Effect of sitagliptin on hepatic histological activity and fibrosis of nonalcoholic steatohepatitis patients: a 1-year randomized control trial

Abstract

Background/purposeDipeptidyl peptidase 4 (DPP-4) expression is directly associated with hepatic lipogenesis and liver injury in nonalcoholic steatohepatitis (NASH). This study has been designed to elucidate the histological improvement of NASH with the DPP-4 inhibitor sitagliptin.Materials and methodsIn this open-label randomized control trial, paired liver biopsy was taken from 40 NASH patients. Sitagliptin 100 mg was given once daily to the SL group and no sitagliptin was given to the L group for 1 year. Patients from both groups were encouraged to exercise moderately and advised to avoid saturated fat, excessive sugar, soft drinks, fast food, and refined carbohydrates to reduce weight.ResultsSteatosis improved in the SL group (from 2.3±0.6 to 1.2±0.8; P=0.000) and the L group (from 2.1±0.6 to 1.6±0.9; P=0.008), ballooning decreased from 1.8±0.6 to 1.3±06 (P=0.002) in the SL group, but not in the L group. Nonalcoholic fatty liver disease activity score (NAS) attenuated in both groups: the SL group (from 5.8±0.9 to 3.9±1.4; P=0.000) and the L group (from 5.3±0.6 to 4.6±1.2; P=0.009). NAS improvement was much higher in the SL group (1.9±1.4) than in the L group (0.7±1.1) (P=0.006), with NAS improving by ≥2 in 13 patients from the SL group and five patients from the L group (P=0.01). Improvement was irrespective of diabetes. Regression analysis explored that sitagliptin had odds of 6.38 and weight reduction had odds of 4.51 for NAS reduction.ConclusionSitagliptin 100 mg once daily for 1 year ameliorates NAS by improving steatosis and ballooning, irrespective of diabetes. Sitagliptin has stronger efficacy than that of weight reduction.

Plasma proteome profiling discovers novel proteins associated with non‐alcoholic fatty liver disease

“…DPP4 inhibitors are also widely used diabetes drugs worldwide. Interestingly, there are currently clinical trials evaluating the efficacy and safety of DPP4 inhibitor sitagliptin for the treatment of NAFLD (Fukuhara et al , ) and in steatosis irrespective of diabetes in NASH (Alam et al , ). Taken together with our proteomic data, it would be interesting to further investigate the potential of circulating DPP4 levels to serve as prognostic marker for both T2D and NAFLD.…”

From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options

“…Several uncontrolled studies have reported that treatment with DPP-IV inhibitors lowers plasma aminotransferase levels. [155][156][157][158][159][160][161] In one study, a lower plasma ALT was only observed in those with the most uncontrolled diabetes at baseline. 162 Kato et al 163 observed that while sitagliptin reduced IHTG compared to glimepiride, this was also associated with significant weight loss, possibly from concomitant lifestyle changes.…”

Incretin‐Based Therapies for the Management of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes

“…In open-label prospective trials, sitagliptin has been found to improve plasma aminotransferases, (12,13) IHTG, (14) and liver histology. (15) But negative results have also been reported with sitagliptin in open-label studies (16,17) and in all three placebo-controlled trials. (18)(19)(20) Negative studies have been also reported with liraglutide, (20,21) but most have been positive with an improvement in hepatic steatosis (HS) (22)(23)(24)(25)(26)(27)(28) or liver histology.…”

“…In animal models of NAFLD, both glucagon‐like peptide‐1 receptor agonists (GLP‐1Ras) and dipeptidyl peptidase‐4 inhibitor (DPP‐IVi) improve many pathways linked to steatohepatitis, although their efficacy at the clinical level has been mixed (see Tables and ). In open‐label prospective trials, sitagliptin has been found to improve plasma aminotransferases, IHTG, and liver histology . But negative results have also been reported with sitagliptin in open‐label studies and in all three placebo‐controlled trials .…”