Emulation of the REWIND Cardiovascular Outcomes Trial in 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
• Intervention / Treatment: Drug: Sitagliptin; Drug: Dulaglutide

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 emulate, as closely as possible in healthcare insurance claims data, the REWIND 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. In addition to closely emulating the trial population, this study also evaluates outcomes in an expanded cohort following the eligibility criteria outlined in a set of completed emulation studies (NCT06659744, NCT07088718, NCT07096063) to enhance generalizability to patients typically encountered in clinical practice. Randomization cannot be emulated 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 REWIND (NCT01394952) trial is a superiority trial that evaluated the effect of dulaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1-RA), vs placebo on time to first occurrence of any major adverse cardiovascular event (MACE), defined as cardiovascular death, myocardial infarction, or stroke among patients with type 2 diabetes mellitus (T2DM) with and without previous cardiovascular disease (CVD).

The database study designed to emulate the REWIND trial will be a new-user active comparative study, where we compare the effect of dulaglutide vs sitagliptin, a dipeptidyl peptidase-4 inhibitor (DPP4i), on MACE among patients with T2DM with and without previous CVD. While the REWIND trial compared dulaglutide vs placebo, we chose to use sitagliptin as an active-comparator proxy for placebo. Sitagliptin was specifically chosen because a major randomized controlled trial on cardiovascular outcomes demonstrated that the drug does not affect the cardiovascular outcomes under investigation. Furthermore, clinical guidelines during the study period recommended both drug classes under investigation as second- or third-line options for glucose lowering and were similarly costly.

• Study Type: Observational
• Enrollment (Estimated): 30000

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

Two populations: (1) Individuals with T2DM, who are either aged 50 years or above with an established cardiovascular disease, aged 55 years or above with a subclinical cardiovascular disease, or aged 60 years or above with at least two cardiovascular risk factors; and (2) individuals typically treated in clinical practice who are at low, moderate, and high cardiovascular risk with T2DM.

Description

Eligible Cohort Entry Dates:

The study will use three data sources: Optum Clinformatics, Merative MarketScan, and Medicare.

Optum: Eligible cohort entry period between September 18, 2014 to August 31, 2025.

MarketScan: Eligible cohort entry period between October 1, 2016 to October 31, 2023.

Medicare: Eligible cohort entry period between September 18, 2014 to October 31, 2020.

FOLLOWING ELIGIBILITY OF THE REWIND TRIAL:

Inclusion Criteria:

• MI, Stroke, Revascularization procedure, Diagnosis of coronary/carotid/peripheral artery disease, diagnosis of hypertensive heart disease
• BMI >= 23.0kg/m2
• Type 2 Diabetes Mellitus
• Chronic Kidney Disease (CKD) Stage 3/4
• Albuminuria
• Tobacco use
• Hypercholesterolemia/-lipidemia
• Stable dose of glucose-lowering drugs, use lipid-lowering drugs, use of blood pressure medication

Exclusion Criteria:

• MEN syndrome or medullary thyroid carcinoma, organ transplant, malignancy
• Severe hypoglycemic episode
• CKD stage 5 or dialysis
• Gastric emptying abnormality or bariatric surgery
• Pregnancy
• Craniocervical Instability (CCI)
• Pancreatitis
• Liver disease
• Weight loss drug
• Uncontrolled diabetes
• Acute coronary/cerebrovascular event
• Concurrent use of both study drugs

EXPANDED POPULATION:

Inclusion Criteria:

• History of MI, stroke, any surgical or percutaneous revascularization procedure, use of antihypertensive/ lipid-lowering drugs, coronary / carotid / peripheral artery disease
• BMI >= 25.0kg/m2
• Type 2 Diabetes

Exclusion Criteria:

• Medullary thyroid carcinoma,
• MEN syndrome type 2
• Malignancy
• Type 1 diabetes or secondary diabetes
• End-stage renal disease or dialysis
• Uncontrolled diabetic retinopathy or maculopathy
• Pregnancy
• Bariatric surgery
• Prior use of pramlintide or any GLP-1-RA except dulaglutide, or any DPP4i except sitagliptin

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Initiation of sitagliptin; Reference group	Drug: Sitagliptin; Initiation of sitagliptin dispensing claim is used as the reference.
Initiation of dulaglutide; Exposure group	Drug: Dulaglutide; Initiation of dulaglutide dispensing claim is used as the exposure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of myocardial infarction, stroke, or all-cause mortality.	To evaluate the effect of dulaglutide vs sitagliptin on the composite of myocardial infarction, stroke, or all-cause mortality in patients with T2DM with and without previous CVD when following the eligibility criteria of the REWIND trial.	Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between study arms, start of any other GLP-1-RA
Myocardial infarction, stroke, or all-cause mortality	To evaluate the effect of dulaglutide vs sitagliptin on the composite of myocardial infarction, stroke, or all-cause mortality in patients with T2DM with and without previous CVD when expanding the eligibility criteria of the REWIND trial.	Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between study arms, start of any other GLP-1-RA

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The individual components of the primary end point, i.e., myocardial infarction, stroke, or all-cause mortality.	To evaluate the effect of dulaglutide vs sitagliptin on the individual components of the primary end point, i.e., myocardial infarction, stroke, or all-cause mortality in two populations: (1) Patients meeting the eligibility criteria of the REWIND trial and (2) a broader patient population when expanding the eligibility criteria of the REWIND trial.	Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between study arms, start of any other GLP-1-RA
Heart failure events (exacerbated symptoms of heart failure resulting in hospitalization, or intravenous diuretic therapy in an urgent care setting).	To evaluate the effect of dulaglutide vs sitagliptin on the occurrence of heart failure events in two populations: (1) Patients meeting the eligibility criteria of the REWIND trial and (2) a broader patient population when expanding the eligibility criteria of the REWIND trial.	Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between study arms, start of any other GLP-1-RA
Unstable angina	To evaluate the effect of dulaglutide vs sitagliptin on the occurrence of unstable angina in two populations: (1) Patients meeting the eligibility criteria of the REWIND trial and (2) a broader patient population when expanding the eligibility criteria of the REWIND trial.	Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between study arms, start of any other GLP-1-RA

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hernia	To evaluate the effect of dulaglutide vs sitagliptin on negative control outcomes, including hernia.	Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between study arms, start of any other GLP-1-RA
Lumbar radiculopathy	To evaluate the effect of dulaglutide vs sitagliptin on negative control outcomes, including lumbar radiculopathy.	Through study completion until the first of outcome, disenrollment, end of study period, discontinuation (45 days grace and risk window), switch between study arms, start of any other GLP-1-RA

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Shirley Wang, PhD, ScM, Brigham and Women's Hospital; Principal Investigator: Nils Krüger, MD, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2026
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: February 11, 2026
• First Submitted That Met QC Criteria: February 11, 2026
• First Posted (Actual): February 18, 2026

Study Record Updates

• Last Update Posted (Actual): February 18, 2026
• Last Update Submitted That Met QC Criteria: February 11, 2026
• Last Verified: February 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; dulaglutide
• Other Study ID Numbers: 2018P002966-REWIND

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No