pharmaceuticals Review Antidiabetic Drugs in NAFLD: The Accomplishment of Two Goals at Once? Matteo Tacelli , Ciro Celsa , Bianca Magro, Aurora Giannetti, Grazia Pennisi, Federica Spatola and Salvatore Petta * Sezione di Gastroenterologia e Epatologia, DiBiMIS, University of Palermo, 90127 Palermo, Italy; [email protected] (M.T.); [email protected] (C.C.); [email protected] (B.M.); [email protected] (A.G.); [email protected] (G.P.); [email protected] (F.S.) * Correspondence: [email protected], Tel.: +39-091-655-2170; Fax: +39-091-655-2156 Received: 17 October 2018; Accepted: 3 November 2018; Published: 8 November 2018 Abstract: Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease in Western countries, accounting for 20–30% of general population and reaching a prevalence of 55% in patients with type 2 diabetes mellitus (T2DM). Insulin resistance plays a key role in pathogenic mechanisms of NAFLD. Many drugs have been tested but no medications have yet been approved. Antidiabetic drugs could have a role in the progression reduction of the disease. The aim of this review is to summarize evidence on efficacy and safety of antidiabetic drugs in patients with NAFLD. Metformin, a biguanide, is the most frequently used drug in the treatment of T2DM. To date 15 randomized controlled trials (RCTs) and four meta-analysis on the use of metformin in NAFLD are available. No significant improvement in histological liver fibrosis was shown, but it can be useful in the treatment of co-factors of NAFLD, like body weight, transaminase or cholesterol levels, and HbA1c levels. A possible protective role in various types of cancer has been reported for Metformin. Thiazolidinediones modulate insulin sensitivity by the activation of PPAR-γ. The RCTs and the meta-analysis available about the role of these drugs in NAFLD show an improvement in ballooning, lobular inflammation, and perhaps fibrosis, but some side effects, in particular cardiovascular, were showed. GLP-1 analogues stimulate insulin secretion by pancreatic beta cell and inhibit glucagon release; Liraglutide is the most used drug in this class and significantly improves steatosis, hepatocyte ballooning and transaminase levels. Scanty data about the role of DPP-4 and SGLT inhibitors were published. No data about insulin effects on NAFLD are available but it was showed a possible association between insulin use and the development of solid neoplasms, in particular HCC. In conclusion, antidiabetic drugs seem to be promising drugs, because they are able to treat both NAFLD manifestations and diabetes, preventing worsening of hepatic damage, but data are still conflicting. All antidiabetic drugs can be safely used in patients with compensated cirrhosis, while insulin is the preferred drug in decompensated Child C cirrhosis. Keywords: non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; Metformin; Thiazolidinediones; Liraglutide; hepatic cirrhosis 1. Introduction Non-Alcoholic Fatty Liver Disease (NAFLD), a spectrum of conditions ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and liver cirrhosis, is the most common cause of chronic liver disease in Western countries [1]. Prevalence of NAFLD is roughly 20–30% in the general population, but it reaches 55% in patients affected by type 2 diabetes mellitus (T2DM) [2,3]. Cohort studies suggest that presence of NAFLD at baseline is an independent predictor of the occurrence of T2DM [4,5]. At same time, presence of T2DM independently predicts the occurrence Pharmaceuticals 2018, 11, 121; doi:10.3390/ph11040121 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2018, 11, x FOR PEER REVIEW 2 of 18 Pharmaceuticals 2018, 11, 121 2 of 19 [6,7]. Insulin resistance plays a key role in pathogenic mechanisms of NAFLD and it acts as a trigger forof fattyprogression liver [6 ,7of]. steatosis Insulin resistancetowards steatohepati plays a keytis, role cirrhosis, in pathogenic and end-stage mechanisms complications of NAFLD and[2]. NAFLDit acts as is aassociated trigger for with progression higher risk of of steatosisdeath, ma towardsinly due steatohepatitis, to cardiovascular cirrhosis, disease and(CVD), end-stage cancer andcomplications liver-related [2]. death NAFLD and is the associated risk increases with higher accordin risk ofg to death, fibrosis mainly stage due [8]. to In cardiovascular spite of increasing disease epidemiological(CVD), cancer and burden, liver-related to date death no andmedication the risk increaseshas been according approved to for fibrosis treatment stage [ 8of]. InNAFLD. spite of Althoughincreasing healthy epidemiological diet and burden, habitual to physical date no medication activity resulting has been in approved weight forloss treatment is advisable of NAFLD. in all NAFLDAlthough patients, healthy dietpharmacological and habitual physicaltreatment activity of prog resultingressive inor weight active lossNASH is advisable remains inan all urgently NAFLD unmetpatients, medical pharmacological need. Treatment treatment should of progressive aim to orreduce active NASHliver-related remains mortality an urgently and unmet progression medical towardsneed. Treatment cirrhosis shouldand its complications aim to reduce [9]. liver-related Identification mortality of adequate and progression surrogate towardsendpoints cirrhosis is essential and toits measure complications efficacy [9]. and Identification effectiveness of adequateof pharmaco surrogatelogical endpoints treatments is essentialof NASH, to so measure regression efficacy or improvementand effectiveness of NASH of pharmacological histological lesions treatments should of be NASH, the goal so regression to reach when or improvement new pharmaceutical of NASH approacheshistological are lesions tested. should be the goal to reach when new pharmaceutical approaches are tested. TheThe aim aim of of this this review review is is to to summarize summarize evidence evidence on on efficacy efficacy and and safety safety of of antidiabetic antidiabetic drugs drugs in in patientspatients with with NAFLD NAFLD (T (Tableable 11 andand FigureFigure1 1).). FigureFigure 1. 1. EffectEffect of of antidiabetic antidiabetic drugs drugs on on metabolic metabolic and and liver liver outcomes outcomes in in patients patients with with non-alcoholic non-alcoholic fattyfatty liver liver disease. disease. SGLT-2: SGLT-2: sodium-glucose sodium-glucose cotransporter cotransporter 2; 2; DPP-4: DPP-4: Dipeptidyl Dipeptidyl peptidase-4; peptidase-4; GLP-1: GLP-1: Glucagon-likeGlucagon-like pepide-1. pepide-1. Pharmaceuticals 2018, 11, 121 3 of 19 Table 1. Studies assessing the effect of antidiabetic drugs on metabolic and liver outcomes in patients with nonalcoholic fatty liver disease. First Name Author, Therapy Dosage Histological Lobular Hepatocellular Antidiabetic Class Trial Design Patients Age Male (%) BMI Diabetes Body Weight HOMA-Index Liver Enzymes Fibrosis Year of Publication and Duration Steatosis Inflammation Ballooning 100 mg/die, 24 Cui, 2016 Sitagliptin vs. Placebo 25 52.9 52 31.9 48 Not Improved Not Improved Not Improved Not Assessed Not Assessed Not Assessed Not Assessed weeks 100 mg/die, 24 Joi, 2017 Sitagliptin vs. Placebo 6 56.7 50 35.9 100 Not Improved Not Improved Not Improved Not Improved Not Improved Not Improved Not Improved weeks DPP-4 inhibitors Sitagliptin vs. 50 mg/die, 16 Sayari, 2018 138 42.9 60 29.6 NA Improved Not Assessed Improved Not Assessed Not Assessed Not Assessed Not Assessed Sitagliptin + Placebo weeks Vildagliptin vs. 100 mg/die, 12 Hussain, 2016 29 28 62 30.7 NA Improved Not Assessed Improved Not Assessed Not Assessed Not Assessed Not Assessed Placebo weeks Metformin plus diet Uygun, 2004 versus diet alone in 18 41 62 29.2 0 1.5 g, 6 months Improved Improved Improved Not Assessed Not Improved Not Assessed Not Improved NASH Metformin versus vit. Bugianesi, 2005 E versus diet in 55 42 73 28.7 0 2 g, 12 months Improved Improved Improved Improved * Improved * Not Assessed Improved * NAFLD Metformin versus Rosiglitazone vs. diet Idilman, 2008 74 47 59 31.5 NA 1.7 g, 12 months Improved Improved Improved Improved Improved Not Assessed Not Improved and exercise alone. 20 NASH Metformin versus Haukeland, 2009 20 47 73 30.8 20 2.5–3 g, 6 months Improved Not Improved Improved Improved Not Improved Not Improved Unchanged Placebo in NASH Metformin plus diet 0.5–1 g, 12 Shields, 2009 versus diet alone in 19 47 68 32.6 0 Improved Improved Improved Not Improved Not Improved Not Improved Not Improved months NASH Metformin plus diet Nar, 2009 versus diet alone in 34 47 26 31 100 1.7 g, 6 months Improved Improved Improved Not Assessed Not Assessed Not Assessed Not Assessed NAFLD Improved (NS) Worsed (NS) in Worsed (NS) in Worsed (NS) in Worsed (NS) in Metformin versus in Metformin Metformin Metformin Metformin Metformin Rosiglitazione versus Improved in group. group. group. group. group. Omer, 2010 Metformin plus 44 ** 49 59 31.6 70 1.7 g, 12 months Not Improved both Improved in Improved in Improved in Improved in Improved in Rosiglitazone in combination combination combination combination combination NAFLD group group group group group Metformin Metformin versus Krakoff, 2010 1073 51 34 34 IFG 1.7 g, 36 months Improved Not Assessed Improved Not Assessed Not Assessed Not Assessed Not Assessed Placebo in NAFLD Metformin plus diet Garinis, 2010 versus diet alone in 20 41 10 36.5 0 1 g, 6 months Improved Improved Not Improved Not Assessed Not Assessed Not Assessed Not