Oral vs. Subcutaneous Semaglutide in Type 2 Diabetes Mellitus

emaglutide is a GLP-1 receptor agonist approved for the treatment of type 2 diabetes mellitus (T2D), available in both once-weekly subcutaneous and once-daily oral formulations. While both have demonstrated efficacy in phase 3 trials (SUSTAIN and PIONEER programs), real-world comparative data-particularly regarding sex-based differences in response-remain limited. This prospective, observational, real-world cohort study aims to compare the 12-month metabolic efficacy and hepatic effects of oral versus subcutaneous semaglutide in patients with T2D, with a specific focus on sex-disaggregated outcomes.

A total of 212 adult outpatients with T2D diagnosed for at least one year were consecutively recruited from the Endocrinology and Metabolism Unit, University Hospital of Palermo. Patients were assigned to either oral or subcutaneous semaglutide (n = 106 per group), based on drug availability and patient preference, not clinical criteria. Both groups were matched for sex.

Inclusion criteria were: age ≥18 years, T2D diagnosis ≥1 year, no prior use of GLP-1 RAs, and baseline HbA1c >6.5% (48 mmol/mol).

Exclusion criteria included: pregnancy, participation in other interventional studies, and known hypersensitivity to semaglutide.

Patients received semaglutide titrated according to label:

Oral group: 3 mg/day for 4 weeks, then 7 mg/day; up-titration to 14 mg/day permitted in case of inadequate glycaemic response.

Subcutaneous group: 0.25 mg/week for 4 weeks, then 0.5 mg/week; up-titration to 1 mg/week allowed based on clinical judgement.

Primary endpoint: change in HbA1c at 12 months. Secondary endpoints: changes in body weight, waist circumference, lipid profile (LDL, HDL, triglycerides), liver enzymes (GOT, GPT), hepatic steatosis index (HSI), fibrosis-4 index (FIB-4), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). The presence and degree of diabetic microvascular complications (retinopathy, nephropathy) were also assessed using established criteria.

Biochemical analyses were performed using standard enzymatic and immunoturbidimetric methods. LDL-C was calculated via the Friedewald formula. All parameters were recorded at baseline and at 12-month follow-up. Differences from baseline were calculated (Δ values), and statistical analysis included Shapiro-Wilk test for normality, t-tests for between-group comparisons, and sex-stratified analyses.

At 12 months, subcutaneous semaglutide led to greater reductions in HbA1c, weight, waist circumference, and triglycerides in the overall cohort. Among men, subcutaneous administration was associated with significantly lower Δ_weight, Δ_HbA1c, and Δ_LDL compared to oral. In women, subcutaneous semaglutide led to significantly lower Δ_HSI and Δ_GOT values, indicating a more favorable hepatic profile. No significant differences were found between sexes in the oral group.

These findings suggest a clinically meaningful interaction between semaglutide formulation and biological sex in real-world settings. The injectable formulation appears more effective in improving cardiometabolic parameters in male patients, while women may experience greater hepatic benefits. This supports the need for a sex-specific and formulation-aware approach to the management of T2D with GLP-1 RAs.

The study was approved by the Ethics Committee of the University Hospital "Paolo Giaccone" (Protocol number: 04/2024). All participants provided written informed consent. The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.