Association of Anti-Tumor Necrosis Factor-a Agents and Advanced Fibrosis in Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease

Abstract

Introduction: Pentoxifylline (PTX) has been used to treat nonalcoholic fatty liver diseases (NAFLDs) due to its anti-tumor necrosis factor-a (anti-TNF) and anti-leukotriene effects. It has been shown to improve histological features of NASH, but data on its association with advanced fibrosis (AF) is limited. Aim of this study was to assess the association of anti-TNF medications (infliximab, adalimumab, certolizumab pegol, and etenercept) and PTX with AF in patients with T2D and NAFLD. Methods: Using ICD-9 codes, all adult patients with the diagnosis of T2D and NAFLD at our institution between January 2000-December 2015 were identified and a retrospective chart review was done. Patients with secondary causes of hepatic steatosis (excessive alcohol consumption, hepatitis C etc.) were excluded. Baseline demographics, clinical and laboratory data were collected. Non-invasive scores to assess AF were calculated (AST/ALT > 1.4, APRI > 1.5, FIB-4 > 2.67, NFS > 0.676). A univariable and a multivariable logistic regression analysis were done to further assess the associations of anti-TNF medications with AF. Results: A total of 96,863 subjects with the diagnosis of T2D and NAFLD were included in the analysis and 39,345 (41%) of these had suspected AF based on at least 1 score (Figure 1). Patients with AF had a mean age of 62.2±10.9 years, 21,148 (54%) were females, 28,886 (73%) were Caucasians and 13,970 (35.5%) were obese with a mean BMI of 35.8±9.8. Hypertension (HTN) was present in 27,705 (70%), hyperlipidemia (HLD) in 22,737 (58%), chronic kidney disease (CKD) in7,908 (20%) and, coronary artery disease (CAD) in 10,579 (27%) of patients with AF (p<0.001). 25,134 (64%) were on oral hypoglycemics, 20,971 (53.3%) on insulin, 25,760 (65.5%) on statins, 3,572(9%) on fibrates (p=0.047), 261(0.66%) on anti-TNFs (p=0.34) and 212 (0.54% were on PTX (p<0.001 for all). After adjusting for age, gender, ethnicity, use of anti-TNFs was not associated with AF (odd ratio (OR) 95% confidence interval (CI) 1.1 (0.95, 1.3) (p=0.17) but risk of having AF was almost twice while being on PTX (OR (95% CI) 1.9 (1.5, 2.3) (p<0.001). Even on multivariate regression analysis PTX use was associated with1.5 times higher risk of having AF (OR (95%CI) 1.5 (1.2, 1.9) (p<0.001).2844_A Figure 1. No Caption available.Conclusion: In this large cohort of T2D with NAFLD, pentoxifylline use was associated with significantly higher risk of AF. Future prospective studies are required to confirm these findings.