Safety and efficacy of oral semaglutide in overweight diabetic patients with non-alcoholic fatty liver disease: an interim analysis

Background and Aim: Currently there are no approved gold standard therapies for non-alcoholic fatty liver disease. Semaglutide is a first-of-its-kind orally active glucagon-like peptide-1 (GLP-1) analogue that has recently been approved by US FDA for treatment of diabetes mellitus. Method: This is a single-centre, single-arm, open-labelled study of oral semaglutide in a tertiary care hospital in southern India. Patients with co-existent liver disease (significant alcohol, viral hepatitis, autoimmune hepatitis etc) were excluded. All patients were administered lifestyle modification with advice for calorie restricted diet and gradually intensifying aerobic exercise regimen. The subjects were initiated on a 3mg dose for one week, followed by a teleconsultation to assess tolerability. From week 2, all subjects who tolerated the drug were administered 7mg drug on an empty stomach. The patients were followed up for 24 weeks. Results: A total of 59 overweight (BMI>23.5kg/m2), diabetic patients with imaging evidence of NAFLD were recruited to the study; however, 9 patients were excluded from final analysis [Laprascopic sleeve gastrectomy (n=2), drug non-compliance(n=2), drug intolerance(n=5)]. The mean age of study population was 50.4, with predominant males (62%), mean BMI-33.7kg/m2 and mean duration of diabetes of 7.8 years were included. The associated co-morbidities were systemic hypertension (26%), hypothyroidism (18%), dyslipidemia (64%), coronary heart disease (10%). At the start of the study, percentage of patients on insulin (34%), metformin (74%), saroglitazar (14%), statins/fibrates (42%), vitamin E (5%). After 24 weeks of semaglutide therapy, there was significant reduction in LSM, CAP, FIB- 4, ALT, cholesterol, LDL, HDL (p<0.005, each). The LSM and CAP improvements were consistently significant in 3 BMI strata (25-30, 30-35, >35Kg/m2) (p<0.016, each). Conclusion: Oral Semaglutide was safe and efficacious and well tolerated in overweight diabetic patients with NAFLD in this interim analysis at 24 weeks. There was a significant reduction in BMI, ALT, liver stiffness, CAP and lipid profile. There were no significant treatment-emergent adverse events. There is a need of randomized placebo-controlled trials to further explore its role in diabetes- associated NAFLD.