Table 3.
The efficiency of chosen treatment options for NAFLD.
| Study | Type of Study | Intervention Group | Medication | Duration | Results | Safety |
|---|---|---|---|---|---|---|
| Phrueksotsai et al. [106] | RCT | 18 patients with DM2 and hepatic steatosis confirmed by abdominal ultrasonography or CT | Dapagliflozin, 10 mg per day | 12 weeks | ↑: HDL (NS), adiponectin (S) ↓: HFC (S), weight (S), BMI (S), body fat (S), ALT (S), HbA1c (S), HOMA-IR (NS), uric acid (NS), LDL (NS) |
Lack of significant adverse effects |
| Yoneda et al. [104] | Randomized, prospective, open-label controlled trial | 21 patients with DM2 and NAFLD measured by hepatic fat fraction of at least 10%, as assessed based on the MRI-proton density fat fraction | Tofogliflozin, 20 mg per day | 24 weeks | ↑: HDL (S), ketone bodies (S) ↓: HFC (S), BW (S), ALT (S), AST (S), GGT (S), liver stiffness—MRE-LSM (NS), HbA1c (S), uric acid (S), oxidative stress (S), hepatocyte apoptosis—CK-18 fragment M30 antigen (S) |
One case of urinary tract infection, lack of life-threatening events |
| Taheri et al. [107] | RCT | 43 patients with an NAFLD diagnosis based on previous ultrasound imaging or liver function test without diabetes comorbidity | Empagliflozin, 10 mg/day | 24 weeks | ↓: liver stiffness (S), liver steatosis (S), AST (S), ALT (S), fasting insulin (S), BW (S), BMI (S), WC (S) | Lack of major adverse effects |
| Takahashi et al. [105] | RCT | 25 patients with DM and NAFLD diagnosed by liver biopsy | Ipragliflozin, 50 mg/day | 72 weeks | ↓: HbA1c (S), BMI (S), fasting glucose (S), VAT(S), SAT (S), AST (S), ALT (S), GGT (S), type IV collagen 7s—marker of fibrosis (S), liver fibrosis reduction by at least one stage (S) | Mild to moderate adverse effects reported by 22.2% of participants |
| Yoneda et al. [104] | Randomized, prospective, open-label controlled trial | 19 patients with DM2 and NAFLD measured by hepatic fat fraction of at least 10%, as assessed based on the MRI-proton density fat fraction | Pioglitazone, 15–30 mg per day | 24 weeks | ↑: BW (S), HDL (S), adiponectin (S) ↓: HFC (S), ALT (S), AST (S), GGT (S), alkaline phosphatase levels (S), liver stiffness—MRE-LSM (S), HbA1c (S), TG (S), oxidative stress (NS), hepatocyte apoptosis—CK-18 fragment M30 antigen (S) |
Adverse effects: edema and weight gain, lack of life-threatening events |
| Wang et al. [113] | A prospective comparative study | 14 patients with DM2 comorbidity with ab NAFLD diagnosis based on fulfillment of diagnostic criteria | Sitagliptin, 100 mg/day | 24 weeks | ↓: HFC (NS), HbA1c (S), FPG (S), WC (S), BMI (S) | Well tolerated |
| Liu et al. [115] | RCT | 38 patients with NAFLD measured by proton MRS and newly diagnosed DM2 | Exenatide s.c. 5 μg twice daily for 4 weeks followed by 10 μg twice daily for 20 weeks | 24 weeks | ↓: HFC (S), FIB-4 (S), VAT (S), SAT (S), ALT, AST, GGT, TC (S), TG (S) LDL-c (S), FFA (S), WC (S), BW (S), BMI (S), SBP (S), DBP (S) | Hypoglycemic events, lack of major adverse effects |
| Flint et al. [116] | RCT | 34 patients with NAFLD measured by MRI-PDFF | Semaglutide s.c. 0.4 mg/day | 72 weeks | ↓: liver steatosis (S), hepatic fat volume (S), total liver volume (S), VAT (S), SAT (S), BW (S), HbA1c (S), ALT (S), AST (S), GGT (S), SBP (S), hs-CRP (S), TG (S) | Reported adverse reactions were similar in the treatment group and placebo; gastrointestinal effects and serious adverse effects reported by 12.1% of subjects |
| Guo et al. [120] | RCT | Patients with DM2 and NAFLD indicated by hepatic steatosis upon imaging or histology | Liraglutide s.c. at onset 0.6 mg/day, increased weekly with forced titration to 1.8 mg plus metformin at 2 g/day | 26 weeks | ↓: HFC (S), SAT (S), VAT (S), AST (S), ALT (S), HOMA-IR (S), BW (S), WC (S), BMI (S), HbA1c (NS), FBG (NS) | Events of mild hypoglycemia, nausea, diarrhea and vomiting |
| Liu et al. [115] | RCT | 38 patients with NAFLD measured by proton MRS and newly diagnosed DM2 | Insulin glargine (Lantus) at doses needed to achieve below 7.0 mmol/L of FPG | 24 weeks | ↓: HFC (S), VAT (NS), ALT (S), GGT (S), HbA1c (S), TG (S), FFA (S), WC (S), FCP (S) | Hypoglycemic events, lack of major adverse effects |
| Nakajima et al. [124] | RCT | 58 patients with MRI-PDFF proven elevated liver fat content | Pemafibrate, 0.2 mg twice a day | 72 weeks | ↓: MRE-based liver stiffness (S), HFC (NS), ALT (S), GGT (S), ALP (S), LDL-c (S), TC (S), TG (S), HDL-c (S) | Therapy well tolerated, mild and moderate severity adverse effects |
| Cho et al. [123] | RCT | 34 patients with liver steatosis proven by ultrasound with or without DM2 | Ezetimibe 10 mg/day plus rosuvastatin 5 mg/day | 24 weeks | ↓: HFC (S), CAP (S), BMI (S), WC (S), LDL-c (S), TG (S), CRP (S) | Lack of significant adverse effects |
| Nadinskaia et al. [126] | Open-label, multicenter, international noncomparative trial | 74 patients with NAFLD diagnosed by ultrasound | Ursodeoxycholic acid 15 mg/kg/day | 6 months | ↑: HDL (S)—only in women’s group ↓: BW (S), FLI (S), TC (S), LDL (S), TG (S), CIMT (S), 10-year ASCVD risk (S—for women, NS—for men), ALT (S for man and women), ALT (S for man), AST (S for men), GGT (S for men) |
No data |
| Pan et al. [128] | Randomized open label trial | young people with ≥5% hepatic fat fraction on proton magnetic resonance spectroscopy | Somatropin at a starting dose of 0.5 mg/day with further titration to IGF-1 z-score | 24 weeks | ↓: HFF (S), BMI (S), ALT (NS), AST (NS), GGT (NS) | Lack of treatment-related reasons to discontinue the study |
| Climax et al. [141] | RCT | 33 patients with NAFLD diagnosed by imaging or histology | Epeleuton at a dose of 1 g twice a day | 16 weeks | ↓: HFC (NS), ALT (NS), HOMA-IR (S), Adipo-IR (S), HbA1c (S), FPG (S), TG (S), TC (S), VLDL-c (S), RLP-c (S), non–HDL-C (NS), circulating inflammatory markers (S) | 45.5% of responders reported adverse events connected with treatment being mild to moderate in severity but probably not related to epeleuton, lack of serious adverse effects |
| Zeybel et al. [99] | Randomized, placebo-controlled phase 2 study | 20 overweight patients with NAFLD diagnosis—liver fat was determined by MRI-PDFF | Combined metabolic activators (CMAs) containing 3.73 g L-carnitine tartrate, 1 g nicotinamide riboside, 12.35 g serine and 2.55 g N-acetyl-l-cysteine)—one dose for first 14 days, followed by 2 doses up to the end of the study | 10 weeks | ↓: HFC (S), ALT (S), AST (S), uric acid (S), creatinine (S), SBP (S), inflammatory protein markers (S) | 12 of 20 subjects reported mild–moderate adverse symptoms, but they decided to be followed up in the study |
| Harrison et al. [102] | Randomized clinical study | 29 patients with NAFLD diagnosis indicated by CT, MR and AST level, including 12 patients with diabetes comorbidity | AXA1125 24 g twice daily | 16 weeks | ↓: HFC (S), HOMA-IR (NS), ALT (NS), liver fibrosis (NS), apoptosis marker—K-18 M65 (S—after 8 weeks, NS—at the endpoint), cT1—imaging marker of inflammation and fibrosis (S) | Mild or moderate adverse effects, 1 subject resigned from the study |
Adipo-IR—measure of adipose tissue insulin resistance; ALT—alanine aminotransferase; AST—aspartate aminotransferase; BMI—body mass index; BW—body weight; CAP—hepatic-steatosis-index-controlled attenuation parameter; CIMT—carotid intima-media thickness; FCP—fasting C peptide; FLI—fatty liver index; FFA—free fatty acid; FIB-4—fibrosis-4 index; FPG—fasting plasma glucose; GGT—γ-glutamyl transpeptidase; HDL—high-density lipoprotein; HFC—hepatic fat content; HFF—hepatic fat fraction; HOMA-IR—homeostatic model assessment of insulin resistance; hs-CRP—high-sensitivity C-reactive protein; LDL—low-density lipoprotein; RCT—randomized controlled trial; rhGH—recombinant human growth hormone; RLP-c—remnant-like particle cholesterol; SAT subcutaneous adipose; TC—total cholesterol; VAT—visceral adipose tissue; VLDL-C—very-low-density lipoprotein cholesterol; WC—waist circumference. ↑—increase, ↓—decrease. S—statistically significant. NS—statistically non-significant.