Second-line Therapies for Patients With Type 2 Diabetes and Moderate Cardiovascular Disease Risk

September 19, 2025 updated by: Rozalina G. McCoy, Mayo Clinic

We will use the target trial framework for causal inference to conduct this observational retrospective cohort study that uses claims data of adults with type 2 diabetes (T2D) included in the de-identified datasets of OptumLabs Data Warehouse (OLDW) and Medicare fee-for-service.

In Aim 1, we will emulate a target trial comparing the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), and sulfonylureas (SU) in adults with T2D at moderate risk of cardiovascular disease (CVD) with regard to major adverse cardiovascular events (MACE), expanded MACE, microvascular complications, severe hypoglycemia, and other adverse events.

In Aim 2, we will compare these four drug classes in the same population of adults with T2D included in OLDW and Medicare fee-for-service data with respect to a set of composite outcomes identified by a group of patients with T2D as being most important to them. Specifically, in Aim 2A, we will prospectively elicit patient preferences toward various treatment outcomes (e.g., hospitalization, kidney disease) using a participatory ranking exercise, then use these rankings to generate individually weighted composite outcomes. Then, in Aim 2B, we will estimate patient-centered treatment effects of four different second-line T2D medications that reflect the patient's value for each outcome.

In Aim 3, we will compare different medications within each of the four therapeutic classes with respect to MACE.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Study Design: We will use the target trial framework for causal inference to conduct this observational cohort study.

Comparators: Aims 1-2 compare the GLP-1RA, SGLT2i, DPP-4i, and SU classes, while Aim 3 compares the individual drugs within each therapeutic class.

Population: Using data from OptumLabs Data Warehouse linked to 100% Medicare FFS claims, we will identify adults (≥21 years) with T2D at moderate risk for CVD who started a GLP-1RA, SGLT2i, DPP-4i, or SU

Outcomes: In AIMs 1 and 3, the primary outcome will be time to MACE (non-fatal MI, non-fatal stroke, all-cause mortality). Secondary outcomes will include times to expanded MACE (MACE, HF hospitalizations, revascularization procedures) and its components, lower extremity complications, severe hypoglycemia, microvascular complications, and other significant adverse events. In AIM 2A, we will elicit patient preferences toward various treatment outcomes using a participatory ranking exercise, use these rankings to generate individually weighted composite outcomes, and then estimate patient-centered treatment effects of GLP-1RA, SGLT2i, DPP4i, and SU reflecting the patient values for each of the outcomes.

Timeframe: January 1, 2014 to December 31, 2021.

Methods: Inverse probability weighting will be used to emulate baseline randomization for pairwise comparisons between the drug classes (AIMs 1-2) and individual drugs within each class (AIM 3). Causal cumulative incidence rates will be estimated in the weighted sample using the targeted maximum likelihood estimator adjusting for time-dependent confounding and loss-to-follow-up.

Study Type

Observational

Enrollment (Actual)

386301

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
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic Rochester

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

21 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Aims 1, 2B, 3: De-identified data sets using laboratory results, electronic health record and mortality data from the OptumLabs Data Warehouse (OLDW) and Medicare fee-for-service data.

Aim 2A: Adults with Type 2 diabetes receiving care from primary care and endocrinology practices in Mayo Clinic Rochester, MN or Mayo Clinic Health System in Minnesota and Wisconsin.

Description

Inclusion Criteria for all Aims

  • ≥ 21 years old.
  • Diagnosis of Type 2 diabetes.
  • Use of ≥ 1 study drug (GLP-1RA, SGLT2i, DPP-4i, SU).

Exclusion Criteria for Aims 1, 2B, 3

  • Fill for any study drug during the baseline period or simultaneous (within 30 days) start of ≥2 study drugs
  • Insulin use
  • Type 1 diabetes
  • High risk of CVD
  • Pregnancy
  • Metastatic cancer

Exclusion Criteria for Aim 2A

  • Insulin use.
  • Cognitive impairment.
  • Terminal or advanced illness.
  • Non-English speaking.
  • Residency in a long-term care setting.

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

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Aims 1, 2B, and 3 Groups
De-identified administrative claims with linked laboratory results, electronic health record (EHR), and mortality data from the OptumLabs Data Warehouse (OLDW) and Medicare fee-for-service data (Medicare parts A, B, D) will be utilized to identify adults (≥21 years) with T2D (established using validated Healthcare Effectiveness Data and Information Set criteria) who first filled any study drug GLP-1RA, SGLT2i, DPP-4i, or SU between 1/1/2014-12/31/2021. This arm was exempt from Mayo Clinic Institutional Review Board review and informed consent requirements were not applicable as this arm used deidentified administrative claims data.
Drug: Glucagon like peptide 1 receptor agonist
Patients in the data who filled a glucagon-like peptide-1 receptor agonist medication
Drug: Sodium-glucose cotransporter 2 inhibitor
Patients in the data who filled a sodium-glucose cotransporter 2 inhibitor
Drug: Dipeptidyl Peptidase 4 Inhibitor
Patients in the data who filled a dipeptidyl peptidase-4 inhibitor
Drug: Sulfonylurea
Patients in the data who filled a sulfonylurea
Aim 2A Group
Adults with Type 2 diabetes treated with one or more of the study medications (GLP-1RA, SGLT2i, DPP-4i, or SU) and not treated with insulin who receive medical care at Mayo Clinic Rochester or Mayo Clinic Health System in Minnesota or Wisconsin. This arm was not exempt from Mayo Clinic Institutional Review Board review and informed consent requirements were applicable as this arm collected prospective data.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
3-point Major Adverse Cardiovascular Event (MACE)
Time Frame: Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
The probability of 3-point MACEs experienced by subjects treated with DPP4i, GLP-1RA, SGLT2i, or Sulfonylureas (SU) defined as non-fatal myocardial infarction (MI), non-fatal stroke, and mortality. The probability was calculated and reported as the hazard ratio.
Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
Expanded Major Adverse Cardiovascular Events (MACE) and Its Components
Time Frame: Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
The probability of 3-point MACEs (non-fatal MI, non-fatal stroke, mortality) plus heart failure hospitalization and revascularization procedure events experienced by subjects treated with DPP4i, GLP-1RA, SGLT2i, or Sulfonylureas (SU). The probability was calculated and reported as the hazard ratio.
Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
Patient Preferences for Second-line Type 2 Diabetes Medication Treatment Outcomes
Time Frame: 1 hour
Patients ranked treatment outcomes using a participatory ranking questionnaire. The questionnaire included a list of 16 health outcomes and eight medication attributes, with opportunities for participants to add outcomes and attributes into the ranking lists. During the exercise, participants were asked to assign each outcome and attribute to one of three mutually exclusive categories: "very important," "somewhat important," or "not very important," based on the degree to which each outcome or attribute would influence their choice of medication. Results shown below reflect the health outcomes/medication attributes that were ranked "very important" by patients.
1 hour

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Non-fatal Myocardial Infarction (MI)
Time Frame: Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
The probability of a non-fatal MI experienced by subjects treated with DPP4i, GLP-1RA, SGLT2i, or Sulfonylureas (SU). The probability was calculated and reported as the hazard ratio.
Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
Non-fatal Stroke Events
Time Frame: Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
The probability of non-fatal stroke events experienced by subjects treated with DPP4i, GLP-1RA, SGLT2i, or Sulfonylureas (SU). The probability was calculated and reported as the hazard ratio.
Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
All-cause Mortality
Time Frame: Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
The probability of all-cause mortality events experienced by subjects treated with DPP4i, GLP-1RA, SGLT2i, Sulfonylureas (SU). The probability was calculated and reported as the hazard ratio.
Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
Severe Hypoglycemia
Time Frame: Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
The probability of emergency department visits or hospitalization for hypoglycemia experienced by subjects treated with DPP4i, GLP-1RA, SGLT2i, or Sulfonylurea (SU). The probability was calculated and reported as the hazard ratio.
Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
Incident End-stage Kidney Disease
Time Frame: Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
The probability of a new diagnosis of stage 5 or end-stage kidney disease experienced by subjects treated with DPP4i, GLP-1RA, SGLT2i, or Sulfonylurea (SU). The probability was calculated and reported as the hazard ratio.
Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
Treatment for Diabetic Retinopathy or Macular Edema
Time Frame: Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
The probability of treatment for diabetic retinopathy and/or macular edema experienced by subjects treated with DPP4i, GLP-1RA, SGLT2i, or Sulfonylurea (SU). The probability was calculated and reported as the hazard ratio.
Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
Lower Extremity Complications
Time Frame: Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period
The probability of foot and/or leg amputation, osteomyelitis, ulcer, abscess or Charcot arthropathy experienced by subjects treated with DPP4i, GLP-1RA, SGLT2i, or Sulfonylurea (SU). The probability was calculated and reported as the hazard ratio.
Retrospective Data between 1/1/2014 - 12/31/2022, up to 8 years, collected over a 2-year period

Collaborators and Investigators

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

Sponsor

Mayo Clinic

Collaborators

Patient-Centered Outcomes Research Institute

Investigators

  • Principal Investigator: Rozalina McCoy, MD, MS, Mayo Clinic

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

Helpful Links

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)

December 1, 2021

Primary Completion (Actual)

September 30, 2023

Study Completion (Actual)

July 22, 2025

Study Registration Dates

First Submitted

January 26, 2022

First Submitted That Met QC Criteria

January 26, 2022

First Posted (Actual)

January 28, 2022

Study Record Updates

Last Update Posted (Estimated)

October 10, 2025

Last Update Submitted That Met QC Criteria

September 19, 2025

Last Verified

September 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 21-007688

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

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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