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

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: Active, not recruiting
• Conditions: Type 2 Diabetes; Cardiac Disease
• Intervention / Treatment: Drug: Glucagon like peptide 1 receptor agonist; Drug: Sodium-glucose cotransporter 2 inhibitor; Drug: Dipeptidyl Peptidase 4 Inhibitor; Drug: Sulfonylurea

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 (Estimated): 500000

Contacts and Locations

Study Locations

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

Participation Criteria

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, Mayo Clinic Health System in Minnesota and Wisconsin, and Emory University/Grady Hospital in Atlanta, GA.

Description

Inclusion Criteria for all Aims

• ≥ 21 years old.
• Diagnosis of Type 2 diabetes.
• Use of ≥ 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

How is the study designed?

Number of groups / cohorts

2

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.	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, Mayo Clinic Health System in Minnesota or Wisconsin, or Emory University/Grady Hospital.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-point MACE	Number of 3-point MACE events defined as non-fatal MI, non-fatal stroke, and mortality	1/1/2014 - 12/31/2021

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Expanded MACE and its components	Number of 3-point MACE (non-fatal MI, non-fatal stroke, mortality) plus heart failure hospitalization and revascularization procedure events	1/1/2014 - 12/31/2021
Non-fatal myocardial infarction (MI)	Number of non-fatal myocardial infarctions	1/1/2014 - 12/31/2021
Non-fatal stroke events	Number of non-fatal stroke events	1/1/2014 - 12/31/2021
All-cause moratality	Number of deaths	1/1/2014 - 12/31/2021
Severe hypoglycemia	Number of emergency department visits or hospitalization for hypoglycemia	1/1/2014 - 12/31/2021
Incident end-stage kidney disease	Number of initiation of dialysis or new diagnosis of stage 5 or end-stage kidney disease	1/1/2014 - 12/31/2021
Treatment for diabetic retinopathy or macular edema	Number of treatments for diabetic retinopathy or macular edema	1/1/2014 - 12/31/2021
Lower extremity complications	Number of foot and/or leg amputation, osteomyelitis, ulcer, Charcot arthropathy	1/1/2014 - 12/31/2021
All-cause hospitalization	Number of hospitalizations	1/1/2014 - 12/31/2021
Severe genitourinary tract infection	Number of severe genitourinary tract infection	1/1/2014 - 12/31/2021

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: Patient-Centered Outcomes Research Institute
• Investigators: Principal Investigator: Rozalina McCoy, MD, MS, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2021
• Primary Completion (Estimated): April 1, 2025
• Study Completion (Estimated): April 1, 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 (Actual): October 2, 2023
• Last Update Submitted That Met QC Criteria: September 29, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Cardiovascular disease; Diabetes; Type 2 diabetes; Comparative effectiveness
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Heart Diseases; Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Glucagon; Sodium-Glucose Transporter 2 Inhibitors; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1
• 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