Different formulations of semaglutide and oxidative stress in subjects with type 2 diabetes and MASLD: an open-label, real-life study

Aim: Semaglutide exerts metabolic effects and cardiovascular protection in type 2 diabetes (T2D), also acting on hepatic steatosis and inflammation. No data are, so far, available on the effect of semaglutide on oxidative stress, neither a comparison of injective (InjS) and oral (OrS) formulations has been performed in subjects with T2D and liver steatosis. Methods: In a real-life, open label, prospective study we compared standard doses of InjS and OrS in targeting liver inflammation and fibrosis and systemic markers of inflammation and oxidative stress by consecutively prescribing InjS or OrS formulation in a 2:1 ratio to sixty T2D + MASLD subjects (T0), observing them for 6 months (T1). Anthropometry, biochemistry and transient elastography (TE) data were collected; hormones, inflammatory cytokines and peroxidation products were measured. Results: At baseline, InjS and OrS subjects were similar, except for waist circumference, liver enzymes and Controlled Attenuation Parameter (CAP), a measure of liver steatosis (InjS > OrS, all p < 0.05). Differences emerged in T0-T1 variation between the formulations in HbA1c, lipid profile, blood pressure. CAP significantly decreased only in InjS. GLP-1 quite similarly increased; insulin, glucagon and GIP did not vary. InjS and OrS did not modify TNFα, IL-10 (an anti-inflammatory cytokine) and MCP-1, while IL-18 was reduced only by InjS. When exploring oxidative stress, AGEs were unaffected, Thiobarbituric acid reactive substances decreased in InjS, 4-Hydroxynonenal was reduced in OrS. Conclusion: In T2D + MASLD subjects, InjS, better than OrS, improves metabolic control; a significant reduction of IL-18 by InjS, and a mild anti-oxidative effect of both formulations are reported for the first time.