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
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
Non-alcoholic fatty liver disease (NAFLD) is defined by presence of hepatic steatosis (fat
 accumulation in liver cells), either by imaging or by biopsy and absence of causes for
 secondary hepatic fat accumulation such as significant alcohol consumption, medications, or
 hereditary disorders. In the majority of patients, NAFLD is associated with risk factors for
 cardiovascular disease such as obesity, diabetes mellitus, and high cholesterol, and may lead
 to irreversible liver damage. Non-alcoholic steatohepatitis (NASH) is a more severe form of
 NAFLD and is present in up to 30% of obese adults. NASH is defined by hepatic steatosis and
 inflammation with hepatocyte injury with or without fibrosis (hardening of the liver).

 The prevalence, morbidity and mortality of NAFLD is increasing, particularly in the
 Asia-Pacific region where there will be an estimated 300 million obese people by 2030. Weight
 loss is the first-line treatment for NAFLD in obese individuals, but the utility of lifestyle
 modification with diet and exercise is limited by difficulties in sustaining compliance and
 by eventual weight regain. Bariatric (weight loss) surgery produces the greatest amount of
 weight loss but is limited by cost, patient acceptance, and complications. The efficacy of
 drugs for NASH, such as vitamin E and medication to lower cholesterol and glucose, remains
 unclear. Liraglutide, a glucagon-like peptide (GLP-1) analogue, is an injectable medication
 which has been shown to induce weight loss and lower glucose in obese adults. 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. This study aims to compare the efficacy and safety
 of lifestyle modification, liraglutide and surgery, for weight loss in conjunction with
 reducing severity of NASH, and for insulin resistance, high cholesterol and other
 cardiovascular risk factors.
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.
Inclusion Criteria:

 -  Body mass index > 27.5 kg/m2

 -  Waist circumference (WC) > 90 cm (male) or > 80 cm (female)

 -  Diagnosis of NASH based on Liver Function Test Results ,Ultrasound Hepato-Biliary
 System (HBS) findings and / or Liver Biopsy

 -  HbA1c < 8%* *Subjects in the bariatric surgery arm will not need to fulfil this
 criterion.

 Exclusion Criteria:

 -  Currently using insulin-sensitising agents (metformin, pioglitazone), weight loss
 medication (orlistat, phentermine). Patients taking any of these drugs will require a
 three month washout period before enrolment.

 -  Pregnancy

 -  Significant cardiovascular or respiratory disease

 -  Renal impairment with eGFR < 60 ml/min

 -  Hepatitis B or C carrier, liver disease other than NAFLD

 -  History of pancreatitis

 -  Personal or family history of multiple endocrine neoplasia type 2 or thyroid carcinoma

 -  Untreated hypothyroidism or hyperthyroidism

 -  Current psychiatric illness

 -  Cardiac pacemaker, metallic prosthetic heart valves and other contraindications to MRI
 scan

 -  Current smoker

 -  Alcohol intake ≥ 14 units/week