***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Nonalcoholic steatohepatitis ( NASH ) is increasing in prevalence and is related to underlying insulin resistance . The aim of this study was to assess the efficacy of metformin on the characteristic histopathologic lesions of NASH . This was a 12-month prospect i ve , r and omized , placebo-controlled trial comparing diet and exercise alone to diet , exercise and metformin in nondiabetic patients with insulin resistance and NASH . Patients were r and omized to either group A or B. Group A received placebo , dietary counseling , recommendations for weight loss and exercise four times per week . Group B received long-acting metformin 500 mg daily ( titrated to 1000 mg daily ) plus dietary counseling , recommendations for weight loss and exercise four times per week . Histopathology was assessed at 12 months and biopsies were scored by two pathologists who were blinded to all data . Twenty-three subjects were screened and 19 were r and omized to either group A ( n = 10 ) or group B ( n = 9 ) . Seven of the 10 subjects in group A completed the study including repeat liver biopsy while all patients in group B completed the study . Body mass index improved in both groups decreasing by 1.7 kg/m2 in group A and 0.9 kg/m 2 in group B ( not significant , control versus treatment ) . Homeostasis model assessment of insulin resistance scores improved in both groups decreasing by 1.14 in group A and 1.58 in group B ( not significant , control versus treatment ) . No significant difference in histopathology was seen between groups on follow-up liver biopsy . Metformin appeared to have little effect in improvement in liver function tests or liver histology in nondiabetic patients with insulin resistance and NASH . Decrease in BMI through diet and exercise significantly improved HOMA-IR scores , serum aminotransferases and liver histology UNLABELLED In uncontrolled clinical studies , ursodeoxycholic acid ( UDCA ) had a beneficial effect on  nonalcoholic steatohepatitis ( NASH ) .  However , a large controlled trial using UDCA ( 13 - 15 mg/kg/day ) was unable to confirm these results . Accordingly , a r and omized , placebo-controlled study was initiated with a high dose of UDCA ( 23 - 28 mg/kg/day ) . The allocation of patients and the evaluation of liver histology were performed according to a modified Brunt score and the nonalcoholic fatty liver disease activity score ( NAS ) . With the modified Brunt score , 185 patients with histologically proven NASH were r and omized [ intention to treat ( ITT ) ] , and 147 were treated per protocol ( PP ) . With the NAS , 137 patients were confirmed to have NASH , 48 had borderline NASH , and 1 did not have NASH . The treatment time was 18 months . At entry , the treatment groups were comparable . A second biopsy sample was obtained from 139 of 185 patients ( NAS : 107/137 ) . The primary criterion for evaluation was a change in the liver histology ; the secondary criteria were single histological variables and liver biochemistry . Significant differences in the overall histology could not be detected between the two treatment groups with the modified Brunt score ( P = 0.881 ) or NAS ( P = 0.355 ) . Only lobular inflammation improved significantly ( P for the modified Brunt score = 0.011 , P for NAS = 0.005 ) . In subgroup analyses , significant improvements in lobular inflammation were also observed in males , younger patients up to 50 years of age , slightly overweight patients , and patients with hypertension and an increased histology score . The fibrosis score did not change ( P for ITT = 0.133 , P for PP = 0.140 ) . With the exception of gamma-glutamyl transferase , UDCA did not improve laboratory data . CONCLUSION High-dose UDCA failed to improve the overall histology in patients with NASH in comparison with placebo Nonalcoholic fatty liver disease ( NAFLD ) is reaching epidemic proportions worldwide ( 1 ) and is the most common chronic liver condition in obese patients with prediabetes or type 2 diabetes mellitus ( T2DM ) . Histologic findings range from isolated steatosis ( with no or minimal inflammation ) to severe nonalcoholic steatohepatitis ( NASH ) and variable perisinusoidal or perivenular fibrosis ( 2 ) . Patients with T2DM and NASH have the highest risk for cirrhosis and hepatocellular carcinoma ( 3 , 4 ) , and the presence of NAFLD seems to worsen microvascular and macrovascular complications of diabetes ( 57 ) . Given that most patients with T2DM have NAFLD ( 812 ) and many are at risk for NASH even if they have normal liver aminotransferase levels ( 6 , 9 , 13 , 14 ) , it is surprising that few trials have focused on this population . This distinction ( patients with NASH with vs. without T2DM ) is relevant because additional metabolic factors , such as hyperglycemia ( 15 , 16 ) , lower adiponectin levels ( 17 , 18 ) , worse dyslipidemia ( 19 , 20 ) , and more severe insulin resistance and hepatic steatosis ( 10 , 16 , 1821 ) , may account for the higher rates of severe liver disease observed in patients with T2DM ( 22 ) . Although the cause of NASH is multifactorial and treatment remains challenging ( 23 ) , a major factor is the increase in liver triglyceride content caused by chronic release of free fatty acids ( FFAs ) from insulin-resistant dysfunctional adipose tissue ( 7 , 2427 ) . Because thiazolidinediones target insulin resistance and adipose tissue dysfunction or inflammation that promotes hepatic lipotoxicity in NASH ( 7 , 22 , 28 ) ( which is also a prominent feature of T2DM [ 15 ] ) , they may be more helpful for treating steatohepatitis in this population . In predominantly nondiabetic patients with NASH , several studies have reported variable degrees of histologic benefit with thiazolidinediones ( 2933 ) . In the largest study to date in patients without T2DM ( 34 ) , pioglitazone was no better than placebo for the primary outcome but was beneficial for secondary outcomes , such as resolution of NASH . However , in patients with prediabetes or T2DM , the only available r and omized , controlled trial is a relatively small proof-of-concept study ( 35 ) . This is disappointing given that there are 29.1 million adults with diabetes ( > 90 % with T2DM ) and 86 million with prediabetes ( 36 ) in the United States , many of whom are at risk for cirrhosis from NASH . Moreover , because pioglitazone may also halt the progression of prediabetes to T2DM ( 37 ) , defining its role in patients with prediabetes and NASH is critical . Finally , safety concerns about the long-term use of thiazolidinediones remain ( 38 , 39 ) ; therefore , studies with extended thiazolidinedione exposure are needed before a pioglitazone-based approach can be embraced in this population . The aim of our study was to assess the efficacy and safety of long-term pioglitazone treatment in improving liver histologic outcomes in patients with NASH and prediabetes or T2DM . Methods Design Overview This was a single-center , parallel-group , r and omized ( 1:1 allocation ) , placebo-controlled study , conducted between December 2008 ( first patient enrolled ) and December 2014 ( final data collection ) . Participants , investigators , and health care providers were blinded to treatment assignment throughout the study . The Institutional Review Board at the University of Texas Health Science Center at San Antonio ( UTHSCSA ) approved the study , and all participants provided written informed consent before enrollment . In October 2009 , while updating registry data for another study , investigators discovered that this trial , which they thought had been registered by other study personnel , was not registered . At the time of registration ( Clinical Trials.gov : NCT00994682 ) , 29 patients ( of 97 anticipated ) were enrolled in the study . None of these patients had had the follow-up metabolic measurements or liver biopsies ( primary outcome ) that were to be performed at 18 months , and no interim analyses were done before the trial was registered . A recent review of Clinical Trials.gov ( November 2015 ) revealed that the initial trial registration data erroneously stated that patients with normal glucose tolerance would be r and omly assigned to treatment or placebo . Given that the trial 's eligibility criteria required patients to have an abnormal oral glucose tolerance test ( OGTT ) result ( that is , prediabetes or T2DM ) , the investigators never planned to enroll patients with normal glucose tolerance . This error in trial registration was corrected by the principal investigator . The trial registry states that the primary end point is liver histologic outcomes ( Kleiner criteria [ 40 ] ) at 18 months , and these data are presented in Appendix Table 1 . In this article , the primary end point is defined as a reduction of at least 2 points in 2 categories of the NAFLD activity score ( NAS ) without worsening of fibrosis , an outcome that was not specified in the original registration . This end point has been accepted by investigators in this field as representing significant change in liver histologic outcomes in clinical trials involving patients with NASH ( 34 , 4143 ) . Some secondary outcomes that were assessed , such as insulin secretion , prevention of the onset of T2DM or reversal of glucose intolerance , measurement of visceral fat by magnetic resonance imaging , bone density measurement via dual-energy x-ray absorptiometry ( DXA ) , plasma measurements of bone metabolism , and molecular metabolic pathways , are not reported in this article . Appendix Table 1 . Liver Histologic Variables at Baseline and After 18 mo , Based on Observed Data * Setting and Participants Participants were recruited from the general population of San Antonio , Texas , via newspaper advertisements and from the endocrinology and hepatology clinics at UTHSCSA and the Veterans Affairs Medical Center . Persons were eligible for the trial if they had histologically confirmed NASH and either prediabetes or T2DM . All patients had a screening 2-hour OGTT to diagnose or confirm a diagnosis of prediabetes or T2DM . Prediabetes was defined as impaired fasting glucose ( 5.6 to 6.9 mmol/L [ 100 to 125 mg/dL ] ) , impaired glucose tolerance ( 7.8 to 11.1 mmol/L [ 140 to 199 mg/dL ] on an OGTT ) , or a hemoglobin A1c level of 5.7 % to 6.4 % . Exclusion criteria included use of thiazolidinediones or vitamin E ; other causes of liver disease ( 22 ) or abnormal laboratory results ( such as an aspartate aminotransferase [ AST ] or alanine aminotransferase [ ALT ] level 3 times the upper limit of normal [ ULN ] ) ; type 1 diabetes mellitus ; or severe heart , hepatic , or renal disease . Detailed inclusion and exclusion criteria are provided in the Appendix . R and omization and Interventions After initial screening ( medical history , physical examination , laboratory tests , and 75-g OGTT ) , patients began receiving placebo and were instructed by the research dietician ( C.D. ) to keep physical activity and diet constant during the run-in phase ( mean duration , 1 month ) . After completion of baseline metabolic measurements , participants were prescribed a hypocaloric diet ( 500kcal/d deficit from the calculated weight-maintaining diet ) and were r and omly assigned in a 1:1 ratio to either pioglitazone ( Actos [ Takeda Pharmaceuticals ] ) , 30 mg/d ( titrated after 2 months to 45 mg/d ) , or placebo . R and omization ( computer-generated ) and patient allocation were performed by the research pharmacist without stratification and using a block factor of 4 , which was unknown to investigators . Takeda Pharmaceuticals provided pioglitazone and placebo pills with identical physical characteristics , which were stored at the research pharmacy and dispensed in identical bottles . Outcomes and Follow-up The primary outcome was a reduction of at least 2 points in 2 histologic categories of the NAS without worsening of fibrosis after 18 months of therapy . Secondary liver histologic outcomes included resolution of NASH ; improvement in individual histologic scores ; or improvement in a combined histologic outcome , defined as a reduction in ballooning with at least a 2-point improvement in the NAS or an absolute NAS of 3 or lower ( with improvement in steatosis or inflammation ) without worsening of fibrosis . Baseline liver biopsy specimens were read by a team of experienced clinical pathologists to establish or rule out the presence of NASH and thus determine whether patients were included or excluded . At the end of the study , all biopsy specimens were reread by an experienced research pathologist ( F.T. ) , who was blinded to patient identity , intervention assignment , and pretreatment or posttreatment sequence ( 0 , 18 , or 36 months ) . Biopsy specimens were read by the research pathologist 2 times , with good to excellent intraobserver variability ( agreement > 75 % for all histologic parameters ) . Diagnosis of definite NASH was defined as zone 3 accentuation of macrovesicular steatosis ( 
    Output:
    
Conclusions : In a meta‐ analysis of r and omized controlled trials of NASH , patients given placebo  have significant histologic , radiologic , and biochemical responses .