Comparative Effectiveness of Oral Semaglutide vs Sitagliptin Among Individuals With Heart Failure With Preserved Ejection Fraction (STEP-HFpEF DM ORAL)

May 23, 2026 updated by: Shirley Vichy Wang, Brigham and Women's Hospital
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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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 Type

Observational

Enrollment (Actual)

25664

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02120
        • Brigham and Women's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Individuals aged 18 years or older with heart failure with preserved ejection fraction.

Description

Eligible Cohort Entry Dates:

  • Optum: Eligible cohort entry period from September 20, 2019 to November 30, 2025.
  • Marketscan: Eligible cohort entry from September 20, 2019 to December 31, 2023.
  • Medicare: Eligible cohort entry from September 20, 2019 to December 31, 2020.

Inclusion Criteria:

  • Heart failure
  • BMI > 27.0kg/m2
  • Type 2 diabetes mellitus
  • LVEF > 45%
  • Age > 18 years
  • Sex: male or female

Exclusion Criteria:

  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Initiation of oral semaglutide
Exposure group: Semaglutide in the oral formulation in any dose.
Drug: Oral semaglutide
Initiation of semaglutide dispensing claim is used as the exposure.
Initiation of sitagliptin
Reference group: Sitagliptin in the oral formulation in any dose
Drug: Sitagliptin
Initiation of sitagliptin dispensing claim is used as the reference.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
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.
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.
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).
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.
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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.
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.
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.
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 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.
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 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.
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 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.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hernia (excluding patients with recent outcome prior to the follow-up time window (30 days)).
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 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.
Lumbar radiculopathy (excluding patients with recent outcome prior to the follow-up time window (30 days)).
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 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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Brigham and Women's Hospital

Investigators

  • Principal Investigator: Shirley Wang, PhD, ScM, Brigham and Women's Hospital
  • Principal Investigator: Nils Kruger, MD, Brigham and Women's Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 24, 2026

Primary Completion (Estimated)

May 30, 2026

Study Completion (Estimated)

May 30, 2026

Study Registration Dates

First Submitted

January 29, 2026

First Submitted That Met QC Criteria

January 29, 2026

First Posted (Actual)

February 5, 2026

Study Record Updates

Last Update Posted (Actual)

May 28, 2026

Last Update Submitted That Met QC Criteria

May 23, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2018P002966-STEP-HFpEF DM ORAL

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Heart Failure

Clinical Trials on Oral semaglutide

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Senegal

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe