In a 28-week randomized controlled trial of 116 non-diabetic adults with obesity or overweight plus comorbidities, oral semaglutide (titrated from 3 mg to 14 mg/day) combined with lifestyle counselling produced a mean weight reduction of 10.47% versus 2.4% in the lifestyle-only control group (p < 0.001). Total fat mass fell by 7.3 kg versus 1.74 kg, visceral fat ratings dropped by 3.67 versus 0.6, and liver-specific markers — ALT, APRI score, liver fat content, and liver stiffness — all improved significantly. HbA1c, fasting insulin, and C-reactive protein also improved substantially with semaglutide.
This trial adds meaningful human evidence that the oral formulation of semaglutide — far more accessible than injectable GLP-1 agonists — can replicate clinically significant metabolic benefits in people without established diabetes. The visceral fat and liver stiffness reductions are particularly relevant given fatty liver's trajectory toward cirrhosis and cardiovascular risk. Notably, the two most validated fibrosis indices, NFS and FIB-4, did not reach significance, tempering enthusiasm about fibrosis reversal within this timeframe. Limitations include the open-label design, a single Indian centre (limiting generalisability), a relatively short 28-week window, and absence of liver biopsy confirmation. Nevertheless, a 10.5% weight reduction in under seven months places oral semaglutide firmly in the range where cardiovascular event reduction has been observed with injectable analogues. For clinicians, this reinforces oral GLP-1 therapy as a serious first-line option for obesity management beyond injectable routes.