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NCT Number: NCT07203677

Comparative Effectiveness of Tirzepatide Versus Sitagliptin in Individuals at Cardiovascular Risk (TIRZSITA-CVOT)

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.

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Key information

Conditions

Type2 Diabetes Mellitus Arterial Occlusive Diseases Arteriosclerosis Atherosclerosis Atherosclerotic Cardiovascular Disease Cardiovascular Diseases Vascular Diseases

Age range

40 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

Brigham and Women's Hospital

Boston, Massachusetts, 02120, United States

About this study

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 assess the comparative effectiveness of tirzepatide vs sitagliptin as a placebo proxy, after the pivotal RCT SURPASS-CVOT (NCT04255433) and its emulation (NCT07088718) demonstrated non-inferiority, leaving both regulators and clinical guideline committees uncertain whether to approve and recommend tirzepatide for a cardiovascular indication. This comparative effectiveness target trial described below draws from eligibility criteria from the SURPASS-CVOT trial and its emulation. Although many features of the target 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 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 purpose of this protocol is to specify the target trial assessing the comparative effectiveness of the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1-RA) tirzepatide vs the dipeptidyl peptidase-4 inhibitors (DPP4i) sitagliptin on atherosclerotic cardiovascular end points in patients with type 2 diabetes and atherosclerotic cardiovascular disease.

The database study will be a new-user active-comparative study, conducted using 2 national United States claims databases, where we compare the effect of tirzepatide vs sitagliptin in preventing atherosclerotic cardiovascular events. Clinical guidelines during the study period recommended both agents under investigation as second-line options for glucose lowering and were similarly costly.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • History of MI or stroke, surgical or percutaneous coronary/carotid peripheral artery revascularization, amputation, diagnosis of coronary/carotid/peripheral artery disease
  • BMI ≥25.0kg/m2
  • Type 2 diabetes
  • Age ≥40 years
  • Male or female sex

Exclusion criteria

  • Medullary thyroid carcinoma, MEN syndrome type 2, malignancy
  • Treatment for diabetic retinopathy/macular edema, heart failure NYHA IV, gastric emptying abnormality/bariatric surgery, end-stage renal disease or dialysis, pregnancy
  • Prior use of pramlintide or any GLP-1-RA except tirzepatide,
  • Pancreatitis, liver disease
  • Cardiovascular event or intervention, hospitalization for heart failure
  • Concurrent use of both drugs i.e. tirzepatide and sitagliptin

Treatment and study plan

Initiation of tirzepatide

Drug

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

Initiation of sitagliptin

Drug

New use of sitagliptin dispensing claim is used as the reference.

Primary outcomes

  1. Major adverse cardiovascular events

    Time frame: 1 day after cohort entry date until the first of outcome or censoring, up to 365 days

    To evaluate the comparative effect of tirzepatide vs sitagliptin on the composite of myocardial infarction, stroke, or all-cause mortality in patients with type 2 diabetes and atherosclerotic cardiovascular disease when following the inclusion and exclusion criteria of the SURPASS-CVOT trial.

Secondary outcomes

  1. Composite of myocardial infarction or stroke

    Time frame: 1 day after cohort entry date until the first of outcome or censoring, up to 365 days

    To evaluate the comparative effect of tirzepatide vs sitagliptin on the composite of myocardial infarction or stroke in patients with type 2 diabetes and atherosclerotic cardiovascular disease when following the inclusion and exclusion criteria of the SURPASS-CVOT trial.

  2. Myocardial infarction

    Time frame: 1 day after cohort entry date until the first of outcome or censoring, up to 365 days

    To evaluate the comparative effect of tirzepatide vs sitagliptin at preventing myocardial infarction in patients with type 2 diabetes and atherosclerotic cardiovascular disease when following the inclusion and exclusion criteria of the SURPASS-CVOT trial.

  3. Stroke

    Time frame: 1 day after cohort entry date until the first of outcome or censoring, up to 365 days

    To evaluate the comparative effect of tirzepatide vs sitagliptin at preventing stroke in patients with type 2 diabetes and atherosclerotic cardiovascular disease when following the inclusion and exclusion criteria of the SURPASS-CVOT trial.

  4. All-cause mortality

    Time frame: 1 day after cohort entry date until the first of outcome or censoring, up to 365 days

    To evaluate the comparative effect of tirzepatide vs sitagliptin at preventing all-cause mortality in patients with type 2 diabetes and atherosclerotic cardiovascular disease when following the inclusion and exclusion criteria of the SURPASS-CVOT trial.

  5. Infection-related mortality

    Time frame: 1 day after cohort entry date until the first of outcome or censoring, up to 365 days

    To evaluate the comparative effect of tirzepatide vs sitagliptin at preventing infection-related mortality in patients with type 2 diabetes and atherosclerotic cardiovascular disease when following the inclusion and exclusion criteria of the SURPASS-CVOT trial.

  6. Composite of myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina.

    Time frame: 1 day after cohort entry date until the first of outcome or censoring, up to 365 days

    To evaluate the comparative effect of tirzepatide vs sitagliptin on the composite of myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina in patients with type 2 diabetes and atherosclerotic cardiovascular disease when following the inclusion and exclusion criteria of the SURPASS-CVOT trial.

  7. Serious bacterial infections

    Time frame: 1 day after cohort entry date until the first of outcome or censoring, up to 365 days

    To evaluate the comparative effect of tirzepatide vs sitagliptin on the safety outcome of serious bacterial infections in patients with type 2 diabetes and atherosclerotic cardiovascular disease when following the inclusion and exclusion criteria of the SURPASS-CVOT trial.

  8. Urinary tract infections

    Time frame: 1 day after cohort entry date until the first of outcome or censoring, up to 365 days

    To evaluate the comparative effect of tirzepatide vs sitagliptin on the safety outcome of urinary tract infections in patients with type 2 diabetes and atherosclerotic cardiovascular disease when following the inclusion and exclusion criteria of the SURPASS-CVOT trial.

  9. Gastrointestinal adverse events

    Time frame: 1 day after cohort entry date until the first of outcome or censoring, up to 365 days

    To evaluate the comparative effect of tirzepatide vs sitagliptin on the safety outcome of gastrointestinal adverse events in patients with type 2 diabetes and atherosclerotic cardiovascular disease when following the inclusion and exclusion criteria of the SURPASS-CVOT trial.

  10. Infections across care settings

    Time frame: 1 day after cohort entry date until the first of outcome or censoring, up to 365 days

    To evaluate the comparative effect of tirzepatide vs sitagliptin on the safety outcome of infections across care settings in patients with type 2 diabetes and atherosclerotic cardiovascular disease when following the inclusion and exclusion criteria of the SURPASS-CVOT trial.

Other outcomes

  1. Hernia and lumbar radiculopathy

    Time frame: 1 day after cohort entry date until the first of outcome or censoring, up to 365 days

    To evaluate the effect of tirzepatide vs sitagliptin on negative control outcomes, including (1) hernia and (2) lumbar radiculopathy in patients with type 2 diabetes and atherosclerotic cardiovascular disease when following the inclusion and exclusion criteria of the SURPASS-CVOT trial.

Sponsors and collaborators

Lead sponsor

Brigham and Women's Hospital

Other

Registry information

Important dates

Study start
2025
Primary completion
2025
Study completion
2025
First posted
Oct 2, 2025
Registry last updated
Apr 30, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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