Comparison of Type 2 Diabetes Pharmacotherapy Regimens

NCT ID: NCT05073692

Last Updated: 2025-11-21

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 241981 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2021-07-01
• Study Completion Date: 2025-03-12

Brief Summary

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.

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.

Conditions

Type 2 Diabetes Mellitus; Cardiovascular Diseases

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: RETROSPECTIVE

Interventions

SU

Exposure to the class of drugs known as Sulfonylureas (SU)

Intervention Type: DRUG

DPP4

Exposure to the class of drugs known as Dipeptidyl peptidase-4 inhibitors (DPP4)

Intervention Type: DRUG

SGLT2i

Exposure to the class of drugs known as Sodium-glucose cotransporter-2 inhibitors (SGLT2i)

Intervention Type: DRUG

GLP-1RA

Exposure to the class of drugs known as Glucagon-like peptide-1 receptor agonists (GLP-1RA)

Intervention Type: DRUG

SGLT2i or GLP-1RA

Exposure to either SGLT2i or GLP-1RA

Intervention Type: DRUG

Linagliptin (DPP4)

Exposure to agent Linagliptin (DPP4)

Intervention Type: DRUG

Exenatide (GLP-1RA)

Exposure to agent Exenatide (GLP1-RA)

Intervention Type: DRUG

Liraglutide (GLP-1RA)

Exposure to agent Liraglutide (GLP-1RA)

Intervention Type: DRUG

Empagliflozin (SGLT2i)

Exposure to agent Empagliflozin (SGLT2i)

Intervention Type: DRUG

Glimepiride (SU)

Exposure to agent Glimepiride (SU)

Intervention Type: DRUG

Glipizide (SU)

Exposure to Glimepiride (SU)

Intervention Type: DRUG

Glimepiride (SU) or Glipizide (SU)

Exposure to agent Glimepiride (SU) or Glipizide (SU)

Intervention Type: DRUG

SU or DPP4 (excluding saxagliptin and alogliptin)

Exposure to either SU or DPP4 excluding Saxagliptin and Alogliptin

Intervention Type: DRUG

Exenatide (GLP-1RA) or Liraglutide (GLP-1RA)

Exposure to either Exenatide (GLP-1RA) or Liraglutide (GLP-1RA)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Geisinger Clinic

OTHER

Sponsor Role: collaborator

Henry Ford Health System

OTHER

Sponsor Role: collaborator

HealthPartners Institute

OTHER

Sponsor Role: collaborator

Patient-Centered Outcomes Research Institute

OTHER

Sponsor Role: collaborator

Kaiser Permanente

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Romain S. Neugebauer, PhD

Role: PRINCIPAL_INVESTIGATOR

Kaiser Permanente

Patrick J O'Connor, MD, MA, MPH

Role: PRINCIPAL_INVESTIGATOR

HealthPartners Institute

Locations

Kaiser Permanente Southern California

Pasadena, California, United States

Romain S. Neugebauer

Pleasanton, California, United States

Kaiser Permanente Hawaii

Honolulu, Hawaii, United States

Henry Ford Health System

Detroit, Michigan, United States

HealthPartners Institute

Bloomington, Minnesota, United States

Geisinger

Danville, Pennsylvania, United States

Countries

United States

References

Thomas TW, Hooker SA, Schmittdiel JA. Principles for Stakeholder Engagement in Observational Health Research. JAMA Health Forum. 2024 Mar 1;5(3):e240114. doi: 10.1001/jamahealthforum.2024.0114.

Reference Type: BACKGROUND

PMID: 38488777 (View on PubMed)

Rodriguez LA, Finertie H, Neugebauer RS, Gosiker B, Thomas TW, Karter AJ, Gilliam LK, Oshiro C, An J, Simonson G, Cassidy-Bushrow AE, Dombrowski S, Nolan M, O'Connor PJ, Schmittdiel JA. Race and ethnicity and pharmacy dispensing of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes. Lancet Reg Health Am. 2024 May 7;34:100759. doi: 10.1016/j.lana.2024.100759. eCollection 2024 Jun.

Reference Type: RESULT

PMID: 38745886 (View on PubMed)

Thapa B, Schmittdiel JA, Arterburn D, Neugebauer R, Dyer W, O'Connor PJ, An J, Cassidy-Bushrow AE, Gilliam LK, Hooker SA, Nolan MB, Oshiro CES, Thomas T, Simonson G, Dombrowski SK, Rodriguez LA. Clinical and Demographic Characteristics Associated With Diabetes Remission in Six Integrated Health Care Systems: A Retrospective Cohort Study. Diabetes Care. 2025 Oct 1;48(10):1737-1743. doi: 10.2337/dc25-0530.

Reference Type: RESULT

PMID: 40734551 (View on PubMed)

Neugebauer R, An J, Dombrowski SK, Oshiro C, Cassidy-Bushrow A, Gilliam L, Simonson G, Karter AJ, Bergenstal R, Finertie H, Yassin MM, Knowlton G, Lin SR, Dyer W, Pimentel N, Izadian K, Schmittdiel J, Thomas TW, Hooker SA, Nolan MB, Wright E, Aurora L, Rodriguez LA, Kaur J, Adams AS, van der Laan MJ, O'Connor PJ. Glucose-Lowering Medication Classes and Cardiovascular Outcomes in Patients With Type 2 Diabetes. JAMA Netw Open. 2025 Oct 1;8(10):e2536100. doi: 10.1001/jamanetworkopen.2025.36100.

Reference Type: RESULT

PMID: 41091469 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

739857

Identifier Type: -

Identifier Source: org_study_id