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

• ClinicalTrials.gov Identifier: NCT05214573
• Recruitment Status: Enrolling by invitation
• First Posted: January 28, 2022
• Last Update Posted: January 28, 2022
• Sponsor: Mayo Clinic
• Collaborator: Patient-Centered Outcomes Research Institute
• Information provided by (Responsible Party): Rozalina G. McCoy, Mayo Clinic

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment
Type 2 Diabetes; Cardiac Disease	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, 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, 2019.

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 Design

• Study Type: Observational
• Estimated Enrollment: 500000 participants
• Observational Model: Cohort
• Time Perspective: Retrospective
• Official Title: Second-line Therapies for Patients With Type 2 Diabetes and Moderate Cardiovascular Disease Risk
• Actual Study Start Date: December 1, 2021
• Estimated Primary Completion Date: August 31, 2024
• Estimated Study Completion Date: August 31, 2025

Groups and Cohorts

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 1/1/2014-12/31/2020.	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.

Outcome Measures

Primary Outcome Measures :

1. 3-point MACE [ Time Frame: 1/1/2014 - 12/31/2021 ]
   Number of 3-point MACE events defined as non-fatal MI, non-fatal stroke, and mortality

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 21 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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.

Criteria

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.

Contacts and Locations

Locations

United States, Minnesota

Mayo Clinic Rochester

Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

Mayo Clinic

Patient-Centered Outcomes Research Institute

Investigators

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

More Information

Additional Information:

Mayo Clinic Clinical Trials 

• Responsible Party: Rozalina G. McCoy, Principal Investigator, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT05214573
• Other Study ID Numbers: 21-007688
• First Posted: January 28, 2022
• Last Update Posted: January 28, 2022
• Last Verified: January 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Rozalina G. McCoy, Mayo Clinic:

Diabetes; Type 2 diabetes; Cardiovascular disease; Comparative effectiveness

Additional relevant MeSH terms:

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