Emulation of the STEP-HFpEF DM Heart Failure Trial in Healthcare Claims Data

NCT06914102 | Completed FDA Drug

• 1 other identifier: 2018P002966-DUP-STEP-HFpEF
• Study Type: observational
• Target: 58,387
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Diabetes Mellitus, Type 2; HFpEF - Heart Failure With Preserved Ejection Fraction

Outcome Measures

Primary Outcomes (1)

• Composite of all-cause mortality or heart failure hospitalization

  To evaluate the effect of semgalutide vs placebo (sitaglitpin) on composite of all-cause mortality or heart failure hospitalization in two populations (1) patients meeting the eligibility criteria of the STEP-HFpEF DM trial, and (2) a broader patient population when relaxing the eligibility criteria of the STEP-HFpEF DM trial.

  Through study completion (1 day after cohort entry date until the first of outcome or censoring)

Secondary Outcomes (8)

• Composite of all-cause mortality or a worsening heart failure event (exacerbated symptoms of heart failure resulting in hospitalization, intravenous diuretic therapy in an urgent care setting), and its respective individual end points.

  Through study completion (1 day after cohort entry date until the first of outcome or censoring)

• Worsening heart failure event (exacerbated symptoms of heart failure resulting in hospitalization or intravenous diuretic therapy in an urgent care setting)

  Through study completion (1 day after cohort entry date until the first of outcome or censoring)

• Intravenous diuretic therapy in an urgent care setting

  Through study completion (1 day after cohort entry date until the first of outcome or censoring)

• Hospitalization for heart failure

  Through study completion (1 day after cohort entry date until the first of outcome or censoring)

• All-cause mortality

  Through study completion (1 day after cohort entry date until the first of outcome or censoring)

Other Outcomes (2)

• Hernia

  Through study completion (1 day after cohort entry date until the first of outcome or censoring)

• Lumbar radiculopathy

  Through study completion (1 day after cohort entry date until the first of outcome or censoring)

Study Arms (2)

Semaglutide

Exposure group

Drug: Semaglutide

Placebo

Reference group

Drug: Placebo

Interventions

Semaglutide DRUG

New use of semaglutide dispensing claim is used as the exposure.

Semaglutide

Placebo DRUG

New use of sitagliptin dispensing claim is used as the reference (active-comparator proxy for placebo).

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The study population included individuals aged 18 years or older with heart failure with preserved ejection fraction when following and relaxing the eligibility criteria of the STEP-HFpEF DM trial.

You may qualify if:

• Male or female, age above or equal to 18 years at the time of signing informed consent.
• BMI ≥ 30.0 kg/m2
• NYHA Class II-IV
• LVEF ≥ 45%
• No hospitalizations due to heart failure between screening (V1) and randomization (V2)
• At least one of the following:
• If BMI \<35.0: NT-proBNP ≥ 220 pg/mL (for patients with sinus rhythm) or NTproBNP ≥660 pg/mL (for patients with persistent/permanent atrial fibrillation); if BMI ≥ 35.0: NT-proBNP ≥ 125 pg/mL (for patients with sinus rhythm) or NTproBNP ≥ 375 pg/mL (for patients with persistent/permanent atrial fibrillation) at screening (NT-proBNP analyzed by the central laboratory) in combination with at least one of the following (documented by echocardiography within 12 months prior to or at screening): i. Septal é \< 7cm/sec or lateral é \< 10 cm/sec or average E/é ≥ 15 ii. PA systolic pressure \>35mmHg iii. Left atrial (LA) enlargement (LA width ≥3.8 cm or LA length ≥ 5.0cm or LA area ≥ 20.0cm2 or LA volume ≥ 55mL or LA volume index ≥29mL/m2) iv. LV hypertrophy with septal thickness or posterior wall thickness ≥1.2cm
• Hospitalization with a primary diagnosis of decompensated heart failure which required intravenous loop diuretic treatment, within the previous 12 months in combination with at least two of the following (documented by echocardiography within 12 months prior to or at screening): i. Septal é \< 7cm/sec or lateral é \< 10cm/sec or average E/é ≥15 ii. PA systolic pressure \>35mmHg iii. LA enlargement (LA width ≥3.8cm or LA length ≥ 5.0cm or LA area ≥20.0cm2 or LA volume ≥ 55mL or LA volume index ≥ 29mL/m2) iv. LV hypertrophy with septal thickness or posterior wall thickness ≥1.2cm
• Diagnosed with T2D ≥ 90 days prior to the day of screening.
• Subject treated with diet, exercise, and/or antidiabetic treatment\* according to local label in stable dosing for at least 30 days prior to screening: o \*OAD(s): unchanged drug(s), dose and dosing frequency o \*Insulin(s): unchanged regimen (basal, basal + bolus, premix combination) with stable total daily insulin dose as judged by the investigator

You may not qualify if:

• Myocardial infarction, stroke, hospitalization for heart failure, unstable angina pectoris or transient ischemic attack within 30 days prior to the day of screening.
• Systolic blood pressure \> 160 mmHg at screening.
• Any other condition judged by the investigator to be the primary cause of dyspnea (such as heart failure due to restrictive cardiomyopathy or infiltrative conditions (e.g. amyloidosis), hypertrophic obstructive cardiomyopathy, primary pulmonary arterial hypertension, chronic obstructive pulmonary disease, right heart failure due to pulmonary disease, complex congenital heart disease, anemia, or more than moderate heart valve disease).
• Bariatric surgery prior to screening or planned bariatric surgery within the trial time course.
• History of type 1 diabetes (history of gestational diabetes is allowed).
• Treatment with any GLP-1 receptor agonist within 90 days prior to the day of screening.
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy.
• Recurrent severe hypoglycemic episodes within the last year as judged by the investigator.
• Treatment with continuous subcutaneous insulin infusion
• Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma.
• Presence of acute pancreatitis within the last 180 days prior to screening.
• History or presence of chronic pancreatitis.
• End-stage renal disease or chronic or intermittent hemodialysis or peritoneal dialysis.
• Presence or history of malignant neoplasm within 5 years prior to the day of screening. Basal and squamous cell cancer and any carcinoma in-situ are allowed.
• Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using a highly effective contraceptive method.

Sponsors & Collaborators

• Brigham and Women's Hospital: lead

Study Sites (1)

Brigham and Women's Hospital

Boston, Massachusetts, 02120, United States

Location

Related Publications (1)

• Kruger N, Schneeweiss S, Fuse K, Matseyko S, Sreedhara SK, Hahn G, Schunkert H, Wang SV. Semaglutide and Tirzepatide in Patients With Heart Failure With Preserved Ejection Fraction. JAMA. 2025 Oct 14;334(14):1255-1266. doi: 10.1001/jama.2025.14092.

  PMID: 40886075 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

semaglutide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Study Officials

• Shirley Wang, PhD, ScM

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

• Nils Krüger, MD

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: March 31, 2025
• First Posted: April 6, 2025
• Study Start: January 14, 2025
• Primary Completion: June 1, 2025
• Study Completion: June 1, 2025
• Last Updated: January 30, 2026

Record last verified: 2025-05

Locations

US (1)