FGF21 Analogues in Patients With Metabolic Diseases: Systematic Review and Meta‐Analysis of Randomised Controlled Trials

ABSTRACT Background and Aims Liver‐related complications are frequent in patients with metabolic diseases, with limited treatment options currently available. This systematic review and meta‐analysis aimed to assess the effect of fibroblast growth factor‐21 (FGF21) analogues on hepatic steatosis, inflammation and fibrosis in patients with metabolic diseases. Methods We conducted a systematic literature search in Pubmed, Scopus and Web of Science for randomised controlled trials (RCTs) assessing the effect of FGF21 analogues on hepatic steatosis evaluated by hepatic fat fraction (HFF), inflammation and fibrosis compared to placebo. Adverse events (AEs) were also recorded. Results Treatment with FGF21 analogues was associated with metabolic‐associated steatohepatitis (MASH) resolution without fibrosis worsening (5 studies, risk ratio [RR] 4.40, 95% confidence interval [CI]: 2.41, 8.03, p < 0.001) and fibrosis improvement by 1 grade without MASH worsening (6 studies, RR 1.79, 95% CI: 1.24, 2.59, p = 0.002). FGF21 analogues significantly lowered HFF compared to placebo (6 studies, SMD ‐1.08, 95% CI: −1.28, −0.88, p < 0.001), while patients receiving FGF21 analogues were more likely to exhibit a reduction in HFF by 30% (10 studies, RR 4.08, 95% CI: 3.08, 5.40, p < 0.001) or 50% (6 studies, RR 10.43, 95% CI: 5.47, 19.87, p < 0.001). HFF normalisation (≤ 5%) was more frequently achieved with FGF21 analogues (6 studies, RR 14.58, 95% CI: 4.70, 45.18, p < 0.001). The results remained robust after sensitivity analyses. Serious AE and AE leading to drug discontinuation were similar in patients receiving FGF21 analogues or placebo. Conclusions FGF21 analogues can reduce hepatic steatosis, inflammation and fibrosis in patients with metabolic diseases, representing a possible treatment option for steatotic liver disease.