Splanchnic haemodynamics in non-alcoholic fatty liver disease: effect of a dietary/pharmacological treatment. A pilot study. Effects of Insulin Glargine and Liraglutide Therapy on Liver Fat as Measured by Magnetic Resonance in Patients With Type 2 Diabetes: A Randomized Trial A Double-Blinded, Randomized, Placebo-Controlled Trial to Evaluate Efficacy, Safety, and Tolerability of Single Doses of Tirasemtiv in Patients with Acetylcholine Receptor-Binding Antibody-Positive Myasthenia Gravis Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET) Effect of Liraglutide Therapy on Liver Fat Content in Patients With Inadequately Controlled Type 2 Diabetes: The Lira-NAFLD Study Comparison of Ipragliflozin and Pioglitazone Effects on Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Randomized, 24-Week, Open-Label, Active-Controlled Trial Randomized trial comparing the effects of gliclazide, liraglutide, and metformin on diabetes with non‐alcoholic fatty liver disease† Orlistat for overweight subjects with nonalcoholic steatohepatitis: A randomized, prospective trial. Effect of metformin treatment on circulating osteoprotegerin in patients with nonalcoholic fatty liver disease Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomised controlled trial Liraglutide for weight management: a critical review of the evidence Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions. A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Effect of insulin-metformin combination on hepatic steatosis in patients with type 2 diabetes. Improvement of physical health and quality of life of alcohol-dependent individuals with topiramate treatment: US multisite randomized controlled trial. Effects of moderate weight loss and orlistat on insulin resistance, regional adiposity, and fatty acids in type 2 diabetes. Does metformin treatment influence bone formation in patients with nonalcoholic fatty liver disease? Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy. Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Clinical trial: pilot study of metformin for the treatment of non‐alcoholic steatohepatitis Metformin in patients with non-alcoholic fatty liver disease: A randomized, controlled trial Effects of liraglutide, a human glucagon-like peptide-1 analogue, on body weight, body fat area and body fat-related markers in patients with type 2 diabetes mellitus. The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease Treatment of non-alcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents. [Decrease of liver fat content by aerobic exercise or metformin therapy in overweight or obese women]. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. A Randomized Controlled Trial of Metformin versus Vitamin E or Prescriptive Diet in Nonalcoholic Fatty Liver Disease Luseogliflozin, A Sodium Glucose Co-transporter 2 Inhibitor, Alleviates Hepatic Impairment in Japanese Patients with Type 2 Diabetes. Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, open- label trial. Metformin in obese children and adolescents: the MOCA trial. Effects of metformin and weight loss on serum alanine aminotransferase activity in the diabetes prevention program. Metformin in the treatment of patients with non‐alcoholic steatohepatitis A phase 2 clinical trial of metformin as a treatment for non‐diabetic paediatric non‐alcoholic steatohepatitis Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. The effects of sibutramine and orlistat on the ultrasonographic findings, insulin resistance and liver enzyme levels in obese patients with non-alcoholic steatohepatitis. Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study Metformin in the treatment of non‐alcoholic steatohepatitis: a pilot open label trial Pioglitazone, but not metformin, reduces liver fat in Type-2 diabetes mellitus independent of weight changes. Twelve week liraglutide or sitagliptin does not affect hepatic fat in type 2 diabetes: a randomised placebo-controlled trial A pilot study of orlistat treatment in obese, non‐alcoholic steatohepatitis patients Exenatide improves type 2 diabetes concomitant with non-alcoholic fatty liver disease. Comparative effects of liraglutide 3 mg vs structured lifestyle modification on body weight, liver fat and liver function in obese patients with non‐alcoholic fatty liver disease: A pilot randomized trial Effects of Oral Antidiabetic Drugs on Changes in the Liver-to-Spleen Ratio on Computed Tomography and Inflammatory Biomarkers in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease. Effects of exenatide, insulin, and pioglitazone on liver fat content and body fat distributions in drug-naive subjects with type 2 diabetes Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial) Effects of liraglutide, metformin and gliclazide on body composition in patients with both type 2 diabetes and non‐alcoholic fatty liver disease: A randomized trial Effects of Concomitant Administration of a Dipeptidyl Peptidase-4 Inhibitor in Japanese Patients with Type 2 Diabetes Showing Relatively Good Glycemic Control Under Treatment with a Sodium Glucose Co-Transporter 2 Inhibitor. Evaluation of metformin therapy using controlled attenuation parameter and transient elastography in patients with non-alcoholic fatty liver disease. Impact of dapagliflozin, an SGLT2 inhibitor, on serum levels of soluble dipeptidyl peptidase-4 in patients with type 2 diabetes and non-alcoholic fatty liver disease. Treatment options for nonalcoholic fatty liver disease: a double-blinded randomized placebo-controlled trial Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. Effect of liraglutide on ectopic fat in polycystic ovary syndrome: A randomized clinical trial Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non‐alcoholic fatty liver disease: A prospective randomized controlled pilot study Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study Reduction of visceral fat by liraglutide is associated with ameliorations of hepatic steatosis, albuminuria, and micro-inflammation in type 2 diabetic patients with insulin treatment: a randomized control trial.
BACKGROUND Previous studies demonstrated that in experimental animals fatty liver is associated with reduced hepatic blood flow and that metformin reverses steatosis , while no data were reported in humans . AIMS To evaluate the clinical relevance of echo-Doppler measurements and the effects of therapy in non-alcoholic fatty liver disease . PATIENTS Twenty patients with biopsy proven non-alcoholic fatty liver disease . METHODS Abdominal echo-Doppler examination was performed at enrolment and , in 11 patients , after 6 months of dietary/pharmacological therapy ( metformin 500 mg three times a day ) . RESULTS Non-alcoholic fatty liver disease was characterised by hepatomegaly , bright echotexture and posterior attenuation . Mean portal blood velocity and flow were low-normal . Brightness and posterior attenuation significantly correlated with fat score in liver biopsies as well as with the hepatic veins spectrum . After therapy , echotexture improved and liver volume significantly decreased . Portal blood velocity and flow significantly increased , intrahepatic arterial indexes decreased and the spectrum of hepatic veins improved . CONCLUSIONS Fatty liver is associated with an impaired hepatic blood flow characterised by increased intrahepatic resistances . Vascular changes are reversed by treatment and can be measured by echo-Doppler which may be useful to evaluate the natural course of non-alcoholic fatty liver disease , and to monitor the putative beneficial effects of therapy OBJECTIVE This study determined the effects of insulin versus liraglutide therapy on liver fat in patients with type 2 diabetes inadequately controlled with oral agents therapy , including metformin . RESEARCH DESIGN AND METHODS Thirty-five patients with type 2 diabetes inadequately controlled on metformin monotherapy or in combination with other oral antidiabetic medications  were r and omized to receive insulin glargine or liraglutide therapy for 12 weeks . The liver proton density fat fraction ( PDFF ) was measured by MRS . The mean liver PDFF , the total liver volume , and the total liver fat index were measured by MRI . The Student t test , the Fisher exact test , and repeated- measures ANOVA were used for statistical analysis . RESULTS Insulin treatment was associated with a significant improvement in glycated hemoglobin ( 7.9 % to 7.2 % [ 62.5 to 55.2 mmol/mol ] , P = 0.005 ) , a trend toward a decrease in MRS-PDFF ( 12.6 % to 9.9 % , P = 0.06 ) , and a significant decrease in liver mean MRI-PDFF ( 13.8 % to 10.6 % , P = 0.005 ) , liver volume ( 2,010.6 to 1,858.7 mL , P = 0.01 ) , and the total liver fat index ( 304.4 vs. 209.3 % ⋅ mL , P = 0.01 ) . Liraglutide treatment was also associated with a significant improvement in glycated hemoglobin ( 7.6 % to 6.7 % [ 59.8 to 50.2 mmol/mol ] , P < 0.001 ) but did not change MRS-PDFF ( P = 0.80 ) , liver mean MRI-PDFF ( P = 0.15 ) , liver volume ( P = 0.30 ) , or the total liver fat index ( P = 0.39 ) . CONCLUSIONS The administration of insulin glargine therapy reduced the liver fat burden in patients with type 2 diabetes . However , the improvements in the liver fat fraction and glycemia control were not significantly different from those in the liraglutide group Tirasemtiv is a fast skeletal troponin activator that sensitizes the sarcomere to calcium and increases muscle force following subtetanic nerve input . In an animal model of myasthenia gravis ( MG ) , single oral doses of tirasemtiv improved muscle force and reduced fatigability . The purpose of this study was to determine the effect of single doses of tirasemtiv on skeletal muscle function and fatigability in patients with generalized MG . Thirty-two patients with acetylcholine receptor-antibody positive MG and muscle weakness received single doses of tirasemtiv ( 250 mg or 500 mg ) or placebo in a double-blind , r and omized treatment sequence with each treatment separated by at least 1 week . Outcome measures included the Quantitative MG Score ( QMG ) , MG Composite , Manual Muscle Testing , and forced vital capacity . At 6 h after dosing , tirasemtiv produced dose-related improvements from baseline in the QMG score ( slope : –0.49 QMG point per 250 mg ; p = 0.02 ) and in percent predicted forced vital capacity ( slope : 2.2 % per 250 mg ; p = 0.04 ) . QMG improved > 3 points in twice as many patients after 500 mg tirasemtiv than after placebo . Both doses of tirasemtiv were well tolerated ; there were no premature terminations or serious adverse events . The results of this study suggest that tirasemtiv may improve muscle function in MG and will be used to support further development of tirasemtiv in neuromuscular diseases BACKGROUND Exenatide , an incretin mimetic for adjunctive treatment of type 2 diabetes ( T2DM ) , reduced hemoglobin A(1c ) ( A1C ) and weight in clinical trials . The objective of this study was to evaluate the effects of > or = 3 years exenatide therapy on glycemic control , body weight , cardiometabolic markers , and safety . METHODS Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended , open-label clinical trial . Patients were r and omized to twice daily ( BID ) placebo , 5 mug exenatide , or 10 mug exenatide for 30 weeks , followed by 5 mug exenatide BID for 4 weeks , then 10 mug exenatide BID for > or = 3 years of exenatide exposure . Patients continued metformin and /or sulfonylureas . RESULTS 217 patients ( 64 % male , age 58 + /- 10 years , weight 99 + /- 18 kg , BMI 34 + /- 5 kg/m(2 ) , A1C 8.2 + /- 1.0 % [ mean + /- SD ] ) completed 3 years of exenatide exposure . Reductions in A1C from baseline to week 12 ( -1.1 + /- 0.1 % [ mean + /- SEM ] ) were sustained to 3 years ( -1.0 + /- 0.1 % ; p < 0.0001 ) , with 46 % achieving A1C < or = 7 % . Exenatide progressively reduced body weight from baseline ( -5.3 + /- 0.4 kg at 3 years ; p < 0.0001 ) . Patients with elevated serum alanine aminotransferase ( ALT ) at baseline ( n = 116 ) had reduced ALT ( -10.4 + /- 1.5 IU/L ; p < 0.0001 ) and 41 % achieved normal ALT . Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline ( -6.1 + /- 0.6 kg vs. -4.4 + /- 0.5 kg ; p = 0.03 ) , however weight change was minimally correlated with baseline ALT ( r = -0.01 ) or ALT change ( r = 0.31 ) . Homeostasis Model Assessment B ( HOMA-B ) , blood pressure , and aspartate aminotransferase ( AST ) all improved . A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis ( n = 151 ) .  Triglycerides decreased 12 % ( p = 0.0003 ) , total cholesterol decreased 5 % ( p = 0.0007 ) , LDL-C decreased 6 % ( p < 0.0001 ) , and HDL-C increased 24 % ( p < 0.0001 ) . Exenatide was generally well tolerated . The most frequent adverse event was mild-to-moderate nausea . The main limitation of this study is the open-label , uncontrolled nature of the study design which does not provide a placebo group for comparison . CONCLUSION Adjunctive exenatide treatment for > or = 3 years in T2DM patients result ed in sustained improvements in glycemic control , cardiovascular risk factors , and hepatic biomarkers , coupled with progressive weight reduction AIM We evaluated the efficacy and safety of ertugliflozin , an SGLT2 inhibitor , in type 2 diabetes mellitus ( T2DM ) inadequately controlled ( HbA1c , 7.0%-10.5 % ) with metformin monotherapy ( ≥1500 mg/d for ≥8 weeks ) . METHODS This was a double-blind , 26-week , multicentre study with ongoing 78-week extension ( Clinical Trials.gov identifier : NCT02033889 ) . A total of 621 participants were r and omized 1:1:1 to placebo , or ertugliflozin 5 or 15 mg/d . The primary endpoint was change from baseline at week 26 in HbA1c . Secondary efficacy endpoints were change from baseline at week 26 in fasting plasma glucose ( FPG ) , body weight , systolic/diastolic blood pressure ( SBP/DBP ) and number of participants with HbA1c < 7.0 % ( 53 mmol/mol ) . Pre-specified adverse events ( AEs ) of special interest and percent change from baseline in bone mineral density ( BMD ) were also assessed at week 26 . RESULTS At week 26 , the placebo-adjusted least-squares mean change from baseline HbA1c ( 8.1 % ) was -0.7 % and -0.9 % for ertugliflozin 5 and 15 mg , respectively ( both P < .001 ) , to final means of 7.3 % and 7.2 % , respectively . The odds of HbA1c < 7.0 % were significantly greater in both ertugliflozin groups vs placebo . Ertugliflozin significantly reduced FPG , body weight , SBP and DBP vs placebo . The incidence of genital mycotic infections was higher in the ertugliflozin groups ( female subjects : placebo , 0.9 % ; ertugliflozin 5 mg , 5.5 % ; ertugliflozin 15 mg , 6.3 % [ P = .032 ] ; male subjects : 0 % ; 3.1 % ; 3.2 % , respectively ) , as was the incidence of urinary tract infections and symptomatic hypoglycaemia . The incidence of hypovolaemia AEs was similar across  groups . Ertugliflozin had no adverse impact on BMD at week 26 . CONCLUSIONS Ertugliflozin added to metformin in patients with inadequately controlled T2DM improved glycaemic control , reduced body weight and BP , but increased the incidence of genital mycotic infections Background : Nonalcoholic fatty liver disease is very frequent in type 2 diabetes , with increased risk of further development of liver fibrosis . Animal studies have shown that GLP-1 receptor agonists may reduce liver lipogenesis . However , data in humans are scarce . Objective : To study the effect of liraglutide 1.2 mg/d on liver fat content ( LFC ) in patients with uncontrolled type 2 diabetes and to evaluate the factors potentially associated with liraglutide-induced modification of LFC . Design , Setting , Participants : LFC was measured by proton magnetic resonance spectroscopy before and after 6 months of liraglutide treatment in 68 patients with uncontrolled type 2 diabetes mellitus . Intervention : Liraglutide 1.2 mg/d . Outcome measure : Change in LFC . Results : Treatment with liraglutide was associated with a significant decrease in body weight , HbA1C , and a marked relative reduction in LFC of 31 % ( P < 0.0001 ) . No significant modification of LFC was observed in a parallel group of patients 6 months after intensification of the antidiabetic treatment with insulin . The reduction in LFC and body weight were highly correlated ( r = 0.490 ; P < 0.0001 ) . In multivariate analysis , the reduction in LFC was independently associated with baseline LFC ( P < 0.0001 ) , age ( P = 0.010 ) , and reduction in body weight ( P < 0.0001 ) , triglycerides ( P = 0.019 ) , and HbA1c ( P = 0.034 ) . In the patients who had no significant decrease in body weight , no significant reduction in LFC was observed . Conclusions : Six months of treatment with liraglutide 1.2 mg/d significantly reduced LFC  in patients with inadequately controlled type 2 diabetes and this effect was mainly driven by body weight reduction . Further studies are needed to confirm that this reduction in LFC may significantly reduce fibrosis progression OBJECTIVE To compare the efficacy of ipragliflozin versus pioglitazone in patients with type 2 diabetes complicated by nonalcoholic fatty liver disease ( NAFLD ) . RESEARCH DESIGN AND METHODS In this open-label , r and omized , active-controlled trial , we r and omly assigned 66 patients with type 2 diabetes and NAFLD to receive ipragliflozin 50 mg ( n = 32 ) or pioglitazone 15–30 mg ( n = 34 ) orally once daily . The primary outcome was a change from baseline in the liver-to-spleen attenuation ratio ( L/S ratio ) on computed tomography at week 24 . RESULTS At week 24 , the mean ± SD L/S ratio had increased by 0.22 ( from 0.80 ± 0.24 to 1.00 ± 0.18 ) in the ipragliflozin group and 0.21 ( from 0.78 ± 0.26 to 0.98 ± 0.16 ) in the pioglitazone group ( P = 0.90 ) . Serum aspartate and alanine aminotransferase levels , HbA1c , and fasting plasma glucose were similarly reduced in the two treatment groups . Nevertheless , body weight and visceral fat area showed significant reductions only in the ipragliflozin group compared with the pioglitazone group ( P < 0.0001 and P = 0.0013 , respectively ) . There were no serious adverse events in either group . CONCLUSIONS Compared with pioglitazone , ipragliflozin exerts equally beneficial effects on NAFLD and glycemic control during the treatment of patients with type 2 diabetes complicated by NAFLD . Furthermore , ipragliflozin significantly reduced body weight and abdominal fat area BACKGROUND The aim of the present study was to compare the effects of gliclazide , liraglutide , and metformin in type 2 diabetes mellitus ( T2DM ) patients with non-alcoholic fatty liver disease ( NAFLD ) . METHODS Eighty-seven subjects were r and omized to receive liraglutide , metformin , or gliclazide for 24 weeks . Primary outcomes included HbA1c levels , intrahepatic fat ( IHF ) content , and liver function . RESULTS Both HbA1c levels and IHF content were reduced after treatment in all three groups . However , HbA1c levels were lower in the liraglutide- and metformin-treated groups than in the gliclazide-treated group , and reductions in IHF content were greater with liraglutide than with gliclazide . Liraglutide and metformin treatments reduced weight and improved liver function . Changes in IHF content were positively correlated with reductions in serum alanine aminotransferase and triglyceride levels , as well as weight . At 24 weeks , reductions in IHF content were greater in subjects with weight loss ≥5 % , changes in waistline ≤0 cm ( including decreases in waistline ) , HbA1c reductions ≥2.5 % , and HbA1c levels < 6.5 % . CONCLUSIONS In T2DM patients with NAFLD , compared with liraglutide and metformin , gliclazide result ed in less improvement in liver function , reductions in IHF content and HbA1c levels , and less weight loss ; in addition , slightly better improvements were achieved with liraglutide than with metformin The aim of this study was to determine if orlistat , an inhibitor of fat absorption , combined with caloric restriction in overweight subjects with nonalcoholic steatohepatitis results in weight loss and improved liver histology .  Fifty overweight subjects ( body mass index = > or=27 ) with biopsy proven nonalcoholic steatohepatitis were r and omized to receive a 1,400 Kcal/day diet plus vitamin E ( 800 IU ) daily with or without orlistat ( 120 mg three times a day ) for 36 weeks . Liver biopsies were repeated at week 36 . Twenty-three subjects in the orlistat/diet/vitamin E group and 18 in the diet/vitamin E group completed the study . The mean age was 47 + /- 9.0 ( st and ard deviation ) years and mean body mass index was 36.4 + /- 6.3 kg/m(2 ) . Four subjects were diabetic . The orlistat group lost a mean of 8.3 % body weight compared to 6.0 % in the diet plus vitamin E group ( not significant ) . Both groups also had similarly improved serum aminotransferases , hepatic steatosis , necroinflammation , ballooning , and nonalcoholic fatty liver disease activity scores . Stratified according to weight loss instead of treatment group , a loss of > or=5 % body weight ( n = 24 ) compared to < 5 % body weight ( n = 17 ) correlated with improvement in insulin sensitivity ( P = 0.001 ) and steatosis ( P = 0.015 ) . Comparing subjects who lost > or=9 % of body weight ( n = 16 ) , to those that did not ( n = 25 ) , improved insulin sensitivity ( P < 0.001 ) , adiponectin ( P = 0.03 ) , steatosis ( P = 0.005 ) , ballooning ( P = 0.04 ) , inflammation ( P = 0.045 ) , and nonalcoholic fatty liver disease activity score ( P = 0.009 ) were seen . Increases in adiponectin strongly correlated with improved ballooning and nonalcoholic fatty liver disease activity score ( P = 0.03 ) . Orlistat did not enhance weight loss or improve liver enzymes , measures of insulin resistance , and histopathology . However , subjects who lost > or=5 % of body weight over 9 months improved insulin resistance and steatosis , and those subjects who lost > or=9 % also achieved improved hepatic histologic changes Purpose / introduction Growing evidence suggests complex interplay between nonalcoholic fatty liver disease ( NAFLD ) and bone health . The present study ’s aim was to examine the impact of metformin treatment on circulating osteoprotegerin ( OPG ) in patients with NAFLD , a population in which this relationship has not yet been studied . Methods In a r and omized , placebo-controlled study , 63 patients with NAFLD were assigned to one of two groups : Group 1 received daily metformin ; Group 2 received a placebo .  Metabolic parameters , insulin resistance markers and OPG levels were examined at baseline and at the end of the study . Results In the placebo group , liver function and OPG levels did not change during the study . Among metformin-treated patients , significant declines in OPG and alkaline phosphatase were observed . CRP and ALT decreased marginally during the 4-month treatment period . While at baseline circulating OPG levels did not differ significantly between the groups , by the end of the study OPG was significantly lower in patients treated with metformin than in the placebo group ( p < 0.0001 ) . Delta OPG was significantly greater in the metformin group than the placebo group ( p = 0.001 ) . In the general linear model , metformin treatment was the only significant independent predictor of endpoint and delta OPG .  Conclusions Metformin treatment was associated with a significant decrease in OPG levels in patients with NAFLD . The effect on OPG was associated with exposure to metformin per se . Clinical trial registration numberNCT01084486 Abstract Aims /hypothesisSystemic fibroblast growth factor (FGF)21 levels and hepatic FGF21 production are increased in non-alcoholic fatty liver disease patients , suggesting FGF21 resistance . We examined the effects of exenatide on FGF21 in patients with type 2 diabetes and in a diet-induced mouse model of obesity ( DIO ) . Methods Type 2 diabetes mellitus patients ( n = 24 ) on diet and /or metformin  were r and omised ( using a table of r and om numbers ) to receive additional treatment consisting of pioglitazone 45 mg/day or combined therapy with pioglitazone ( 45 mg/day ) and exenatide ( 10 μg twice daily ) for 12 months in an open label parallel study at the Baylor Clinic . Results Twenty-one patients completed the entire study and were included in the analysis . Pioglitazone treatment ( n = 10 ) reduced hepatic fat as assessed by magnetic resonance spectroscopy , despite a significant increase in body weight ( Δ = 3.7 kg ) ; plasma FGF21 levels did not change ( 1.9 ± 0.6 to 2.2 ± 0.6 ng/ml [ mean±SEM ] ) . However , combined pioglitazone and exenatide therapy ( n = 11 ) was associated with a significant reduction of FGF21 levels ( 2.3 ± 0.5 to 1.1 ± 0.3 ng/ml ) and a greater decrease in hepatic fat . Besides weight gain observed in the pioglitazone-treated patients , lower extremity oedema was observed as a side effect in two of the ten patients . Three patients who received pioglitazone and exenatide combination therapy complained of significant nausea that was self-limiting and did not require them to leave the study . In DIO mice , exendin-4 for 4 weeks significantly reduced hepatic triacylglycerol content , decreased hepatic FGF21 protein and mRNA , and enhanced phosphorylation of hepatic AMP-activated protein kinase ( AMPK ) and acetyl-CoA carboxylase , although no significant difference in weight and body fat was observed . Hepatic FGF21 correlated inversely with hepatic AMPK phosphorylation Conclusions /interpretationIn type 2 diabetes mellitus , combined pioglitazone and exenatide therapy is associated with a reduction in plasma FGF21 levels , as well as a greater decrease in hepatic fat than that achieved with pioglitazone therapy . In DIO mice , exendin-4 treatment reduces hepatic triacylglycerol and FGF21 protein , and enhances hepatic AMPK phosphorylation , suggesting an improvement of hepatic FGF21 resistance . Trial registration number : Clinical Trials.gov NCT 01432405 Funding : American Diabetes Association , the Ron MacDonald Foundation at St Luke ’s Episcopal Hospital , Amylin Pharmaceuticals , Eli-Lilly , NIH Molecular Medicine Scholars Training Grant , NIH Diabetes and Endocrinology Research Center ( DERC ) at Baylor College of Medicine , and the T.T. and W.F. Chao Foundation Summary Objective To review the efficacy , safety , and clinical applicability of liraglutide for weight management from phase III clinical trials . Methods A search of the English language literature was performed using PubMed search terms : “ liraglutide ” , “ glucagon‐like peptide‐1 receptor agonist ” , and “ r and omized clinical trial ” . Articles and bibliographies relevant to the subject were review ed and additional references known to the authors were included . Results Five r and omized , placebo‐controlled trials of liraglutide for weight management were identified . In addition to recommended diet and physical activity , liraglutide consistently result ed in a 4 to 6 kg weight loss , with a greater proportion of patients achieving at least 5 and 10 % weight loss compared with placebo . The most common adverse effects were gastrointestinal and primarily occurred early in the treatment course . Comparative data suggest that weight loss  with liraglutide is greater than that seen with orlistat or lorcaserin , but slightly less that seen with phentermine/topiramate . Liraglutide 1.8 mg was recently shown to have cardiovascular benefit in a large outcomes trial ; applicability of these results for the 3.0 mg formulation in a more diverse weight loss population at high cardiovascular risk is not currently known . Barriers to real‐world clinical use as a first‐line agent include gastrointestinal side effects , high cost , and need for injection . Conclusions Liraglutide helps to induce and sustain weight loss in patients with obesity . Its efficacy is comparable to other available agents but it offers the unique benefit of improved glycemic control . Additional studies are needed to determine its long term efficacy and safety profile BACKGROUND Insulin resistance plays an important role in the pathogenesis of NAFLD . Pharmacological treatment of patients with NAFLD is still evolving . Insulin sensitizing drugs like metformin may be effective in these patients . Twenty five adult patients with NAFLD who did not achieve normalization of alanine transaminases ( ALT ) after 6 months of lifestyle interventions and UDCA were treated with metformin 500 mg tid for 6 months . Insulin resistance was determined by HOMA- IR . Liver function tests were done monthly and patients were defined having no response , partial response or complete biochemical response depending on the change in ALT . Results were compared with 25 patients with NAFLD from the same cohort treated only with lifestyle interventions ( disease controls ) . RESULTS Thirteen ( 52 % ) patients had class III ( n = 5 ) or class IV ( n = 8) disease amounting to histological NASH . Of these 13 patients none had severe inflammation and none had stage 4 fibrosis ( cirrhosis ) . All 25 patients with NAFLD had insulin resistance in comparison to healthy controls . In comparison to disease controls ( 127.5 + /- 41.8 vs. 118 + /- 21.6 p = NS ) , all patients treated with metformin had partial biochemical response ( mean ALT 122.2 + /- 26.8 vs 74.3 + /- 4.2 p < 0.01 ) and 14 ( 56 % ) of them achieved complete normalization of ALT . CONCLUSIONS Metformin is effective to achieve biochemical response in patients with NAFLD who do not respond to lifestyle interventions  and UDCA BACKGROUND & AIMS Few controlled studies have addressed the issue of effective medical treatment for nonalcoholic fatty liver disease ( NAFLD ) . We herein assessed the effect of orlistat in patients with NAFLD . METHODS We performed a r and omized , double-blind , placebo-controlled study on 52 patients with NAFLD diagnosed by ultrasound ( US ) and confirmed by liver biopsy ( 40 patients ) . The patients were r and omized to receive either orlistat ( 120 mg 3 times daily for 6 months ) or placebo . All patients participated in an identical behavioral weight loss program . All patients underwent monthly evaluation by abdominal US ; liver enzyme levels , lipid profiles , insulin levels , and anthropometric parameters were monitored , and all patients underwent nutritional follow-up evaluation . Twenty-two patients underwent a second liver biopsy examination at the end of the study . RESULTS Fifty-two patients were recruited and 44 ( mean age , 47.7 y ; mean body mass index , 33 ) completed the study .  Serum glucose and insulin levels ( P<.03 ) were significantly higher in the orlistat group , which also presented a higher degree of fibrosis . Body mass index was reduced significantly in each group , with a nonsignificant difference between the groups . Serum alanine transaminase ( ALT ) levels decreased significantly in both groups , with an almost 2-fold reduction in the orlistat group ( 48 % vs 26.4 % ) . There was a statistically significant reversal of fatty liver by US only in the orlistat group ( P<.05 ) . CONCLUSIONS Orlistat improves serum ALT levels and steatosis on US in NAFLD patients , beyond its effect on weight reduction OBJECTIVE Hepatic steatosis occurs in up to 78 % of patients with type 2 diabetes . Studies evaluating the effect of metformin on hepatic steatosis are conflicting . Insulin is believed to be detrimental due to its lipogenic effect . Since insulin-metformin combination is commonly used for the treatment of diabetes , it is important to assess the effect of this combined therapy on hepatic steatosis . We evaluated the change in hepatic steatosis following the initiation of insulin and metformin in patients with type 2 diabetes . METHODS Newly diagnosed treatment-naïve patients with type 2 diabetes had their hepatic triglyceride ( TG ) content measured by magnetic resonance spectroscopy at baseline and after 3 months of treatment with BiAsp 30 insulin , in combination with metformin . Insulin was administered twice daily and titrated to achieve normal capillary blood glucose levels . Metformin was titrated during the first month from 500 mg daily to 1000 mg bid . RESULTS The average hepatic TG content in 19 enrolled subjects was 11.83+/-7.61 % ( range , 0.93 - 23.16 % ) and correlated with body mass index ( r=.567 ) . Three months of treatment reduced hepatic steatosis by 45 % , with 75 % of the study subjects achieving a normal level . The change in hepatic TG content was partially explained by changes in HbA1c ( P=.006 ) and cholesterol ( P=.003 ) levels . CONCLUSIONS The combined treatment with insulin and metformin significantly reduced hepatic steatosis in patients with newly diagnosed type 2 diabetes BACKGROUND Topiramate can improve drinking outcomes via a hypothesized mechanism of facilitating gamma-aminobutyric acid function and inhibiting glutaminergic pathways in the corticomesolimbic system . We sought to determine whether topiramate 's antidrinking effects are bolstered by improvements in physical and psychosocial well-being . METHODS In a 17-site , 14-week , double-blind , r and omized controlled trial , we compared the effects of topiramate ( up to 300 mg/d ) vs placebo on physical health , obsessional thoughts and compulsions about using alcohol , and psychosocial well-being among 371 alcohol-dependent subjects who received weekly adherence enhancement therapy .  RESULTS Topiramate was more efficacious than placebo in reducing body mass index ( calculated as weight in kilograms divided by height in meters squared ) ( mean difference , 1.08 ; 95 % confidence interval [ CI ] , 0.81 - 1.34 ; P < .001 ) , all liver enzyme levels ( P < .01 for all comparisons ) , plasma cholesterol level ( mean difference , 13.30 mg/dL ; 95 % CI , 5.09 - 21.44 mg/dL ; P = .002 ) , and systolic ( mean difference , 9.70 mm Hg ; 95 % CI , 6.81 - 12.60 mm Hg ; P < .001 ) and diastolic ( mean difference , 6.74 mm Hg ; 95 % CI , 4.57 - 8.90 mm Hg ; P < .001 ) blood pressure to about prehypertension levels-effects that might lower the risk of fatty liver degeneration and cirrhosis as well as cardiovascular disease . Topiramate compared with placebo significantly ( P < .05 for all comparisons ) decreased obsessional thoughts and compulsions about using alcohol , increased subjects ' psychosocial well-being , and improved some aspects of quality of life , thereby diminishing the risk of relapse and longer-term negative outcomes . Paresthesia , taste perversion , anorexia , and difficulty with concentration were reported more frequently for topiramate than for placebo . CONCLUSION Topiramate appears to be generally effective at improving the drinking outcomes and physical and psychosocial well-being of alcoholic subjects OBJECTIVE Moderate weight loss is recommended for overweight and obese patients with type 2 diabetes , and conjunctive use of weight loss medication has been advocated . The current study examined weight loss-dependent and -independent effects of the intestinal lipase inhibitor orlistat at 6 months of treatment , using behavioral intervention ( Int ) combined with r and omized , double-blinded , placebo (P)-controlled treatment with orlistat ( O ) . RESEARCH DESIGN AND METHODS Metabolic control , insulin sensitivity ( IS ) , regional fat distribution , and fat content in liver and muscle were measured in 39 volunteers with type 2 diabetes in whom all antidiabetic medication was withdrawn 1 month preceding r and omization .  Weight loss was equivalent in the Int+O and Int+P groups , respectively ( -10.3 + /- 1.3 vs. -8.9 + /- 1.1 % ) , and there were identical decreases in visceral adipose tissue ( VAT ) , fat mass ( FM ) , thigh adiposity , and hepatic steatosis . RESULTS Weight loss result ed in substantial improvement ( P < 0.001 ) in HbA(1c ) ( -1.6 + /- 0.3 vs. -1.0 + /- 0.4 % ; NS between groups ) . IS improved significantly more with orlistat ( Delta2.2 + /- 0.4 vs. Delta1.2 + /- 0.4 mg . min(-1 ) . kg(-1 ) fat-free mass [ FFM ] ; P < 0.05 ) , and plasma free fatty acid ( FFA ) levels were strongly correlated with IS ( r = 0.56 ; P < 0.001 ) . Orlistat caused greater reductions in fasting plasma FFA ( Delta-154 + /- 22 vs. Delta-51 + /- 33 micro mol/l ; P < 0.05 ) , insulin-suppressed FFA ( Delta-119 + /- 23 vs. Delta-87 + /- 34 micro mol/l ; P < 0.05 ) , and fasting plasma glucose ( FPG ; -62 + /- 9 vs. -32 + /- 8 mg/dl ; P = 0.02 ) . Changes in HbA(1c ) were correlated with DeltaIS ( r = -0.41 ; P < 0.01 ) but not with weight loss per se . CONCLUSIONS At equivalent weight loss , conjunctive use of orlistat result ed in greater improvement in FFA levels and IS Antidiabetic drug metformin that improves insulin sensitivity and used in the treatment of nonalcoholic fatty liver disease ( NAFLD ) , may affect the bone health . Our study was design ed to investigate a possible effect of metformin on bone formation marker , procollagen type I N-terminal propeptide ( P1NP ) in patients with NAFLD.In a r and omized , placebo controlled study , 63 patients with NAFLD were assigned to one of 2 groups : Group 1 received daily metformin and Group 2 received placebo .  Metabolic parameters , insulin resistance markers , and P1NP were determined . Although circulating P1NP levels did not differ significantly between the groups at baseline , at the end of the study , P1NP was significantly lower in patients treated with metformin than in the placebo group ( p<0.007 ) . Within-group analysis indicated that P1NP levels significantly decreased ( p=0.023 ) in patients receiving metformin during 4-month follow-up period , while no change in P1NP was observed in placebo group ( p=0.359 ) . In general linear model metformin treatment was the only significant independent predictor of endpoint P1NP.Metformin treatment was associated with decrease in P1NP levels in patients with NAFLD . The effect on P1NP was independent of glucose lowering effect and caused from exposure to metformin per se AIM To conduct a prospect i ve r and omized trial to investigate the effect of glucagon-like peptide-1 ( GLP-1 ) analogues on ectopic fat stores . METHODS A total of 44 obese subjects with type 2 diabetes uncontrolled on oral antidiabetic drugs were r and omly assigned to receive exenatide or reference treatment according to French guidelines . Epicardial adipose tissue ( EAT ) , myocardial triglyceride content ( MTGC ) , hepatic triglyceride content ( HTGC ) and pancreatic triglyceride content ( PTGC ) were assessed 45 min after a st and ardized meal with 3 T magnetic resonance imaging and proton magnetic resonance spectroscopy before and after 26 weeks of treatment . RESULTS The study population had a mean glycated haemoglobin ( HbA1c ) level of 7.5 ± 0.2 % and a mean body mass index of 36.1 ± 1.1 kg/m(2 ) . Ninety five percent had hepatic steatosis at baseline ( HTGC ≥ 5.6 % ) . Exenatide and reference treatment led to a similar improvement in HbA1c ( -0.7 ± 0.3 % vs. -0.7 ± 0.4 % ; p = 0.29 ) , whereas significant weight loss was observed only in the exenatide group ( -5.5 ± 1.2 kg vs. -0.2 ± 0.8 kg ; p = 0.001 for the difference between groups ) . Exenatide induced a significant reduction in EAT ( -8.8 ± 2.1 % ) and HTGC ( -23.8 ± 9.5 % ) , compared with the reference treatment ( EAT : -1.2 ± 1.6 % , p = 0.003 ; HTGC : + 12.5 ± 9.6 % , p = 0.007 ) . No significant difference was observed in other ectopic fat stores , PTGC or MTGC . In the group treated with exenatide , reductions in liver fat and EAT were not associated with homeostatic model assessment of insulin resistance index , adiponectin , HbA1c or fructosamin change , but were significantly related to weight loss ( r = 0.47 , p = 0.03 , and r = 0.50 , p = 0.018 , respectively ) . CONCLUSION Our data indicate that exenatide is an effective treatment to reduce liver fat content and epicardial fat in obese patients with type 2 diabetes , and these effects are mainly weight loss dependent Aim To investigate the efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease ( NAFLD ) patients . Methods This is an open-label , r and omized , a single-center study . Sixty-four patients , with impaired glucose metabolism and elevated alanine aminotransferase for at least 6 months before enrollment and NAFLD activity score at least 5 in liver biopsy , were r and omized as group 1 and received metformin 1700 mg/day , group 2 received rosiglitazone 4 mg/day , and group 3 received a combination of metformin 1700 mg/day and rosiglitazone 4 mg/day for 12 months . Results Baseline demographic and laboratory findings were similar in all the three groups , except baseline insulin level that was significantly higher in group 1 and group 3 versus group 2 ( P<0.05 ) . Serum transaminase levels showed a significant decrease after treatment in both group 2 and group 3 . Serum & ggr;-glutamyl transpeptidase levels decreased significantly only in the group 3 . However , there was no significant change in liver tests of group 1 . Postpr and ial glucose levels showed significant decrease in all of the three groups . Homeostasis model assessment -insulin resistance was reduced significantly in only group 2 . NAFLD score was significantly decreased on follow-up biopsy of the patients in group 2 and group 3 . Fibrosis did not change significantly after the treatment . Conclusion Rosiglitazone therapy seems to be more effective in metabolic control and histological improvement in NAFLD patients with impaired glucose metabolism Both rosiglitazone and metformin increase hepatic insulin sensitivity , but their mechanism of action has not been compared in humans . The objective of this study was to compare the effects of rosiglitazone and metformin treatment on liver fat content , hepatic insulin sensitivity , insulin clearance , and gene expression in adipose tissue and serum adiponectin concentrations in type 2 diabetes . A total of 20 drug-naive patients with type 2 diabetes ( age 48 + /- 3 years , fasting plasma glucose 152 + /- 9 mg/dl , BMI 30.6 + /- 0.8 kg/m2 ) were treated in a double-blind r and omized fashion with either 8 mg rosiglitazone or 2 g metformin for 16 weeks . Both drugs similarly decreased HbA1c , insulin , and free fatty acid concentrations . Body weight decreased in the metformin ( 84 + /- 4 vs. 82 + /- 4 kg , P < 0.05 ) but not the rosiglitazone group . Liver fat ( proton spectroscopy ) was decreased with rosiglitazone by 51 % ( 15 + /- 3 vs. 7 + /- 1 % , 0 vs. 16 weeks , P = 0.003 ) but not by metformin ( 13 + /- 3 to 14 + /- 3 % , NS ) . Rosiglitazone ( 16 + /- 2 vs. 20 + /- 1 ml.kg(-1).min(-1 ) , P = 0.02 ) but not metformin increased insulin clearance by 20 % . Hepatic insulin sensitivity in the basal state increased similarly in both groups . Insulin-stimulated glucose uptake increased significantly with rosiglitazone but not with metformin .  Serum adiponectin concentrations increased by 123 % with rosiglitazone but remained unchanged during metformin treatment . The decrease of serum adiponectin concentrations correlated with the decrease in liver fat ( r = -0.74 , P < 0.001 ) . Rosiglitazone but not metformin significantly increased expression of peroxisome proliferator-activated receptor-gamma , adiponectin , and lipoprotein lipase in adipose tissue . In conclusion , rosiglitazone but not metformin decreases liver fat and increases insulin clearance . The decrease in liver fat by rosiglitazone is associated with an increase in serum adiponectin concentrations . Both agents increase hepatic insulin sensitivity , but only rosiglitazone increases peripheral glucose uptake Background Non‐alcoholic steatohepatitis ( NASH ) is a form of progressive fatty liver disease that is strongly associated with insulin resistance , which suggests that insulin sensitizing agents such as metformin may be beneficial for NASH Objective . The antidiabetic agent metformin is regularly discussed as a promising treatment for non-alcoholic fatty liver disease ( NAFLD ) , which is characterized by insulin resistance . However , the evidence for its beneficial effects is limited , and conflicting reports have been published . The purpose of this study was to conduct a r and omized , double-blind , placebo-controlled trial to test whether metformin improves liver histology in patients with non-alcoholic fatty liver disease . Material and methods . Forty-eight patients with biopsy-proven NAFLD were r and omized to treatment with metformin ( n=24 ) or placebo ( n=24 ) for 6 months . A second liver biopsy was obtained in all subjects who completed the trial ( n=44 ) . Data analyses are restricted to this group ( per- protocol analyses ) . The primary outcome was changes in histologically assessed liver steatosis . Secondary outcomes were changes in NAFLD activity (NAS)-score , liver steatosis assessed by computed tomography ( CT ) , liver transaminases , body-weight , metabolic variables and inflammatory markers . Results . No significant differences between treatment with metformin or placebo were observed for changes in liver steatosis , assessed either histologically or by CT , NAS-score , liver transaminases or on markers of insulin resistance or inflammation . In contrast , beneficial effects of metformin were observed on changes in body-weight ( p<0.001 ) , serum levels of cholesterol ( p=0.004 ) , LDL-cholesterol ( p<0.001 ) , glucose ( p=0.032 ) and on HbA1c ( p=0.020 ) . Conclusions . Treatment with metformin for 6 months was no better than placebo in terms of improvement in liver histology in patients with NAFLD . Nevertheless , the use of metformin could still be beneficial in this group as it is associated with a reduction in serum levels of lipids and glucose . ( Clinical Trials.gov number , NCT00303537 OBJECTIVE To evaluate the effects of six-month liraglutide treatment on body weight , visceral and subcutaneous fat and related markers in Japanese type 2 diabetic patients . METHODS A total of 59 patients with type 2 diabetes were treated with liraglutide ( 0.3 mg/day for ≥1 week and then 0.6 mg/day for ≥1 week , gradually increasing the dose to 0.9 mg/day ) for six months . Changes in body weight , body mass index ( BMI ) , HbA1c , the fasting blood glucose level , visceral and subcutaneous fat areas , hepatic and renal CT values and the associated markers proinsulin , adiponectin and pentraxin ( PTX ) 3 were measured . RESULTS The study included one treatment-naïve patient , 10 patients who were switched from oral antidiabetic drugs and 35 patients who were switched from insulin therapy .  At six months after treatment , the prepr and ial blood glucose levels were higher ( 148.8±40.5 mg/dL ) than the baseline values ( 130.8±36.7 , p<0.05 ) ; however , body weight , BMI and abdominal circumference were lower , and the liver/kidney CT ratio improved significantly from 1.64±0.44 at baseline to 1.78±0.42 . An analysis of the patients who were not pretreated with insulin resistance ameliorators showed that six months of liraglutide treatment significantly decreased the subcutaneous but not visceral fat areas , significantly decreased the serum adiponectin levels and significantly increased the serum PTX3 levels . CONCLUSION In addition to its glucose-lowering effects , liraglutide exhibits weight loss promotion actions , reducing subcutaneous fat areas in particular . The weight and total fat area reduction properties of liraglutide are likely to be beneficial when this medication is used in combination with other oral antidiabetic drugs and insulin Insulin resistance is a major feature of type 2 diabetes mellitus , obesity and nonalcoholic fatty liver disease ( NAFLD ) . Several studies pointed out the possible role of increased leptin in NAFLD in humans . The aim of this study is to determine the effect of metformin on plasma leptin levels in obese patients with type 2 diabetes mellitus and NAFLD compared with lifestyle interventions .  Thirty-four obese patients with newly diagnosed type 2 diabetes mellitus were prospect ively followed for 6 months . All patients had ultrasonographic evidence of NAFLD at baseline . The patients were r and omized into two groups : group 1 ( n = 15 ) followed lifestyle changes only and group 2 ( n = 19 ) received metformin ( 1,700 mg/day ) . At the end of treatment , BMI , WHR , HbA1c , fasting glucose , leptin , HOMA-IR , alanine aminotransferase values decreased in both groups . No significant difference in the end-points was observed between two groups . Only in group 2 , LDL decreased and HDL increased significantly . Liver echogenity decreased significantly at the end of study in both groups . The percentage of patients who no longer had evidence of NAFLD was not significantly different between the groups ( 20 % of patients on lifestyle intervention vs. 16 % of patients on metformin ) . The data demonstrate that , metformin and lifestyle interventions equally affected the plasma leptin levels , BMI and degree of NAFLD in obese patients with type 2 diabetes mellitus . In addition , the effects of metformin on the variables were not found to be mediated by leptin The presence of fatty liver per ultrasound and liver-associated enzymes were measured in a select cohort of youth with both obesity and insulin resistance , and the effect of metformin on these parameters evaluated . Fifty obese , multiethnic , insulin-resistant adolescents ( mean age 15.1 yr , mean body mass index 39.8 kg/m2 ) were r and omized to receive lifestyle recommendations plus either twice per day doses of 850 mg of metformin or placebo .  Fasting and post-glucose challenge biochemistries and liver ultrasounds were compared at baseline and 6 months . The prevalence of fatty liver was 74 % , elevated alanine aminotransferase ( ALT ) 14 % , aspartate aminotransferase ( AST ) 14 % , and gamma-glutamyl transferase ( GGT ) 17 % . Fatty liver was mild in 23 % , moderate in 31 % , and severe in 46 % . Fatty liver was more common in male and Hispanic subjects and elevated ALT more common in Hispanic subjects . Subjects with fatty liver appeared more insulin resistant ( higher fasting insulin and triglycerides , lower high-density lipoprotein cholesterol ) and had higher ALT and AST . At 6 months , mean ALT , GGT , and fasting insulin improved significantly in all subjects . Fatty liver prevalence ( p < 0.04 ) , severity ( p < 0.04 ) , and fasting insulin ( p < 0.025 ) improved significantly with metformin compared to placebo . Non-alcoholic fatty liver disease ( NAFLD ) occurs with a high prevalence and severity in obese , insulin-resistant adolescents . While metformin plus lifestyle intervention appears promising , defining NAFLD therapies capable of preventing fibrosis and cirrhosis requires further study INTRODUCTION Nonalcoholic fatty liver disease ( NAFLD ) is characterized by high intrahepatic triglyceride level . It is associated with an increased prevalence of cardiovascular disease , independently of underlying cardiometabolic risk factors . Metformin is used as a pharmacological treatment ; the adherence is low because of the presence of adverse effects . Aerobic exercise could be an alternative therapy , but its effectiveness compared with metformin has not been established in the treatment of NAFLD . The aim of this study was to establish the effectiveness of aerobic exercise and its influence in reducing cardiovascular risk in overweight or obese women with NAFLD . MATERIAL AND METHODS Sedentary women 25 - 60 years old with body mass index ( BMI ) > 24.9 kg/m2 and liver fat content < 50 HU , were r and omly divided into two parallel groups : exercise group ( EG ) or metformin group ( MG ) . The EG performed an aerobic exercise program of 60 min/5 days/ week at 60 - 85 % of heart rate reserve ; the MG took 1 g/day of metformin each morning . The duration of the intervention was 12 weeks . The liver fat content , metabolic and cardiorespiratory- fitness parameters were evaluated at the beginning and end of the program . The study complied with the Helsinki ethics codes for human research . RESULTS The study included a sample of 16 women , with 8 per group . The treatments modified the liver fat content by 14.6 % ( CI95 % 0.92 , 28.36 ) and 10.37 % ( CI95 % -1.74 , 22.48 ) for the EG and MG , respectively . In the EG , the insulin levels and HOMA-IR decreased ( P < 0.05 ) , and the cardiovascular fitness improved . CONCLUSIONS An aerobic exercise program of 12 weeks with a volume training of 300 min/week and a moderate to vigorous intensity ( 60 - 85 % VO2peak ) modified the liver fat content and improved cardiovascular risk factors during the intervention . Exercise contributed to a holistic approach by modifying a number of the components of metabolic syndrome , cardiorespiratory-fitness , and cardiovascular risk CONTEXT Nonalcoholic fatty liver disease ( NAFLD ) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or nonalcoholic steatohepatitis ( NASH ) . No treatment has been established . OBJECTIVE To determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin . DESIGN , SETTING , AND PATIENTS R and omized , double-blind , double-dummy , placebo-controlled clinical trial conducted at 10 university clinical research centers in 173 patients ( aged 8 - 17 years ) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010 . Interventions Daily dosing of 800 IU of vitamin E ( 58 patients ) , 1000 mg of metformin ( 57 patients ) , or placebo ( 58 patients ) for 96 weeks . MAIN OUTCOME MEASURES The primary outcome was sustained reduction in alanine aminotransferase ( ALT ) defined as 50 % or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment . Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures . RESULTS Sustained reduction in ALT level was similar to placebo ( 10/58 ; 17 % ; 95 % CI , 9 % to 29 % ) in both the vitamin E ( 15/58 ; 26 % ; 95 % CI , 15 % to 39 % ; P = .26 ) and metformin treatment groups ( 9/57 ; 16 % ; 95 % CI , 7 % to 28 % ; P = .83 ) . The mean change in ALT level from baseline to 96 weeks was -35.2 U/L ( 95 % CI , -56.9 to -13.5 ) with placebo vs -48.3 U/L ( 95 % CI , -66.8 to -29.8 ) with vitamin E ( P = .07 ) and -41.7 U/L ( 95 % CI , -62.9 to -20.5 ) with metformin ( P = .40 ) . The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo ( 95 % CI , -0.2 to 0.3 ) vs -0.5 with vitamin E ( 95 % CI , -0.8 to -0.3 ; P = .006 ) and -0.3 with metformin ( 95 % CI , -0.6 to -0.0 ; P = .04 ) ; and in NAFLD activity score , -0.7 with placebo ( 95 % CI , -1.3 to -0.2 ) vs -1.8 with vitamin E ( 95 % CI , -2.4 to -1.2 ; P = .02 ) and -1.1 with metformin ( 95 % CI , -1.7 to -0.5 ; P = .25 ) . Among children with NASH , the proportion who resolved at 96 weeks was 28 % with placebo ( 95 % CI , 15 % to 45 % ; 11/39 ) vs 58 % with vitamin E ( 95 % CI , 42 % to 73 % ; 25/43 ; P = .006 ) and 41 % with metformin ( 95 % CI , 26 % to 58 % ; 16/39 ; P = .23 ) . Compared with placebo , neither therapy demonstrated significant improvements in other histological features . CONCLUSION Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00063635 OBJECTIVES : Metformin proved useful in the treatment of nonalcoholic fatty liver disease ( NAFLD ) , but its superiority over nutritional treatment and antioxidants has never been demonstrated . We aim ed to compare the usefulness of metformin versus prescriptive diet or vitamin E. METHODS : In an open label , r and omized trial , nondiabetic NAFLD patients were given metformin ( 2 g/day ; n = 55 ) for 12 months . The control cases were given either vitamin E ( 800 IU/day ; n = 28 ) or were treated by a prescriptive , weight-reducing diet ( n = 27 ) . Outcome measures were liver enzymes , insulin resistance ( homeostasis model assessment ) , parameters of the metabolic syndrome , and histology . RESULTS : Aminotransferase levels improved in all groups , in association with weight loss . The effects in the metformin arm were larger ( p < 0.0001 ) , and alanine aminotransferase normalized in 56 % of cases ( odds ratio ( OR ) versus . controls , 3.11 ; 95 % confidence interval ( CI ) , 1.56–6.20 ; p = 0.0013 ) . In multivariate analysis , metformin treatment was associated with higher rates of aminotransferase normalization , after correction for age , gender , basal aminotransferases , and change in body mass index ( OR , 5.98 ; 95 % CI , 2.05–17.45 ) . Differences were maintained when the two control groups were separately analyzed . The distribution of positive criteria for the metabolic syndrome was reduced only in the metformin arm ( p = 0.001 , signed rank test ) . A control biopsy in 17  metformin-treated cases ( 14 nonresponders ) showed a significant decrease in liver fat ( p = 0.0004 ) , necroinflammation , and fibrosis ( p = 0.012 for both ) . No side effects were observed during metformin treatment . CONCLUSIONS : Metformin treatment is better than a prescriptive diet or vitamin E in the therapy of NAFLD patients receiving nutritional counseling . Limited histological data support an association between improved aminotransferases and biopsy findings , which require confirmation in a double-blind trial with appropriate statistical power based on liver histology Luseogliflozin , a selective inhibitor of sodium glucose co-transporter 2 ( SGLT2 ) , was previously shown to improve the blood glucose and hemoglobin A1c ( HbA1c ) levels of patients with type 2 diabetes in a clinical setting . Although patients with type 2 diabetes often have hepatic impairment , few reports have been published concerning the influence of luseogliflozin on HbA1c and hepatic function in patients with type 2 diabetes accompanied by hepatic impairment . The present study was undertaken to evaluate the influence of luseogliflozin on HbA1c and hepatic function in patients with type 2 diabetes divided into 2 groups according to hepatic function parameters ( a normal group and an elevated group ) . In this study , luseogliflozin significantly improved both HbA1c and body weight to similar extents in both the normal group and the elevated group , accompanied by marked reductions in the aspartate aminotransferase ( AST ) , alanine aminotransferase ( ALT ) , and γ-glutamyl transpeptidase ( γ-GTP ) levels . These results suggested that luseogliflozin can be safely used in patients with type 2 diabetes who also exhibit hepatic impairment . The results additionally suggest the possibility that luseogliflozin might be capable of alleviating hepatic impairment in patients with type 2 diabetes UNLABELLED Medication combinations that improve the efficacy of thiazolidinediones or ameliorate weight-gain side effects of therapy represent an attractive potential treatment for ( NASH ) . The aim of this r and omized , open-label trial was to assess the efficacy of rosiglitazone and metformin in combination versus rosiglitazone and losartan , compared to rosiglitazone alone , after 48 weeks of therapy . A total of 137 subjects with biopsy-proven NASH were enrolled and r and omly assigned to receive either 4 mg twice-daily of rosiglitazone , 4 mg of rosiglitazone and 500 mg of metformin twice-daily , or 4 mg of rosiglitazone twice-daily and 50 mg of losartan once-daily for 48 weeks . Patients were screened for other etiologies of chronic liver disease , including daily alcohol intake in excess of 20 g. Repeat liver biopsy was performed after 48 weeks of therapy and review ed in a blinded fashion by a single expert hepatopathologist . The primary aim of the study was to assess for differences between treatment groups in the improvement of steatosis , hepatocellular inflammation , and fibrosis . In total , 108 subjects completed the trial . Primary outcome revealed no significant difference between treatment groups in all histologic parameters ( steatosis , P = 0.137 ; hepatocellular inflammation , P = 0.320 ; fibrosis , P = 0.229 ) . Overall improvement in steatosis , hepatocellular inflammation , ballooning degeneration , and fibrosis was observed ( P ≤ 0.001 ) . Serum aminotransferases were reduced in all three groups ( P < 0.001 within treatment , P > 0.05 between groups ) . Metformin did not significantly mitigate weight gain ( P = 0.051 ) . CONCLUSIONS Forty-eight weeks of combination therapy with rosiglitazone and metformin or rosiglitazone and losartan confers no greater benefit than rosiglitazone alone with respect to histopathology CONTEXT Childhood obesity is increasingly associated with type 2 diabetes ( T2D ) . Metformin reduces the risk for T2D in adult obese nondiabetic patients , but the evidence in obese children and young people is inconclusive . OBJECTIVE The objective of the study was to assess the effect of metformin on body mass index sd score ( BMI -SDS ) , metabolic risk factors , and adipokines . DESIGN This was a prospect i ve , r and omized , double-blind , placebo-controlled trial . SETTING The study was conducted at six pediatric endocrine centers in the United Kingdom . PARTICIPANTS One hundred fifty-one obese children and young people with hyperinsulinemia and /or impaired fasting glucose or impaired glucose tolerance ( metformin : 74 , placebo : 77 ) . The study was comprised of 67.5 % females , 65.6 % postpubertal individuals , and 23.8 % British Asian or Afro-Caribbean participants . The age range was 8 - 18 yr , the mean age was 13.7 ( SD 2.3 ) yr , and the mean BMI -SDS was + 3.4 ( SD 0.5 ) . INTERVENTIONS The intervention included metformin 1 g in the morning and 500 mg in the evening vs. placebo for 6 months . MAIN OUTCOME MEASURE The main outcome measure was a reduction in BMI -SDS at 6 months . Secondary outcomes included insulin and glucose levels from oral glucose tolerance tests , alanine aminotransferase ( ALT ) , and adiponectin to leptin ratio ( ALR ) at 3 and 6 months . RESULTS Metformin was associated with a significant reduction in BMI -SDS compared with placebo at 6 months [ mean difference -0.1 SD ( 95 % confidence interval -0.18 to -0.02 ) , P = 0.02 ] . Significant improvements at 3 months were found in the metformin group : fasting glucose , -0.16 mmol/liter ( -0.31 to -0.00 ) , P = 0.047 ; ALT , 19 % ( 5 - 36 % ) , P = 0.008 ; and ALR , 32 % ( 4 - 67 % ) , P = 0.02 . CONCLUSIONS Metformin therapy has a beneficial treatment effect over placebo for BMI -SDS , fasting glucose , ALT , and ALR ratio at 3 months , with changes in BMI -SDS sustained at 6 months Nonalcoholic fatty liver disease ( NAFLD ) is associated with obesity , insulin resistance , and impaired glucose tolerance . We investigated whether metformin or changes in metabolic measurements ( weight , fasting plasma glucose ( FPG ) , or fasting insulin ( FI ) ) improved serum alanine aminotransferase ( ALT ) activity , as a marker for NAFLD , in the Diabetes Prevention Program ( DPP ) . From 1996 to 1999 , 2,153 participants without marked elevations of serum ALT at baseline were r and omized ( 1,081 to placebo , 1,072 to metformin ) and treated for an average of 3.2 years .  ALT increased during the first 2 years of the study , and was slightly but significantly lower in the participants r and omized to metformin . In regression models adjusted for sex , baseline age , FPG , and FI , these differences remained significant , but disappeared after adjustment for weight , FPG , and FI changes at each examination . The 3-year cumulative incidence for development of abnormal ALT concentrations was not significantly different ( ( mean + /- s.e . ) 21.4 + /- 1.4 % and 24.6 + /- 1.4 % , P = 0.11 ) in the metformin vs. placebo groups but was lower in individuals in both groups that lost more weight by the end of year 1 ( metformin : 19.4 + /- 2.4 % vs. 27.5 + /- 3.7 % , for highest vs. lowest quartile of weight loss ; placebo : 18.7 + /- 3.4 % vs. 28.8 + /- 2.6 % ) . Over 3 years of follow-up in persons at high risk for development of diabetes , serum ALT was consistently lower in those treated with metformin compared with placebo . This effect was mediated by weight loss , indicating that the effects of metformin therapy on ALT is via its effects on weight Background : Increased insulin resistance is the major pathogenic mechanism in the development of non‐alcoholic steatohepatitis Background : Children with non‐alcoholic steatohepatitis are insulin‐resistant and metformin has been proposed as a potential therapy . However , paediatric safety and efficacy data are absent BACKGROUND Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis . Currently , there is no established treatment for this disease . METHODS We r and omly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily ( 80 subjects ) , vitamin E at a dose of 800 IU daily ( 84 subjects ) , or placebo ( 83 subjects ) , for 96 weeks . The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis , as assessed with the use of a composite of st and ardized scores for steatosis , lobular inflammation , hepatocellular ballooning , and fibrosis . Given the two planned primary comparisons , P values of less than 0.025 were considered to indicate statistical significance . RESULTS Vitamin E therapy , as compared with placebo , was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis ( 43 % vs. 19 % , P=0.001 ) , but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant ( 34 % and 19 % , respectively ; P=0.04 ) . Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone , as compared with placebo ( P<0.001 for both comparisons ) , and both agents were associated with reductions in hepatic steatosis ( P=0.005 for vitamin E and P<0.001 for pioglitazone ) and lobular inflammation ( P=0.02 for vitamin E and P=0.004 for pioglitazone ) but not with improvement in fibrosis scores ( P=0.24 for vitamin E and P=0.12 for pioglitazone ) . Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo ; the rates of other side effects were similar among the three groups . CONCLUSIONS Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes . There was no benefit of pioglitazone over placebo for the primary outcome ; however , significant benefits of pioglitazone were observed for some of the secondary outcomes . ( Clinical Trials.gov number , NCT00063622 . OBJECTIVE Non-alcoholic steatohepatitis ( NASH ) is frequent in obese subjects and has a relatively benign course ; however , it may progress to cirrhosis . Weight loss in these patients may alleviate the findings of NASH . The aim of this study was to investigate the effects of pharmacological anti-obesity therapies on the findings of NASH . SUBJECTS There were thirteen patients ( 9 women , 4 men ) in sibutramine group and 12 patients ( 8 women , 4 men ) in orlistat group . The mean ages and body-mass indexes of the two groups were 42.5 years , 37.3 kg/m2 and 43.2 years , 36.1 kg/m2 , respectively . METHOD The obese subjects with NASH were given sibutramine or orlistat for six months . Additionally , all patients were given a low caloric diet .  Liver enzymes ( AST , ALT , GGT and ALP ) , insulin resistance ( analysed by HOMA ) and hepatic ultrasound ( US ) findings were assessed at baseline and after 6 months . RESULTS Both sibutramine and orlistat significantly reduced body weight ( 10.2 and 8.4 % , respectively ) , insulin resistance ( 47 and 40 % , respectively ) , AST ( 41 and 39 % , respectively ) , ALT ( 59 and 58 % , respectively ) , and GGT serum levels ( 27 and 25 % , respectively ) . The ultrasonographic regression in steatosis was observed in 11 patients who received sibutramine and 8 patients who received orlistat . During the treatment , unexpectedly significant increases in total alkaline phosphatase levels were found in both sibutramine and orlistat groups ( 9 and 14 % , respectively ) . CONCLUSION The present study shows that both sibutramine-induced and orlistat-induced weight losses result in reduction of insulin resistance , and improvements in biochemical markers and US findings of NASH . Because the GGT levels decreased in both groups , the increased ALP levels might have another source Objective : We aim ed at evaluating whether the addition of low-dose metformin to dietary treatment could be an effective approach in nondiabetic patients with nonalcoholic fatty liver disease ( NAFLD ) . Methods : We carried out a 6-month prospect i ve study in a series of overweight or obese patients with ultrasonographic diagnosis of hepatic steatosis . In total , 50 patients were enrolled and r and omized into two groups : the first group ( n=25 ) was given metformin ( 1 g per day ) plus dietary treatment and the second group ( n=25 ) was given dietary treatment alone . Results : At the end of the study , the proportion of patients with echographic evidence of fatty liver was reduced in both the metformin ( P<0.0001 ) and the diet group ( P=0.029 ) . Moreover , patient body mass index and waist circumference significantly decreased in both groups ( P<0.001 ) . Fasting glucose , insulin resistance ( evaluated as homeostasis model assessment of insulin resistance ( HOMA-IR ) ) and serum adiponectin decreased in both groups , although these changes reached statistical significance only in the metformin group . In this group , HOMA-IR decreased from 3.3±1.6 to 2.4±1.2 ( P=0.003 ) , whereas it decreased from 3.2±1.6 to 2.8±1.1 ( not significant , NS ) in the diet group . Similarly , the proportion of patients with impaired fasting glucose declined from 35 to 5 % ( P=0.04 ) in the metformin and from 32 to 12 % ( NS ) in the diet group . At baseline , ∼40 % of patients in both groups met the diagnostic criteria of metabolic syndrome . This proportion decreased to 20 % in the metformin group ( P=0.008 ) and to 32 % in the diet group ( NS ) . Conclusions : In our 6-month prospect i ve study , both low-dose metformin and dietary treatment alone ameliorated liver steatosis and metabolic derangements in patients with NAFLD . However , metformin was more effective than dietary treatment alone in normalizing several metabolic parameters in these patients Background : Insulin sensitizing agents may be useful in treatment of non‐alcoholic fatty liver disease BACKGROUND Pioglitazone ( Pio ) treatment induces weight gain in Type 2 diabetes mellitus ( T2DM ) , which could worsen hepatic lipid accumulation , and alter adiponectin and high-sensitivity C-reactive protein ( hs-CRP ) . OBJECTIVE To compare changes in hepatic lipid , serum adiponectin and hs-CRP in diabetics treated with Pio ( with and without weight gain ) against metformin ( Met ) treatment , which produces weight loss . DESIGN Fifty-one men and women with T2DM , naive to thiazolidinediones  , entered a 16-week , open-label , parallel arm study , where participants were r and omized to one of three groups : ( 1 ) Pio plus the American Diabetes Association diet ( Pio+ADA ) ; ( 2 ) Pio plus a portion control weight loss diet ( Pio+PC ) , or ( 3 ) metformin plus ADA diet ( Met+ADA ) . METHODS Hepatic lipid was assessed with abdominal computed tomography ( CT ) and the serum adiponectin and hs-CRP by enzyme-linked immunosorbent assay at baseline and study end . RESULTS Forty-eight subjects completed the study . The Pio+ADA group gained ( mean+/-S.E.M. ) 2.15+/-1.09 kg , while Pio+PC and Met+ADA group lost -2.59+/-1.25 and -3.21+/-0.7 kg , respectively . Pio-treated groups ( Pio+ADA and Pio+PC ) significantly decreased hepatic fat as indicated by increased liver density on CT scan [ 10.1+/-2.4 : 11.4+/-1.0 Hounsfield units ( HU ) ] , compared with Met+ADA group ( -2.4+/-3.1 HU ) . The Pio groups demonstrated significantly increased serum adiponectin , ( 8.6+/-1.5 ; 7.4+/-1.6 microg/ml ) independent of weight change , compared to Met+ADA ( -0.14+/-0.6 microgm/ml ) group which lost weight . Serum hs-CRP decreased in groups showing weight loss ( Pio+PC , -3.1+/-1.7 mg/l ; Met+ADA , -1.5+/-1.2 mg/l ) compared to Pio+ADA ( 1.8+/-3.0 mg/l ) group that gained weight . CONCLUSIONS Pio treatment in T2DM significantly reduced hepatic lipid and increased adiponectin independent of weight change , while decreasing hs-CRP with weight loss Aims /hypothesisGlucagon-like peptide (GLP)-1-based therapies have been suggested to improve hepatic steatosis . We assessed the effects of the GLP-1 receptor agonist liraglutide and the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin on hepatic steatosis and fibrosis  in patients with type 2 diabetes . Methods In this 12 week , parallel , r and omised , placebo-controlled trial , performed at the VU University Medical Center between July 2013 and August 2015 , 52 overweight patients with type 2 diabetes treated with metformin and /or sulphonylurea agent ( [ mean ± SD ] age 62.7 ± 6.9 years , HbA1c 7.3 ± 0.7 % or 56 ± 1 mmol/mol ) were allocated to once daily liraglutide 1.8 mg ( n = 17 ) , sitagliptin 100 mg ( n = 18 ) or matching placebos ( n = 17 ) by computer generated numbers . Both participants and research ers were blinded to group assignment . Hepatic fat content was measured using proton magnetic resonance spectroscopy ( 1H-MRS ) . Hepatic fibrosis was estimated using three vali date d formulae . Results One patient dropped out in the sitagliptin group owing to dizziness , but no serious adverse events occurred . At week 12 , no between-group differences in hepatic steatosis were found . Liraglutide reduced steatosis by 10 % ( 20.9 ± 3.4 % to 18.8 ± 3.3 % ) , sitagliptin reduced steatosis by 12.1 % ( 23.9 ± 3.0 % to 21.0 ± 2.7 % ) and placebo lessened it by 9.5 % ( 18.7 ± 2.7 % to 16.9 ± 2.7 % ) . Neither drug affected hepatic fibrosis scores compared with placebo . Conclusions /interpretationTwelve-week liraglutide or sitagliptin treatment does not reduce hepatic steatosis or fibrosis in type 2 diabetes . Trial registration Clinical Trials.gov NCT01744236 Funding Funded by the European Community ’s Seventh Framework Programme ( FP7/2007 - 2013 ) under grant agreement no. 282521 – the SAFEGUARD project Background : Treatment options for non‐alcoholic steatohepatitis ( NASH ) are limited . Weight loss remains the most recommended therapy . Orlistat is an effective adjunct to dietary weight loss therapy OBJECTIVE To investigate the effects of exenatide on blood glucose , body weight and hepatic enzymes in patients with type 2 diabetes mellitus ( T2DM ) and concomitant non-alcoholic fatty liver disease ( NAFLD ) . SUBJECTS AND METHODS One hundred and seventeen patients with T2DM and NAFLD were r and omly divided into exenatide group and metformin group . Patients were treated with exenatide and metformin , respectively , for 12 weeks . RESULTS After 12 weeks of treatment , body weight , body mass index ( BMI ) , waist-to-hip ratio , HbA1c , FPG , 2-h PPG , ALT , AST , γ-GT , and hs-CRP were significantly reduced , and the AST/ALT ratio and adiponectin were markedly increased in both groups . BMI , waist-to-hip ratio , 2-h PPG , ALT , AST , γ-GT , and hs-CRP were markedly lower , and AST/ALT ratio and adiponectin in the exenatide group were dramatically higher than in the metformin group . CONCLUSION Compared with metformin , exenatide is better to control blood glucose , reduces body weight and improves hepatic enzymes , attenuating NAFLD in patients with T2DM concomitant with NAFLD We compared the effects of weight loss induced by the glucagon-like peptide 1-agonist liraglutide with a structured lifestyle intervention in obese adults with non-alcoholic fatty liver disease ( NAFLD ) . Obese ( body mass index ≥30 kg/m2 , mean weight 96.0 ± 16.3 kg ) non-diabetic Asian adults , with NAFLD diagnosed by liver fat fraction ( LFF ) ≥ 5.5 % on magnetic resonance imaging without other causes of hepatic steatosis , were r and omized to a supervised program of dieting ( restriction by 400 kilocalories/d ) plus moderate-intensity aerobic exercise ( ~200 min/wk ; DE group , n = 12 ) , or liraglutide at the 3 mg daily dose approved for weight loss ( LI group , n = 12 ) , for 26 weeks . Both DE and LI groups had significant ( P < .01 ) and similar reductions in weight ( -3.5 ± 3.3 vs -3.5 ± 2.1 kg , respectively , P = .72 ) , LFF ( -8.9 ± 13.4 vs -7.2 % ± 7.1 % , P = .70 ) , serum alanine aminotransferase ( -42 ± 46 vs -34 ± 27 U/L , P = .52 ) and aspartate aminotransferase ( -23 ± 24 vs -18 ± 15 U/L , P = .53 ) . In this first r and omized study comparing the 2 weight-loss modalities for improving NAFLD , liraglutide was as effective as structured lifestyle modification PURPOSE Oral antidiabetic drugs ( OADs ) such as pioglitazone and metformin have beneficial effects in patients with nonalcoholic steatohepatitis . We prospect ively assessed the effects of OADs on nonalcoholic fatty liver disease ( NAFLD ) in 886 men with type 2 diabetes mellitus and in a murine model of NAFLD . METHODS Patients were r and omized to receive pioglitazone , metformin , sitagliptin , or a non-OAD ( control ) for 6 months . All the patients received dietary and exercise guidance once a month during this study . Changes in the liver-to-spleen ratio on computed tomography ( CT ) and NAFLD-related parameters were measured from baseline to the end of treatment . FINDINGS The liver/spleen ratio improved significantly in the pioglitazone and metformin groups compared with the control group ( both P < 0.01 ) , but not in the sitagliptin group ( P = 0.73 ) . The mean changes from baseline were -3.464 ± 10.156 % , 19.236 ± 9.896 % , 4.783 ± 1.467 % , and 1.328 ± 0.802 % in the control , pioglitazone , metformin , and sitagliptin groups , respectively . Multivariable analysis showed that the liver/spleen ratio was strongly correlated with high-sensitivity C-reactive protein concentration in the pioglitazone group ( F = 9.973 ; P < 0.01 ) and abdominal visceral fat volume in the metformin group ( F = 6.049 ; P < 0.05 ) . CONCLUSIONS Pioglitazone elicited the greatest improvements in features of NAFLD in type 2 diabetes mellitus . ( Trial Registration : www.is rct n.org/ , IS RCT N33414972 , http://www.is rct n.org/ ) Abstract Ectopic accumulation of lipids in nonadipose tissues plays a primary role in the pathogenesis of type 2 diabetes mellitus ( T2DM ) . This study was to examine the effects of exenatide , insulin , and pioglitazone on liver fat content and body fat distributions in T2DM . Thirty-three drug-naive T2DM patients ( age 52.7 ± 1.7 years , HbA1c 8.7 ± 0.2 % , body mass index 24.5 ± 0.5 kg/m2 ) were r and omized into exenatide , insulin , or pioglitazone for 6 months . Intrahepatic fat ( IHF ) , visceral fat ( VF ) , and subcutaneous fat ( SF ) were measured using proton nuclear magnetic resonance spectroscopy . Plasma tumor necrosis factor α ( TNFα ) and adiponectin were assayed by ELISA . HbA1c declined significantly in all three groups . Body weight , waist , and serum triglycerides decreased with exenatide . After interventions , IHF significantly reduced with three treatments ( exenatide Δ = −68 % , insulin Δ = −58 % , pioglitazone Δ = −49 % ) . Exenatide  reduced VF ( Δ = −36 % ) and SF ( Δ = −13 % ) , and pioglitazone  decreased VF ( Δ = −30 % ) with no impact on SF , whereas insulin had no impact on VF or SF . Levels of TNFα  ( exenatide/insulin/pioglitazone ) decreased , and levels of adiponectin  ( exenatide/pioglitazone ) increased . Analysis showed that ΔIHF correlated with ΔHbA1c and Δweight . Besides , ΔIHF correlated with Δtriglycerides and ΔTNFα , but the correlations fell short of significance after BMI adjustment . By linear regression analysis , ΔHbA1c alone explained 41.5 % of the variance of ΔIHF , and ΔHbA1c + Δweight explained 57.6 % of the variance . Liver fat content can be significantly reduced irrespective of using exenatide , insulin , and pioglitazone . Early glycaemic control plays an important role in slowing progression of fatty liver in T2DM OBJECTIVE Sodium – glucose cotransporter 2 ( SGLT-2 ) inhibitors have been shown to reduce liver fat in rodent models . Data regarding the effect of SGLT-2 inhibitors on human liver fat are scarce . This study examined the effect of empagliflozin ( an SGLT-2 inhibitor ) on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease ( NAFLD ) by using MRI-derived proton density fat fraction ( MRI-PDFF ) . RESEARCH DESIGN AND METHODS Fifty patients with type 2 diabetes and NAFLD were r and omly assigned to either the empagliflozin group ( st and ard treatment for type 2 diabetes plus empagliflozin 10 mg daily ) or the control group ( st and ard treatment without empagliflozin ) for 20 weeks . Change in liver fat was measured by MRI-PDFF . Secondary outcome measures were change in alanine transaminase ( ALT ) , aspartate transaminase ( AST ) , and γ-glutamyl transferase ( GGT ) levels . RESULTS When included in the st and ard treatment for type 2 diabetes , empagliflozin was significantly better at reducing liver fat ( mean MRI-PDFF difference between the empagliflozin and control groups −4.0 % ; P < 0.0001 ) . Compared with baseline , significant reduction was found in the end-of-treatment MRI-PDFF for the empagliflozin group ( 16.2 % to 11.3 % ; P < 0.0001 ) and a nonsignificant change was found in the control group ( 16.4 % to 15.5 % ; P = 0.057 ) . The two groups showed a significant difference for change in serum ALT level ( P = 0.005 ) and nonsignificant differences for AST ( P = 0.212 ) and GGT ( P = 0.057 ) levels . CONCLUSIONS When included in the st and ard treatment for type 2 diabetes , empagliflozin reduces liver fat and improves ALT levels in patients with type 2 diabetes and NAFLD Abstract Aims / Introduction To compare the effects of gliclazide , liraglutide and metformin on body composition in patients with type 2 diabetes mellitus with non‐alcoholic fatty liver disease . Material s and Methods A total of 85 patients were r and omly allocated to receive gliclazide ( n = 27 ) , liraglutide ( n = 29 ) or metformin ( n = 29 ) monotherapy for 24 weeks . Body composition was measured using dual‐energy X‐ray absorptiometry . Results Liraglutide and metformin reduced total , trunk , limb , and roid and gynoid fat mass ; this also led to weight reduction . However , gliclazide treatment produced no significant changes in weight or fat mass , likely because reductions in fat mass were concomitant with increases in lean tissue mass . Blood glucose concentrations and glycated hemoglobin levels improved in all treatment arms ; levels of the latter were lower in patients treated with liraglutide and metformin . Serum alanine aminotransferase concentrations decreased in all treatment arms , whereas serum aspartate aminotransferase concentrations were reduced only by liraglutide and metformin . In all patients , weight loss and total , trunk , limb , and and roid fat mass reductions were positively correlated with decreases in serum alanine aminotransferase and aspartate aminotransferase levels , whereas reductions in waist circumference were positively correlated with lower serum alanine aminotransferase levels . Conclusions Compared with gliclazide , liraglutide and metformin monotherapies result in greater weight loss , reductions in body fat mass , and better blood glucose control among type 2 diabetes mellitus patients with non‐alcoholic fatty liver disease . Reductions in weight , fat mass and waist circumference favorably affect hepatic function We conducted this study to determine whether additional administration of a dipeptidyl peptidase-4 ( DPP-4 ) inhibitor might provide further improvement of the glycemic control in Japanese type 2 diabetes patients showing relatively good glycemic control under treatment with a sodium glucose co-transporter 2 ( SGLT2 ) inhibitor . Five SGLT2 inhibitor ( luseogliflozin , dapagliflozin , tofogliflozin , empagliflozin and canagliflozin ) preparations and five DPP-4 inhibitor ( sitagliptin , vildagliptin , alogliptin , anagliptin and linagliptin ) preparations were used . The results showed that monotherapy with SGLT2 inhibitor produced significant decreases of the body weight and BMI , hemoglobin A1c ( HbA1c ) also decreased , but not to a significant extent . However , decreases of the serum aspartate aminotransferase ( AST ) , alanine aminotransferase ( ALT ) , γ-glutamyltransferase ( γ-GTP ) and uric acid were observed in this group . On the other h and , in type 2 diabetes patients treated concomitantly with a DPP-4 inhibitor and SGLT2 inhibitor , significant decrease of the HbA1c was observed , indicating the favorable effect of the concomitant therapy . The body weight and BMI decreased . As for the serum lipid profile , elevation of the serum HDL-cholesterol ( HDL-C ) was observed . Furthermore , AST , ALT , γ-GTP and uric acid decreased in the combined treatment group . Then , the therapeutic responses to concurrent administration with SGLT2 inhibitor of each of the 5 individual DPP-4 inhibitors used in this study were analyzed . The results showed that concomitant administration of sitagliptin , a DPP-4 inhibitor , with the SGLT2 inhibitor yielded the best results in terms of the lowering of the HbA1c and improvement of the serum lipid profile BACKGROUND Non-alcoholic fatty liver disease ( NAFLD ) is among the most common causes of liver disease worldwide . There is growing evidence on pathogenesis and pathophysiology of NAFLD . However , there is still no universally accepted pharmacotherapy protocol . METHODS The study was conducted on 42 patients with NAFLD . They were r and omized to dietary treatment alone ( n = 21 ) or to diet and metformin therapy ( n = 21 ) . Liver ultrasonography , controlled attenuation parameter ( CAP ) , liver stiffness ( LS ) , complete blood count , anthropometric and biochemical parameters were obtained before treatment ( baseline ) , and after 3 and 5 months of the therapy . RESULTS Patients treated with diet and metformin exhibited significantly decreased CAP values at 3 and 5 months of the therapy compared to baseline ( 319 dB/m vs. 285 dB/m ; p < 0.05 ; 319 dB/m vs. 295 dB/m ; p < 0.05 respectively ) . Five months of diet and the metformin therapy result ed in significant reduction of LS value ( 6.2 kPa vs. 5.2 kPa ; p < 0.05 ) , while patients treated with diet alone had no significant changes in liver CAP and LS measurements . CONCLUSIONS Metformin therapy combined with dietary treatment seems to be effective for the reduction of hepatic steatosis and fibrosis . However , considering limitations of the study and inconsistent results of previous investigations in this area , there is a need for further research on metformin efficacy in this group of patients AIMS Soluble dipeptidyl peptidase-4 ( sDPP-4 ) is secreted by hepatocytes and induces adipose tissue inflammation and insulin resistance . Sodium-glucose co-transporter-2 ( SGLT2 ) inhibitors can improve hepatic steatosis by inhibiting hepatic de novo lipogenesis . We investigated the effects of dapagliflozin ( an SGLT2 inhibitor ) on serum levels of sDPP-4 in patients with type 2 diabetes and non-alcoholic fatty liver disease ( NAFLD ) . METHODS Fifty-seven patients with type 2 diabetes and NAFLD were r and omized to a  dapagliflozin group ( 5 mg/d for 24 weeks ) ( n = 33 ) or the control group ( n = 24 ) . Serum levels of sDPP-4 were measured with a commercial ELISA kit . Visceral adipose tissue ( VAT ) and subcutaneous adipose tissue ( SAT ) areas were measured by dual bioelectrical impedance analysis . RESULTS In a total of 57 patients  , baseline serum sDPP-4 was positively correlated with aspartate aminotransferase ( AST ) , alanine aminotransferase ( ALT ) , γ-glutamyl transferase ( GGT ) and HOMA-IR Both VAT and SAT areas decreased significantly in the dapagliflozin group alone . Liver enzymes were decreased at 24 weeks in the dapagliflozin group , but were unchanged in the control group . Although both groups showed significant reduction of serum sDPP-4 after 24 weeks of treatment , the magnitude of decrease was significantly larger in the dapagliflozin group . Changes in liver enzymes during treatment with dapagliflozin were positively correlated with the change in serum sDPP-4 , but not with changes in VAT volume or HbA1c . CONCLUSIONS Improvement of liver dysfunction after treatment with dapagliflozin was associated with a decrease in serum sDPP-4 , suggesting that reduction of serum sDPP-4 by SGLT2 inhibitors may be a therapeutic strategy for NAFLD/NASH in patients with type 2 diabetes that is independent of glucose lowering or weight loss Introduction Nonalcoholic fatty liver disease ( NAFLD ) is the most common liver disease worldwide and is becoming the most frequent indication of liver transplantation . Cardiovascular disease is the main cause of death in these patients . There is no Food and Drug Association-approved medication for NAFLD patients . We aim ed to provide more robust evidence on the use of medications that are inexpensive and available , namely , metformin , silymarin , pioglitazone , and vitamin E , for treating NAFLD . Material s and methods We conducted a r and omized double-blinded , placebo-controlled trial on 150 consecutive patients with NAFLD who were assigned to five groups : lifestyle plus placebo , metformin 500 mg/day , silymarin 140 mg/day , pioglithasone 15 mg/day , and vitamin E 400 IU/day , all for 3 months  . Anthropometric and biochemical variables were measured at baseline and 3 months later . Results The mean age of the patients was 47.0±9.1 ( range : 18–65 ) years and the sex distribution was 73 ( 48.7 % ) women and 77 ( 51.3 % ) men . Patients in all groups showed a significant improvement in anthropometric parameters such as waist circumference and BMI . There was no statistically significant difference in alanine transaminase and aspartate transaminase in the control group after treatment ( P=0.51 , 0.18 , respectively ) ; however , both liver enzymes decreased significantly in the other groups . Discussion and conclusion This r and omized double-blinded placebo-controlled clinical trial suggested a significant benefit of silymarin , pioglitazone , and vitamin E in improving liver aminotransferases in patients with NAFLD after only 3 months , without exerting any specific side effects BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide , but few effective long-term treatments are available . In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 ( SGLT2 ) , exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes . METHODS In this double-blind , r and omized trial , we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin , an oral SGLT2 inhibitor , at a dose of 100 mg daily or placebo .  All the patients had an estimated glomerular filtration rate ( GFR ) of 30 to < 90 ml per minute per 1.73 m2 of body-surface area and albuminuria ( ratio of albumin [ mg ] to creatinine [ g ] , > 300 to 5000 ) and were treated with renin-angiotensin system blockade . The primary outcome was a composite of end-stage kidney disease ( dialysis , transplantation , or a sustained estimated GFR of < 15 ml per minute per 1.73 m2 ) , a doubling of the serum creatinine level , or death from renal or cardiovascular causes . Prespecified secondary outcomes were tested hierarchically . RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee . At that time , 4401 patients had undergone r and omization , with a median follow-up of 2.62 years . The relative risk of the primary outcome was 30 % lower in the canagliflozin group than in the placebo group , with event rates of 43.2 and 61.2 per 1000 patient-years , respectively ( hazard ratio , 0.70 ; 95 % confidence interval [ CI ] , 0.59 to 0.82 ; P = 0.00001 ) . The relative risk of the renal-specific composite of end-stage kidney disease , a doubling of the creatinine level , or death from renal causes was lower by 34 % ( hazard ratio , 0.66 ; 95 % CI , 0.53 to 0.81 ; P<0.001 ) , and the relative risk of end-stage kidney disease was lower by 32 % ( hazard ratio , 0.68 ; 95 % CI , 0.54 to 0.86 ; P = 0.002 ) . The canagliflozin group also had a lower risk of cardiovascular death , myocardial infa rct ion , or stroke ( hazard ratio , 0.80 ; 95 % CI , 0.67 to 0.95 ; P = 0.01 ) and hospitalization for heart failure ( hazard ratio , 0.61 ; 95 % CI , 0.47 to 0.80 ; P<0.001 ) . There were no significant differences in rates of amputation or fracture . CONCLUSIONS In patients with type 2 diabetes and kidney disease , the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years . ( Funded by Janssen Research and Development ; CREDENCE Clinical Trials.gov number , NCT02065791 . ) Women with polycystic ovary syndrome ( PCOS ) were treated with the GLP-1 receptor agonist liraglutide to investigate the effect on liver fat content , visceral adipose tissue ( VAT ) and the prevalence of nonalcoholic fatty liver disease ( NAFLD ) . In a double-blind , placebo-controlled , r and omized clinical trial 72 women with PCOS , with a BMI > 25 kg/m2 and /or insulin resistance , were treated with liraglutide or received placebo 1.8 mg/d ( 2:1 ) for 26 weeks . Liver fat content was assessed by 1 HMR spectroscopy , VAT by MRI , body composition by DXA , and glucose metabolism by oral glucose tolerance test . Compared with placebo , liraglutide treatment reduced body weight by 5.2 kg ( 5.6 % ) , liver fat content by 44 % , VAT by 18 % , and the prevalence of NAFLD by two-thirds ( all P < .01 ) . Sex-hormone-binding-globulin ( SHBG ) levels increased by 19 % ( P = .03 ) , and free testosterone decreased by 19 % ( P = .054 ) . HbA1c , fasting glucose and leptin were reduced ( all : P < .05 ) , whereas measures of insulin resistance , adiponectin and glucagon did not change . In conclusion , 26 weeks of liraglutide treatment in PCOS result ed in significant reductions in liver fat content , VAT and the prevalence of NAFLD This study aim ed to assess the effect of luseogliflozin on liver fat deposition and compare luseogliflozin to metformin in type 2 diabetes ( T2D ) patients with non-alcoholic fatty liver disease ( NAFLD ) . Thirty-two T2D patients with NAFLD diagnosed by computed tomography or abdominal sonography were recruited . Participants were r and omly assigned to receive either luseogliflozin ( 2.5 mg , newly administered ) or metformin ( 1500 mg , newly or additionally administrated ) . Data on the liver-to-spleen attenuation ratio ( L/S ) , visceral fat area , body mass index , glycated hemoglobin ( HbA1c ) , alanine aminotransferase ( ALT ) , fasting plasma glucose , C-peptide immunoreactivity ( CPR ) , and CPR index were collected at baseline and after 6 months . The change in L/S was significantly greater in the luseogliflozin group than in the metformin group . Similarly , the changes in the visceral fat area , HbA1c , and body mass index were significantly greater in the luseogliflozin group than in the metformin group . The changes in ALT , fasting glucose , CPR , and CPR index were not significant in both groups . In conclusion , luseogliflozin significantly reduced liver fat deposition as compared to metformin , which may indicate clinical relevant benefits for NAFLD BACKGROUND Glucagon-like peptide-1 ( GLP-1 ) analogues reduce hepatic steatosis , concentrations of liver enzymes , and insulin resistance in murine models of fatty liver disease . These analogues are licensed for type 2 diabetes , but their efficacy in patients with non-alcoholic steatohepatitis is unknown . We assessed the safety and efficacy of the long-acting GLP-1 analogue , liraglutide , in patients with non-alcoholic steatohepatitis . METHODS This multicentre , double-blinded , r and omised , placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide ( 1·8 mg daily ) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis . Patients were r and omly assigned ( 1:1 ) using a computer-generated , central ly administered procedure , stratified by trial centre and diabetes status . The trial was design ed using A'Hern 's single-group method , which required eight ( 38 % ) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinical ly significant . Patients , investigators , clinical trial site staff , and pathologists were masked to treatment assignment throughout the study . The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment ( 48 weeks ) , as assessed central ly by two independent pathologists . Analysis was done by intention-to-treat analysis , which included all patients who underwent end-of-treatment biopsy . The trial was registered with Clinical Trials.gov , number NCT01237119 . FINDINGS Between Aug 1 , 2010 , and May 31 , 2013 , 26 patients were r and omly assigned to receive liraglutide and 26 to placebo . Nine ( 39 % ) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two ( 9 % ) of 22 such patients in the placebo group ( relative risk 4·3 [ 95 % CI 1·0 - 17·7 ] ; p=0·019 ) . Two ( 9 % ) of 23 patients in the liraglutide group versus eight ( 36 % ) of 22 patients in the placebo group had progression of fibrosis ( 0·2 [ 0·1 - 1·0 ] ; p=0·04 ) . Most adverse events were grade 1 ( mild ) to grade 2 ( moderate ) in severity , transient , and similar in the two treatment groups for all organ classes and symptoms , with the exception of gastrointestinal disorders in 21 ( 81 % ) of 23 patients in the liraglutide group and 17 ( 65 % ) of 22 patients in the placebo group , which included diarrhoea ( ten [ 38 % ] patients in the liraglutide group vs five [ 19 % ] in the placebo group ) , constipation ( seven [ 27 % ] vs none ) , and loss of appetite ( eight [ 31 % ] vs two [ 8 % ] ) . INTERPRETATION Liraglutide was safe , well tolerated , and led to histological resolution of non-alcoholic steatohepatitis , warranting extensive , longer-term studies . FUNDING Wellcome Trust , National Institute of Health Research , and Novo Nordisk Liraglutide , an analogue of human glucagon-like peptide 1 , reduces cardiovascular events in patients with type 2 diabetes ; however , it has still been unknown by which mechanisms liraglutide could reduce cardiovascular events . Type 2 diabetic patients with insulin treatment were enrolled in this r and omized , open-label , comparative study . Participants were r and omly assigned to liraglutide plus insulin ( liraglutide group ) and insulin treatment ( control group ) at 1:1 allocation . Primary endpoint was the change in viscera fat are ( VFA , cm2 ) at 24 weeks . Liver attenuation index ( LAI ) measured by abdominal computed tomography , urinary albumin-to-creatinine ratio ( ACR , mg/g ) , and C-reactive protein ( CRP ) levels , skeletal muscle index ( SMI ) , and quality of life ( QOL ) related to diabetes treatment were also determined . Seventeen patients ( 8 ; liraglutide group , 9 ; control group , mean age 59 ± 13 years ; 53 % female ) completed this study . Liraglutide treatment significantly reduced VFA at 24 weeks ; whereas , SFA was unchanged . ACR , LAI , and CRP levels were significantly reduced by liraglutide at 24 weeks and there was no difference in SMI between the two groups . Changes in VFA from baseline to 24 weeks were significantly associated with those in LAI , albuminuria , and HbA1c . Liraglutide treatment significantly improved QOL scores associated with anxiety and dissatisfaction with treatment and satisfaction with treatment . No severe adverse events were observed in both groups . Our data suggest that liraglutide could reduce visceral adiposity in parallel with attenuation of hepatic fat accumulation , albuminuria and micro-inflammation and improve QOL related to diabetes care in insulin-treated patients with type 2 diabetes
Non-alcoholic fatty liver disease ( NAFLD ) is a common comorbidity in individuals with obesity .
Although multiple pharmacotherapeutics are in development , currently there are limited strategies specifically targeting NAFLD .
This systematic review summarizes the existing literature on hepatic effects of medications used for weight loss .
Glucagon-like peptide 1 ( GLP-1 ) agonists are the best-studied in this regard , and evidence consistently demonstrates reduction in liver fat content , sometimes accompanied by improvements in histological features of steatohepatitis and reductions in serum markers of hepatic injury such as alanine aminotransferase ( ALT ) .
It remains unclear whether these benefits are independent of the weight loss caused by these agents .