Abstract
Background/Objectives: Acetyl-CoA carboxylase (ACC) inhibitors block the initial step of de novo lipogenesis and potentially ameliorate liver pathology in nonalcoholic fatty liver disease (NAFLD). However, increased expression of glycerol-3-phosphate acyltransferase 1 resulting from reduced PUFA may cause hypertriglyceridemia. This systematic review and meta-analysis assessed the efficacy and safety of dual ACC 1/2 inhibitors in adult NAFLD patients, either with or without metabolic dysfunction. Methods: Six databases were searched for randomized controlled trials (RCTs). The primary outcomes were changes in liver fat and fibrosis. Study quality was assessed using the RoB 2 tool. Pooled mean differences (MDs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a fixed-effects model. Results: Six RCTs comprising 655 participants were included; most had low risk of bias. Interventions included firsocostat, clesacostat, and combined regimens with semaglutide, selonsertib, and cilofexor or ervogastat. Compared with placeo, ACC inhibitor monotherapy significantly reduced liver fat (mean difference [MD]: -48.38; 95% CI: -58.54 to -38.22; p < 0.00001) and ALT (MD: -16.07; 95% CI: -24.97 to -7.17; p = 0.0004) but increased ALP (MD: 11.95; 95% CI: 6.98, to 16.92; p < 0.00001) and GGT levels (MD: 23.90; 95% CI: 12.58 to 35.23; p < 0.0001). Hypertriglyceridemia risk was markedly elevated (odds ratio [OR]: 10.33; 95% CI: 4.93 to 21.65; p < 0.00001). No significant improvement in fibrosis was observed by magnetic resonance elastography. Serious adverse events were infrequent, and overall treatment-emergent adverse events were comparable between groups; however, the incidence of hypertriglyceridemia was consistently more frequent with ACC inhibitors. Conclusions: Dual ACC 1/2 inhibitors reduce hepatic steatosis and ALT levels but do not improve fibrosis. Their consistent association with hypertriglyceridemia raises concerns regarding potential long-term cardiometabolic risks, particularly in NAFLD patients with metabolic dysfunction.