead to remarkable changes in the acute postprandial and chronic secretion of different gastro-intestinal hormones. Based on the new mechanisms for the regulation of the rate of production of triglyceride-rich lipoproteins in the gut and the strong involvement of the gastro-intestinal hormones in this process [[8]Hsieh J. Hayashi A.A. Webb J. Adeli K. Postprandial dyslipidemia in insulin resistance: mechanisms and role of intestinal insulin sensitivity.Atheroscler Suppl. 2008; 9: 7-13Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar], the intestinal effects on the drug combination studied are decisive for the observed prevention of NAFLD. Moreover, the modulation of gastro-intestinal hormone responses may explain a dramatic weight reduction observed under combination of acarbose and ezetimibe in this study. In conclusion, the combination of ezetimibe and acarbose is a very promising pharmacological strategy to prevent, and possibly to treat, the NAFLD. The dysregulation of intestinal lipid and carbohydrate metabolism, i.e. "intestinal insulin resistance" [[8]Hsieh J. Hayashi A.A. Webb J. Adeli K. Postprandial dyslipidemia in insulin resistance: mechanisms and role of intestinal insulin sensitivity.Atheroscler Suppl. 2008; 9: 7-13Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar], seems to be an important mechanism in the pathogenesis of NAFLD. The Authors have declared that they received funding from the drug companies involved in order to carry out their research in this manuscript. We thank all study participants for their cooperation. We thank Ms. June Irghardt for the manuscript reading. This study was supported by a grant from Bayer Vital Pharma (Leverkusen, Germany).