Background
Methods
Data sources and searches
Study selection
Data abstraction and quality assessment
Grading strength of evidence
Results
Author, year country trial name (quality rating) | Population demographics | Interventions (group sizes) duration | Efficacy/effectiveness outcomes A vs. B | Harms A vs. B |
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Aithal, 2008 [12] UK (fair) | Nondiabetic adults with biopsy-confirmed NASH Age: 53 y % female: 39 Ethnicity: NR BMI, kg/m2: 30.3 | A: Pioglitazone 30 mg/d (n = 37) B: Placebo (n = 37) Duration: 12 months | Number (%) with improvement (P value), between-groups P value: Fibrosis: 9/31 (29%) (P = 0.006) vs. 6/30 (20%) (P = 0.81), P = 0.05 Steatosis: 15/31 (48%) (P = 0.001) vs. 11/30 (37%) (P = 0.03), P = 0.19 Changes from baseline (P value), between-groups P value: Weight, kg: 2.6 (P = 0.005) vs. − 3.5 (P = 0.69), P = 0.02 ALT: − 37.7 (P = 0.02) vs. − 6.9 (P = 0.41), P = 0.009 | Serious AEs: NR Withdrawal due to AEs: 3/37 (8.1%) vs. 4/37 (10.8%) |
Anushiravani, 2019 [22] Iran (good) | Adults with probable NAFLD with or without elevated ALT/AST Age: 47 y % female: 49 Ethnicity: NR BMI, kg/m2: 25.1 vs. 26.1 | A. Pioglitazone 15 mg/d (n = 30) B. Placebo (n = 30) Duration: 3 months | Changes from baseline (P value), between-groups P value: BMI: − 0.6 vs. − 0.7 kg/m2; P = NS ALT: − 8.6 vs. − 0.6; P < 0.001 AST: − 6.7 vs. − 0.9; P < 0.001 | None |
Belfort, 2006 [19] US (good) | Adults with type 2 diabetes or impaired glucose tolerance and biopsy-confirmed NASH Age: 51 y % female: 55 Ethnicity: NR BMI, kg/m2: 33.2 | A: Pioglitazone 30 mg/d for 2 months, then 45 mg/d (n = 29) B: Placebo (n = 25) Duration: 6 months | Percent with fibrosis improvement: 46% vs. 33%, P = 0.08 Changes from baseline (P value), between-groups P value: AST: − 19 (P < 0.001) vs. − 9 (P = 0.08), P = 0.04 ALT: − 39 (P < 0.001) vs. − 21 (P = 0.033), P < 0.001 Weight, kg: 2.5 (P < 0.001) vs. − 0.5 (P = 0.53), P = 0.003 BMI: 1.1 (P < 0.001) vs. − 0.2 (P = 0.62), P = 0.005 | Serious AEs: NR Withdrawal due to AEs: 1/29 (3.5%) vs. 1/25 (4.0%) |
Cusi, 2016 [18] US (good) | Patients with prediabetes or type 2 diabetes and nonalcoholic steatohepatitis proven by biopsy Age: 50.5 Sex: 70.3 % male Ethnicity: 24.8% White, 67.3% Hispanic, 0.08% Other BMI: 34.4 Mean NAS: 4.5 Mean fibrosis stage: 1.0 HbA1C with diabetes: 6.95%, without diabetes 5.7% Participants with diagnosed NASH: 86.1% Mean ALT: 59.5 | A. Pioglitazone 45 mg per day (n = 50) B. Placebo, (n = 51) All patients were prescribed a hypocaloric diet. Both groups followed with open-label phase with Pioglitazone for 18 months Duration: 18 months | Greater than 2 point reduction of NAS without worsening fibrosis: 29% vs. 17%, P < 0.001 Fibrosis; greater than 1 point improvement: 39% vs. 25%, P > 0.05 Fibrosis mean change in score improved with pioglitazone: 0 vs. − 0.5, P < 0.05 Weight: pioglitazone group gained 2.5 kg, P < 0.05 BMI: treatment group increase of 2.5 kg, P < 0.05 | NR |
Rana, 2016 [10] India (fair) | Patients with ultrasound diagnosed NAFLD without history of use of insulin sensitizers or hypolipidemic drug use Age: NR Sex: NR Ethnicity: Indian Liver status: AST 55.14 IU/mL; ALT 64.30 (AST and ALT were different at baseline between treatment groups) BMI: 27.95 | A. Metformin (31) B. Rosuvastatin (34) C. Pioglitazone (33) Duration: 24 weeks | Change in ultrasound score (fatty liver) at 24 weeks: our analysis A vs. C: 0.065 vs. − 0.697 (P < 0.001) B vs. C: − 1.265 vs. − 0.697 (P = 0.008) Weight change at 24 weeks: our analysis A vs. C: − 4.76 vs. 0.03 (P < 0.001) B vs. C: − 4.25 vs. 0.03 (P < 0.001) AST change at 24 weeks: our analysis A vs. C: − 14.07 vs. − 23.73 (P = 0.04) B vs. C: 8.35 vs. − 23.73 (P < 0.001) ALT change at 24 weeks: our analysis A vs. C: − 15.55 vs. − 24.67 (P = 0.13) B vs. C: 8.06 vs. − 24.67 (P < 0.001) | NR |
Razavizade, 2013 [14] Iran (fair) | Adults with NAFLD assessed via ultrasonography and predictive formula Age: 35.3 y % female: 15 Ethnicity: NR BMI, kg/m2: 27.7 Diabetes: 7.5% | A: Metformin 1000 mg/d (n = 40) B: Pioglitazone 30 mg/d (n = 40) Duration: 4 months | Changes from baseline (P value), between-groups P value: Liver fat fraction: − 2.53 (P < 0.01) vs. − 3.23 (P < 0.01), P = 0.48 AST: − 10.83 (P < 0.01) vs. − 13.75 (P < 0.01), P = 0.56 ALT: − 21.75 (P < 0.01) vs. − 37.53 (P < 0.01), P = 0.07 Weight, kg: − 2.73 (P < 0.01) vs. − 1.18 (P = 0.04), P = 0.05 | Serious AEs: NR Withdrawal due to AEs: none |
Sanyal, 2010 [13] US PIVENS (fair) | Nondiabetic adults with biopsy-confirmed NASH Age: 46.3 y % female: 60 Ethnicity, % white: 88 BMI, kg/m2: 34 | A: Pioglitazone 30 mg/d (n = 80) B: Vitamin E 800 IU/d (n = 84) C: Placebo (n = 83) | Changes from baseline (P value vs. placebo): NASH improvement, n (%): 27/80 (34%) (P = 0.04) vs. 36/84 (43%) (P = 0.001) vs. 16/83 (19%) NAFLD activity score: − 1.9 (P < 0.001) vs. − 1.9 (P < 0.001) vs. − 0.5 Steatosis: − 0.8 (P < 0.001) vs. − 0.7 (P < 0.001) vs. − 0.1 Fibrosis: − 0.4 (P = 0.10) vs. − 0.3 (P = 0.19) vs. − 0.1 AST: − 20.4 (P < 0.001) vs. − 21.3 (P < 0.001) vs. − 3.8 ALT: − 40.8 (P < 0.001) vs. − 37.0 (P = 0.001) vs. − 20.1 Weight, kg: 4.7 (P < 0.001) vs. 0.4 (P = 0.65) vs. 0.7 | Serious AEs: NR Withdrawal due to AEs: None |
Sharma, 2012 [11] India (fair) | Adults with biopsy-confirmed NASH Age: 38.9 y % female: 46 Ethnicity: NR BMI, kg/m2: 24.9 Diabetes: NR | A: Pentoxifylline 1200 mg/d (n = 29) B: Pioglitazone 30 mg/d (n = 30) Duration: 24 weeks | Changes from baseline (P value), between-groups P value: Brunt score: − 0.34 (P = 0.10) vs. − 1.2 (P = 0.005), P = 0.04 Steatosis: − 0.83 (P = 0.02) vs. − 1.18 (P = 0.005), P = 0.60 Fibrosis: 0.08 (P = 0.70) vs. − 0.46 (P = 0.19), P = 0.26 | Serious AEs: NR Withdrawal due to AEs: None |
Ratziu, 2008 [17] France FLIRT (fair) | Adults with biopsy-confirmed NASH Age: 53.6 % female: 41 Ethnicity: NR BMI, kg/m2: 31 Diabetes: 32% | A: Rosiglitazone 8 mg/d (4 mg/d for first month) (n = 32) B: Placebo (n = 31) Duration: 12 months | Changes from baseline, between-groups P value: NAFLD activity score: − 1 vs. 0, P = 0.60 Steatosis, % reduction: − 20% vs. − 5%, P = 0.02 Fibrosis: 0.03 vs. − 0.18, P = 0.43 ALT, number (%) achieving normalization: 12/32 (38%) vs. 2/31 (7%), P = 0.005 ALT, mean % change from baseline: − 28% vs. − 2%; mean reduction, − 44% vs. 0% AST, mean % change from baseline: − 8% vs. 9%; mean reduction, − 62% vs. + 15% | Serious AEs: NR Withdrawal due to AEs: 1/32 (3.1%) vs. 0/31 Dose reduction due to AEs: 5/32 (15.6%) vs. 1/31 (3.2%) |
Torres, 2011 [16] US (fair) | Adults with biopsy-confirmed NASH Age: 49.4 y % female: 36 Ethnicity, %: Caucasian: 65 Hispanic: 22 BMI, kg/m2: 33.2 Diabetes: 16.7% | A: Rosiglitazone 8 mg/d (n = 50) B: Rosiglitazone 8 mg/d + metformin 1000 mg/d (n = 50) C: Rosiglitazone 8 mg/d + losartan 50 mg/d (n = 50) Duration: 48 weeks | Subjects with final biopsy: 26 vs. 28 vs. 35 Changes from baseline, between-groups P value: Resolution of definite NASH, n (%): 12/26 (46%) vs. 10/28 (36%) vs. 10/35 (29%), NR NAFLD activity score: − 1.77 vs. − 1.32 vs. − 1.37, P = 0.671 Steatosis: − 0.85 vs. − 0.82 vs. − 0.74, P = 0.905 Fibrosis: − 0.70 vs. − 0.59 vs. − 0.32, P = 0.302 AST: − 39.6 vs. − 35.0 vs. − 48.7, NS (exact P value NR) ALT: − 17.4 vs. − 19.9 vs. − 21.7, NS (exact P value NR) Weight, kg: 0.9 vs. − 1.2 vs. 3.7, P = 0.051 | Serious AEs: NR Withdrawal due to AEs: not reported by group |
Author, year country trial name (quality rating) | Population demographics | Interventions (group sizes) duration | Efficacy/effectiveness outcomes A vs. B | Harms A vs. B |
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Armstrong, 2013 [21] Multinational LEAD & LEAD-2 (fair) | Patients with type 2 diabetes who were unable to maintain glycemic control (HbA1c ≥ 7%) with diet and exercise alone, or with oral antidiabetic treatment Age: 55.9 years Gender, % Female: 46.5 Ethnicity, %: White: 78.6 Asian/Hawaiian/Pacific Islander: 12.7 Black/African American: 5.8 Other: 2.1 BMI: NR NAFLD/NASH Stage: NR Liver enzymes (IU/L): Total ALT mean (SD): 29.4 (16.6) Normal ALT mean (SD): 19.1 (5.6) Abnormal ALT mean (SD): 39.4 (17.7) | LEAD A: Liraglutide 0.6 mg/day (475) B: Liraglutide 1.2 mg/day (896) C: Liraglutide 1.8 mg/day (1363) D: Placebo (524) Duration: 26 weeks LEAD-2 0.6, 1.2, or 1.8 mg/day liraglutide, 4 mg/day glimepiride or placebo, all in combination with metformin | LEAD In patients with elevated ALT, liraglutide 1.8 significantly reduced ALT compared with placebo (and was dose responsive); however, after correcting for change in weight, the difference was no longer significant: Mean difference − 1.41, P = 0.21, with similar finding after correcting for reduction in HbA1c: Mean difference 0.57, P = 0.63. Lower doses of liraglutide had similar effects as placebo LEAD2 64% of patients had elevated liver fat on CT; as above liraglutide improved liver fat in a dose dependent way; however, there was no significant differences between liraglutide and placebo after correcting either for weight loss or HbA1c (P = 0.90 and 0.73, respectively) | LEAD WAE: 9% vs. 9% vs. 3% (liraglutide vs. placebo, P < 0.001) SAE: 7% vs. 6% vs. 6% GI disorders: 46% vs. 45% vs. 18% (liraglutide vs. placebo, P < 0.001) LEAD2 NR |
Armstrong, 2016 [9] UK LEAN (good) | Patients had histologically confirmed NASH Age: 51 Sex: 60% male Ethnicity: White: 88% Asian: 4% Black: 2% Other: 6% Liver status: NAS: 4.9; ALT: 72 IU/mL; F3-F4: 52% BMI: 36 Diabetes: 33% | A. Liraglutide 1.8 mg (26) B. Placebo (26) Duration: 48 weeks | Resolution of NASH: 39% vs. 9% (RR 4.3, 95% CI 1.0 to 17.7) Change in NAS: − 1.3 vs. − 0.8, P = 0.24 Change in fibrosis stage: − 0.2 vs. 0.2, P = 0.11 Patients with improvement in fibrosis: 26% vs. 14%, P = 0.46 Patient with worsening fibrosis: 9% vs. 36%, P = 0.04 Change in ALT: − 26.6 vs. − 10.2, P = 0.16 Change in AST: − 27 vs. + 9 IU/L; P = 0.025 | WAE: 8% vs. 4% (P = 0.56) SAE: 8% vs. 8% GI disorders: 81% vs. 65% (P = 0.27) |
Shao, 2014 [8] China (fair) | Patients with type 2 diabetes, obesity, NAFLD, and elevated liver enzymes with normal renal function Age: 43 Sex: 48% male Ethnicity: Chinese Mild NAFLD: 40% Moderate NAFLD: 42% Severe: 18% BMI: 30 HbA1c: 7.64% | A. exenatide + glargine (30) B. Intensive insulin: Insulin aspart + insulin glargine (30) Duration: 12 weeks | Reversal rate of NAFLD based on ultrasound: A vs. B: 93% vs. 67% , P < 0.01 Differences in weight change post minus pretreatment: A vs. B: − 7.77 kg vs. 3.27, P < 0.001 No difference between groups in change in HbA1c: A vs. B: − 1.42% vs. − 1.31%, P > 0.05 | NR |
Author, year country trial name (quality rating) | Population demographics | Interventions (group sizes) duration | Efficacy/effectiveness outcomes | Harms |
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A vs. B | A vs. B | |||
Anushiravani, 2019 [22] Iran (good) | Adults with probable NAFLD with or without elevated ALT/AST Age: 47 y % female: 49 Ethnicity: NR BMI, kg/m2: 25.1 vs. 26.1 | A. Metformin 500 mg/d (n = 30) B. Placebo (n = 30) Duration: 3 months | Changes from baseline (P value), between-groups P value: BMI: − 0.6 vs. − 0.7 kg/m2; P = NS ALT: − 10.1 vs. − 0.6; P < 0.001 AST: − 6.4 vs. − 0.9; P < 0.001 | None |
Haukeland, 2009 [15] Norway (fair) | Adults with biopsy-confirmed NAFLD Age: 47.4 y % female: 27.2 Ethnicity, % white: 86.4% BMI, kg/m2: 30.8 Diabetes: 27.3% | A: Metformin 2500 mg/d (3000 mg if weight > 90 kg) (n = 24) B: Placebo (n = 24) Duration: 6 months | Percentage with improvement (P value change from baseline); between-groups P value: Steatosis: 25% (P = 0.10) vs. 38% (P = 0.03); P = 0.052 Fibrosis: 5% (P = 1.00) vs. 17% (P = 0.17); P = 0.36 NAFLD activity score: 20% (P = 0.23) vs. 50% (P = 0.12); P = 0.06 Changes from baseline (P value); between-groups P value: Weight, kg: − 4.3 (P < 0.001) vs. 0.3 (P = 0.45); P < 0.001 BMI: 1.3 (P < 0.001) vs. 0.1 (P = 0.59); P < 0.001 | Serious AEs: NR Withdrawal due to AEs: 2/24 (8.3%) vs. 0/24 (0%) |
Omer, 2010 [20] Turkey (fair) | Adults with type 2 diabetes or impaired glucose tolerance and biopsy-confirmed NAFLD Age: 48.9 y % female: 45.3 Ethnicity: NR BMI, kg/m2: 30.6 Diabetes: NR | A: Metformin 1700 mg/d + rosiglitazone 4 mg/d (n = 22) B: Metformin 1700 mg/d (n = 22) C: Rosiglitazone 4 mg/d (n = 20) Duration: 12 months | Changes from baseline (P value): NAFLD score (n = 10–13): − 3.9 (P = 0.026) vs. 0.7 (P = 0.726) vs. − 2.6 (P = 0.012) AST: − 15.4 (P = 0.01) vs. − 13.0 (P = NS) vs. − 13.2 (P = 0.005) ALT: − 22.7 (P = 0.017) vs. − 16.7 (P = NS) vs. − 36.2 (P < 0.0001) BMI: − 1.3 (P = 0.006) vs. − 3.2 (P = 0.002) vs. − 0.3 (P = NS) | Serious AEs: NR Withdrawal due to AEs: Not adequately reported |
Rana, 2016 [10] India (fair) | Patients with ultrasound diagnosed NAFLD without history of use of insulin sensitizers or hypolipidemic drug use Age: NR Sex: NR Ethnicity: Indian Liver status: AST 55.14 IU/mL; ALT 64.30 (AST and ALT were different at baseline between treatment groups) BMI: 27.95 | A. Metformin (31) B. Rosuvastatin (34) C. Pioglitazone (33) Duration: 24 weeks | Change in ultrasound score (fatty liver) at 24 weeks: our analysis A vs. B: 0.065 vs. − 1.265 (P < 0.001) A vs. C: 0.065 vs. − 0.697 (P < 0.001) Weight change at 24 weeks: our analysis A vs. B: − 4.76 vs. − 4.25 (P = 0.13) A vs. C: − 4.76 vs. 0.03 (P < 0.001) AST change at 24 weeks: our analysis A vs. B: − 14.07 vs. 8.35 (P < 0.001) A vs. C: − 14.07 vs. − 23.73 (P = 0.04) ALT change at 24 weeks: our analysis A vs. B: − 15.55 vs. 8.06 (P < 0.001) A vs. C: − 15.55 vs. − 24.67 (P = 0.13) | NR |
Razavizade, 2013 [14] Iran (fair) | Adults with NAFLD assessed via ultrasonography and predictive formula Age: 35.3 y % female: 15 Ethnicity: NR BMI, kg/m2: 27.7 Diabetes: 7.5% | A: Metformin 1000 mg/d (n = 40) B: Pioglitazone 30 mg/d (n = 40) Duration: 4 months | Changes from baseline (P value), between-groups P value: Liver fat fraction: − 2.53 (P < 0.01) vs. − 3.23 (P < 0.01), P = 0.48 AST: − 10.83 (P < 0.01) vs. − 13.75 (P < 0.01), P = 0.56 ALT: − 21.75 (P < 0.01) vs. − 37.53 (P < 0.01), P = 0.07 Weight, kg: − 2.73 (P < 0.01) vs. − 1.18 (P = 0.04), P = 0.05 | Serious AEs: NR Withdrawal due to AEs: None. |
Author, year country trial name (quality rating) | Population demographics | Interventions (group sizes) duration | Efficacy/effectiveness outcomes A vs. B | Harms A vs. B |
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Deng, 2017 [7] China (good) | Patients with type 2 diabetes for less than 2 years without complications and fatty liver diagnosed by ultrasound Age: 64 Sex: 75% male Ethnicity: Liver status: ALT 35 IU/mL; AST: 32 IU/mL BMI: 24 Diabetes: HbA1c 7.4% | A. Sitagliptin 50 to 100 mg (36) B. Diet and exercise Duration: 52 weeks | No difference in change in AST (P = 0.99) or ALT (P = 0.97) between treatment with sitagliptin vs. diet and exercise Greater decrease in HbA1c with sitagliptin (− 0.81) vs. diet and exercise (− 0.25), P < 0.01 at 52 weeks (also at 13, 26, and 39 weeks) | NR |