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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Initiation of oral semaglutide | Exposure group: Semaglutide in the oral formulation in any dose. |
| |
| Initiation of sitagliptin | Reference group: Sitagliptin in the oral formulation in any dose |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Oral semaglutide | Drug | Initiation of semaglutide dispensing claim is used as the exposure. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Hernia (excluding patients with recent outcome prior to the follow-up time window (30 days)). | To evaluate the effect of oral semaglutide vs sitagliptin on a negative control outcome of hernia in clinical practice. | 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. |
Eligible Cohort Entry Dates:
Inclusion Criteria:
Exclusion Criteria:
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Individuals aged 18 years or older with heart failure with preserved ejection fraction.
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| Name | Affiliation | Role |
|---|---|---|
| Shirley Wang, PhD, ScM | Brigham and Women's Hospital | Principal Investigator |
| Nils Krüger, MD | Brigham and Women's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brigham and Women's Hospital | Boston | Massachusetts | 02120 | United States |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan: Study Protocol with Statistical Analysis Plan Amendment 1 |
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| Sitagliptin | Drug | Initiation of sitagliptin dispensing claim is used as the reference. |
|
| 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. | 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. | 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. | 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. | 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. |
| Lumbar radiculopathy (excluding patients with recent outcome prior to the follow-up time window (30 days)). | To evaluate the effect of oral semaglutide vs sitagliptin on a negative control outcome of lumbar radiculopathy in clinical practice. | 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. |
| May 20, 2026 |
| May 23, 2026 |
| Prot_SAP_001.pdf |
| Prot | Yes | No | No | Study Protocol: Study Protocol with Statistical Analysis Plan | Jan 24, 2026 | Feb 6, 2026 | Prot_000.pdf |
| Prot | Yes | No | No | Study Protocol: Study Protocol with Statistical Analysis Plan Amendment 2 | Jun 22, 2026 | Jun 26, 2026 | Prot_002.pdf |
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C000591245 | semaglutide |
| D000068900 | Sitagliptin Phosphate |
| ID | Term |
|---|---|
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011719 | Pyrazines |
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