human
***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: 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 AIM No pharmacological therapies have been established for non-alcoholic fatty liver disease ( NAFLD ) . Sodium glucose cotransporter 2 inhibitor ( SGLT2I ) was developed for the treatment of adults with type 2 diabetes mellitus ( T2DM ) . The aim of this retrospective study is to evaluate the efficacy of SGLT2I in NAFLD patients with T2DM . METHODS Twenty-four biopsy-proven NAFLD patients with T2DM who received SGLT2I for 24 weeks were retrospectively enrolled as the SGLT2I group . Another 21 NAFLD patients with T2DM treated with dipeptidyl peptidase-4 inhibitor ( DPP4I ) for 24 weeks were selected as the DPP4I group . Clinical data were evaluated at baseline and at 4 , 12 , and 24 weeks . Seventeen patients in the SGLT2I group were evaluated by body composition before and after therapy . RESULTS Not only body weight and hemoglobin A1c but also transaminase activities were significantly decreased in the SGLT2I group . Reductions in transaminase activities were similar between SGLT2I and DPP4I groups . In the SGLT2I group , body mass index and fasting plasma glucose also decreased after the treatment . CONCLUSION Sodium glucose cotransporter 2 inhibitor can be a novel promising agent for the treatment for NAFLD patients with T2DM . Prospect i ve r and omized controlled trials are warranted to confirm this efficacy of SGLT2I on NAFLD with T2DM Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release . In type 2 diabetes ( T2D ) , along with decrements in plasma glucose and insulin levels and increments in glucagon release , sodium – glucose cotransporter 2 ( SGLT2 ) inhibitors induce stimulation of endogenous glucose production ( EGP ) and a suppression of tissue glucose disposal ( TGD ) . We measured fasting and postmeal glucose fluxes in 25 subjects without diabetes using a double glucose tracer technique  ; in these subjects and in 66 previously reported patients with T2D , we also estimated lipolysis ( from [2H5]glycerol turnover rate and circulating free fatty acids , glycerol , and triglycerides ) , lipid oxidation ( LOx ; by indirect calorimetry ) , and ketogenesis ( from circulating β-hydroxybutyrate concentrations ) . In both groups , empagliflozin administration raised EGP , lowered TGD , and stimulated lipolysis , LOx , and ketogenesis . The pattern of glycosuria-induced changes was similar in subjects without diabetes and in those with T2D but quantitatively smaller in the former . With chronic ( 4 weeks ) versus acute ( first dose ) drug administration , glucose flux responses were attenuated , whereas lipid responses were enhanced ; in patients with T2D  , fasting β-hydroxybutyrate levels rose from 246 ± 288 to 561 ± 596 µmol/L ( P < 0.01 ) . We conclude that by shunting substantial amounts of carbohydrate into urine , SGLT2-mediated glycosuria results in a progressive shift in fuel utilization toward fatty substrates . The associated hormonal milieu ( lower insulin-to-glucagon ratio ) favors glucose release and ketogenesis Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background : Because of specific method ological difficulties in conducting r and omized trials , surgical research remains dependent predominantly on observational or non‐r and omized studies . Few vali date d instruments are available to determine the method ological quality of such studies either from the reader 's perspective or for the purpose of meta‐ analysis . The aim of the present study was to develop and vali date such an instrument 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 Aims /hypothesisThe EFFECT-II study aim ed to investigate the effects of dapagliflozin and omega-3 ( n-3 ) carboxylic acids ( OM-3CA ) , individually or combined , on liver fat content in individuals with type 2 diabetes and non-alcoholic fatty liver disease ( NAFLD ) . Methods This r and omised placebo-controlled double-blind parallel-group study was performed at five clinical research centres at university hospitals in Sweden . 84 participants with type 2 diabetes and NAFLD were r and omly assigned 1:1:1:1 to four treatments by a central ised r and omisation system , and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments . Each group received oral doses of one of the following : 10 mg dapagliflozin ( n = 21 ) , 4 g OM-3CA ( n = 20 ) , a combination of both ( n = 22 ) or placebo ( n = 21 ) . The primary endpoint was liver fat content assessed by MRI ( proton density fat fraction [ PDFF ] ) and , in addition , total liver volume and markers of glucose and lipid metabolism as well as of hepatocyte injury and oxidative stress were assessed at baseline and after 12 weeks of treatment ( completion of the trial ) . Results Participants had a mean age of 65.5 years ( SD 5.9 ) , BMI 31.2 kg/m2 ( 3.5 ) and liver PDFF 18 % ( 9.3 ) . All active treatments significantly reduced liver PDFF from baseline , relative changes : OM-3CA , −15 % ; dapagliflozin , −13 % ; OM-3CA + dapagliflozin , −21 % . Only the combination treatment reduced liver PDFF ( p = 0.046 ) and total liver fat volume ( relative change , −24 % , p = 0.037 ) in comparison with placebo . There was an interaction between the PNPLA3 I148 M polymorphism and change in liver PDFF in the active treatment groups ( p = 0.03 ) . Dapagliflozin monotherapy , but not the combination with OM-3CA , reduced the levels of hepatocyte injury biomarkers , including alanine aminotransferase , aspartate aminotransferase , γ-glutamyl transferase ( γ-GT ) , cytokeratin ( CK ) 18-M30 and CK 18-M65 and plasma fibroblast growth factor 21 ( FGF21 ) . Changes in γ-GT correlated with changes in liver PDFF ( ρ = 0.53 , p = 0.02 ) . Dapagliflozin alone and in combination with OM-3CA  improved glucose control and reduced body weight and abdominal fat volumes . Fatty acid oxidative stress biomarkers were not affected by treatments . There were no new or unexpected adverse events compared with previous studies with these treatments . Conclusions /interpretationCombined treatment with dapagliflozin and OM-3CA significantly reduced liver fat content . Dapagliflozin monotherapy reduced all measured hepatocyte injury biomarkers and FGF21 , suggesting a disease-modifying effect in NAFLD.Trial registration : Clinical Trials.gov NCT02279407 Funding : The study was funded by AstraZeneca Aims /hypothesisIn addition to beneficial effects on glycaemia and cardiovascular death , empagliflozin improves adiposity indices . We investigated the effect of empagliflozin on aminotransferases ( correlates of liver fat ) in individuals with type 2 diabetes . Methods Changes from baseline alanine aminotransferase ( ALT ) and aspartate aminotransferase ( AST ) were assessed in the EMPA-REG OUTCOME ® trial ( n = 7020 ) , pooled data from four 24-week placebo-controlled trials ( n = 2477 ) and a trial of empagliflozin vs glimepiride over 104 weeks ( n = 1545 ) . Analyses were performed using data from all participants and by tertiles of baseline aminotransferases . Results In the EMPA-REG OUTCOME ® trial , mean ± SE changes from baseline ALT at week 28 were −2.96 ± 0.18 and −0.73 ± 0.25 U/l with empagliflozin and placebo , respectively ( adjusted mean difference : −2.22 [ 95 % CI −2.83 , −1.62 ] ; p < 0.0001 ) . Reductions in ALT were greatest in the highest ALT tertile ( placebo-adjusted mean difference at week 28 : −4.36 U/l [ 95 % CI −5.51 , −3.21 ] ; p < 0.0001 ) . The adjusted mean difference in change in ALT was −3.15 U/l ( 95 % CI −4.11 , −2.18 ) with empagliflozin vs placebo at week 24 in pooled 24-week data , and −4.88 U/l ( 95 % CI −6.68 , −3.09 ) with empagliflozin vs glimepiride at week 28 . ALT 
    Output:
    
agent
***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: 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 AIM No pharmacological therapies have been established for non-alcoholic fatty liver disease ( NAFLD ) . Sodium glucose cotransporter 2 inhibitor ( SGLT2I ) was developed for the treatment of adults with type 2 diabetes mellitus ( T2DM ) . The aim of this retrospective study is to evaluate the efficacy of SGLT2I in NAFLD patients with T2DM . METHODS Twenty-four biopsy-proven NAFLD patients with T2DM who received SGLT2I for 24 weeks were retrospectively enrolled as the SGLT2I group . Another 21 NAFLD patients with T2DM treated with dipeptidyl peptidase-4 inhibitor ( DPP4I ) for 24 weeks were selected as the DPP4I group . Clinical data were evaluated at baseline and at 4 , 12 , and 24 weeks . Seventeen patients in the SGLT2I group were evaluated by body composition before and after therapy . RESULTS Not only body weight and hemoglobin A1c but also transaminase activities were significantly decreased in the SGLT2I group . Reductions in transaminase activities were similar between SGLT2I and DPP4I groups . In the SGLT2I group , body mass index and fasting plasma glucose also decreased after the treatment . CONCLUSION Sodium glucose cotransporter 2 inhibitor can be a novel promising agent for the treatment for NAFLD patients with T2DM . Prospect i ve r and omized controlled trials are warranted to confirm this efficacy of SGLT2I on NAFLD with T2DM Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release . In type 2 diabetes ( T2D ) , along with decrements in plasma glucose and insulin levels and increments in glucagon release , sodium – glucose cotransporter 2 ( SGLT2 ) inhibitors induce stimulation of endogenous glucose production ( EGP ) and a suppression of tissue glucose disposal ( TGD ) . We measured fasting and postmeal glucose fluxes in 25 subjects without diabetes using a double glucose tracer technique  ; in these subjects and in 66 previously reported patients with T2D , we also estimated lipolysis ( from [2H5]glycerol turnover rate and circulating free fatty acids , glycerol , and triglycerides ) , lipid oxidation ( LOx ; by indirect calorimetry ) , and ketogenesis ( from circulating β-hydroxybutyrate concentrations ) . In both groups , empagliflozin administration raised EGP , lowered TGD , and stimulated lipolysis , LOx , and ketogenesis . The pattern of glycosuria-induced changes was similar in subjects without diabetes and in those with T2D but quantitatively smaller in the former . With chronic ( 4 weeks ) versus acute ( first dose ) drug administration , glucose flux responses were attenuated , whereas lipid responses were enhanced ; in patients with T2D  , fasting β-hydroxybutyrate levels rose from 246 ± 288 to 561 ± 596 µmol/L ( P < 0.01 ) . We conclude that by shunting substantial amounts of carbohydrate into urine , SGLT2-mediated glycosuria results in a progressive shift in fuel utilization toward fatty substrates . The associated hormonal milieu ( lower insulin-to-glucagon ratio ) favors glucose release and ketogenesis Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background : Because of specific method ological difficulties in conducting r and omized trials , surgical research remains dependent predominantly on observational or non‐r and omized studies . Few vali date d instruments are available to determine the method ological quality of such studies either from the reader 's perspective or for the purpose of meta‐ analysis . The aim of the present study was to develop and vali date such an instrument 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 Aims /hypothesisThe EFFECT-II study aim ed to investigate the effects of dapagliflozin and omega-3 ( n-3 ) carboxylic acids ( OM-3CA ) , individually or combined , on liver fat content in individuals with type 2 diabetes and non-alcoholic fatty liver disease ( NAFLD ) . Methods This r and omised placebo-controlled double-blind parallel-group study was performed at five clinical research centres at university hospitals in Sweden . 84 participants with type 2 diabetes and NAFLD were r and omly assigned 1:1:1:1 to four treatments by a central ised r and omisation system , and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments . Each group received oral doses of one of the following : 10 mg dapagliflozin ( n = 21 ) , 4 g OM-3CA ( n = 20 ) , a combination of both ( n = 22 ) or placebo ( n = 21 ) . The primary endpoint was liver fat content assessed by MRI ( proton density fat fraction [ PDFF ] ) and , in addition , total liver volume and markers of glucose and lipid metabolism as well as of hepatocyte injury and oxidative stress were assessed at baseline and after 12 weeks of treatment ( completion of the trial ) . Results Participants had a mean age of 65.5 years ( SD 5.9 ) , BMI 31.2 kg/m2 ( 3.5 ) and liver PDFF 18 % ( 9.3 ) . All active treatments significantly reduced liver PDFF from baseline , relative changes : OM-3CA , −15 % ; dapagliflozin , −13 % ; OM-3CA + dapagliflozin , −21 % . Only the combination treatment reduced liver PDFF ( p = 0.046 ) and total liver fat volume ( relative change , −24 % , p = 0.037 ) in comparison with placebo . There was an interaction between the PNPLA3 I148 M polymorphism and change in liver PDFF in the active treatment groups ( p = 0.03 ) . Dapagliflozin monotherapy , but not the combination with OM-3CA , reduced the levels of hepatocyte injury biomarkers , including alanine aminotransferase , aspartate aminotransferase , γ-glutamyl transferase ( γ-GT ) , cytokeratin ( CK ) 18-M30 and CK 18-M65 and plasma fibroblast growth factor 21 ( FGF21 ) . Changes in γ-GT correlated with changes in liver PDFF ( ρ = 0.53 , p = 0.02 ) . Dapagliflozin alone and in combination with OM-3CA  improved glucose control and reduced body weight and abdominal fat volumes . Fatty acid oxidative stress biomarkers were not affected by treatments . There were no new or unexpected adverse events compared with previous studies with these treatments . Conclusions /interpretationCombined treatment with dapagliflozin and OM-3CA significantly reduced liver fat content . Dapagliflozin monotherapy reduced all measured hepatocyte injury biomarkers and FGF21 , suggesting a disease-modifying effect in NAFLD.Trial registration : Clinical Trials.gov NCT02279407 Funding : The study was funded by AstraZeneca Aims /hypothesisIn addition to beneficial effects on glycaemia and cardiovascular death , empagliflozin improves adiposity indices . We investigated the effect of empagliflozin on aminotransferases ( correlates of liver fat ) in individuals with type 2 diabetes . Methods Changes from baseline alanine aminotransferase ( ALT ) and aspartate aminotransferase ( AST ) were assessed in the EMPA-REG OUTCOME ® trial ( n = 7020 ) , pooled data from four 24-week placebo-controlled trials ( n = 2477 ) and a trial of empagliflozin vs glimepiride over 104 weeks ( n = 1545 ) . Analyses were performed using data from all participants and by tertiles of baseline aminotransferases . Results In the EMPA-REG OUTCOME ® trial , mean ± SE changes from baseline ALT at week 28 were −2.96 ± 0.18 and −0.73 ± 0.25 U/l with empagliflozin and placebo , respectively ( adjusted mean difference : −2.22 [ 95 % CI −2.83 , −1.62 ] ; p < 0.0001 ) . Reductions in ALT were greatest in the highest ALT tertile ( placebo-adjusted mean difference at week 28 : −4.36 U/l [ 95 % CI −5.51 , −3.21 ] ; p < 0.0001 ) . The adjusted mean difference in change in ALT was −3.15 U/l ( 95 % CI −4.11 , −2.18 ) with empagliflozin vs placebo at week 24 in pooled 24-week data , and −4.88 U/l ( 95 % CI −6.68 , −3.09 ) with empagliflozin vs glimepiride at week 28 . ALT 
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