Emulating the PIONEER6 Diabetes Trial Using Healthcare Claims

Emulation of the Effects of Oral Semaglutide on Cardiovascular Outcomes in Individuals With Type 2 Diabetes: PIONEER6 Trial

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: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: New use of oral semaglutide; Drug: New initiation of sitagliptin

Detailed Description

This is a non-randomized, non-interventional study that is part of the 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 trial listed below/above. Although many features of the trial cannot be directly emulated in healthcare claims, key design features, including outcomes, exposures, and inclusion/exclusion criteria, were selected to proxy those features from the trial. Randomization is also not emulable 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 PIONEER6 trial, is a is a non-inferiority trial to evaluate the effects of oral semaglutide versus placebo in terms of cardiovascular safety (CV death, nonfatal MI, or nonfatal stroke) in patients with type 2 diabetes.

The database study designed to emulate PIONEER6 will be a new-user active comparative study, where we compare the effect of oral semaglutide versus sitagliptin on MACE outcome among patients with T2DM. Sitagliptin was selected to act as an active-comparator proxy for placebo. Sitagliptin and the class of dipeptidyl peptidase-4 (DPP-4) inhibitors have been demonstrated not to have an effect on MACE in a series of RCTs, and they are used in similar stages of disease/line of therapy as semaglutide, as well as being similarly costly.

• Study Type: Observational
• Enrollment (Actual): 26126

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

The study population includes patients with Type 2 Diabetes (Type2DM), >=50 years with established cardiovascular disease OR >=60 years with subclinical cardiovascular disease.

Description

Eligible cohort entry dates:

Market availability of oral semaglutide in the US began on 19th September 2019.

Optum: Study period between 20th Sept 2019 - 29th February 2024 Marketscan: Study period between 20th Sept 2019 - 31st Dec 2022 Medicare: Study period between 20th Sept 2019 - 31st Dec 2020

Inclusion Criteria:

• Type 2 diabetes mellitus
• Age above or equal to 50 years at screening and clinical evidence of cardiovascular disease: prior myocardial infarction, prior stroke or prior transient ischemic attack, prior coronary, carotid or peripheral arterial revascularization, more than 50% stenosis on angiography or imaging of coronary, carotid or lower extremities arteries, chronic heart failure - New York Heart Association (NYHA) class II-III, chronic renal impairment documents by estimated eGFR <60ml/min/1.73 m2 per MDRD
• Age 60 years or older with subclinical evidence of cardiovascular disease. Subclinical cardiovascular risk factors as one of the following: persistent microalbuminuria (30-299mg/g) or proteinuria, ankle/brachial index less than 0.9

Exclusion Criteria:

• Type 1 diabetes mellitus, secondary or gestational diabetes
• Use of glucagon-like peptide-1 (GLP-1) receptor agonist (exenatide, liraglutide, or other) or pramlintide within 90 days prior to screening
• Use of any dipeptidyl peptidase 4 (DPP-IV) inhibitor within 30 days prior to screening
• History of diabetic ketoacidosis, chronic pancreatitis or idiopathic acute pancreatitis
• Any of the following: myocardial infarction, stroke, or hospitalization for unstable angina or transient ischemic attack within the past 60 days prior to screening
• Chronic heart failure New York Heart Association (NYHA) class IV
• Personal or family history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma
• Chronic hemodialysis or peritoneal dialysis
• End stage liver disease
• A prior solid organ transplant or awaiting solid organ transplant
• Diagnosis of malignant neoplasm in the previous 5 years
• Female of childbearing potential who is pregnant, breast-feeding or intends to become pregnant or is not using an adequate contraceptive method
• Proliferative retinopathy or maculopathy requiring treatment
• History of major surgical procedures involving the stomach potentially affecting absorption of trial product (e.g., subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery)
• Missing age or gender
• Nursing home admission

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
New use of oral semaglutide; Exposure group	Drug: New use of oral semaglutide; New use of oral semaglutide dispensing claim is used as the exposure.
New use of sitagliptin; Reference group	Drug: New initiation of sitagliptin; New use of sitagliptin dispensing claim is used as the reference.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major adverse cardiac event (MACE), including myocardial infarction, stroke, and all cause death	Hazard ratio	Through study completion (1 day after cohort entry date until the first of outcome or censoring)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cataract surgery (negative control)	Hazard ratio	Through study completion (1 day after cohort entry date until the first of outcome or censoring)

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2024
• Primary Completion (Actual): March 6, 2025
• Study Completion (Actual): March 6, 2025

Study Registration Dates

• First Submitted: October 24, 2024
• First Submitted That Met QC Criteria: October 24, 2024
• First Posted (Actual): October 26, 2024

Study Record Updates

• Last Update Posted (Actual): May 25, 2025
• Last Update Submitted That Met QC Criteria: May 21, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus, Type 2; Diabetes Mellitus; Glucagon-Like Peptide-1 Receptor Agonists; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Enzyme Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Sitagliptin Phosphate; Semaglutide
• Other Study ID Numbers: 2018P002966-DUP-PIONEER

Drug and device information, study documents

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