Retrospective Comparative Study of Oral Versus Subcutaneous Semaglutide in Patients with Type 2 Diabetes Mellitus.

Toffoli B, Michieletto M, Bernardi S, Candido R

International journal of molecular sciences22 May 2026

PMID42278227PMCIDPMC13256121DOI10.3390/ijms27114694PepBankPUB-42278227

Summary

Semaglutide represents a unique therapeutic option for patients with type 2 diabetes mellitus (T2DM), being the first and currently only glucagon-like peptide-1 receptor agonist (GLP-1RA) available in both subcutaneous and oral formulations. This study aimed to compare the effectiveness of oral versus subcutaneous (sc) semaglutide on metabolic parameters and cardiovascular risk factors in T2DM patients. This is a retrospective real-world study including adult patients with T2DM taking oral or sc semaglutide followed at the ASUGI Diabetes Center. We analyzed data from 434 patients (median age 70 years, diabetes duration 13 years), treated with oral (n = 232) or sc (n = 202) semaglutide. The oral formulation had a higher discontinuation rate. Among these patients, 130 patients in the oral group and 145 in the sc group had an 18-month follow-up. When comparing these groups, patients taking sc semaglutide had a significantly higher baseline BMI. However, multivariate linear regression models suggested that both formulations were comparably effective in reducing HbA1c and BMI, with baseline values being the primary predictors of response. To address BMI imbalances, propensity score matching was performed, identifying 55 matched pairs. Both oral and sc semaglutide reduced HbA1c and BMI and there were no significant differences in the median change in HbA1c and BMI between groups. Interestingly, oral semaglutide was associated with a significantly greater reduction in diastolic blood pressure compared to the sc formulation. Furthermore, concomitant therapy with SGLT2 inhibitors significantly enhanced the reduction in total and LDL cholesterol. Oral and subcutaneous semaglutide show comparable effectiveness in lowering HbA1c and BMI in a real-world setting.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study8

6 results from studies that gave the peptide. 6 results from people.

01HumanObservational studySafety outcome
In adults with type 2 diabetes, the oral formulation of semaglutide had a higher discontinuation rate than the subcutaneous formulation.
In plain wordsIn adults with type 2 diabetes, more people stopped oral semaglutide than injected semaglutide.
Peptide
Semaglutide
Outcome
IncreaseDiscontinuation rate, oral versus subcutaneous
Study
n = 434
Comparator
Subcutaneous semaglutide
Outcome group
Adverse events · Whole body
Studied dose
Dose not stated · oralAs given in this study (human).
Source sentences
Summary
The oral formulation had a higher discontinuation rate.
1 context sentence(design, population, supporting numbers)
Summary · context
This is a retrospective real-world study including adult patients with T2DM taking oral or sc semaglutide followed at the ASUGI Diabetes Center.
Show in the study text Report a problemFND-4227822706
02HumanObservational studyEfficacy outcome
In adults with type 2 diabetes, both oral and subcutaneous semaglutide reduced HbA1c.
In plain wordsIn adults with type 2 diabetes, both oral and injected semaglutide lowered HbA1c.
Peptide
Semaglutide
Outcome
DecreaseHbA1c reduction with oral and subcutaneous semaglutide
Study
n = 110
Outcome group
Glycemic control · Metabolic and weight
Studied dose
Dose not stated · oral and subcutaneousAs given in this study (human).
Source sentences
Summary
Both oral and sc semaglutide reduced HbA1c and BMI and there were no significant differences in the median change in HbA1c and BMI between groups.
1 context sentence(design, population, supporting numbers)
Summary · context
This is a retrospective real-world study including adult patients with T2DM taking oral or sc semaglutide followed at the ASUGI Diabetes Center.
Show in the study text Report a problemFND-4227822701
03HumanObservational studyEfficacy outcome
In adults with type 2 diabetes, both oral and subcutaneous semaglutide reduced BMI.
In plain wordsIn adults with type 2 diabetes, both oral and injected semaglutide lowered body mass index.
Peptide
Semaglutide
Outcome
DecreaseBMI reduction with oral and subcutaneous semaglutide
Study
n = 110
Outcome group
Body weight · Metabolic and weight
Studied dose
Dose not stated · oral and subcutaneousAs given in this study (human).
Source sentences
Summary
Both oral and sc semaglutide reduced HbA1c and BMI and there were no significant differences in the median change in HbA1c and BMI between groups.
1 context sentence(design, population, supporting numbers)
Summary · context
This is a retrospective real-world study including adult patients with T2DM taking oral or sc semaglutide followed at the ASUGI Diabetes Center.
Show in the study text Report a problemFND-4227822702
04HumanObservational studyEfficacy outcome
In adults with type 2 diabetes, the median HbA1c change with oral semaglutide did not differ significantly from subcutaneous semaglutide.
In plain wordsIn adults with type 2 diabetes, oral semaglutide lowered HbA1c about as much as injected semaglutide.
Peptide
Semaglutide
Outcome
No significant changeHbA1c change, oral versus subcutaneous
Study
n = 110
Comparator
Subcutaneous semaglutide
Outcome group
Glycemic control · Metabolic and weight
Studied dose
Dose not stated · oralAs given in this study (human).
Source sentences
Summary
Both oral and sc semaglutide reduced HbA1c and BMI and there were no significant differences in the median change in HbA1c and BMI between groups.
1 context sentence(design, population, supporting numbers)
Summary · context
This is a retrospective real-world study including adult patients with T2DM taking oral or sc semaglutide followed at the ASUGI Diabetes Center.
Show in the study text Report a problemFND-4227822703
05HumanObservational studyEfficacy outcome
In adults with type 2 diabetes, the median BMI change with oral semaglutide did not differ significantly from subcutaneous semaglutide.
In plain wordsIn adults with type 2 diabetes, oral semaglutide lowered body mass index about as much as injected semaglutide.
Peptide
Semaglutide
Outcome
No significant changeBMI change, oral versus subcutaneous
Study
n = 110
Comparator
Subcutaneous semaglutide
Outcome group
Body weight · Metabolic and weight
Studied dose
Dose not stated · oralAs given in this study (human).
Source sentences
Summary
Both oral and sc semaglutide reduced HbA1c and BMI and there were no significant differences in the median change in HbA1c and BMI between groups.
1 context sentence(design, population, supporting numbers)
Summary · context
This is a retrospective real-world study including adult patients with T2DM taking oral or sc semaglutide followed at the ASUGI Diabetes Center.
Show in the study text Report a problemFND-4227822704
06HumanObservational studyEfficacy outcome
In adults with type 2 diabetes, oral semaglutide was associated with a significantly greater reduction in diastolic blood pressure than subcutaneous semaglutide.
In plain wordsIn adults with type 2 diabetes, oral semaglutide was linked to a larger fall in diastolic blood pressure than injected semaglutide.
Peptide
Semaglutide
Outcome
DecreaseDiastolic blood pressure, oral versus subcutaneous
Study
n: not reported in source
Comparator
Subcutaneous semaglutide
Outcome group
Blood pressure · Cardiovascular
Studied dose
Dose not stated · oralAs given in this study (human).
Source sentences
Summary
Interestingly, oral semaglutide was associated with a significantly greater reduction in diastolic blood pressure compared to the sc formulation.
1 context sentence(design, population, supporting numbers)
Summary · context
This is a retrospective real-world study including adult patients with T2DM taking oral or sc semaglutide followed at the ASUGI Diabetes Center.
Show in the study text Report a problemFND-4227822705

Studies that did not test the peptide alone2

In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Semaglutide.

07HumanNot a test of Semaglutide aloneObservational studyEfficacy outcome
In adults with type 2 diabetes on semaglutide, concomitant SGLT2 inhibitor therapy significantly enhanced the reduction in total cholesterol.
In plain wordsIn adults with type 2 diabetes on semaglutide, adding an SGLT2 inhibitor was linked to a larger fall in total cholesterol.
Peptide
Semaglutide
Outcome
DecreaseTotal cholesterol with concomitant SGLT2 inhibitor
Study
n: not reported in source
Outcome group
Lipids · Metabolic and weight
Source sentences
Summary
Furthermore, concomitant therapy with SGLT2 inhibitors significantly enhanced the reduction in total and LDL cholesterol.
1 context sentence(design, population, supporting numbers)
Summary · context
This is a retrospective real-world study including adult patients with T2DM taking oral or sc semaglutide followed at the ASUGI Diabetes Center.
In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.
Show in the study text Report a problemFND-4227822707
08HumanNot a test of Semaglutide aloneObservational studyEfficacy outcome
In adults with type 2 diabetes on semaglutide, concomitant SGLT2 inhibitor therapy significantly enhanced the reduction in LDL cholesterol.
In plain wordsIn adults with type 2 diabetes on semaglutide, adding an SGLT2 inhibitor was linked to a larger fall in LDL cholesterol.
Peptide
Semaglutide
Outcome
DecreaseLDL cholesterol with concomitant SGLT2 inhibitor
Study
n: not reported in source
Outcome group
Lipids · Metabolic and weight
Source sentences
Summary
Furthermore, concomitant therapy with SGLT2 inhibitors significantly enhanced the reduction in total and LDL cholesterol.
1 context sentence(design, population, supporting numbers)
Summary · context
This is a retrospective real-world study including adult patients with T2DM taking oral or sc semaglutide followed at the ASUGI Diabetes Center.
In this study, Semaglutide was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Semaglutide.
Show in the study text Report a problemFND-4227822708

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
11 Oct 2026, 00:04 UTC
Study results updated
Version 1
9 Oct 2026, 03:06 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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