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A randomized triple-blind controlled clinical trial evaluation of sitagliptin in the treatment of patients with non-alcoholic fatty liver diseases without diabetes.

ABSTRACT: The current study aimed to evaluate the efficacy of sitagliptin vs. placebo in treating non-alcoholic fatty liver disease (NAFLD). In a triple-blind randomized clinical trial, we assigned 120 eligible subjects with NAFLD to receive daily dosing of 50 mg sitagliptin (n = 60) or the placebo (n = 60) for 56 weeks and lifestyle modification in both groups. Laboratory and anthropometric outcomes were measured, and liver stiffness was assessed using a fibroscan. The primary outcome measures were changes from baseline in fibrosis scores and liver transferases. Out of 120 patients randomized into sitagliptin and placebo groups, 76 patients completed the trial, of whom 44 were in the sitagliptin and 32 in the placebo groups. Patients receiving sitagliptin showed a significant decrease in the fibrosis scores (P = 0.001). The reductions in the alanine aminotransferase (AST) (P = 0.036) and aspartate AST (P < 0.001) levels were also statistically significant. The effect of sitagliptin in reducing fibrosis scores was significantly greater in normal-weight and overweight individuals than in obese individuals (p = 0.036, and p = 0.018, respectively), whereas the effects of sitagliptin on AST levels were greater among overweight/obese patients (p = 0.028, and p = 0.016, respectively). Sitagliptin reduced fibrosis scores and liver enzymes in NAFLD patients after 56 weeks of therapy. The changes in fibrosis scores were more prominent in patients with normal weight and overweight than obese patients, whereas the effects on AST levels were greater among overweight/obese patients. Other randomized trials with larger sample sizes and longer treatment durations may be required before precise results can be reached.

Clinical trial registration

[https://www.irct.ir/trial/46140], identifier [IRCT20140430017505N2].

SUBMITTER: Doustmohammadian A

PROVIDER: S-EPMC9365981 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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A randomized triple-blind controlled clinical trial evaluation of sitagliptin in the treatment of patients with non-alcoholic fatty liver diseases without diabetes.

Doustmohammadian Azam A Nezhadisalami Ahmad A Safarnezhad Tameshke Fahimeh F Motamed Nima N Maadi Mansooreh M Farahmand Mohammad M Sohrabi Masoudreza M Clark Cain C T CCT Ajdarkosh Hossein H Faraji Amir Hossein AH Nikkhah Mehdi M Sobhrakhshankhah Elham E Ebrahimi Ramin R Zamani Farhad F

Frontiers in medicine 20220728

The current study aimed to evaluate the efficacy of sitagliptin vs. placebo in treating non-alcoholic fatty liver disease (NAFLD). In a triple-blind randomized clinical trial, we assigned 120 eligible subjects with NAFLD to receive daily dosing of 50 mg sitagliptin (<i>n</i> = 60) or the placebo (<i>n</i> = 60) for 56 weeks and lifestyle modification in both groups. Laboratory and anthropometric outcomes were measured, and liver stiffness was assessed using a fibroscan. The primary outcome measu ...[more]

PMID: 35966875

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Project description:Background & aimsUncontrolled studies show sitagliptin, an oral DPP-4 inhibitor, may improve alanine aminotransferase and liver histology in non-alcoholic fatty liver disease (NAFLD) patients. We aimed to compare sitagliptin vs. the efficacy of a placebo in reducing liver fat measured by MRI-derived proton density-fat fraction (MRI-PDFF).MethodsThis randomized, double-blind, allocation-concealed, placebo-controlled trial included 50 NAFLD patients with prediabetes or early diabetes randomized to sitagliptin orally 100mg/day or placebo for 24weeks. Primary outcome was liver fat change measured by MRI-PDFF in colocalized regions of interest within each of nine liver segments. Additional advanced assessments included MR spectroscopy (MRS) for internal validation of MRI-PDFF's accuracy, and magnetic resonance elastography (MRE) and FIBROSpect® II to assess liver fibrosis.ResultsSitagliptin was not significantly better than placebo in reducing liver fat measured by MRI-PDFF (mean difference between sitagliptin and placebo arms: -1.3%, p=0.4). Compared to baseline, there were no significant differences in end-of-treatment MRI-PDFF for sitagliptin (18.1% to 16.9%, p=0.27) or placebo (16.6% to 14.0%, p=0.07). The groups had no significant differences for changes in alanine aminotransferase, aspartate aminotransferase, low-density lipoprotein, homeostatic model assessment insulin resistance, and MRE-derived liver stiffness. In both groups at baseline and post-treatment, MRI-PDFF and MRS showed robust correlation coefficients ranging from r(2)=0.96 to r(2)=0.99 (p<0.0001), demonstrating the strong internal validity of the findings. FIBROSpect® II showed no changes in the sitagliptin group but was significantly increased in the placebo group (p=0.03).ConclusionsSitagliptin was safe but not better than placebo in reducing liver fat in prediabetic or diabetic patients with NAFLD.Lay summaryIn a randomized, double-blind, placebo-controlled study, the anti-diabetic drug sitagliptin was no more effective than placebo for improving liver fat and liver fibrosis in patients with non-alcoholic fatty liver disease. This study demonstrates that non-invasive magnetic resonance imaging techniques, including magnetic resonance imaging-proton density-fat fraction and magnetic resonance elastography, can be used to assess treatment response in non-alcoholic fatty liver disease clinical trials.

Project description:PurposeDipeptidyl peptidase-4 inhibitors (DPP-4I), key regulators of the actions of incretin hormones, exert anti-hyperglycemic effects in type 2 diabetes mellitus (T2DM) patients. A major unanswered question concerns the potential ability of DPP-4I to improve intrahepatic lipid (IHL) content in nonalcoholic fatty liver disease (NAFLD) patients. The aim of this study was to evaluate the effects of sitagliptin on IHL in NAFLD patients.MethodsA prospective, 24-week, single-center, open-label, comparative study enrolled 68 Chinese NAFLD patients with T2DM. Subjects were randomly divided into 4 groups: control group who did not take medicine (14 patients); sitagliptin group who received sitagliptin treatment (100mg per day) (17 patients); metformin group who received metformin (500mg three times per day) (17 patients); and sitagliptin plus metformin group who received sitagliptin (100mg per day) and metformin (500 mg three times per day) (20 patients). IHL, physical examination (waist circumstances, WC; body mass index, BMI), glucose-lipid metabolism (fasting plasma glucose, FPG; hemoglobin A1c, Hb1A1c; triglycerides; cholesterol; alanine aminotransferase, ALT; aspartate aminotransferase, AST) were measured at baseline and at 24 weeks.Results1) WC and BMI were decreased significantly in all groups except control group (all P<0.05). 2) There was no statistically significant difference in IHL among the sitagliptin, metformin, and sitagliptin plus metformin groups before and after treatment(all P>0.05). Only the metformin group showed a statistically significant difference in IHL before and after treatment(P<0.05). 3) Sitagliptin treatment led to a significant decrease in FBG and HbA1c when compared with the control group (all P<0.01). Additionally, HhA1c was significant decreased in the sitagliptin group when compared with the metformin group (P< 0.05). 4) HbA1c and FBG were decreased by 0.8% and 0.7 mmol/l respectively and the percentage of patients with HbA1c less than 7% was 65% with sitagliptin treatment.ConclusionSitagliptin improves abnormalities in glucose metabolism, but not reduces the IHL in T2DM with NAFLD, indicating that sitagliptin might be a therapeutic option for treatment of NAFLD indirectly while not directly on IHL. Clinical Trial Registration: https://clinicaltrials.gov/, identifier CTR# NCT05480007.

Project description:Screening for non-alcoholic fatty liver disease (NAFLD) is key step for primary management of fatty liver in the clinical setting. Excess weight subjects carry a greater metabolic risk even before exhibiting pathological patterns, including diabetes. We characterized the cross-sectional relationship between routine circulating biomarkers and NAFLD in a large sample of diabetes-free subjects with overweight or obesity, to elucidate any independent relationship. A population sample of 1232 consecutive subjects with a body mass index of at least 25 kg/m2, not receiving any drug or supplemental therapy, was studied. Clinical data and routine biochemistry were analyzed. NAFLD was defined using the validated fatty liver index (FLI), classifying subjects with a score ≥ 60% as at high risk. Due to extreme skewing of variables of interest, resampling matching for age and sex was performed. Our study population was characterized by a majority of females (69.90%) and a prevalence of NAFLD in males (88.90%). As a first step, propensity score matching was explicitly performed to balance the two groups according to the FLI cut-off. Based on the resulting statistical trajectories, corroborated even after data matching, we built two logistic regression models on the matched population (N = 732) to verify any independent association. We found that each unit increase of FT3 implicated a 50% increased risk of NAFLD (OR 1.506, 95%CI 1.064 to 2.131). When including glycated haemoglobin (HbA1c) in the model, free-triiodothyronine (FT3) lost significance (OR 1.557, 95%CI 0.784 to 3.089) while each unit increase in HbA1c (%) indicated a significantly greater NAFLD risk, by almost two-fold (OR 2.32, 95%CI 1.193 to 4.512). Glucose metabolism dominates a key pathway along the hazard trajectories of NAFLD, turned out to be key biomarker in monitoring the risk of fatty liver in diabetes-free overweight subjects. Each unit increase in HbA1c (%) indicated a significantly greater NAFLD risk, by almost two-fold, in our study.

Dataset Information

A randomized triple-blind controlled clinical trial evaluation of sitagliptin in the treatment of patients with non-alcoholic fatty liver diseases without diabetes.

Clinical trial registration

Publications

A randomized triple-blind controlled clinical trial evaluation of sitagliptin in the treatment of patients with non-alcoholic fatty liver diseases without diabetes.

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