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. It is intended to emulate, as closely as is possible in healthcare insurance claims data, the SURPASS-CVOT 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 guidance on the reference standard treatment effect estimate. However, failure to replicate RCT findings is not necessarily 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 SURPASS-CVOT trial is a non-inferiority trial that aims to evaluate the effect of tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1-RA), vs dulaglutide, a GLP-1-RA, 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) and an established cardiovascular disease (CVD). In addition, the trial aims to determine noninferiority with a magnitude of difference that also supports superiority against putative placebo and for superiority to dulaglutide will be performed. With estimated study completion in summer 2025, results of the trial are yet to be announced. Therefore, we aim to predict the results of the SURPASS-CVOT trial by emulating its design with protocol registration and statistical analysis conducted before the results of the trial are made public.

The database study designed to emulate the SURPASS-CVOT trial will be a new-user active-comparative study, conducted using 2 national United States claims databases, where we compare the effect of tirzepatide vs dulaglutide on the composite end point of all-cause mortality, myocardial infarction, or stroke. Clinical guidelines during the study period recommended both agents under investigation as second-line options for glucose lowering and were similarly costly.

FOLLOWING ELIGIBILITY CIRTERIA OF THE SURPASS-CVOT TRIAL

Inclusion Criteria:

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

Exclusion Criteria:

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

Individuals aged 40 years or older with T2DM and an established CVD