Table 1.
Studies assessing the effect of antidiabetic drugs on metabolic and liver outcomes in patients with nonalcoholic fatty liver disease.
| Antidiabetic Class | First Name Author, Year of Publication | Trial Design | Patients | Age | Male (%) | BMI | Diabetes | Therapy Dosage and Duration | Body Weight | HOMA-Index | Liver Enzymes | Histological Steatosis | Lobular Inflammation | Hepatocellular Ballooning | Fibrosis |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DPP-4 inhibitors | Cui, 2016 | Sitagliptin vs. Placebo | 25 | 52.9 | 52 | 31.9 | 48 | 100 mg/die, 24 weeks | Not Improved | Not Improved | Not Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed |
| Joi, 2017 | Sitagliptin vs. Placebo | 6 | 56.7 | 50 | 35.9 | 100 | 100 mg/die, 24 weeks | Not Improved | Not Improved | Not Improved | Not Improved | Not Improved | Not Improved | Not Improved | |
| Sayari, 2018 | Sitagliptin vs. Sitagliptin + Placebo | 138 | 42.9 | 60 | 29.6 | NA | 50 mg/die, 16 weeks | Improved | Not Assessed | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Hussain, 2016 | Vildagliptin vs. Placebo | 29 | 28 | 62 | 30.7 | NA | 100 mg/die, 12 weeks | Improved | Not Assessed | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Metformin | Uygun, 2004 | Metformin plus diet versus diet alone in NASH | 18 | 41 | 62 | 29.2 | 0 | 1.5 g, 6 months | Improved | Improved | Improved | Not Assessed | Not Improved | Not Assessed | Not Improved |
| Bugianesi, 2005 | Metformin versus vit. E versus diet in NAFLD | 55 | 42 | 73 | 28.7 | 0 | 2 g, 12 months | Improved | Improved | Improved | Improved * | Improved * | Not Assessed | Improved * | |
| Idilman, 2008 | Metformin versus Rosiglitazone vs. diet and exercise alone. 20 NASH | 74 | 47 | 59 | 31.5 | NA | 1.7 g, 12 months | Improved | Improved | Improved | Improved | Improved | Not Assessed | Not Improved | |
| Haukeland, 2009 | Metformin versus Placebo in NASH | 20 | 47 | 73 | 30.8 | 20 | 2.5–3 g, 6 months | Improved | Not Improved | Improved | Improved | Not Improved | Not Improved | Unchanged | |
| Shields, 2009 | Metformin plus diet versus diet alone in NASH | 19 | 47 | 68 | 32.6 | 0 | 0.5–1 g, 12 months | Improved | Improved | Improved | Not Improved | Not Improved | Not Improved | Not Improved | |
| Nar, 2009 | Metformin plus diet versus diet alone in NAFLD | 34 | 47 | 26 | 31 | 100 | 1.7 g, 6 months | Improved | Improved | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Omer, 2010 | Metformin versus Rosiglitazione versus Metformin plus Rosiglitazone in NAFLD | 44 ** | 49 | 59 | 31.6 | 70 | 1.7 g, 12 months | Improved in both | Not Improved | Improved (NS) in Metformin group. Improved in combination group | Worsed (NS) in Metformin group. Improved in combination group | Worsed (NS) in Metformin group. Improved in combination group | Worsed (NS) in Metformin group. Improved in combination group | Worsed (NS) in Metformin group. Improved in combination group | |
| Krakoff, 2010 | Metformin versus Placebo in NAFLD | 1073 | 51 | 34 | 34 | IFG | 1.7 g, 36 months | Improved | Not Assessed | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Garinis, 2010 | Metformin plus diet versus diet alone in NAFLD | 20 | 41 | 10 | 36.5 | 0 | 1 g, 6 months | Improved | Improved | Not Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Tock, 2010 | Metformin plus lifestyle change versus lifestyle changes alone in NAFLD | 21 | 17 | NA | >30 | 0 | 1 g, 12 months | Improved | Improved | Not Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Lavine, 2011 | Metformin versus Vit. E versus Placebo | 57 | 13 | 82.5 | 34 | 0 | 1 g, 24 months | Not Improved | Not Improved | Not Improved | Not Improved | Not Improved | Improved | Not Improved | |
| Sofer, 2011 | Metformin versus Placebo in NAFLD | 32 | 52 | 53 | 32.6 | 19 | 1.7 g, 4 months | Not Assessed | Not Improved | Not Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Hajiaghamohammadi, 2012 | Metformin versus Pioglitazone versus Silymarin | 22 | 33 | 64 | 27 | 0 | 500 mg, 2 months | Improved | Improved | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Shavakhi, 2013 | Metformin plus probiotics versus Metformin plus Placebo | 70 | 40 | 46 | NA | 0 | 1 g, 6 months | Improved | Not Assessed | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Feng, 2017 | Metformin versus Liraglutide versus Gliclazide | 31 | 46 | 65.5 | 27 | 100 | 2 g, 6 months | Improved | Not Assessed | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Thiazolidinediones | Sanyal, 2004 | Vit.E vs. Vit.E + Pioglitazone | 10 | 47 | 60 | 32.5 | no | 30 mg/die, 6 months | Not Assessed | Not Assessed | Not Improved | Not Improved | Improved | Improved | Not Improved |
| Belfort, 2006 | Diet + Placebo vs. dieta + Pioglitazone | 26 | 51 | 53 | 33 | 30–45 mg/die, 6 months | Improved | Not Assessed | Improved | Improved | Improved | Improved | Improved | ||
| Idilman, 2008 | Diet and phisical activity vs. Diet and phisical activity + rosiglitazone | 24 | 47.9 | 77 | 31.2 | 8 mg/die, 12 months | Improved | Improved | Improved | Improved | Improved | Improved | Not Improved | ||
| Ratziu, 2008 | rosiglitazone vs. Placebo | 32 | 53 | 59 | 31.5 | 28 | 4–8 mg/die, 12 months | Not Improved | Improved | Improved | Not Improved | Not Improved | Not Improved | Not Improved | |
| Aithal, 2008 | lifestyle + Placebo vs. lifestyle + piglitazone | 37 | 52 | 70 | 30.5 | 0 | 30 mg/die, 12 months | Not Improved | Not Assessed | Improved | Improved | Improved | Improved | Not Improved | |
| Sanyal, 2010 | Placebo vs. vit.E vs. Pioglitazone | 80 | 41 | 34 | 0 | 20 mg/die, 24 months | Not Improved | Not Assessed | Improved | Improved | Improved | Not Improved | Not Improved | ||
| Torres, 2011 | rosiglitazone vs. rosiglitazone + Metformin vs. rosiglitazone + losartan | 108 | 49.7 | 63 | 33 | 16 | 8 mg/die, 12 months | Improved in pio+met | Improved | Improved | Improved | Improved | Improved | Improved | |
| Cusi, 2016 | diet vs. diet + Pioglitazone | 50 | 52 | 72 | 34.3 | 48 | 45 mg/die, 18 months | Improved | Improved | Not Improved | Improved | Improved | Improved | Improved | |
| Tikkainene, 2004 | rosiglitazone vs. Metformin | 9 | 50 | 30 | 30.6 | 100 | 8 mg/die, 4 months | Not Improved | Not Assessed | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Omer, 2010 | Metformin vs. Rosglitazone vs. Metformin + Rosglitazone | 62 | 48.9 | 48.4 | 30.6 | 100 | 4 mg/day, 12 months | Improved in Met+Ros | Improved in Ros | Improved | Improved | Not Assessed | Not Assessed | Not Improved | |
| Gupta, 2010 | Pioglitazone vs. Pioglitazone + diet vs. Metformin | 6 | 57 | 45 | 35 | 100 | 30 mg/die, 4 months | Improved in pio+dieta | Not Assessed | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Shah, 2011 | Insulin + Pioglitazone vs. Insulin + Placebo | 12 | na | na | 35 | 100 | 45 mg/die, 4 months | Not Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Hajiaghamohammadi, 2012 | Pioglitazone vs. Metformin vs. silimarin | 22 | 33 | 63.4 | 27.36 | na | 15 mg/die | Not Improved | Improved | Not Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Ito, 2017 | Pioglitazone vs. ipragliflozin | 34 | 59 | 53 | 29.9 | 100 | 15 mg/die, 6 months | Not Improved | Improved | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Yaghoubi, 2017 | lifestyle vs. Pioglitazone vs. fenofibrate | 30 | 35 | NA | 26 | NA | 30 mg/die, 12 weeks | Improved | Not Assessed | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| SGLT-2 inhibitors | Ito, 2017 | ipragliflozin vs. Pioglitazone | 32 | 57.3 | 44 | 30.7 | 100 | 50 mg/die, 24 weeks | Improved | Not Improved | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed |
| Kuchay, 2018 | Empagliflozin plus standard treatment for diabetes vs. only standard treatment | 22 | 50.7 | 59 | 30 | 100 | 10 mg/die, 20 weeks | Improved | Not Assessed | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| GLP-1 analogues | Armstrong, 2016 | Liraglutide versus Placebo in NASH | 26 | 50 | 69 | 34.2 | 35 | 1.8 mg/day for 48 weeks | Improved | Not Improved | Not Improved | Improved | Not Improved | Improved | Improved |
| Smits, 2016 | Liraglutide versus Sitagliptin versus Placebo in NAFLD | 17 | 61 | 70.6 | 32.8 | 100 | 1.8 mg/day for 12 weeks | Not Improved | Not Assessed | Not Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Khoo, 2017 | Liraglutide versus lifestyle changes in NAFLD | 24 | 44 | 100 | 32.2 | 0 | 3 mg/day for 26 weeks | Improved | Improved | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Feng, 2017 | Liraglutide versus Gliclazide versus Metformin | 29 | 47 | 72.4 | 28.1 | 100 | 1.8 mg/day for 24 weeks | Improved | Not Assessed | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Fan, 2013 | Exenatide versus Metformin | 49 | 51 | 57.1 | 28.2 | 100 | 10 microg twice a day for 12 weeks | Improved | Not Improved | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed | |
| Shao, 2014 | Exenatide plus insulin versus intensive insulin therapy | 15 | 42 | 50 | 30.6 | 100 | 10 microg twice a day for 12 weeks | Improved | Not Assessed | Improved | Not Assessed | Not Assessed | Not Assessed | Not Assessed |
* Second biopsy was available in only 17 patients treated with Metformin and in no cases of control groups; ** 22 only Metformin, 22 Metformin plus rosiglitazone. DPP-4: dipeptidyl peptidase-4, SGLT-2: sodium-glucose cotransporter 2, GLP-1: glucagon-like pepide-1, IFG: impaired fasting glucose