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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Type 2 Diabetes, Cardiac Disease

Intervention / Treatment
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* Drug: Glucagon like peptide 1 receptor agonist
* Drug: Sodium-glucose cotransporter 2 inhibitor
* Drug: Dipeptidyl Peptidase 4 Inhibitor
* Drug: Sulfonylurea


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Aims 1, 2B, and 3 Groups<br>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<br>* Patients in the data who filled a glucagon-like peptide-1 receptor agonist medication<br>Drug: Sodium-glucose cotransporter 2 inhibitor<br>* Patients in the data who filled a sodium-glucose cotransporter 2 inhibitor<br>Drug: Dipeptidyl Peptidase 4 Inhibitor<br>* Patients in the data who filled a dipeptidyl peptidase-4 inhibitor<br>Drug: Sulfonylurea<br>* Patients in the data who filled a sulfonylurea<br>|
| Aim 2A Group<br>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?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Type 2 diabetes, Cardiovascular disease, Comparative effectiveness