Effects and Safety of Sitagliptin in Non-Alcoholic Fatty Liver
                    Disease: A Systematic Review and Meta-Analysis

Yuhan Zhang; Tian Cai; Junyu Zhao; Congcong Guo; Jinming Yao; Peng Gao; Jianjun Dong; Lin Liao

doi:10.1055/a-1186-0841

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2020; 52(07): 517-526
DOI: 10.1055/a-1186-0841

Endocrine Care

Effects and Safety of Sitagliptin in Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis

Yuhan Zhang

¹Department of Endocrinology and Metabology, Shandong University, Jinan, China

²Laboratory of Endocrinology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China

,

Tian Cai

³Division of Traditional Chinese Medicine, Tai’an Hospital of Traditional Chinese Medicine, Tai’an, China

,

Junyu Zhao

¹Department of Endocrinology and Metabology, Shandong University, Jinan, China

⁴Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China

,

Congcong Guo

⁵Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China

,

Jinming Yao

¹Department of Endocrinology and Metabology, Shandong University, Jinan, China

⁴Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China

,

Peng Gao

²Laboratory of Endocrinology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China

,

Jianjun Dong

⁶Division of Endocrinology, Qilu Hospital of Shandong University, Jinan, China

,

Lin Liao

¹Department of Endocrinology and Metabology, Shandong University, Jinan, China

⁴Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China

⁵Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China

› Author Affiliations

Abstract

Non-alcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease. However, the treatment is limited. The aim of this meta-analysis was to evaluate the effects and safety of sitagliptin, a selective inhibitor of dipeptidyl peptidase-4 (DPP-4I), in treating NAFLD. Studies were sourced from electronic databases including PubMed, CENTRAL (Cochrane Controlled Trials Register), Embase, Medline, Web of Science, Clinical Trials, and CNKI to identify all randomized controlled clinical trials (RCTs) and non-RCTs in adult patients with NAFLD. Key outcomes were changes in serum levels of liver enzymes and improvement in hepatic histology and fat content measured by imaging or liver biopsy. Stata14.0 and RevMan5.3 were used for the meta-analysis. Seven studies with 269 NAFLD patients were included. Compared to the control group, sitagliptin treatment improved serum gamma-glutamyl transpeptidase (GGT) levels in the RCT subgroup (SMD = 0.79, 95% CI: 0.01–1.58). However, there was no significant improvement in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels following sitagliptin treatment. Four of the included studies performed liver imaging, but sitagliptin treatment did not result in a significant reduction in liver fat content. Only five participants developed sitagliptin-related gastrointestinal discomfort. Our study suggests that sitagliptin effects individuals with NAFLD by improving serum GGT. Although sitagliptin is safe and well tolerated in NAFLD patients, it exerts no beneficial effects on liver transaminase and liver fat content in these patients.

Key words

Sitagliptin - non-alcoholic fatty liver disease - NAFLD - DPP-4 - meta-analysis

Full Text

References

References
1 Chalasani N, Younossi Z, Lavine JE. et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012; 142: 1592-1609
2 Younossi ZM, Koenig AB, Abdelatif D. et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64: 73-84
3 Kunde SS, Lazenby AJ, Clements RH. et al. Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women. Hepatology 2005; 42: 650-656
4 Arulanandan A, Ang B, Bettencourt R. et al. Association between quantity of liver fat and cardiovascular risk in patients with nonalcoholic fatty liver disease independent of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2015; 13: 1513-1520 e1511
5 Li Z, Xue J, Chen P. et al. Prevalence of non-alcoholic fatty liver disease in mainland of China: A meta-analysis of published studies. J Gastroenterol Hepatol 2014; 29: 42-51
6 Noureddin M, Rinella ME. Non-alcoholic Fatty liver disease, diabetes, obesity, and hepatocellular carcinoma. Clin Liver Dis 2015; 19: 361-379
7 Targher G, Lonardo A, Byrne CD. Non-alcoholic fatty liver disease and chronic vascular complications of diabetes mellitus. Nat Rev Endocrinol 2018; 14: 99-114
8 Younossi ZM, Blissett D, Blissett R. et al. The economic and clinical burden of non-alcoholic fatty liver disease in the United States and Europe. Hepatology 2016; 64: 1577-1586
9 Brandon J, Perumpail MAK, Yoo EricR, Cholankeril George. et al. Clinical epidemiology and disease burden of non-alcoholic fatty liver disease. World J Gastroenterol 2017; 23: 8263-8276
10 Katsagoni CN, Georgoulis M, Papatheodoridis GV. et al. Effects of lifestyle interventions on clinical characteristics of patients with non-alcoholic fatty liver disease: A meta-analysis. Metabolism 2017; 68: 119-132
11 Thoma C, Day CP, Trenell MI. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: A systematic review. J Hepatol 2012; 56: 255-266
12 Kleiner DE, Makhlouf HR. Histology of non-alcoholic fatty liver disease and nonalcoholic steatohepatitis in adults and children. Clin Liver Dis 2016; 20: 293-312
13 Ahmed A, Wong RJ, Harrison SA. Non-alcoholic fatty liver disease review: Diagnosis, treatment, and outcomes. Clin Gastroenterol Hepatol 2015; 13: 2062-2070
14 Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol 2018; 53: 362-376
15 Mantovani A, Byrne CD, Bonora E. et al. Non-alcoholic fatty liver disease and risk of incident type 2 diabetes: A meta-analysis. Diabetes Care 2018; 41: 372-382
16 Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10: 330-344
17 Dong Y, Lv Q, Li S. et al. Efficacy and safety of glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2017; 41: 284-295
18 Pratley RE, Nauck M, Bailey T. et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: A 26-week, randomised, parallel-group, open-label trial. Lancet 2010; 375: 1447-1456
19 Kim SC, Schneeweiss S, Glynn RJ. et al. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes may reduce the risk of autoimmune diseases: A population-based cohort study. Ann Rheum Dis 2015; 74: 1968-1975
20 Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 2013; 17: 819-837
21 Miyazaki M, Kato M, Tanaka K. et al. Increased hepatic expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease and its association with insulin resistance and glucose metabolism. Mol Med Rep 2012; 5: 729-733
22 Nargis T, Chakrabarti P. Significance of circulatory DPP4 activity in metabolic diseases. IUBMB Life 2018; 70: 112-119
23 Balaban YH, Korkusuz P, Simsek H. et al. Dipeptidyl peptidase IV (DDP IV) in NASH patients. Ann Hepatol 2007; 6: 242-250
24 Xu B, Shen T, Chen L. et al. The effect of sitagliptin on lipid metabolism of fatty liver mice and related mechanisms. Med Sci Monitor 2017; 23: 1363-1370
25 Sujishi T, Fukunishi S, Ii M. et al. Sitagliptin can inhibit the development of hepatic steatosis in high-fructose diet-fed ob/ob mice. J Clin Biochem Nutr 2015; 57: 244-253
26 Pathak R, Kumar A, Palfrey HA. et al. The incretin enhancer, sitagliptin, exacerbates expression of hepatic inflammatory markers in rats fed a high-cholesterol diet. Inflamm Res 2019; 68: 581-595
27 Asakawa M, Mitsui H, Akihisa M. et al. Efficacy and safety of sitagliptin for the treatment of diabetes mellitus complicated by chronic liver injury. Springerplus 2015; 4: 346
28 Iwasaki T, Yoneda M, Inamori M. et al. Sitagliptin as a novel treatment agent for non-alcoholic Fatty liver disease patients with type 2 diabetes mellitus. Hepatogastroenterology 2011; 58: 2103-2105
29 Seko Y, Sumida Y, Tanaka S. et al. Effect of sodium glucose cotransporter 2 inhibitor on liver function tests in Japanese patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus. Hepatol Res 2017; 47: 1072-1078
30 Ohki T, Isogawa A, Iwamoto M. et al. The effectiveness of liraglutide in nonalcoholic fatty liver disease patients with type 2 diabetes mellitus compared to sitagliptin and pioglitazone. SciWorld J. 2012 496453.
31 Fukuhara T, Hyogo H, Ochi H. et al. Efficacy and safety of sitagliptin for the treatment of nonalcoholic fatty liver disease with type 2 diabetes mellitus. Hepatogastroenterology 2014; 61: 323-328
32 Cui J, Philo L, Nguyen P. et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial. J Hepatol 2016; 65: 369-376
33 Smits MM, Tonneijck L, Muskiet MH. et al. Twelve week liraglutide or sitagliptin does not affect hepatic fat in type 2 diabetes: A randomised placebo-controlled trial. Diabetologia 2016; 59: 2588-2593
34 Moher D, Liberati A, Tetzlaff J. et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009; 62: 1006-1012
35 Barsic N, Lerotic I, Smircic-Duvnjak L. et al. Overview and developments in non-invasive diagnosis of nonalcoholic fatty liver disease. World J Gastroenterol 2012; 18: 3945-3954
36 Furlan AD, Pennick V, Bombardier C. et al. 2009 updated method guidelines for systematic reviews in the Cochrane Back Review Group. Spine (Phila Pa 1976) 2009; 34: 1929-1941
37 Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010; 25: 603-605
38 Wan X, Wang W, Liu J. et al. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014; 14: 135
39 Alam S, Ghosh J, Mustafa G. et al. Effect of sitagliptin on hepatic histological activity and fibrosis of nonalcoholic steatohepatitis patients: a 1-year randomized control trial. Hepat Med 2018; 10: 23-31
40 Joy TR, McKenzie CA, Tirona RG. et al. Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebo-controlled trial. World J Gastroenterol 2017; 23: 141-150
41 Zhang W, Wang X, Kai J. Therapeutic effect of sitagliptin combined with metformin on type II diabetes complicated with fatty liver. Med J West China 2016; 28: 1575-1578
42 Bulusu S, Sharma M. What does serum gamma-glutamyltransferase tell us as a cardiometabolic risk marker?. Ann Clin Biochem 2016; 53: 312-332
43 Aberkane H, Stoltz JF, Galteau MM. et al. Erythrocytes as targets for gamma-glutamyltranspeptidase initiated pro-oxidant reaction. Eur J Haematol 2002; 68: 262-271
44 Stefano GB, Kream RM. Nitric Oxide regulation of mitochondrial processes: Commonality in medical disorders. Ann Transplant 2015; 20: 402-407
45 Koenig G, Seneff S. Gamma-glutamyltransferase: A predictive biomarker of cellular antioxidant inadequacy and disease risk. Dis Markers 2015; 818570
46 A public service on clinical lab testing from the laboratory professionals who do the testing, Internet description of GGT provided by Lab Tests Online, 2015 https://labtestsonline.org/understanding/analytes/ggt/tab/test/
47 Alam S, EASM Noor, Chowdhury ZR. et al. Non-alcoholic steatohepatitis in non-alcoholic fatty liver disease patients of Bangladesh. World J Hepatol 2013; 5: 281-287
48 Sokar SS, El-Sayad ME, Ghoneim ME. et al. Combination of sitagliptin and silymarin ameliorates liver fibrosis induced by carbon tetrachloride in rats. Biomed Pharmacother 2017; 89: 98-107
49 Wang X, Hausding M, Weng SY. et al. Gliptins suppress inflammatory macrophage activation to mitigate inflammation, fibrosis, oxidative stress, and vascular dysfunction in models of nonalcoholic steatohepatitis and liver fibrosis. Antioxid Redox Signal 2018; 28: 87-109
50 Maximos M, Bril F, Portillo Sanchez P. et al. The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease. Hepatology 2015; 61: 153-160
51 Goessling W, Massaro JM, Vasan RS. et al. Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. Gastroenterology 2008; 135: 1935-1944 e1931
52 Martin-Rodriguez JL, Gonzalez-Cantero J, Gonzalez-Cantero A. et al. Diagnostic accuracy of serum alanine aminotransferase as biomarker for nonalcoholic fatty liver disease and insulin resistance in healthy subjects, using 3T MR spectroscopy. Medicine 2017; 96: e6770
53 Kim D, Kim W, Joo SK. et al. Predictors of Nonalcoholic Steatohepatitis and Significant Fibrosis in Non-Obese non-alcoholic fatty liver disease. Liver Int 2019; 39: 332-341
54 Seko Y, Sumida Y, Tanaka S. et al. Serum alanine aminotransferase predicts the histological course of non-alcoholic steatohepatitis in Japanese patients. Hepatol Res 2015; 45: E53-E61
55 Cales P, Laine F, Boursier J. et al. Comparison of blood tests for liver fibrosis specific or not to NAFLD. J Hepatol 2009; 50: 165-173
56 Carbone LJ, Angus PW, Yeomans ND. Incretin-based therapies for the treatment of non-alcoholic fatty liver disease: A systematic review and meta-analysis. Journal of Gastroenterology and Hepatology 2016; 31: 23-31
57 Ayers D, Kanters S, Goldgrub R. et al. Network meta-analysis of liraglutide versus dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes in Japanese patients. Curr Med Res Opin 2017; 33: 1653-1661
58 Armstrong MJ, Gaunt P, Aithal GP. et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): A multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016; 387: 679-690
59 Aschner P, Kipnes MS, Lunceford JK. et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2006; 29: 2632-2637
60 Degn KB, Juhl CB, Sturis J. et al. One week's treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes 2004; 53: 1187-1194
61 Raji A, Long J, Lam RLH. et al. Efficacy and safety of sitagliptin in hispanic/latino patients with type 2 diabetes: A pooled analysis from ten randomized, placebo-controlled phase 3 clinical trials. Diabetes Ther 2018; 9: 1581-1589
62 Shen T, Xu B, Lei T. et al. Sitagliptin reduces insulin resistance and improves rat liver steatosis via the SIRT1/AMPKalpha pathway. Exp Ther Med 2018; 16: 3121-3128
63 Akaslan SB, Degertekin CK, Yilmaz G. et al. Effects of sitagliptin on non-alcoholic fatty liver disease in diet-induced obese rats. Metab Syndr Relat Disord 2013; 11: 243-250
64 Okura Y, Namisaki T, Moriya K. et al. Combined treatment with dipeptidyl peptidase-4 inhibitor (sitagliptin) and angiotensin-II type 1 receptor blocker (losartan) suppresses progression in a non-diabetic rat model of steatohepatitis. Hepatol Res 2017; 47: 1317-1328
65 Huang JH, Chen ZY, Zheng QS. et al. Dose conversion among different animals and healthy volunteers in pharmacological study. Chin Clin Pharmacol Therap 2004; 1069-1072
66 Gross BN, Cross LB, Foard J. et al. Elevated hepatic enzymes potentially associated with sitagliptin. Ann Pharmacother 2010; 44: 394-395
67 Toyoda-Akui M, Yokomori H, Kaneko F. et al. A case of drug-induced hepatic injury associated with sitagliptin. Intern Med 2011; 50: 1015-1020
68 Faillie JL, Babai S, Crepin S. et al. Pancreatitis associated with the use of GLP-1 analogs and DPP-4 inhibitors: A case/non-case study from the French Pharmacovigilance Database. Acta Diabetol 2014; 51: 491-497
69 Abrahami D, Douros A, Yin H. et al. Incretin based drugs and risk of cholangiocarcinoma among patients with type 2 diabetes: Population based cohort study. BMJ 2018; 363: k4880
70 Abrahami D, Douros A, Yin H. et al. Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: Population based cohort study. BMJ 2018; 360: k872
71 Giorda CB, Picariello R, Tartaglino B. et al. Incretin-based therapy and risk of cholangiocarcinoma: A nested case-control study in a population of subjects with type 2 diabetes. Acta Diabetol 2020; 57: 401-408
72 Moran GW, O'Neill C, Padfield P. et al. Dipeptidyl peptidase-4 expression is reduced in Crohn’s disease. Regul Pept 2012; 177: 40-45
73 Rehman MB, Tudrej BV, Soustre J. et al. Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: Meta-analysis of placebo-controlled randomized clinical trials. Diabetes Metab 2017; 43: 48-58
74 Smits MM, Tonneijck L, Muskiet MH. et al. Pancreatic effects of liraglutide or sitagliptin in overweight patients with type 2 diabetes: A 12-week randomized, placebo-controlled trial. Diabetes Care 2017; 40: 301-308

Supplementary Material

Supplementary Material