4. Discussion
In this systematic review and meta-analysis of 8 RCTs, including 967
patients, the safety and efficacy of FGF21 analogs were compared to
placebo in patients with NASH. The main findings from the combined
analysis were: (1) NASH resolution was not different between the two
groups; (2) FGF21 analogs reduced glycated hemoglobin; (3) triglyceride
levels were lower in patients using FGF21 analogs; (4) the intervention
group had a higher incidence of adverse events.
The mechanism of NASH development, progression, and complications is
likely to be related to metabolic syndrome, diabetes, and
dyslipidemia.21-23 Ideally, treatment for this
condition would simultaneously address both local hepatic and metabolic
factors.24-26 In this regard, FGF21 analogs
demonstrate efficacy in inhibiting adipose tissue lipolysis and liver
lipogenesis, contributing to a significant decrease in intrahepatic
triglyceride concentrations.27,28 However, in the
FALCON 1 trial, 197 patients with stage of III or IV fibrosis were
randomized to receive once-weekly subcutaneous injections of
pegbelfermin (PGBF) or placebo for 48 weeks. In the 148 patients who
underwent PGBF, a higher NASH resolution was not
found.10 The study also did not meet its primary
outcomes, such as 1-stage fibrosis improvement without NASH worsening or
NASH improvement without fibrosis worsening probably due to a lack of
dose-related changes in PGBF response rates. The effect of FGF21 analogs
on NASH resolution in the remained trials, however, found a benefit in
the same endpoint for patients who were randomized to receive
Pegbelfermin,11 Pegozafermin,18 and
Efruxifermin 15,16 as compared with placebo.
There also exists uncertainty as to the optimal dose of FGF21 analogs
for NASH disease. The dosage of FGF21 analogs varied substantially
between the included studies, ranging from 3 mg to 70 mg. Accordingly,
the lack of clinical benefit with FGF21 analogs for NASH in previous
studies could be related to the relatively reduced number of patients
exposed to FGF21 analogs within groups by dose. Therefore, we performed
a dedicated analysis of studies with low, medium, and high doses for
NASH resolution, finding no difference between groups. However, a
leave-one-out analysis excluding the FALCON-1 trial10showed a higher incidence of NASH resolution in patients receiving FGF21
analogs, regardless of the dose. In that trial, the study population had
significant NASH disease activity and fibrosis at baseline in
non-invasive assessments. In addition, the FALCON 1 study cirrhosis
progression rate at week 24 was higher than those seen in previous
studies at later time points 29,30 and in a natural
history study.31 Thus, in the absence of definitive
improvement in clinical outcomes, our findings do not appear to support
FGF21 analogs in all NASH patients, considering the administration of
these therapeutic agents in non-severe fibrosis and NASH disease.
Furthermore, NAFLD is intrinsically linked to insulin resistance, with a
prevalence about 2 to 5 times higher in individuals with type 2 diabetes
compared to non-diabetics.32-35 This association, in
turn, amplifies the risks of hepatic fibrosis and
mortality.36,37 Therefore, controlling HbA1c is
essential for a better prognosis among patients 38,39Recent studies demonstrate benefits in insulin resistance, suggesting a
potential positive impact on the development of type 2 diabetes (DM2).15-17As observed in the HARMONY study, by suppressing
lipolysis, FGF21 analogs increase the action of insulin in adipose
tissue.17 These data corroborate the findings of our
meta-analysis, in which the drug is associated with a reduction in
glycated hemoglobin.
It is well established that the function of fibroblast growth factor 21
is related to the regulation of glucose and lipid metabolism, as well as
the development of adaptive responses to stress and nutrient
deprivation.40 In addition to lipid metabolism, FGF-21
stimulates lipolysis in brown adipose tissue during fasting, hepatic
ketogenesis, and free fatty acid oxidation, acting in an autocrine and
paracrine manner in the liver.41 The resulting free
fatty acids from the lipolysis process provide substrates for these
metabolic processes and stimulate PPARα activity in the liver, leading
to increased protein and FGF21 gene
transcription.42,43 This is consistent with our
analysis, which suggests that FGF21 analogs are associated with a
reduction in triglyceride levels, probably due to free fatty acid
oxidation.
Although the data is promising, addressing potential side effects is
essential before considering these drugs as standard treatment for NASH.
Overall, FGF21 analogs have been considered safe, with frequent but
manageable adverse events such as gastrointestinal disorders and
injection site reactions.44 In a recently published
RCT, adverse events were reported in 79% of patients receiving weekly
pegofazemin. However, only one severe event, acute pancreatitis, was
deemed by the investigator to be drug-related.18 In
the HARMONY study, among the 63 adverse events reported in patients in
the intervention group, only one case of ulcerative esophagitis in a
patient with a history of gastroesophageal reflux disease was considered
severe and was attributed to the use of
efruxifermin.17
Our study has some important limitations. First, the follow-up time
differs significantly between studies. Second, the drug dosage used was
also heterogeneous among studies. To address this, we performed a
subgroup analysis by dosage (low, median, and high) for the main
outcomes. Third, patients with different fibrosis stages were included.
Unfortunately, the intended subgroup analysis by fibrosis stage was not
possible due to lack of data, since the studies had a variety of
fibrosis worsening and they did not report outcomes according to this
baseline characteristic. These factors contributed to high heterogeneity
in the pooled analysis. In light of this, leave-one-out sensitivity
analyses were performed.