Oral vs. Subcutaneous Semaglutide in Type 2 Diabetes Mellitus

NCT ID: NCT07056803

Last Updated: 2025-07-17

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 212 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2024-01-01
• Study Completion Date: 2025-06-25

Brief Summary

This real-world, comparative cohort study aims to evaluate the 12-month effectiveness of oral versus subcutaneous semaglutide in patients with type 2 diabetes mellitus (T2D), with a specific focus on sex-based differences in metabolic response. A total of 212 patients were enrolled and evenly assigned to either oral or subcutaneous semaglutide. The primary outcome was the change in HbA1c, while secondary outcomes included variations in weight, lipid profile, liver function, and hepatic steatosis index. Subcutaneous semaglutide resulted in greater improvements in HbA1c, weight, and LDL cholesterol in men, while women exhibited a more favorable hepatic response. These findings support the need for sex-specific considerations in T2D therapy personalization.

Detailed Description

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.

Conditions

Diabetes Mellitus Type 2

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

oral semaglutide

oral semaglutide

Oral semaglutide

Intervention Type: DRUG

Starting dose 3 mg for a month, followed by 7 mg for a month increased up to 14 mg a month

subcutaneous semaglutide

subcutaneous semaglutide

subcutaneous semaglutide

Intervention Type: DRUG

subcutaneous semaglutide can be started at 0,25 mg a week for a month, to be increased at 0,5 mg a week, up to 1 mg a week

Interventions

Oral semaglutide

Starting dose 3 mg for a month, followed by 7 mg for a month increased up to 14 mg a month

Intervention Type: DRUG

subcutaneous semaglutide

subcutaneous semaglutide can be started at 0,25 mg a week for a month, to be increased at 0,5 mg a week, up to 1 mg a week

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• age over 18 years
• diagnosis of T2D at least one year before the recruitment
• no treatment with prior GLP-1 RA
• baseline HbA1c >6.5% (48 mmol/mol)

Exclusion Criteria

• pregnancy
• known allergy or hypersensitivity to semaglutide
• participation in another clinical trial during the treatment period

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Palermo

OTHER

Sponsor Role: lead

Responsible Party

Valentina Guarnotta

Principal investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Policlinico Paolo Giaccone

Palermo, , Italy

Countries

Italy

Other Identifiers

04

Identifier Type: -

Identifier Source: org_study_id