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.
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. Randomized controlled trials (RCTs) have demonstrated cardiovascular benefits of the modern incretin therapies semaglutide and tirzepatide in selected populations. SUSTAIN-6 (NCT01720446) and SURPASS-CVOT (NCT04255433) showed reductions in cardiovascular events with semaglutide and tirzepatide among patients with T2DM at high cardiovascular risk, findings that were also replicated in clinical practice settings (NCT06659744, NCT07088718).1-3 The REWIND trial (NCT01394952) demonstrated similar cardiovascular efficacy for dulaglutide and suggested benefit in both patients with and without prior cardiovascular disease.4 These findings raise the broader question of whether cardiovascular benefits of modern incretin therapies extend to individuals without established atherosclerotic cardiovascular disease (ASCVD) when used in routine clinical practice. To address this question, this comparative effectiveness study using a target trial emulation framework will assess the incretin therapies dulaglutide, semaglutide, and tirzepatide vs sitagliptin (used as an active comparator placebo proxy) on major adverse cardiovascular events (MACE) among individuals with type 2 diabetes (T2DM) and overweight with or without ASCVD. 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 analyses will be new-user active-comparative studies, conducted using 3 national United States claims databases, where we compare the effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on preventing atherosclerotic cardiovascular events.
Study Type
OBSERVATIONAL
Enrollment
60,000
Initiation of dulaglutide dispensing claim is used as the exposure.
Initiation of semaglutide dispensing claim is used as the exposure.
Initiation of tirzepatide dispensing claim is used as the exposure.
Brigham and Women's Hospital
Boston, Massachusetts, United States
Composite of myocardial infarction, stroke, or all-cause mortality.
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the composite of myocardial infarction, stroke, or all-cause mortality in individuals with T2DM and overweight with ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Composite of myocardial infarction, or stroke.
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the composite of myocardial infarction or stroke in individuals with T2DM and overweight with ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Composite of myocardial infarction, stroke, or all-cause mortality.
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the composite of myocardial infarction, stroke, or all-cause mortality in individuals with T2DM and overweight without ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Composite of myocardial infarction, or stroke.
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the composite of myocardial infarction or stroke in individuals with T2DM and overweight without ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
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Initiation of sitagliptin dispensing claim is used as the reference.
Myocardial infarction
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the occurrence of myocardial infarction in individuals with T2DM and overweight with ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Stroke
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the occurrence of stroke in individuals with T2DM and overweight with ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
All-cause mortality
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the occurrence of all-cause mortality in individuals with T2DM and overweight with ASCVD
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Composite of myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization.
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the composite of myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization in individuals with T2DM and overweight with ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Composite of myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or hospitalization for heart failure.
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the composite of myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or hospitalization for heart failure in individuals with T2DM and overweight with ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Unstable angina
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the occurrence of unstable angina in individuals with T2DM and overweight with ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Coronary revascularization
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the occurrence of coronary revascularization in individuals with T2DM and overweight with ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Heart failure
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on time to first hospitalization for any cause in individuals with T2DM and overweight with ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Time to first hospitalization for any cause.
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on time to first hospitalization for any cause in individuals with T2DM and overweight with ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Myocardial infarction
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the occurrence of myocardial infarction in individuals with T2DM and overweight without ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Stroke
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the occurrence of stroke in individuals with T2DM and overweight without ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
All-cause mortality
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the occurrence of all-cause mortality in individuals with T2DM and overweight without ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Composite of myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization.
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the composite of myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization in individuals with T2DM and overweight without ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Composite of myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or hospitalization for heart failure.
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the composite of myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or hospitalization for heart failure in individuals with T2DM and overweight without ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Unstable angina
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the occurrence of unstable angina in individuals with T2DM and overweight without ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Coronary revascularization
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the occurrence of coronary revascularization in individuals with T2DM and overweight without ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Heart failure
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the occurrence of heart failure in individuals with T2DM and overweight without ASCVD
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Time to first hospitalization for any cause
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on time to first hospitalization for any cause in individuals with T2DM and overweight without ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Urinary tract infections
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the safety outcome of urinary tract infections in individuals with T2DM and overweight with ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Serious infections
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the safety outcome of serious infections in individuals with T2DM and overweight with ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Gastrointestinal adverse events
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the safety outcome of gastrointestinal adverse events in individuals with T2DM and overweight with ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Urinary tract infections
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the safety outcome of urinary tract infections in individuals with T2DM and overweight without ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Serious infections
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the safety outcome of serious infections in individuals with T2DM and overweight without ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i
Gastrointestinal adverse events
To evaluate the comparative effect of dulaglutide, semaglutide, and tirzepatide vs sitagliptin on the safety outcome of gastrointestinal adverse events in individuals with T2DM and overweight without ASCVD.
Time frame: Through study completion until first of outcome, disenrollment, end of study period, 365 days after cohort entry, discontinuation (45 days grace and risk window), switch between study arms, nursing home admission, or start of any other GLP-1-RA or DPP4i