Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebo-controlled trial

Joy, Tisha; McKenzie, Charles A.; Tirona, Rommel G.; Summers, Kelly L.; Seney, Shannon; Chakrabarti, Subrata; Malhotra, Neel; Beaton, Melanie

doi:10.3748/wjg.v23.i1.141

Cited by 130 publications

(109 citation statements)

References 37 publications

Supporting

Mentioning

100

Contrasting

Unclassified

Order By: Relevance

“…Comments: The study by Joy et al was limited by its small sample size, and inclusion of patients with relatively mild NASH (baseline NAS score was 3.8 ± 0.8), so it is unclear whether a greater impact would have been found in patients with more‐severe disease. The study by Cui et al was limited by the lack of histological assessment Both studies were placebo‐controlled, double‐blinded studies Both studies involved a short follow‐up duration …”

Section: Modulation Of Ir In Nafldmentioning

confidence: 99%

“…Both studies were placebo‐controlled, double‐blinded studies Both studies involved a short follow‐up duration …”

Section: Modulation Of Ir In Nafldmentioning

confidence: 99%

“…In patients with both NAFLD and diabetes, studies have shown mixed results for changes in serum transaminases . In two small placebo‐controlled RCTs in patients with NAFLD, sitagliptin had no beneficial effect on liver steatosis, liver enzymes, or IR …”

Section: Modulation Of Ir In Nafldmentioning

confidence: 99%

See 2 more Smart Citations

Modulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease

et al. 2019

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD) has an estimated prevalence of 25% in the general population, and cirrhosis secondary to nonalcoholic steatohepatitis (NASH) is predicted to become the leading cause of liver transplantation, yet there is a lack of effective licensed treatments for these conditions. There is a close relationship between insulin resistance (IR) and NAFLD, with prevalence of NAFLD being 5‐fold higher in patients with diabetes compared to those without. IR is implicated both in pathogenesis of NAFLD and in disease progression from steatosis to NASH. Thus, modulation of IR represents a potential strategy for NAFLD treatment. This review highlights key proposed mechanisms linking IR and NAFLD, such as changes in rates of adipose tissue lipolysis and de novo lipogenesis, impaired mitochondrial fatty acid β‐oxidation (FAO), changes in fat distribution, alterations in the gut microbiome, and alterations in levels of adipokines and cytokines. Furthermore, this review will discuss the main pharmacological strategies used to treat IR in patients with NAFLD and their efficacy based on recently published experimental and clinical data. These include biguanides, glucagon‐like peptide 1 receptor (GLP‐1) agonists, dipeptidyl peptidase 4 (DPP‐4) inhibitors, peroxisome proliferator‐activated receptor (PPAR‐γ/α/δ) agonists, sodium glucose cotransporter 2 (SGLT2) inhibitors, and farnesoid X receptor (FXR) agonists, with further novel treatments on the horizon. Ideally, treatment would improve IR, reduce cardiovascular risk, and produce demonstrable improvements in NASH histology—this is likely to be achieved with a combinatorial approach.

show abstract

Section: Modulation Of Ir In Nafldmentioning

confidence: 99%

“…Both studies were placebo‐controlled, double‐blinded studies Both studies involved a short follow‐up duration …”

Section: Modulation Of Ir In Nafldmentioning

confidence: 99%

See 1 more Smart Citation

Modulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease

et al. 2019

View full text Add to dashboard Cite

show abstract

“…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 . Negative studies have been also reported with liraglutide, but most have been positive with an improvement in hepatic steatosis (HS) or liver histology .…”

Section: Effect Of Sitagliptin In Nafldmentioning

confidence: 97%

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

Cusi

2019

Hepatology

View full text Add to dashboard Cite

“…We previously reported that the DPP4 inhibitor (DPP4‐I) sitagliptin at a clinically comparable dose successfully ameliorated liver fibrosis by inhibiting platelet‐derived growth factor‐BB‐induced phosphorylation of Smad2/3, p38 mitogen activated protein kinase (MAPK), and extracellular signal‐regulated kinase (ERK)1/2 in As‐HSCs . However, two randomized controlled trials recently showed that sitagliptin alone does not ameliorate liver fibrosis and liver fat in patients with non‐alcoholic fatty liver disease (NAFLD) . Accordingly, OCA + sitagliptin treatment might be beneficial for patients with NASH fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Combined effect of a farnesoid X receptor agonist and dipeptidyl peptidase‐4 inhibitor on hepatic fibrosis

Shimozato

Namisaki

Kaji

et al. 2019

Hepatology Research

View full text Add to dashboard Cite

Aim Non‐alcoholic steatohepatitis (NASH) has a broad clinicopathological spectrum (inflammation to severe fibrosis). The farnesoid X receptor agonist obeticholic acid (OCA) ameliorates the histological features of NASH; satisfactory antifibrotic effects have not yet been reported. Here, we investigated the combined effects of OCA + a dipeptidyl peptidase‐4 inhibitor (sitagliptin) on hepatic fibrogenesis in a rat model of NASH. Methods Fifty Fischer 344 rats were fed a choline‐deficient L‐amino‐acid‐defined (CDAA) diet for 12 weeks. The in vitro and in vivo effects of OCA + sitagliptin were assessed along with hepatic fibrogenesis, lipopolysaccharide–Toll‐like receptor 4 (TLR4) regulatory cascade and intestinal barrier function. Direct inhibitory effects of OCA + sitagliptin on activated hepatic stellate cells (Ac‐HSCs) were assessed in vitro. Results Treatment with OCA + sitagliptin potentially inhibited hepatic fibrogenesis along with Ac‐HSC proliferation and hepatic transforming growth factor (TGF)‐β1, α1(I)‐procollagen, and tissue inhibitor of metalloproteinase‐1 (TIMP‐1) mRNA expression and hydroxyproline levels. Obeticholic acid inhibited hepatic TLR4 expression and increased hepatic matrix metalloproteinase‐2 expression. Obeticholic acid decreased intestinal permeability by ameliorating CDAA diet‐induced zonula occludens‐1 disruption, whereas sitagliptin directly inhibited Ac‐HSC proliferation. The in vitro suppressive effects of OCA + sitagliptin on TGF‐β1 and α1(I)‐procollagen mRNA expression and p38 phosphorylation in Ac‐HSCs were almost consistent. Sitagliptin directly inhibited the regulation of Ac‐HSC. Conclusions Treatment with OCA + sitagliptin synergistically affected hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing Ac‐HSC proliferation. Thus, OCA + sitagliptin could be a promising therapeutic strategy for NASH.

show abstract

Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebo-controlled trial

Abstract: Sitagliptin does not improve fibrosis score or NAS after 24 wk of therapy. The MRI IDEAL technique may be useful for non-invasive measurement of hepatic steatosis.

Cited by 130 publications

References 37 publications

Modulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease

Modulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease

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

Combined effect of a farnesoid X receptor agonist and dipeptidyl peptidase‐4 inhibitor on hepatic fibrosis

Contact Info

Product

Resources

About