Emulation of the REWIND Cardiovascular Outcomes Trial in Healthcare Claims Data.

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.

• Dulaglutide (Drug): Initiation of dulaglutide dispensing claim is used as the exposure.
• Sitagliptin (Drug): Initiation of sitagliptin dispensing claim is used as the reference.

Primary outcomes

• Time to first occurrence of myocardial infarction, stroke, or all-cause mortality [From cohort entry through first occurrence of outcome, disenrollment, end of the study period, treatment discontinuation +45-day grace/risk window, treatment switch between arms, nursing home admission, start of another GLP-1 RA, assessed up to 1 year.]: The primary outcome is the time from cohort entry to the first occurrence of any component of the composite endpoint: myocardial infarction, stroke, or all-cause mortality in patients with T2DM with and without previous CVD, comparing dulaglutide versus sitagliptin, when following the eligibility criteria of the REWIND trial.
• Time to first occurrence of myocardial infarction, stroke, or all-cause mortality [From cohort entry through first occurrence of outcome, disenrollment, end of the study period, treatment discontinuation +45-day grace/risk window, treatment switch between arms, nursing home admission, start of another GLP-1 RA, assessed up to 1 year.]: The outcome is the time from cohort entry to the first occurrence of any component of the composite endpoint: myocardial infarction, stroke, or all-cause mortality in patients with T2DM with and without previous CVD, comparing dulaglutide versus sitagliptin, when expanding the eligibility criteria of the REWIND trial.

Secondary outcomes

• Time to first occurrence of myocardial infarction, stroke, or all-cause mortality, assessed as individual components [From cohort entry through first occurrence of outcome, disenrollment, end of the study period, treatment discontinuation +45-day grace/risk window, treatment switch between arms, nursing home admission, start of another GLP-1 RA, assessed up to 1 year.]: The outcomes are the times from cohort entry to the first occurrence of each individual component of the primary composite endpoint: myocardial infarction, stroke, and all-cause mortality, comparing dulaglutide versus sitagliptin in a patient population defined by expanded REWIND eligibility criteria.
• Time to first occurrence of a heart failure event [From cohort entry through first occurrence of outcome, disenrollment, end of the study period, treatment discontinuation +45-day grace/risk window, treatment switch between arms, nursing home admission, start of another GLP-1 RA, assessed up to 1 year.]: The outcome is the time from cohort entry to the first heart failure event, defined as exacerbated symptoms of heart failure resulting in hospitalization or intravenous diuretic therapy in an urgent care setting, comparing dulaglutide versus sitagliptin in a broader patient population defined by expanded REWIND eligibility criteria.
• Time to first occurrence of unstable angina [From cohort entry through first occurrence of outcome, disenrollment, end of the study period, treatment discontinuation +45-day grace/risk window, treatment switch between arms, nursing home admission, start of another GLP-1 RA, assessed up to 1 year.]: The outcome is the time from cohort entry to the first occurrence of unstable angina, comparing dulaglutide versus sitagliptin in a broader patient population defined by expanded REWIND eligibility criteria.

Other outcomes

• Time to first occurrence of hernia [From cohort entry through first occurrence of outcome, disenrollment, end of the study period, treatment discontinuation +45-day grace/risk window, treatment switch between arms, nursing home admission, start of another GLP-1 RA, assessed up to 1 year.]: The outcome is the time from cohort entry to the first occurrence of hernia, comparing dulaglutide versus sitagliptin in two populations: patients meeting the eligibility criteria of the REWIND trial and a broader patient population defined by expanded REWIND eligibility criteria.
• Time to first occurrence of lumbar radiculopathy [From cohort entry through first occurrence of outcome, disenrollment, end of the study period, treatment discontinuation +45-day grace/risk window, treatment switch between arms, nursing home admission, start of another GLP-1 RA, assessed up to 1 year.]: The outcome is the time from cohort entry to the first occurrence of umbar radiculopathy, comparing dulaglutide versus sitagliptin in two populations: patients meeting the eligibility criteria of the REWIND trial and a broader patient population defined by expanded REWIND eligibility criteria.

Sex: All, ages: 50 Years to any

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 Protocol (PDF, 2026-02-03)

• Shirley Wang, PhD, ScM, Principal investigator, Brigham and Women's Hospital
• Nils Krüger, MD, Principal investigator, Brigham and Women's Hospital