Effects of Combined Exenatide and Pioglitazone Therapy on Hepatic Fat Content in Type 2 Diabetes

Abstract

We examined the effects of combined pioglitazone (peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist) and exenatide (GLP-1 receptor agonist) therapy on hepatic fat content and plasma adiponectin levels in patients with type 2 diabetes (T2DM). Twenty-one T2DM patients (age = 52 ± 3 years, BMI = 32.0 ± 1.5, hemoglobin A 1c (HbA 1c ) = 8.2 ± 0.4%) on diet and/or metformin received additional treatment with either pioglitazone 45 mg/day for 12 months (n = 10) or combined therapy with pioglitazone (45 mg/day) and exenatide (10 µg subcutaneously twice daily) for 12 months (n = 11). At baseline, hepatic fat content and plasma adiponectin levels were similar between the two treatment groups. Pioglitazone reduced fasting plasma glucose (FPG) (P < 0.05), fasting free fatty acid (FFA) (P < 0.05), and HbA 1c (Δ = 1.0%, P < 0.01), while increasing plasma adiponectin concentration by 86% (P < 0.05). Hepatic fat (magnetic resonance spectroscopy (MRS)) was significantly reduced following pioglitazone treatment (11.0 ± 3.1 to 6.5 ± 1.9%, P < 0.05). Plasma triglyceride concentration decreased by 14% (P < 0.05) and body weight increased significantly (Δ = 3.7 kg). Combined pioglitazone and exenatide therapy was associated with a significantly greater increase in plasma adiponectin (Δ = 193%) and a significantly greater decrease in hepatic fat (12.1 ± 1.7 to 4.7 ± 1.3%) and plasma triglyceride (38%) vs. pioglitazone therapy despite the lack of a significant change in body weight (Δ = 0.2 kg). Hepatic injury biomarkers aspartate aminotransferase and alanine aminotransferase (ALT) were significantly decreased by both treatments; however, the reduction in ALT was significantly greater following combined pioglitazone and exenatide therapy. We conclude that combined in patients with T2DM, pioglitazone and exenatide therapy is associated with a greater reduction in hepatic fat content as compared to the addition of pioglitazone therapy (Δ = 61% vs. 41%, P < 0.05).

Evolution of Exenatide as a Diabetes Therapeutic

“…ExBID also had beneficial effects on liver fat content in patients with type 2 diabetes, in whom nonalcoholic fatty liver disease is prevalent [85]. ExBID significantly increased plasma adiponectin, reduced hepatic fat content (from mean 12.1% to 4.7%), and plasma triglyceride concentrations (-38%), despite no significant change in body weight.…”

Incretins

“…Although the reduction in hepatic steatosis was often associated with substantial weight loss, one study reported a significant reduction in hepatic fat content and improvements in plasma liver enzyme levels without changes in body weight after treatment with exenatide and pioglitazone, when compared with pioglitazone monotherapy, over 12 months in patients with type 2 diabetes (Sathyanarayana et al 2011). Exenatide was also associated with an increase in adiponectin levels, indicating that direct effect of GLP-1 signalling on hepatic lipid oxidation may underlie the attenuation of hepatic fat accumulation.…”

“…In both preclinical and clinical studies of NAFLD and type 2 diabetes, GLP-1 receptor agonists have been reported to reduce hepatic steatosis along with improvement in plasma levels of liver enzymes (Eguchi et al 2014;Jendle et al 2009;Klonoff et al 2008;Sathyanarayana et al 2011). Although the reduction in hepatic steatosis was often associated with substantial weight loss, one study reported a significant reduction in hepatic fat content and improvements in plasma liver enzyme levels without changes in body weight after treatment with exenatide and pioglitazone, when compared with pioglitazone monotherapy, over 12 months in patients with type 2 diabetes (Sathyanarayana et al 2011).…”

Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation

“…Samson et al [13] found that combined pioglitazone and exenatide therapy was associated with a greater decrease in hepatic fat than that achieved with pioglitazone therapy alone in patients with T2DM. Sathyanarayana et al [36] also concluded that combined pioglitazone and exenatide therapy was associated with a greater reduction in hepatic fat content compared to the addition of pioglitazone therapy (P < 0.05) in patients with T2DM. Hopkins et al [37] treated patients with T2DM with a GLP-1RA for 6 mo, and found that the liver fat content was reduced from 21.3% ± 19.3% to 12.7% ± 10.6%.…”