Pilot study of liraglutide effects in non‐alcoholic steatohepatitis and non‐alcoholic fatty liver disease with glucose intolerance in <scp>J</scp>apanese patients (<scp>LEAN</scp>‐<scp>J</scp>)

Eguchi, Yuichiro; Kitajima, Yoichiro; Hyogo, Hideyuki; Takahashi, Hirokazu; Kojima, Motoyasu; Ono, Masafumi; Araki, Norimasa; Tanaka, Kenichi; Yamaguchi, Miyuki; Matsuda, Yayoi; Ide, Yasushi; Otsuka, Taiga; Ozaki, Iwata; Ono, Naofumi; Eguchi, Takahisa; Anzai, Keizo

doi:10.1111/hepr.12351

Cited by 158 publications

(175 citation statements)

References 54 publications

(103 reference statements)

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“…This effect appears to be mediated by its action on weight loss [42] . Similar results were also found in another study of NASH patients, and liraglutide therapy significantly improved their body mass index, visceral fat accumulation, aminotransferases, glucose abnormalities and histological features [43] . However, another study found that GLP-1 agonists treatment with exenatide or liraglutide for 6 months in patients with T2DM dramatically improves hepatic steatosis measured by using 1 H MRS; however, the change did not correlate with changes in body weight and abdominal fat, but it did correlate with reduction in HbA1c [44] .…”

Section: Human Clinical Studiessupporting

confidence: 86%

Review on the effect of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of non-alcoholic fatty liver disease

Zhao

Zhou

et al. 2015

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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Non-alcoholic fatty liver disease (NAFLD) is a common liver disease and it represents the hepatic manifestation of metabolic syndrome, which includes type 2 diabetes mellitus (T2DM), dyslipidemia, central obesity and hypertension. Glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors were widely used to treat T2DM. These agents improve glycemic control, promote weight loss and improve lipid metabolism. Recent studies have demonstrated that the GLP-1 receptor (GLP-1R) is present and functional in human and rat hepatocytes. In this review, we present data from animal researches and human clinical studies that showed GLP-1 analogues and DPP-4 inhibitors can decrease hepatic triglyceride (TG) content and improve hepatic steatosis, although some effects could be a result of improvements in metabolic parameters. Multiple hepatocyte signal transduction pathways and mRNA from key enzymes in fatty acid metabolism appear to be activated by GLP-1 and its analogues. Thus, the data support the need for more rigorous prospective clinical trials to further investigate the potential of incretin therapies to treat patients with NAFLD.

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Section: Human Clinical Studiessupporting

confidence: 86%

Review on the effect of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of non-alcoholic fatty liver disease

Zhao

Zhou

et al. 2015

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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“…Furthermore, a few data support a beneficial impact of liraglutide on liver inflammation markers in NAFLD patients with T2DM [67] , in obese women with polycystic ovary syndrome and NAFLD [68] and in one T2DM patient with concomitant cryptogenic cirrhosis [69] . In a recent pilot Japanese study, treatment with liraglutide had a good safety profile and significantly improved liver function and histological features in NASH patients with glucose intolerance [70] . A clinical case of suspected liraglutide-induced autoimmune hepatitis has been recently reported [71] .…”

Section: Hepatic Safetymentioning

confidence: 99%

Pharmacokinetics in Patients with Chronic Liver Disease and Hepatic Safety of Incretin-Based Therapies for the Management of Type 2 Diabetes Mellitus

Scheen

2014

Clin Pharmacokinet

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SUMMARYPatients with type 2 diabetes have an increased risk of chronic liver disease such as nonalcoholic fatty liver disease and steatohepatitis, and about one third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type 2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarizes the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and -Obese patients with type 2 diabetes often have non-alcoholic fatty liver disease or steatohepatitis and the use of incretin-based therapies appears mostly favourable in these patients regarding both efficacy and safety.-There is no reported clinical experience with the use of either DPP-4 inhibitors or GLP-1 receptor agonists in diabetic patients with moderate to severe hepatic impairment, so that caution is required in patients with advanced cirrhosis.

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“…3L). These results suggest that E6 may be useful for the treatment of fatty liver diseases such as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (44,45). Given the very high potency, the relatively long serum half-life, and the necessity of parenteral administration, E6 is an ideal candidate for microstructure array (MSA)-based transdermal delivery.…”

Section: Resultsmentioning

confidence: 99%

Engineering a long-acting, potent GLP-1 analog for microstructure-based transdermal delivery

Yang

Zou

Chao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Antidiabetic treatments aiming to reduce body weight are currently gaining increased interest. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist administered twice daily via s.c. injection, improves glycemic control, often with associated weight reduction. To further improve the therapeutic efficacy of exendin-4, we have developed a novel peptide engineering strategy that incorporates a serum protein binding motif onto a covalent side-chain staple and applied to the peptide to enhance its helicity and, as a consequence, its potency and serum half-life. We demonstrated that one of the resulting peptides, E6, has significantly improved half-life and glucose tolerance in an oral glucose tolerance test in rodents. Chronic treatment of E6 significantly decreased body weight and fasting blood glucose, improved lipid metabolism, and also reduced hepatic steatosis in diet-induced obese mice. Moreover, the high potency of E6 allowed us to administer this peptide using a dissolvable microstructure-based transdermal delivery system. Pharmacokinetic and pharmacodynamic studies in guinea pigs showed that a single 5-min application of a microstructure system containing E6 significantly improved glucose tolerance for 96 h. This delivery strategy may offer an effective and patient-friendly alternative to currently marketed GLP-1 injectables and can likely be extended to other peptide hormones.GLP-1 receptor agonist | helix stabilization | half-life extension | microstructure array | lipidated cross-linker B -family G protein-coupled receptors (GPCRs) include receptors for peptide hormones such as glucagon, glucagonlike peptides 1 and 2 (GLP-1 and -2), parathyroid hormone (PTH), and corticotropin-releasing factor. Attempts to generate smallmolecule modulators of these receptors have had limited success, whereas peptide ligands have been proven as effective therapeutic agents, as exemplified by exenatide (aka exendin-4 or Ex-4), a GLP-1 receptor agonist for diabetes, and teriparatide, a PTH1 receptor agonist for osteoporosis (1). However, peptide-based drugs generally suffer from short half-lives due to proteolytic degradation and fast renal clearance, rendering higher doses and frequent injections necessary, which negatively affects patient compliance (2). To improve their pharmacological properties, peptides have been chemically modified by conformational restriction (3-13) to increase potency and reduce proteolysis, and also by lipidation (14-16), polymer conjugation (17-23), and protein fusion (24-26) to decrease renal clearance. Although these latter conjugates can have enhanced circulatory half-lives, they often suffer from reduced potency and, as a result, require injection of relatively large quantities of the modified peptides.GLP-1 receptor agonists (GLP-1RAs) represent a unique approach to the treatment of diabetes, with benefits beyond glucose control, including favorable effects on body weight, blood pressure, cholesterol levels, and beta-cell function (27). Two short-acting (exenatide and liraglutide; on...

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Pilot study of liraglutide effects in non‐alcoholic steatohepatitis and non‐alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN‐J)

Abstract: Our pilot study demonstrated that treatment with liraglutide had a good safety profile and significantly improved liver function and histological features in NASH patients with glucose intolerance.

Cited by 158 publications

References 54 publications

Review on the effect of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of non-alcoholic fatty liver disease

Review on the effect of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of non-alcoholic fatty liver disease

Pharmacokinetics in Patients with Chronic Liver Disease and Hepatic Safety of Incretin-Based Therapies for the Management of Type 2 Diabetes Mellitus

Engineering a long-acting, potent GLP-1 analog for microstructure-based transdermal delivery

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