Emulation of the EMPEROR-Preserved Trial Using Healthcare Claims Data

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: Type 2 Diabetes Mellitus; Chronic Heart Failure; Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: Empagliflozin; Drug: Sitagliptin

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.

This study is part of a series that applies the Benchmark, Expand, and Calibration (BenchExCal) approach, in which an initial trial emulation is benchmarked against a completed randomized controlled trial (RCT) to inform a subsequent database study for related clinical questions or expanded indications. In this empirical example, the related clinical question has also been evaluated in a completed randomized trial, allowing comparison of the expanded database emulation with the corresponding RCT findings.

It is intended to emulate, as closely as is possible in healthcare insurance claims data the EMPEROR-Preserved trial described below. Although many features of the trial cannot be directly replicated in healthcare claims, key design features, including outcomes, exposures, and inclusion/exclusion criteria, were selected to proxy those features from the trial. Randomization cannot be achieved in healthcare claims data but was proxied through a statistical balancing of measured covariates according to standard practice. Investigators assume that the RCT provides the reference standard treatment effect estimate and that failure to replicate RCT findings is indicative of the inadequacy of the healthcare claims data for emulation for a range of possible reasons and does not provide information on the validity of the original RCT finding.

The EMPEROR-Preserved trial is a superiority trial to evaluate the effect of empagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), vs placebo on cardiovascular death and hospitalisation for heart failure among individuals with chronic heart failure with preserved ejection fraction.

The database study is designed to emulate the EMPEROR-Preserved trial. It will be a new-user active-comparator cohort study, conducted using 3 national United States claims databases, where we compare the effect of empagliflozin vs sitagliptin, a dipeptidyl peptidase-4 inhibitor (DPP4i), on all-cause mortality and hospitalisation for heart failure. While the EMPEROR-Preserved trial was conducted in participants with and without T2DM, both subgroups showed similar effect estimates in their results. Furthermore, while the trial compared empagliflozin to placebo, we chose to use sitagliptin as an active comparator proxy for placebo to minimize confounding by indication. Sitagliptin was specifically chosen because a major randomized controlled trial on cardiovascular outcomes demonstrated that it does not affect the cardiovascular outcomes under investigation. Furthermore, clinical guidelines during the study period recommended both SGLT2 inhibitors and DPP4 inhibitors as second- or third-line options for glucose lowering, and the therapies are similarly costly, reducing concerns about channelling of patients based on socioeconomic status.

• Study Type: Observational
• Enrollment (Actual): 39614

Contacts and Locations

Study Locations

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

Participation Criteria

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 and preserved ejection fraction and type 2 diabetes

Description

Study period:

Optum: Eligible cohort entry period from August 1, 2014 to August 31, 2024. Marketscan: Eligible cohort entry period from August 1, 2014 to September 31, 2023.

Medicare: Eligible cohort entry period from August 1, 2014 to September 31, 2020.

Inclusion Criteria:

• At least 18 years of age
• Heart failure with preserved ejection fraction
• Structural heart disease
• Previous HHF
• BMI < 45 kg/m2
• Type 2 diabetes mellitus
• Use of oral diuretics

Exclusion Criteria:

• Concurrent use of both study drugs on cohort entry date
• MI, CABG or other major cardiovascular surgery, GI surgery or disorder, stroke or TIA [Day -91, Day 0]
• Implantable cardiac defibrillator [Day -91, Day 0]
• Hypotension [Day -91, Day 0]
• Major surgery [Day -91, Day 0]
• GI surgery or disorder [Day -91, Day 0]
• Cancer [Day -730, Day 0]
• Heart transplant [all available data, Day 0]
• Pacemaker [all available data, Day 0]
• Liver disease [all available data, Day 0]
• Atrial fibrillation [Day -183, Day 0]
• Hypertension [Day -183, Day 0]
• Impaired renal function [Day -183, Day 0]
• Anemia [Day -183, Day 0]
• History of ketoacidosis [Day -183, Day 0]
• Pregnancy [Day -183, Day 0]
• Cardiomyopathy [Day -365, Day 0]
• Valvular heart disease [Day -365, Day 0]
• Chronic pulmonary disease [Day -365, Day 0]
• Combined comorbidity score [Day -365, Day 0]
• Chronic alcohol and or drug abuse [Day -365, Day 0]
• Noncompliance [Day -365, Day 0]
• Acute decompensated HF [Day -30, Day 0]
• Use of SGLT2i or DPP4i [Day -183, Day 0]

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Sitagliptin; Reference group	Drug: Sitagliptin; Initiation of sitagliptin described in electronic health records is used as the reference.
Empagliflozin; Exposure group	Drug: Empagliflozin; Initiation of empagliflozin described in electronic health records is used as the exposure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
A composite of hospitalization for heart failure or all-cause mortality	To evaluate the comparative effect of empagliflozin vs sitagliptin on hospitalisation for heart failure or all-cause mortality in patients with heart failure and preserved ejection fraction.	1 day after cohort entry date 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 SGLT2i or DPP4i.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cataract surgery	To evaluate the comparative effect of empagliflozin vs sitagliptin on the control outcome cataract surgery.	1 day after cohort entry date 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 SGLT2i or DPP4i.
Lumbar radiculopathy	To evaluate the comparative effect of empagliflozin vs sitagliptin on the control outcome lumbar radiculopathy (excluding patients with recent outcome prior to the follow-up time window (30 days)).	day after cohort entry date 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 SGLT2i or DPP4i.
Hernia	To evaluate the comparative effect of empagliflozin vs sitagliptin on the control outcome hernia (excluding patients with recent outcome prior to the follow-up time window (30 days)).	1 day after cohort entry date 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 SGLT2i or DPP4i.

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Food and Drug Administration (FDA)
• Investigators: Principal Investigator: Shirley Wang, PhD, ScM, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 13, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: May 14, 2026
• First Submitted That Met QC Criteria: May 14, 2026
• First Posted (Actual): May 20, 2026

Study Record Updates

• Last Update Posted (Actual): May 20, 2026
• Last Update Submitted That Met QC Criteria: May 14, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Pyrazines; Triazoles; Sitagliptin Phosphate; empagliflozin
• Other Study ID Numbers: 2018P002966-EMPERORPreserved

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No