Type 2 DiabetesNCT07390110
Comparative Effectiveness of Oral Semaglutide vs Sitagliptin Among Individuals With Heart Failure With Preserved Ejection Fraction (STEP-HFpEF DM ORAL)
An observational study of Type 2 Diabetes and Heart Failure, run by Brigham and Women's Hospital at 1 site in United States.
Trial summary
Investigators are building an empirical evidence base for real world data through large-scale emulation of randomized controlled trials. The investigators' goal is to understand for what types of clinical questions real world data analyses can be conducted with confidence and how to implement such studies. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Type 2 Diabetes, Heart Failure
- What is being tested?
- Oral semaglutide and Sitagliptin
- Type of treatment
- Pill or oral medicine
- How many people
- 25,664 participants
- Where
- 1 siteUnited States
- Study dates
- 24 Jan 2026to 30 Jun 2026
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Individuals aged 18 years or older with heart failure with preserved ejection fraction.
Who may be able to join
- Heart failure
- BMI > 27.0kg/m2
- Type 2 diabetes mellitus
- LVEF > 45%
- Age > 18 years
- Sex: male or female
Who cannot join
- Multiple endocrine neoplasia type 2 or medullary thyroid carcinoma, other malignancy
- Type 1 diabetes mellitus, uncontrolled diabetic retinopathy or maculopathy, bariatric surgery, end-stage renal disease or dialysis, nursing home admission
- Any use of GLP-1-RA including injectable semaglutide except oral semaglutide, pregnancy, treatment with continuous subcutaneous insulin infusion
- Concurrent use of both study drugs
Trial locations and contacts
1 site in 1 country.
United States1 site
Brigham and Women's Hospital
Boston, Massachusetts, 02120
About this study
Investigators are building an empirical evidence base for real world data through large-scale emulation of randomized controlled trials. The investigators' goal is to understand for what types of clinical questions real world data analyses can be conducted with confidence and how to implement such studies.
Read the detailed description
This is a non-randomized, non-interventional study that is part of the Randomized Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology (RCT-DUPLICATE) initiative (www.rctduplicate.org) of the Brigham and Women's Hospital, Harvard Medical School. It is intended to assess the comparative effectiveness of oral semaglutide vs sitagliptin as a placebo proxy using a target trial emulation framework. The SOUL trial (NCT03914326) and its database emulation study (NCT06659718) demonstrated a reduction in atherosclerotic cardiovascular events with oral semaglutide among patients with type 2 diabetes and high cardiovascular risk. The STEP-HF-EF DM trial (NCT04916470) and its database emulation study (NCT06914102) found the injectable formulation of semaglutide to lower the risk for heart failure hospitalization in patients with cardiometabolic HFpEF, and its non-inferiority to tirzepatide (NCT06914141). However, the effectiveness of oral semaglutide in reducing the risk of heart failure events remains unclear.
The comparative effectiveness target trial described below draws from eligibility criteria from the STEP-HFpEF DM trial but is designed to include a much larger and more diverse group of patients than the trial allowed. Although many features of the target trial cannot be directly replicated in healthcare claims, measurements of key design features, including outcomes, exposures, and inclusion/exclusion criteria, were designed to proxy those features from the target trial. Randomization cannot be achieved in healthcare claims data but was proxied through a statistical balancing of measured covariates according to standard practice.
The database study will be a new-user active-comparative study, conducted using 3 national United States claims databases, where we compare the effect of oral semaglutide vs sitagliptin on heart failure outcomes.
- Conditions
- Type 2 Diabetes, Heart Failure
- Being tested
- Oral semaglutide, Sitagliptin
- Medical subject headings
- Diabetes Mellitus, Type 2, Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Oral semaglutideDrug
Initiation of semaglutide dispensing claim is used as the exposure.
SitagliptinDrug
Initiation of sitagliptin dispensing claim is used as the reference.
| Study group | Role | What they receive |
|---|---|---|
| Initiation of oral semaglutide | Exposure group: Semaglutide in the oral formulation in any dose. Receives: Drug: Oral semaglutide | |
| Initiation of sitagliptin | Reference group: Sitagliptin in the oral formulation in any dose Receives: Drug: Sitagliptin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Composite of worsening heart failure event (exacerbated symptoms of heart failure resulting in hospitalization, intravenous diuretic therapy in an urgent care setting) or all-cause mortality.
To evaluate the comparative effect of oral semaglutide vs sitagliptin on the composite of worsening heart failure events or all-cause mortality in patients with heart failure with preserved ejection fraction in clinical practice.
Measured: Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between the arms, start of any other GLP-1-RA including injectable semaglutide.
Worsening heart failure event (exacerbated symptoms of heart failure resulting in hospitalization, intravenous diuretic therapy in an urgent care setting).
To evaluate the comparative effect of oral semaglutide vs sitagliptin on worsening heart failure events with heart failure with preserved ejection fraction in clinical practice.
Measured: Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between the arms, start of any other GLP-1-RA including injectable semaglutide.
Secondary outcomes (5)
Heart failure hospitalization.
To evaluate the comparative effect of oral semaglutide vs sitagliptin on heart failure hospitalization in patients with heart failure with preserved ejection fraction in clinical practice.
Measured: Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between the arms, start of any other GLP-1-RA including injectable semaglutide.
Worsening heart failure event requiring intravenous diuretic therapy in an urgent care setting.
To evaluate the comparative effect of oral semaglutide vs sitagliptin on worsening heart failure events in patients with heart failure with preserved ejection fraction in clinical practice.
Measured: Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between the arms, start of any other GLP-1-RA including injectable semaglutide.
Urinary tract infections.
To evaluate the comparative effect of oral semaglutide vs sitagliptin on the safety outcome of urinary tract infections in clinical practice.
Measured: Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between the arms, start of any other GLP-1-RA including injectable semaglutide.
Serious infections.
To evaluate the comparative effect of oral semaglutide vs sitagliptin on the safety outcome of serious infections in clinical practice.
Measured: Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between the arms, start of any other GLP-1-RA including injectable semaglutide.
Gastrointestinal adverse events.
To evaluate the comparative effect of Oral semaglutide vs sitagliptin on the safety outcome of gastrointestinal adverse events in clinical practice.
Measured: Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between the arms, start of any other GLP-1-RA including injectable semaglutide.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Feb 2026
- Study start24 Jan 2026
- Primary completion30 Jun 2026
- Study completion30 Jun 2026
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Type 2 DiabetesStudies of the same condition, open and under way.
- More trials run by Brigham and Women's HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 25,664 participants (actual)
Sponsor and investigators
- Lead sponsor
- Brigham and Women's Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Shirley Vichy Wang, Brigham and Women's Hospital
- Investigators
- Shirley Wang, PhD, ScM, Principal investigator, Brigham and Women's HospitalNils Krüger, MD, Principal investigator, Brigham and Women's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07390110
- Sponsor's protocol ID
- 2018P002966-STEP-HFpEF DM ORAL
- Status last verified
- Jan 2026
- First submitted
- 29 Jan 2026
- Last updated
- 21 Sep 2026
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparative Effectiveness of Oral Semaglutide vs Sitagliptin Among Individuals With Heart Failure With Preserved Ejection Fraction (STEP-HFpEF DM ORAL)
- ClinicalTrials.gov ID
- NCT07390110
- Acronym / sponsor ID
- 2018P002966-STEP-HFpEF DM ORAL
- Conditions
- Type 2 Diabetes, Heart Failure
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 25,664 participants (actual)
- Lead sponsor
- Brigham and Women's HospitalUniversity, hospital or other
- Study start
- 24 Jan 2026 (actual)
- Primary completion
- 30 Jun 2026 (actual)
- Study completion
- 30 Jun 2026 (actual)
- First posted
- 5 Feb 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Investigators are building an empirical evidence base for real world data through large-scale emulation of randomized controlled trials. The investigators' goal is to understand for what types of clinical questions real world data analyses can be conducted with confidence and how to implement such studies.
Detailed description
This is a non-randomized, non-interventional study that is part of the Randomized Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology (RCT-DUPLICATE) initiative (www.rctduplicate.org) of the Brigham and Women's Hospital, Harvard Medical School. It is intended to assess the comparative effectiveness of oral semaglutide vs sitagliptin as a placebo proxy using a target trial emulation framework. The SOUL trial (NCT03914326) and its database emulation study (NCT06659718) demonstrated a reduction in atherosclerotic cardiovascular events with oral semaglutide among patients with type 2 diabetes and high cardiovascular risk. The STEP-HF-EF DM trial (NCT04916470) and its database emulation study (NCT06914102) found the injectable formulation of semaglutide to lower the risk for heart failure hospitalization in patients with cardiometabolic HFpEF, and its non-inferiority to tirzepatide (NCT06914141). However, the effectiveness of oral semaglutide in reducing the risk of heart failure events remains unclear.
The comparative effectiveness target trial described below draws from eligibility criteria from the STEP-HFpEF DM trial but is designed to include a much larger and more diverse group of patients than the trial allowed. Although many features of the target trial cannot be directly replicated in healthcare claims, measurements of key design features, including outcomes, exposures, and inclusion/exclusion criteria, were designed to proxy those features from the target trial. Randomization cannot be achieved in healthcare claims data but was proxied through a statistical balancing of measured covariates according to standard practice.
The database study will be a new-user active-comparative study, conducted using 3 national United States claims databases, where we compare the effect of oral semaglutide vs sitagliptin on heart failure outcomes.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Initiation of oral semaglutide | – | Drug: Oral semaglutideExposure group: Semaglutide in the oral formulation in any dose. |
| Initiation of sitagliptin | – | Drug: SitagliptinReference group: Sitagliptin in the oral formulation in any dose |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Individuals aged 18 years or older with heart failure with preserved ejection fraction.
Key inclusion criteria (6 listed)
- Heart failure
- BMI > 27.0kg/m2
- Type 2 diabetes mellitus
- LVEF > 45%
- Age > 18 years
Key exclusion criteria (4 listed)
- Multiple endocrine neoplasia type 2 or medullary thyroid carcinoma, other malignancy
- Type 1 diabetes mellitus, uncontrolled diabetic retinopathy or maculopathy, bariatric surgery, end-stage renal disease or dialysis, nursing home admission
- Any use of GLP-1-RA including injectable semaglutide except oral semaglutide, pregnancy, treatment with continuous subcutaneous insulin infusion
- Concurrent use of both study drugs
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Oral semaglutideInitiation of semaglutide dispensing claim is used as the exposure. | Drug | Initiation of oral semaglutide |
| SitagliptinInitiation of sitagliptin dispensing claim is used as the reference. | Drug | Initiation of sitagliptin |
Primary outcome
Composite of worsening heart failure event (exacerbated symptoms of heart failure resulting in hospitalization, intravenous diuretic therapy in an urgent care setting) or all-cause mortality.
Time frame: Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between the arms, start of any other GLP-1-RA including injectable semaglutide.
To evaluate the comparative effect of oral semaglutide vs sitagliptin on the composite of worsening heart failure events or all-cause mortality in patients with heart failure with preserved ejection fraction in clinical practice.
Worsening heart failure event (exacerbated symptoms of heart failure resulting in hospitalization, intravenous diuretic therapy in an urgent care setting).
Time frame: Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between the arms, start of any other GLP-1-RA including injectable semaglutide.
To evaluate the comparative effect of oral semaglutide vs sitagliptin on worsening heart failure events with heart failure with preserved ejection fraction in clinical practice.
5 secondary outcomes
Heart failure hospitalization.
Time frame: Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between the arms, start of any other GLP-1-RA including injectable semaglutide.
Worsening heart failure event requiring intravenous diuretic therapy in an urgent care setting.
Time frame: Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between the arms, start of any other GLP-1-RA including injectable semaglutide.
Urinary tract infections.
Time frame: Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between the arms, start of any other GLP-1-RA including injectable semaglutide.
Serious infections.
Time frame: Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between the arms, start of any other GLP-1-RA including injectable semaglutide.
Gastrointestinal adverse events.
Time frame: Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between the arms, start of any other GLP-1-RA including injectable semaglutide.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2026.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Shirley Wang, PhD, ScM principal investigator
Brigham and Women's Hospital
Nils Krüger, MD principal investigator
Brigham and Women's Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Type 2 Diabetes and Heart Failure, run by Brigham and Women's Hospital at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Composite of worsening heart failure event (exacerbated symptoms of heart failure resulting in hospitalization, intravenous diuretic therapy in an urgent care setting) or all-cause mortality. (time frame: Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between the arms, start of any other GLP-1-RA including injectable semaglutide.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2026.