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Page 6 of 11 Brodosi et al. Hepatoma Res 2020;6:82 I http://dx.doi.org/10.20517/2394-5079.2020.88

Sodium-glucose co-transporter-2 inhibitors (Gliflozins)
Empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, and many other SGLT-2Is under development
block renal exchange of glucose in the proximal tubule, being responsible for the reuptake of 90% of the
[70]
pre-urinary glucose . They entered the market in the last decade; registration and CVOT trials showed
[71]
that gliflozins reduce cardiovascular events and, particularly, heart failure , prevent the deterioration of
[72]
renal function , and induce a moderate weight loss . The risk of genitourinary tract infections are the
[73]
[74]
principal adverse events associated with gliflozin use .
Their effects of SGLT-2Is on liver fat have not been systematically studied, but a few data have recently
become available, based either on RCTs or epidemiological studies. In a RCT involving 84 patients,
dapagliflozin significantly reduced hepatic fat content measured by magnetic resonance imaging
(dapagliflozin, from 17.3% to 15.1%, P < 0.05; placebo from 15.1% to 14.5%, P not significant), as well as
[75]
liver enzymes (AST, ALT, GGT) when compared to placebo . Similar results on liver fat were reported in
a prospective RCT with empagliflozin involving 50 patients (mean difference between patients treated with
[76]
and without empagliflozin, -4%; P < 0.0001) , and in another RCT in 20 patients treated with canagliflozin
(from 17.6% ± 7.5% to 12.0% ± 4.6% after 6 months and 12.1% ± 6.1% after 12 months; P < 0.005 for both) .
[77]
In real-world studies, a larger reduction in liver enzymes is commonly observed during treatment with
[81]
[80]
SGLT-2Is when compared with other antidiabetic drugs [78-81] , such as sulfonylureas or DPP-4Is . In
a large observational study involving 3,667 patients with T2DM, after a mean follow-up of 4.8 months,
ALT levels (independently of weight and HbA ) were lower in the group treated with canagliflozin and
1c
dapagliflozin, compared with those treated with liraglutide and sitagliptin .
[82]
Very few data are available on SGLT-2Is and histological changes in NAFLD patients. In a prospective
open-label study involving five patients who underwent serial liver biopsies, all patients treated with
canagliflozin had an improvement in liver steatosis and NAS at 24 weeks, together with a decrease in
[83]
fibrosis stage in two of them . The authors also confirmed these results in nine patients after 24 weeks of
canagliflozin treatment, with reduced lobular inflammation, ballooning, and fibrosis stage in 33%, 22%, and
[83]
33% of patients, respectively .
A significant proportion of the beneficial effects of gliflozins might be derived by reduced body weight. A
network meta-analysis of 29 RCTs confirmed that gliflozin treatment was significantly associated with a
[84]
higher probability to achieve significant weight loss (≥ 5%) vs. placebo . In a recent study, canagliflozin
was also reported to reduce the risk of prostate, lung, and pancreatic cancers, without deleterious effects on
[85]
HCC .

CONCLUSION
Progress in pharmacotherapy of T2DM has opened interesting areas of research and treatment for patients
with NAFLD. The use of old drugs should be systematically abandoned in favor of safer and effective
treatments, also addressing the associated cardiovascular and cancer risks, as well as the impending risk
of hypoglycemia that may be particularly harmful for frail patients with NASH and non-NASH cirrhosis.
A decalogue summarizing the novel evidence is reported in Table 2. Needless to say that the use of novel
drugs must be accompanied by intense lifestyle interventions, the only effective strategy to reduce the
burden of NAFLD in the long term, as well as by adherence to international guidelines, supporting a
change from treatment-to-target to treatment-to-cure, while being respectful of patients’ frailty and
[86]
economic resources .
Insulin treatment remains the most effective therapy to control glucose metabolism in very advanced
stages; the risk of hypoglycemia and insulin-associated lipogenesis and weight gain - as well as difficulties