Comparing Effects of Liraglutide and Bariatric Surgery on Weight Loss, Liver Function, Body Composition, Insulin Resistance, Endothelial Function and Biomarkers of Non-alcoholic Steatohepatitis (NASH) in Obese Asian Adults

The morbidity and mortality from non-alcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, are rapidly increasing as a result of the global explosion in obesity, particularly in the Asia-Pacific region where there will be an estimated 300 million obese people by 20302. Non-alcoholic steatohepatitis (NASH), a subset of NAFLD, which is present in up to 30% of obese adults, leads to irreversible liver cirrhosis, and is associated with type 2 diabetes, cardiovascular disease and increased morbidity and mortality. Weight loss has established efficacy on NASH-associated cardiometabolic abnormalities and disease activity and severity. Diet and exercise produce a modest effect on NASH which is limited by weight regain, even with intensive lifestyle modification. Bariatric surgery produces the greatest amount of weight loss, but is less acceptable to many patients than lifestyle modification or medical therapy, and is limited by cost and complications, particularly post-surgical malabsorption and potential psychological complications. The efficacy of previously-studied medications on NASH, such as statins, insulin sensitizers and ursodeoxycholic acid, remains unclear. This study therefore aims to compare the efficacy and safety of a medication which induces weight loss and reduces insulin resistance, with that of lifestyle modification (diet and exercise), and bariatric surgery, for improvement in NASH severity, insulin resistance and other markers of cardiovascular risk. Liraglutide is an injectable glucagon-like peptide-1 (GLP-1) analogue which is indicated for treatment of type 2 diabetes in adults. It has been shown to induce weight loss and reduction in insulin resistance in type 2 diabetic and obese patients. Treatment with clinically relevant doses of liraglutide for at least 20 weeks leads to weight loss in obese patients with or without type 2 diabetes. However, there is little information on the effects of GLP-1 analogues on NASH, particularly in comparison to other modalities of weight loss such as surgery. Our study will also compare the accuracy of magnetic resonance imaging (MRI), the current noninvasive reference standard method for measuring hepatic fat content, with liver biopsy for staging of NASH. Biopsy is the current gold standard, but carries higher procedural risks, and is less convenient and acceptable to patients than non-invasive methods of evaluating severity and activity of NASH. Hence liver biopsy for week 0, 26 and week 52 is optional based on patient consent. We will also measure biomarkers for altered hepatic lipid partitioning and adipokine action, increased oxidative stress and free fatty acid lipotoxicity, which have been implicated in the pathogenesis of NAFLD, and which may be useful non-invasive methods for evaluating the severity of NASH and the efficacy of treatment.