Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Aithal, 2008

Type of study:

RCT (parallel, double-blind)

Country:

United Kingdom

Funding and conflicts of interest: Funding by several pharmaceutical companies. No further conflicts of interest reported.

Inclusion criteria:

Nondiabetic patients aged 18-70 years with histology-proven MASH.

Exclusion criteria:

History of alcohol excess, presence of other liver diseases, use of drugs associated with fatty live, use of lipid lowering if the dose had been stable for < 3 months, weight-reduction medication, pregnant or lactating

women, current or previous heart failure,

and renal impairment.

N total at baseline:

Intervention: 37

Control: 37

Important prognostic factors²:

Mean age (range):

I: 52 (28-71)

C: 55 (27-73)

Sex:

I: 70% M

C: 51% M

Mean BMI (SD)

I: 29.8 (± 3.0)

C: 30.8 (± 4.1)

N patients with fibrosis at baseline (stage 1-4)

I:  23 (74%)

C: 25 (83%)

N patients with cirrhosis at baseline (stage 1-4)

Not reported

Groups are largely comparable at baseline, although difference in gender ratios is noteworthy.

30 mg pioglitazone; once daily + hypocaloric diet (500 kcal less + 30-40 minutes moderate exercise for ≥ 5 days per week, for 12 months.

Placebo; once daily + hypocaloric diet (500 kcal less + 30-40 minutes moderate exercise for ≥ 5 days per week, for 12 months

Length of follow-up:

12 months

Loss-to-follow-up:

6 (16%) patients from the intervention group withdrew from the study.

Reasons: Personal reasons (n = 2), found to be diabetic after randomization (n = 2), diarrhoea and vomiting (n = 1), headaches and epistaxis (n = 1)

Control:

7 (19%) patients from the intervention group withdrew from the study.

Reasons: Personal reasons (n = 3), right upper-quadrant pain (n = 1), weight gain (n = 1), rash (n = 1), vertigo (n = 1)

Incomplete outcome data:

See ‘Loss-to-follow-up’ above

No further incomplete outcome data reported.

Steatosis, fibrosis, adverse events

Steatosis:

n (%) of patients with a change of ≥ 1 of 4-point scale, intervention vs. placebo

Improvement: 15 (48%) vs. 11 (37%)

Deterioration: 1 (3%) vs. 3 (10%)

Fibrosis:

n (%) of patients with a change of ≥ 1 of 4-point scale, intervention vs. placebo

Improvement: 9 (29%) vs. 6 (20%)

Deterioration: 0 (0%) vs. 6 (20%)

Adverse events:

Intervention: Digestive system (n = 5), skin (n = 4), head/neck (n = 3), nervous system (n = 2), musculoskeletal (n = 4), genitourinary system (n = 1)

Control: Digestive system (n = 9), skin (n = 5), head/neck (n = 1), cardiorespiratory system (n = 5), nervous system (n = 6), musculoskeletal (n = 4)

Unclear why the study used a ‘relatively low dose’ of pioglitazone, as stated by the authors.

Power calculation required 33 patients in each study arm for analysis, which was not met.

Pioglitazone led to significant weight gain compared to placebo (not visible in this table), although compliance to the intervention (including diet and exercise) is not stated to differ significantly between the groups; a possible explanation is not given.

Caution is needed with respect to generalizability, as all included patients were nondiabetic. Funding source is of some concern.

Sanyal, 2010

Type of study:

RCT (parallel, double-blind)

Country:

United States

Funding and conflicts of interest: Funding by pharmaceutical company Takeda Pharmaceuticals (amongst others), authors received reimbursements and consulting fees from different pharmaceutical companies. One author received fees for serving on the data and safety monitoring board for Takeda Pharmaceuticals.

Inclusion criteria:

Nondiabetic adult patients, definite or possible steatohepatitis with an activity score of ≥ 5 or definite steatohepatitis (confirmed by two pathologists) with an activity score of 4, score for hepatocellular

ballooning ≥ 1

Exclusion criteria:

Excessive alcohol consumption (women >20 g/day, men >30 g/day) for at least 3 consecutive months

during the previous 5 years, presence of cirrhosis, hepatitis C

or other liver diseases, heart failure (New York Heart Association class II to IV), use of drugs known to cause steatohepatitis.

N total at baseline:

Intervention A (pioglitazone): 80

Intervention B (vitamin E): 84

Control: 83

Important prognostic factors²:

Mean age (SD):

IA: 47 (± 12.6)

IB: 47 (± 12.1)                 

C: 45 (± 11.2)

Sex:

IA: 41% M

IB: 38% M

C: 42% M

Mean BMI (SD):

IA: 34 (± 6)

IB: 34 (± 7)

C: 35 (± 7)

N patients with fibrosis at baseline (stage 1-4)

IA: 69 (86%)

IB: 70 (83%)

C: 67 (81%)

N patients with cirrhosis at baseline

IA: 1

IB: 1

C: 3

Groups are largely comparable at baseline.

Intervention A:

30 mg pioglitazone + vitamin E–like placebo; once daily + recommendations about lifestyle changes and diet, for 96 weeks

Intervention B:

800 IU vitamin E (RRR-α-tocopherol) + pioglitazone-like placebo; once daily + recommendations about lifestyle changes and diet, for 96 weeks

Placebo (of both pioglitazone and vitamin E); once daily + recommendations about lifestyle changes and diet, for 96 weeks

Length of follow-up:

120 weeks

Loss-to-follow-up:

Intervention A:

14 patients (18%) stopped treatment before 96 weeks.

Reasons: withdrawment by physician (n = 1), loss to follow-up (n = 11), decline to participate (n = 2)

Intervention B:

6 patients (7%) stopped treatment before 96 weeks.

Reasons: withdrawment by physician (n = 3), loss to follow-up (n = 2), decline to participate (n = 1)

Control:

12 patients (14%) stopped treatment before 96 weeks.

Reasons: withdrawment by physician (n = 1), loss to follow-up (n = 11)

Incomplete outcome data:

See ‘Loss-to-follow-up’

Steatosis, NAS, fibrosis, adverse events, quality of life

Steatosis:

n (%) of patients with a change of ≥ 1 of 4-point scale

Improvement:

IA: 55 (69%), IB: 45 (54%), C: 26 (31%)

Deterioration:

IA: 3 (4%), IB: 7 (8%), C: 17 (21%)

MASH (MASH resolution):

n (%) of patient with absence of MASH 96 weeks after baseline

IA: 38 (47%), IB: 30 (36%), C: 17 (21%)

MASH (NAS):

n (%) of patients with a change of ≥ 2 points of NAS (without worsening of fibrosis) on a 8-point scale

Improvement:

IA:65 (81%) , IB: 63 (75%), C: 41 (50%)

Deterioration:

IA: 7 (9%), IB: 9 (11%), C: 26 (31%)

Fibrosis:

n (%) of patients with a change of ≥ 1 of 4-point scale

Improvement:

IA: 35 (44%), IB: 34 (41%), C: 26 (31%)

Deterioration:

IA: 14 (17%), IB 16 (19%), C: 18 (22%)

Adverse events:

IA: Mild (n = 25), moderate (n = 16), severe (n = 2)

IB: Mild (n = 24), moderate (n = 19), severe (n = 7), life-threatening (n = 4), death (n = 1)

C: Mild (n = 20), moderate (n = 20), severe (n = 10)

Quality of life:

Mean change in SF-36 score, physical component

IA vs. C: -0.9 vs. -0.3

IB vs. C: +0.4 vs. -0.3

Mean change in SF-36 score, mental component

IA vs. C: -1.9 vs. +0.4

IB vs. C: -0.5 vs. +0.4

Patients with incomplete outcome data, which is a large group, were included in the categories ‘no improvement’ for each outcome; no explanation for this method was given.

Results are not easily generalizable as only nondiabetic patients are included. Funding source and conflicts of interest are of some concern.

Cusi, 2016

Type of study:

RCT (parallel, double-blind)

Country:

United States

Funding and conflicts of interest: Funding by non-profit organizations. Main author received grants from pharmaceutical companies in the past. 

Inclusion criteria:

Adults with histology-proven MASH and either prediabetes or diabetes mellitus type 2.

Exclusion criteria:

Use of thiazolidinediones

or vitamin E; other causes of liver disease or abnormal laboratory results; type 1 diabetes mellitus; or severe heart, hepatic or renal disease.

N total at baseline:

Intervention: 50

Control: 51

Important prognostic factors²:

Mean age (SD):

I: 52 (± 10)  

C: 49 (± 11)

Sex:

I: 72% M

C: 69% M

Mean BMI (SD):

I: 34.3 (± 4.8)

C: 34.5 (± 4.8)

N patients with fibrosis at baseline (stage 1-4)

I: 35 (70%)

C: 31 (61%)

N patients with cirrhosis at baseline (stage 1-4)

Not reported

Groups are largely comparable at baseline.

30 mg pioglitazone (45 mg after two months); once daily + hypocaloric diet (500 kcal deficit, for 18 months

Placebo; once daily + hypocaloric (500 kcal deficit, for 18 months

Length of follow-up:

18 months (+ open label phase of 18 months with pioglitazone, separate analysis)

Loss-to-follow-up:

Intervention:

9 (18%)

Reasons: Consent withdrawn or unclear

Control:

9 (18%)

Reasons: Consent withdrawn, adverse event or unclear

Incomplete outcome data:

See ‘Loss-to-follow-up’ above

No further incomplete outcome data reported.

Steatosis, MASH resolution, NAS, fibrosis, adverse events

Steatosis:

n (%) of patients with a reduction of ≥ 1 of 4-point scale, intervention vs. placebo

35 (71%) vs. 13 (26%)

MASH (MASH resolution):

n (%) of patient with absence of MASH with definite MASH at baseline after 18 months of therapy, intervention vs. placebo

26 (51%) vs. 10 (19%)

MASH (NAS):

n (%) of patients with a reduction of ≥ 2 points of NAS (without worsening of fibrosis) on a 8-point scale, intervention vs. placebo

29 (58%) vs. 9 (17%)

Fibrosis:

n (%) of patients with improvement of ≥ 1 of 4-point scale (without worsening of MASH), intervention vs. placebo

20 (39%) vs. 13 (25%)

Adverse events:

Mild adverse events:

Intervention: 91

Control: 9595

Moderate to severe events:

Intervention: Cardiovascular (n = 12), gastrointestinal (n = 1), endocrinologic (n = 5), neurologic (n = 3) gynecologic (n = 1), urologic (n = 1), hematologic (n = 2), other (n = 2)

Control: Cardiovascular (n = 5), gastrointestinal (n = 2), endocrinologic (n = 10), neurologic (n = 4), urologic (n = 1), hematologic (n = 1), other (n = 3)

Number of mild adverse events seems quite high, although evenly spread among the two groups. 

Baseline biopsies were reread after the end of the study to patients with definite MASH, defined as zone 3 accentuation of macrovesicular steatosis

(any grade), hepatocellular ballooning (any degree),

and lobular inflammatory infiltrates (any amount). Appendix reveals that at least seven patients from the intervention group and six patients from the control group were not considered as patients with definite MASH. 

Inclusion of only patients with T2D or prediabetes make the results less generalizable. 

Bril, 2019

Type of study:

RCT (parallel, double-blind)

Country:

Unites States

Funding and conflicts of interest: No financial support by pharmaceutical companies. Authors report to have no conflicts of interest. 

Inclusion criteria:

Patients aged 18-70 with diagnosed type 2 diabetes mellitus and histology confirmed MASH.

Exclusion criteria:

Use of thiazolidinediones, glucagon-like peptide 1 agonists, sodium-glucose cotransporter 2 inhibitors, or vitamin E; other etio-logies of liver disease,

drugs that can produce hepatic steatosis (amiodarone, tamoxifen,

methotrexate, etc.); type 1 diabetes mellitus; or severe heart, pulmonary, or renal disease

N total at baseline⁵

Intervention: 36

Control: 32

Important prognostic factors²:

Mean age (SD):

I: 60 (± 9)   

C: 57 (± 11)

Sex:

I: 91% M

C: 94% M

Mean BMI (SD):

I: 33.8 (± 4.6)

C: 33.6 (± 4.0)

N patients with fibrosis at baseline (stage 1-4)

Not reported

N patients with cirrhosis at baseline (stage 1-4)

Not reported

Groups are largely comparable at baseline.

400 IU vitamin E; twice daily + education on lifestyle modification, for 18 months

Placebo; twice daily + education on lifestyle modification, for 18 months

Length of follow-up:

18 months

Loss-to-follow-up:

Intervention:

3 (8%) patients discontinued treatment

Reasons: Death (n = 2), loss to follow-up (n = 1)

Control:

8 (25%) patients discontinued treatment

Reasons: withdrew consent (n = 4), decision of physician (n = 1), elevated ALT (n = 1), loss to follow-up (n = 1)

Incomplete outcome data:

See ‘Loss-to-follow-up’ above. Two extra patients refused to take a second live biopsy. Unclear to which study arm they belonged.

Steatosis, MASH resolution, NAS, fibrosis, adverse events

Steatosis:

n (%) of patients with a reduction of ≥ 1 of 4-point scale, intervention vs. placebo

24 (68%) vs. 15 (46%)

MASH (MASH resolution)⁶:

n (%) of patients with absence of ballooning and inflammation and no worsening of fibrosis, intervention vs. placebo

14 (40%) vs. 5 (17%)

MASH (NAS)⁶:

n (%) of patients with a reduction of ≥ 2 points of NAS (without worsening of fibrosis) on a 8-point scale, intervention vs. placebo

13 (36%) vs. 7 (22%)

Fibrosis:

n (%) of patients with a reduction of ≥ 1 of 4-point scale (without worsening of MASH), intervention vs. placebo

19 (50%) vs. 10 (30%)

Adverse events:

Intervention: Cardiovascular (n = 8 of which two died), gastrointestinal (n = 7), respiratory (n = 10), endocrinologic (n = 12), gynecologic (n = 1), infectious diseases (n = 2), urologic (n = 1), other (n = 10)

Control: Cardiovascular (n = 4), gastrointestinal (n = 10), respiratory (n = 8), endocrinologic (n = 8), gynecologic (n = 1), other (n = 7)

Loss to follow-up in control group is relatively high compared to the intervention group.

Difference in resolution of MASH between intervention and control group is non-significant for analyses according to authors (level of significance: p = 0.025)

Results should be viewed with caution due to inclusion of only T2D patients, almost exclusively male.

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Aithal, 2008

Definitely yes;

Reason: Randomization was performed with a computer program, with inclusion of anthropometric data, blood count, standard liver chemistry etc. 

Probably yes;

Reason: Patients were randomly allocated to either pioglitazone or placebo. No specific information on allocation.

Definitely yes;

Reason: Patients, data collectors and analysts blinded. No information on health care workers (if present), but these are likely to have a minor role.

Probably yes;

Reason: Loss-to-follow-up was 16% (n = 6) in intervention group and 19% (n = 7) in control group. Reasons for follow-up vary between and within the study groups.

Definitely yes;

Reason: All relevant outcomes stated in methods were reported.

Probably no;

Reason: Funding by several pharmaceutical companies, unclear whether these had had an active role in the study and whether a restricted or unrestricted grant was given. Analysis was a per-protocol analysis.

Some concerns (all outcome measures)

Reasons: role of funding source not fully clear, allocation concealment not fully clear, no use of ITT analysis.

Sanyal, 2010

Definitely yes;

Reason: Randomization was performed with a computer program.

Probably yes;

Reason: Patients were randomly allocated to either pioglitazone, vitamin E or placebo. No specific information on allocation.

Probably yes;

Reason: Study is ‘double-blind’, although no explanation on blinding method is given. Placebo and intervention pills for pioglitazone and vitamin E had a similar appearance.

Probably yes;

Reason: Loss-to-follow-up was 7-17%, but several patients still took baseline and end-biopsies (full outcome data). Reasons for loss to follow-up are comparable among study groups. Patients with incomplete outcome data, were included in the categories ‘no improvement’ for each outcome; no explanation for this method is given.

Definitely yes;

Reason: All relevant outcomes stated n methods were reported.

Probably no;

Reason: Funding by several pharmaceutical companies. One author performed several tasks for one of the funding sources. Unclear whether the funding sources had an active role in the study and whether a restricted or unrestricted grant was given. 

Some concerns (all outcome measures)

Reasons: role of funding source not fully clear, allocation concealment not fully clear

Cusi, 2016

Definitely yes;

Reason: Randomization was performed with a computer program.

Definitely yes;

Reason: Patients were randomly allocated to either pioglitazone or placebo. Allocation by research pharmacist, not visible for investigators. Placebo and intervention pills for pioglitazone and vitamin E had a similar appearance.

Definitely yes;

Reason: Patients, health care providers, investigators and outcome assessors blinded. Data collection probably took place by the investigators. 

Definitely yes:

Reason: Loss-to-follow-up was 18% in both treatment arms with similar reasons. Multiple imputation was used for missing data.

Definitely yes;

Reason: All relevant outcomes stated in methods were reported.

Definitely yes;

Reason: No other problems noted.

LOW (all outcome measures)

Reasons: low risk of bias for all aspects

Bril, 2019

Definitely yes;

Reason: Randomization was performed with a computer program.

Definitely yes;

Reason: Patients were randomly allocated to either vitamin E or placebo via a computer program. Allocation by research pharmacist, not visible for investigators. Placebo and intervention pills for vitamin E had a similar appearance.

Probably yes;

Reason: Study is ‘double-blind’, although no clear explanation of blinding method is given. Patients and outcome assessors blinded. Placebo and intervention pills for pioglitazone and vitamin E had a similar appearance.

Probably yes;

Reason: Large difference in loss-to-follow-up between two treatment arms (I: 8%, C: 25%) with varying reasons for discontinuing study, although study population is relatively small.

Definitely yes;

Reason: All relevant outcomes stated in methods were reported.

Definitely yes;

Reason: No other problems noted.

SOME CONCERN (all outcome measures)

Reasons: low risk of bias for all aspects. However, there was difference in loss to follow-up between study groups. This might be less important due to small study population.

Reference

Reason for exclusion

Kumar J, Memon RS, Shahid I, Rizwan T, Zaman M, Menezes RG, Kumar S, Siddiqi TJ, Usman MS. Antidiabetic drugs and non-alcoholic fatty liver disease: A systematic review, meta-analysis and evidence map. Dig Liver Dis. 2021 Jan;53(1):44-51. doi: 10.1016/j.dld.2020.08.021. Epub 2020 Sep 8. PMID: 32912770.

No combination of correct intervention with MASH patients. 

Xu R, Tao A, Zhang S, Deng Y, Chen G. Association between vitamin E and non-alcoholic steatohepatitis: a meta-analysis. Int J Clin Exp Med. 2015 Mar 15;8(3):3924-34. PMID: 26064294; PMCID: PMC4443128.

outdated SR

Singh S, Khera R, Allen AM, Murad MH, Loomba R. Comparative effectiveness of pharmacological interventions for nonalcoholic steatohepatitis: A systematic review and network meta-analysis. Hepatology. 2015 Nov;62(5):1417-32. doi: 10.1002/hep.27999. Epub 2015 Oct 1. PMID: 26189925.

outdated SR

Sawangjit R, Chongmelaxme B, Phisalprapa P, Saokaew S, Thakkinstian A, Kowdley KV, Chaiyakunapruk N. Comparative efficacy of interventions on nonalcoholic fatty liver disease (NAFLD): A PRISMA-compliant systematic review and network meta-analysis. Medicine (Baltimore). 2016 Aug;95(32):e4529. doi: 10.1097/MD.0000000000004529. PMID: 27512874; PMCID: PMC4985329.

outdated SR

Malik A, Nadeem M, Amjad W, Farooq U, Malik S, Malik M. COMPARATIVE NETWORK META-ANALYSIS FOR EFFICACY OF PHARMACOLOGICAL MODALITIES FOR NON-ALCOHOLIC FATTY LIVER DISEASE(NAFLD). J Gastrol. 2021 May 1; 160: 840. doi: 10.1016/S0016-5085(21)02735-9.

Full article not available

Ahmed NR, Kulkarni VV, Pokhrel S, Akram H, Abdelgadir A, Chatterjee A, Khan S. Comparing the Efficacy and Safety of Obeticholic Acid and Semaglutide in Patients With Non-Alcoholic Fatty Liver Disease: A Systematic Review. Cureus. 2022 May 8;14(5):e24829. doi: 10.7759/cureus.24829. PMID: 35693370; PMCID: PMC9173657.

Phase II studies Included

Hameed B, Terrault NA, Gill RM, Loomba R, Chalasani N, Hoofnagle JH, Van Natta ML; NASH CRN. Clinical and metabolic effects associated with weight changes and obeticholic acid in non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2018 Mar;47(5):645-656. doi: 10.1111/apt.14492. Epub 2018 Jan 14. PMID: 29333665; PMCID: PMC5931362.

Results from interim-analyse of FLINT trial

Polyzos SA, Mantzoros CS. Adiponectin as a target for the treatment of nonalcoholic steatohepatitis with thiazolidinediones: A systematic review. Metabolism. 2016 Sep;65(9):1297-306. doi: 10.1016/j.metabol.2016.05.013. Epub 2016 May 27. PMID: 27506737.

Outdated SR

Mahady SE, Webster AC, Walker S, Sanyal A, George J. The role of thiazolidinediones in non-alcoholic steatohepatitis - a systematic review and meta analysis. J Hepatol. 2011 Dec;55(6):1383-90. doi: 10.1016/j.jhep.2011.03.016. Epub 2011 Apr 14. PMID: 21703200.

Outdated SR

Perumpail BJ, Li AA, John N, Sallam S, Shah ND, Kwong W, Cholankeril G, Kim D, Ahmed A. The Role of Vitamin E in the Treatment of NAFLD. Diseases. 2018 Sep 24;6(4):86. doi: 10.3390/diseases6040086. PMID: 30249972; PMCID: PMC6313719.

Narrative review

Yaghoubi M, Jafari S, Sajedi B, Gohari S, Akbarieh S, Heydari AH, Jameshoorani M. Comparison of fenofibrate and pioglitazone effects on patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2017 Dec;29(12):1385-1388. doi: 10.1097/MEG.0000000000000981. PMID: 29023319.

Incorrect control group

Hajiagha Mohammadi A A, Khajeh Jahromi S, Ahmadi Gooraji S, Bastani A. Comparison of the Therapeutic Effects of Melatonin, Metformin and Vitamin E on Non-Alcoholic Fatty Liver Disease: A Randomized Clinical Trial. J Adv Med Biomed Res 2022; 30 (140) :232-240. doi: 10.30699/jambs.30.140.232

No difference between MAFLD and MASH patients

Ekhlasi G, Kolahdouz Mohammadi R, Agah S, Zarrati M, Hosseini AF, Arabshahi SS, Shidfar F. Do symbiotic and Vitamin E supplementation have favorite effects in nonalcoholic fatty liver disease? A randomized, double-blind, placebo-controlled trial. J Res Med Sci. 2016 Nov 2;21:106. doi: 10.4103/1735-1995.193178. PMID: 28250783; PMCID: PMC5322689.

Incorrect outcome measurements

Balmer ML, Siegrist K, Zimmermann A, Dufour JF. Effects of ursodeoxycholic acid in combination with vitamin E on adipokines and apoptosis in patients with nonalcoholic steatohepatitis. Liver Int. 2009 Sep;29(8):1184-8. doi: 10.1111/j.1478-3231.2009.02037.x. Epub 2009 Apr 28. PMID: 19422479.

Incorrect intervention (vitamin E with other compound)

Chehrehgosha H, Sohrabi MR, Ismail-Beigi F, Malek M, Reza Babaei M, Zamani F, Ajdarkosh H, Khoonsari M, Fallah AE, Khamseh ME. Empagliflozin Improves Liver Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Diabetes Ther. 2021 Mar;12(3):843-861. doi: 10.1007/s13300-021-01011-3. Epub 2021 Feb 14. PMID: 33586120; PMCID: PMC7882235.

No difference between MAFLD and MASH patients

Huang JF, Dai CY, Huang CF, Tsai PC, Yeh ML, Hsu PY, Huang SF, Bair MJ, Hou NJ, Huang CI, Liang PC, Lin YH, Wang CW, Hsieh MY, Chen SC, Lin ZY, Yu ML, Chuang WL. First-in-Asian double-blind randomized trial to assess the efficacy and safety of insulin sensitizer in nonalcoholic steatohepatitis patients. Hepatol Int. 2021 Oct;15(5):1136-1147. doi: 10.1007/s12072-021-10242-2. Epub 2021 Aug 12. PMID: 34386935.

Phase II study

Zang S, Chen J, Song Y, Bai L, Chen J, Chi X, He F, Sheng H, Wang J, Xie S, Xie W, Yang Y, Zhang J, Zheng M, Zou Z, Wang B, Shi J; Chinese NAFLD Clinical Research Network (CNAFLD CRN). Haptoglobin Genotype and Vitamin E Versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis in China: A Multicenter, Randomized, Placebo-Controlled Trial Design. Adv Ther. 2018 Feb;35(2):218-231. doi: 10.1007/s12325-018-0670-8. Epub 2018 Feb 6. PMID: 29411270.

Co-intervention (personalized dietary and lifestyle advice) + ongoing study

Siddiqui MS, Van Natta ML, Connelly MA, Vuppalanchi R, Neuschwander-Tetri BA, Tonascia J, Guy C, Loomba R, Dasarathy S, Wattacheril J, Chalasani N, Sanyal AJ; NASH CRN. Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis. J Hepatol. 2020 Jan;72(1):25-33. doi: 10.1016/j.jhep.2019.10.006. Epub 2019 Oct 18. PMID: 31634532; PMCID: PMC6920569.

Incorrect outcome measurements

Gastaldelli A, Harrison SA, Belfort-Aguilar R, Hardies LJ, Balas B, Schenker S, Cusi K. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology. 2009 Oct;50(4):1087-93. doi: 10.1002/hep.23116. PMID: 19670459.

Incorrect outcome measurements

Brunt EM, Kleiner DE, Wilson LA, Sanyal AJ, Neuschwander-Tetri BA; Nonalcoholic Steatohepatitis Clinical Research Network. Improvements in Histologic Features and Diagnosis Associated With Improvement in Fibrosis in Nonalcoholic Steatohepatitis: Results From the Nonalcoholic Steatohepatitis Clinical Research Network Treatment Trials. Hepatology. 2019 Aug;70(2):522-531. doi: 10.1002/hep.30418. Epub 2019 Mar 7. PMID: 30549292; PMCID: PMC6570584.

Study Includeds results from ongoing study

Kakazu E, Kondo Y, Ninomiya M, Kimura O, Nagasaki F, Ueno Y, Shimosegawa T. The influence of pioglitazone on the plasma amino acid profile in patients with nonalcoholic steatohepatitis (NASH). Hepatol Int. 2013 Jun;7(2):577-85. doi: 10.1007/s12072-012-9395-y. Epub 2012 Aug 14. PMID: 26201790.

Incorrect outcome measurements

Voican CS, Perlemuter G. Insulin resistance and oxidative stress: two therapeutic targets in non-alcoholic steatohepatitis. J Hepatol. 2011 Feb;54(2):388-91. doi: 10.1016/j.jhep.2010.07.054. Epub 2010 Nov 10. PMID: 21112115.

Commentary article

Rinella ME, Dufour JF, Anstee QM, Goodman Z, Younossi Z, Harrison SA, Loomba R, Sanyal AJ, Bonacci M, Trylesinski A, Natha M, Shringarpure R, Granston T, Venugopal A, Ratziu V. Non-invasive evaluation of response to obeticholic acid in patients with NASH: Results from the REGENERATE study. J Hepatol. 2022 Mar;76(3):536-548. doi: 10.1016/j.jhep.2021.10.029. Epub 2021 Nov 15. PMID: 34793868.

Interim analysis

Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006 Nov 30;355(22):2297-307. doi: 10.1056/NEJMoa060326. PMID: 17135584.

Phase II study

Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, David E, Rizzetto M, Marchesini G. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005 May;100(5):1082-90. doi: 10.1111/j.1572-0241.2005.41583.x. PMID: 15842582.

Incorrect control group (metformin)

Bell LN, Wang J, Muralidharan S, Chalasani S, Fullenkamp AM, Wilson LA, Sanyal AJ, Kowdley KV, Neuschwander-Tetri BA, Brunt EM, McCullough AJ, Bass NM, Diehl AM, Unalp-Arida A, Chalasani N; Nonalcoholic Steatohepatitis Clinical Research Network. Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: a pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study. Hepatology. 2012 Oct;56(4):1311-8. doi: 10.1002/hep.25805. Epub 2012 Aug 21. PMID: 22532269; PMCID: PMC3432683.

Includeds results from ongoing study

Anushiravani A, Haddadi N, Pourfarmanbar M, Mohammadkarimi V. Treatment options for nonalcoholic fatty liver disease: a double-blinded randomized placebo-controlled trial. Eur J Gastroenterol Hepatol. 2019 May;31(5):613-617. doi: 10.1097/MEG.0000000000001369. PMID: 30920975.

Incorrect control group (diet)

Blazina I, Selph S. Diabetes drugs for nonalcoholic fatty liver disease: a systematic review. Syst Rev. 2019 Nov 29;8(1):295. doi: 10.1186/s13643-019-1200-8. PMID: 31783920; PMCID: PMC6884753.

Focus on diabetes drugs

Mantovani A, Byrne CD, Scorletti E, Mantzoros CS, Targher G. Efficacy and safety of anti-hyperglycaemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: An updated systematic review of randomized controlled trials. Diabetes Metab. 2020 Nov;46(6):427-441. doi: 10.1016/j.diabet.2019.12.007. Epub 2020 Jan 7. PMID: 31923578.

Focus on anti-hyperglycaemic drugs

Kulkarni AV, Tevethia HV, Arab JP, Candia R, Premkumar M, Kumar P, Sharma M, Reddy DN, Padaki NR. Efficacy and safety of obeticholic acid in liver disease-A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol. 2021 May;45(3):101675. doi: 10.1016/j.clinre.2021.101675. Epub 2021 Mar 17. PMID: 33722778.

Included interim analysis (inlcuding. FLINT study and REGENERATE study)

Mantovani A, Byrne CD, Targher G. Efficacy of peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors for treatment of non-alcoholic fatty liver disease: a systematic review. Lancet Gastroenterol Hepatol. 2022 Apr;7(4):367-378. doi: 10.1016/S2468-1253(21)00261-2. Epub 2022 Jan 12. PMID: 35030323.

Full article not available

Abdel-Maboud M, Menshawy A, Menshawy E, Emara A, Alshandidy M, Eid M. The efficacy of vitamin E in reducing non-alcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression. Therap Adv Gastroenterol. 2020 Dec 7;13:1756284820974917. doi: 10.1177/1756284820974917. PMID: 33335561; PMCID: PMC7724271.

No sub-analysis for only vitamin E (without co-intervention)

Jalili R, Somi MH, Hosseinifard H, Salehnia F, Ghojazadeh M, Makhdami N, Shirmohammadi M. The Evaluation of Effective Drugs for the Treatment of Non-Alcoholic Fatty Liver Disease: A Systematic Review and Network Meta-Analysis. Adv Pharm Bull. 2020 Sep;10(4):542-555. doi: 10.34172/apb.2020.065. Epub 2020 Aug 9. PMID: 33072533; PMCID: PMC7539311.

Includeds results from phase II studies

Said A, Akhter A. Meta-Analysis of Randomized Controlled Trials of Pharmacologic Agents in Non-alcoholic Steatohepatitis. Ann Hepatol. 2017 Jul-Aug;16(4):538-547. doi: 10.5604/01.3001.0010.0284. PMID: 28611274.

Outdated SR

Sridharan K, Sivaramakrishnan G, Sequeira RP, Elamin A. Pharmacological interventions for non-alcoholic fatty liver disease: a systematic review and network meta-analysis. Postgrad Med J. 2018 Oct;94(1116):556-565. doi: 10.1136/postgradmedj-2018-135967. Epub 2018 Oct 19. PMID: 30341231.

Focus on pharmacological interventions

Kovalic AJ. Pharmacotherapeutic Impact on Nonalcoholic Steatohepatitis Histology: A Systematic Review and Network Meta-analysis. J Clin Exp Hepatol. 2022 Jul-Aug;12(4):1057-1068. doi: 10.1016/j.jceh.2022.01.011. Epub 2022 Feb 1. PMID: 35814516; PMCID: PMC9257887.

Includeds results from phase II studies and ongoing study

Panunzi S, Maltese S, Verrastro O, Labbate L, De Gaetano A, Pompili M, Capristo E, Bornstein SR, Mingrone G. Pioglitazone and bariatric surgery are the most effective treatments for non-alcoholic steatohepatitis: A hierarchical network meta-analysis. Diabetes Obes Metab. 2021 Apr;23(4):980-990. doi: 10.1111/dom.14304. Epub 2021 Jan 15. PMID: 33368954.

Studies with incorrect control group Included in meta-analysis

Lian J, Fu J. Pioglitazone for NAFLD Patients With Prediabetes or Type 2 Diabetes Mellitus: A Meta-Analysis. Front Endocrinol (Lausanne). 2021 Apr 28;12:615409. doi: 10.3389/fendo.2021.615409. Erratum in: Front Endocrinol (Lausanne). 2022 Feb 16;13:840299. PMID: 33995271; PMCID: PMC8115121.

Includeds study with incorrect intervention product (berberine)

Majzoub AM, Nayfeh T, Barnard A, Munaganuru N, Dave S, Singh S, Murad MH, Loomba R. Systematic review with network meta-analysis: comparative efficacy of pharmacologic therapies for fibrosis improvement and resolution of NASH. Aliment Pharmacol Ther. 2021 Oct;54(7):880-889. doi: 10.1111/apt.16583. Epub 2021 Aug 25. PMID: 34435378; PMCID: PMC8711247.

Included phase II studies, not all relevant outcome measures reported

Vadarlis A, Antza C, Bakaloudi DR, Doundoulakis I, Kalopitas G, Samara M, Dardavessis T, Maris T, Chourdakis M. Systematic review with meta-analysis: The effect of vitamin E supplementation in adult patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2021 Feb;36(2):311-319. doi: 10.1111/jgh.15221. Epub 2020 Sep 10. PMID: 32810309.

No subgroup analysis for only vitamin E (without co-intervention)

Abdalla H, Sumithra M, Chitra V. Therapeutic use of obeticholic acid for the mitigation of non-alcoholic-fatty liver disease: A systematic review. Int Jour of Pharmaceut Research. 2021 Mar 16; 13 (2): 2219-2225. doi:
10.31838/ijpr/2021.13.02.264

 Not available

Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatitis: A Meta-analysis. JAMA Intern Med. 2017 May 1;177(5):633-640. doi: 10.1001/jamainternmed.2016.9607. Erratum in: JAMA Intern Med. 2017 May 1;177(5):747. PMID: 28241279; PMCID: PMC5470366.

Outdated SR

He L, Liu X, Wang L, Yang Z. Thiazolidinediones for nonalcoholic steatohepatitis: A meta-analysis of randomized clinical trials. Medicine (Baltimore). 2016 Oct;95(42):e4947. doi: 10.1097/MD.0000000000004947. PMID: 27759627; PMCID: PMC5079311.

Outdated SR

Usman M, Bakhtawar N. Vitamin E as an Adjuvant Treatment for Non-alcoholic Fatty Liver Disease in Adults: A Systematic Review of Randomized Controlled Trials. Cureus. 2020 Jul 6;12(7):e9018. doi: 10.7759/cureus.9018. PMID: 32775098; PMCID: PMC7405968.

No subgroup analysis for only vitamin E (without co-intervention)

Sato K, Gosho M, Yamamoto T, Kobayashi Y, Ishii N, Ohashi T, Nakade Y, Ito K, Fukuzawa Y, Yoneda M. Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Nutrition. 2015 Jul-Aug;31(7-8):923-30. doi: 10.1016/j.nut.2014.11.018. Epub 2014 Dec 24. PMID: 26059365.

Outdated SR