Subcutaneous semaglutide outperformed oral semaglutide for weight loss and blood sugar control in men, while women on the injection showed greater liver health improvements in this 12-month real-world study.
n=212 patients, 12 monthsReal-world comparison of oral vs. subcutaneous semaglutide revealed significant sex-specific differences in metabolic outcomes, with 98% of patients completing the study.
What the researchers found
In 212 type 2 diabetes patients (106 per group) followed for 12 months, subcutaneous semaglutide showed advantages over the oral formulation that differed by sex.
In men, the injectable form produced significantly greater reductions in weight (p=0.010), HbA1c (p=0.037), and LDL cholesterol (p=0.038) compared to oral semaglutide. In women, subcutaneous semaglutide led to significantly lower hepatic steatosis index (p=0.024) and greater reduction in GOT/AST liver enzyme levels (p=0.035) compared to men on the same treatment. Two hundred and eight of 212 patients completed the study (98% retention).
Why it matters
Semaglutide is one of the most widely prescribed GLP-1 receptor agonist peptides, but most clinical trials have not examined whether men and women respond differently to oral versus injectable formulations. This real-world evidence suggests that a one-size-fits-all approach may leave benefits on the table — men may gain more metabolic benefit from injections, while women may see particular liver health advantages. This supports the growing movement toward sex-aware, personalized diabetes management.
How the study worked
This was an interventional pilot study conducted in a real-world clinical setting. Two hundred and twelve patients with type 2 diabetes were equally assigned to receive either oral or subcutaneous semaglutide (106 per group). The primary endpoint was change in HbA1c (a measure of long-term blood sugar control). Secondary endpoints included changes in weight, lipid profiles, liver markers, and other metabolic parameters. All outcomes were analyzed for the overall cohort and then stratified by sex to detect differential responses.
What this study cannot tell us
This is a pilot study with a relatively small sample size (212 patients). It was not randomized or blinded, which introduces potential selection bias. The study was conducted at a single center, limiting generalizability. The oral and subcutaneous formulations have different dosing regimens and bioavailability, which complicates direct comparison. Sex-stratified subgroup analyses reduce statistical power further. Longer follow-up would be needed to confirm durability of the observed differences.
How to read the evidence
This is a real-world interventional pilot study with a moderate sample size and 12-month follow-up. While it provides valuable clinical data, it lacks randomization and blinding, and the sex-stratified subgroups are relatively small, placing it at a moderate evidence level.
When this study was published
Published in 2026, this is a very current study reflecting the latest real-world evidence on semaglutide formulation differences and sex-specific treatment responses.
The bigger picture
GLP-1 receptor agonists like semaglutide are transforming diabetes and obesity treatment. As these peptide drugs become available in multiple formulations, understanding who benefits most from each version becomes clinically important. This study adds to emerging evidence that biological sex influences drug response — a factor often overlooked in treatment guidelines. The liver-specific benefits in women are particularly noteworthy given the rising prevalence of metabolic-associated fatty liver disease.
Questions still open
- What biological mechanisms explain why men and women respond differently to oral versus subcutaneous semaglutide?
- Would these sex-specific differences hold up in a larger randomized controlled trial?
- Do similar sex-based response differences exist for other GLP-1 receptor agonist peptides like tirzepatide or liraglutide?
Common questions
Is the semaglutide injection really more effective than the pill?
Why would men and women respond differently to the same medication?
Read the original research
Sex specific responses to oral vs. subcutaneous semaglutide in type 2 diabetes mellitus: A 12-month real-world study.
Nutrition, metabolism, and cardiovascular diseases : NMCD, 36(3), 104462
Citation
Piccione, Alessandra; Bonsangue, Maria; Barone, Martina; Vigneri, Enrica; Mineo, Mariagrazia Irene; Tomasello, Laura; Maniscalco, Laura; Pantò, Felicia; Arnaldi, Giorgio; Guarnotta, Valentina. (2026). Sex specific responses to oral vs. subcutaneous semaglutide in type 2 diabetes mellitus: A 12-month real-world study.. Nutrition, metabolism, and cardiovascular diseases : NMCD, 36(3), 104462. https://doi.org/10.1016/j.numecd.2025.104462