Endocrine Abstracts

Background and Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a diagnosis of inclusion relying on a set of metabolic risk factors and the presence of hepatic steatosisis; viscerl obesity, insulin resistance, type 2 diabetes (T2D) may often coexist in MAFLD patients. MAFLD is present in up to 80%f of T2D patients. Pioglidazone, a peroxisome proliferator-activated receptor agonist reduce hepatic/visceral fat (HVF) and improve necroinflammation in liver. Dulaglutide, a weekly glucagon-like peptide-1 (GLP-1) receptor agonist, significantly reduces liver fatty content (LFC) and improves GGT levels in NAFLD. Aim of this study was to evaluate dual treatment (pioglidazone plus dulaglutide) vs pioglidazone alone in recruited MAFLD/T2D patients.

Method: MAFLD was assessed using ultrasound-fatty liver index that allows to grade steatosis severity (US-FLI score ≥3) and liver fibrosis (F1-F2 staged according to the METAVIR score). Eligible patients (pioglidazone, 30 mg/die, os undergoing treatment for at least 1yr) added 1.5 mg subcutaneous dulaglutide weekly for 36 weeks. Fifty-seven MAFLD/T2D patients were studied (baseline, 3, 6 and 9 months). Plasma markers of hepatic dysfunction (ALT, AST, γ GT), cardiometabolic risk (triglycerides, total, non-HDL cholesterol, Apo-B100, Apo-B48, HbA1c, 1.5-anhydroglucitol [1,5-AG]), inflammation (hs C-reaction protein, TNF-α, IL-10/IL-6 ratio) were studied.

Results: Significant reduction in HVF (P<0.05) and LFC percentage (P<0.02), IL10/IL-6 ratio (P<0.002) and ALT (P<0.05), Apo-B100 (P<0.001), non-HDL cholesterol (P<0.05) and HbA1c (P<0.02) at 9 months were observed. HbA1c was inversely correlated with 1,5-AG and the factors significantly associated with advanced fibrosis were IL-10/IL-6 and 1.5-AG (P=0.008) (by multivariate logistic regression analysis). Only 5 patients experienced a worsening of METAVIR score/US-FLI and metabolic/inflammation biomarkers. Dual therapy were well tolerated and most events were gastrointestinal (nausea, diarrhea, vomiting, abdominal pain, decreased appetite, and fatigue) in nature.

Conclusion: Our study has several limitations. First, the sample size is relatively small. Second, the duration of drug treatment itself is longer due to the addition of drug (dulaglutide) to monotherapy (pioglitazone). Hence, it is difficult to distinguish the effect of the combination of drugs from that of long-term treatment. Notwithstanding the limitations described, it may be argued that MAFLD/T2D dual therapy (pioglidazone plus dulaglutide) showed metabolic and LFC improvement vs monotherapy (pioglidazone) group and reduction in liver stiffness, and ALT levels. Body weight gain (subcutaneous fat increase) mediated by pioglitazone monotherapy decreased following concomitant use of dulaglutide. Dual therapy might be effective for the treatment of MAFLD/T2D patients, as well as improving glycemic control and visceral obesity.