Comparison of Type 2 Diabetes Pharmacotherapy Regimens (ON TARGET DM)

November 11, 2025 updated by: Kaiser Permanente

Comparison of Type 2 Diabetes Pharmacotherapy Regimens Using Targeted Learning

This study is designed to help patients with type 2 diabetes and their clinicians: (a) identify which glucose lowering medications have the most favorable effects on heart health and other patient-important outcomes, (b) inform the timing of medication initiation, and (c) identify whether medication benefits apply equally to all adults with type 2 diabetes, or may be different based on age, sex, race/ethnicity, baseline heart health status, baseline renal function, or other factors.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The study will conduct head-to-head comparisons of type 2 diabetes mellitus (T2DM) treatment strategies using observational data from real-world clinical settings to assess cardiovascular disease (CVD) outcomes and other patient-centered outcomes in T2DM patients with moderate baseline CVD risk who are treated with each of these four classes of glucose-lowering medications known as SGLT2, GLP-1RA, DPP4, and SU. To mitigate bias concerns related to confounding and informative loss to follow-up, analyses will be based on modern causal inference methods combined with machine learning that emulate intention-to-treat (ITT) and per-protocol (PP) analyses of pragmatic randomized trials with active comparators to provide the most robust and precise estimates of relative and absolute effects we would expect in usual care settings.

Specific Aims and Hypotheses:

Aim 1. Compare the effect off SGLT21, GLP-1RA, DPP4, and SU on each study outcome in adults with T2DM when each type of medication is (a) initiated as second-line therapy after metformin, and (b) initiated as first-, second-, or third-line therapy, or after any history of glucose-lowering therapy independent of prior metformin use.

Aim 2. Compare the effect on each study outcome of earlier versus later initiation of SGLT2i, GLP-1RA, DPP4, SU as first-, or second-, or third-line therapy, or after any history of glucose-lowering therapy triggered by various changes in A1C, or CVD risk, or other patient characteristics.

Aim 3. Assess in each of the prior analyses whether the treatment effects on study outcomes vary across categories of baseline CVD risk and CVD event history, renal function, congestive heart failure status, age, sex and race/ethnicity, or other patient characteristics.

Glucose-lowering medications will be compared at both the class and agent level. The key outcomes that will be considered are MACE 3-point, Myocardial Infarction, Stroke, Heart Failure, Hospitalization, Coronary or Carotid Artery Stent or Bypass Procedure, CVD Mortality, Overall Mortality. Additional patient-centered outcomes will be specified based on insights from stakeholder members of the research team.

Study Type

Observational

Enrollment (Actual)

241981

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Pasadena, California, United States, 91101
        • Kaiser Permanente Southern California
      • Pleasanton, California, United States, 94588
        • Romain S. Neugebauer
    • Hawaii
      • Honolulu, Hawaii, United States, 96817
        • Kaiser Permanente Hawaii
    • Michigan
      • Detroit, Michigan, United States, 48202
        • Henry Ford Health System
    • Minnesota
      • Bloomington, Minnesota, United States, 55425
        • HealthPartners Institute
    • Pennsylvania
      • Danville, Pennsylvania, United States, 17821
        • Geisinger

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Patients from six large care delivery systems with integrated administrative and EHR clinical data sources (Geisinger in Pennsylvania, Henry Ford Health System in Michigan, HealthPartners Institute in Minnesota and Wisconsin, and Kaiser Permanente of Northern California, Southern California, and Hawaii) who were new users of glucose-lowering medications between 01/01/2014 and 12/31/2021.

Description

  • Dispensing of either of the set of drugs being compared
  • No prior dispensing of nor contraindication for any of the drugs compared
  • Evidence of Type 2 Diabetes Mellitus diagnosis
  • Age 18 or older
  • Not currently pregnant
  • No evidence of dementia or short-term life expectancy from prior cancer diagnoses
  • History of ≥2 years of continuous health plan membership
  • ≥1 A1c test in the past 18 months

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Retrospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of 3-point Major Adverse Cardiovascular Events (MACE)
Time Frame: 2.5 years
3-point MACE is defined as a single outcome measure, which is a composite measure of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular disease death.
2.5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Kaiser Permanente

Collaborators

Patient-Centered Outcomes Research Institute
Henry Ford Health System
HealthPartners Institute
Geisinger Clinic

Investigators

  • Principal Investigator: Romain S. Neugebauer, PhD, Kaiser Permanente
  • Principal Investigator: Patrick J O'Connor, MD, MA, MPH, HealthPartners Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 1, 2021

Primary Completion (Actual)

December 31, 2024

Study Completion (Actual)

March 12, 2025

Study Registration Dates

First Submitted

September 14, 2021

First Submitted That Met QC Criteria

October 1, 2021

First Posted (Actual)

October 11, 2021

Study Record Updates

Last Update Posted (Actual)

November 21, 2025

Last Update Submitted That Met QC Criteria

November 11, 2025

Last Verified

November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 739857

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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