Effect of telmisartan on histological activity and fibrosis of non-alcoholic steatohepatitis: A 1-year randomized control trial

Alam, Shahinul; Kabir, J.; Mustafa, Golam; Gupta, UtpalDas; Hasan, Sajid; Alam, AKMKhorshed

doi:10.4103/1319-3767.173762

Cited by 51 publications

(29 citation statements)

References 28 publications

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“… 27 However, GGT was previously described as a better baseline and dynamic marker of histological changes than ALT and AST in NASH. 28 , 29 It is plausible that sitagliptin improved HOMA IR and fasting blood sugar in this study, in accordance with previous studies. 12 …”

Section: Discussionsupporting

confidence: 92%

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

Alam¹,

Ghosh²,

Mustafa³

et al. 2018

HMER

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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.

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Section: Discussionsupporting

confidence: 92%

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

Alam¹,

Ghosh²,

Mustafa³

et al. 2018

HMER

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“…Telmisartan, valsartan and olmesartan were also used in other studies, with treatment durations ranging from two to 12 months. The study by Alam et al [ 22 ] recommended lifestyle modification for all participants. Patients in the study by Torres et al [ 20 ] were administered an equal dose of rosiglitazone, whereas a placebo was used in the study by McPherson et al [ 24 ].…”

Section: Resultsmentioning

confidence: 99%

Clinical application of angiotensin receptor blockers in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis

et al. 2018

Oncotarget

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ObjectiveNon-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, ranging from simple steatosis to progressive steatohepatitis and cirrhosis. Because of their anti-inflammatory and anti-fibrotic effects, angiotensin receptor blockers (ARBs) are potential therapeutic agents for NAFLD. The present systematic review assessed the effectiveness of ARBs in NAFLD management.ResultsAccounting for data overlap and exclusion criteria, randomized controlled trial -based and single-arm meta-analyses were conducted for four studies with 362 patients and eight studies with 525 patients, respectively. Although alanine aminotransferase levels were not significantly affected by ARB treatment (standardized mean difference 0.20; 95% confidence interval (CI) [−0.04, 0.44]; P = 0.10), a fixed-effect model revealed a decreasing trend in alanine transaminase levels. Low-density lipoprotein levels were reduced by ARB treatment (MD 5.21; 95% CI [3.01, 7.40]; P < 0.00001), and total cholesterol also decreased in response to ARBs (MD 2.10; 95% CI [−0.37, 4.57]; P = 0.10). However, the fibrosis score and NAFLD activity score were not significantly improved by ARB treatment (MD 0.10; 95% CI [−0.58, 0.78]; P = 0.77) (MD −0.25; 95% CI [−1.05, 0.55]; P = 0.53).Materials and MethodsKeywords were used to identify studies in PubMed, EMBASE, CENTRAL, Web of Science and CNKI published up to July 31, 2017. Single-arm and RCT-based meta-analyses of the available data were performed using RevMan (version 5.3).ConclusionsAlthough ARBs significantly decreased plasma low-density lipoprotein and total cholesterol levels, the current evidence is insufficient to support the efficacy of ARBs in managing fibrosis in NAFLD patients.

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“…These results are consistent with a clinical study that reported significantly improved NAFLD and fibrosis scores for telmisartan plus lifestyle modifications relative to lifestyle modifications alone in human patients with NASH. 57 Differential effects of pacritinib and telmisartan in the STAM model likely reflect the additional mechanism of action, PPARγ partial agonism, associated with telmisartan. This has effects on hepatic fatty oxidation, hepatic lipogenesis, and peripheral as well as hepatic insulin sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Pilot study of the antifibrotic effects of the multikinase inhibitor pacritinib in a mouse model of liver fibrosis

Al-Fayoumi¹,

Hashiguchi

Shirakata

et al. 2018

JEP

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BackgroundFibrotic diseases result from an exuberant response to chronic inflammation. Myelofibrosis is the end result of inflammation in bone, caused by an inflammatory process triggered by production of abnormal myeloid cells driven by mutations affecting the JAK–STAT pathway. Inflammatory cytokine overproduction leads to increased mesenchymal cell proliferation, culminating in fibrosis. Although JAK2 inhibitors, such as the JAK1/2 inhibitor ruxolitinib and the JAK2/FLT3/CSF1R/IRAK1 inhibitor pacritinib suppress abnormal clone expansion in myelofibrosis, ruxolitinib does not appear to prevent or reverse bone-marrow fibrosis in most patients. In two Phase III clinical trials, pacritinib, however, demonstrated improvements in platelet counts and hemoglobin and reductions in transfusion burden in some patients with baseline cytopenias, suggesting it may improve bone-marrow function. Unlike ruxolitinib, pacritinib suppresses signaling through IRAK1, a key control point for inflammatory and fibrotic signaling.PurposeTo investigate potential antifibrotic effects of pacritinib in an animal model of liver fibrosis relevant to the observed course of human disease.MethodsPacritinib, negative control (vehicle), and positive control (the angiotensin 2-receptor antagonist and PPARγ partial agonist telmisartan) were assessed in the murine Stelic animal model, which mimics the clinically observed progression from hepatic steatosis to nonalcoholic steatohepatitis, liver fibrosis, and hepatocellular carcinoma. Histopathological analysis used hematoxylin and eosin staining. Body and liver weight changes, nonalcoholic fatty-liver disease activity scores, and plasma cytokeratin 18 fragment levels (a biomarker of hepatic necrosis) were measured.ResultsPacritinib-treated mice had significantly (P<0.01) reduced fibrotic areas in liver compared to vehicle control and significantly (P<0.05) lower levels of CK18. The antifibrotic effect of pacritinib was comparable to that of telmisartan, but without significant effects on fat accumulation.ConclusionThese results, the first to demonstrate hepatic antifibrotic effects for pacritinib in an animal model of liver disease, provide preliminary support for potential clinical applications of pacritinib in fibrotic diseases other than myelofibrosis.

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Effect of telmisartan on histological activity and fibrosis of non-alcoholic steatohepatitis: A 1-year randomized control trial

Cited by 51 publications

References 28 publications

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

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

Clinical application of angiotensin receptor blockers in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis

Pilot study of the antifibrotic effects of the multikinase inhibitor pacritinib in a mouse model of liver fibrosis

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