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Table 1 Studies of thiazolidinediones to treat nonalcoholic fatty liver disease

From: Diabetes drugs for nonalcoholic fatty liver disease: a systematic review

Author, year country trial name (quality rating)

Population demographics

Interventions (group sizes) duration

Efficacy/effectiveness outcomes A vs. B

Harms A vs. B

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