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

Completed

Conditions: Type 2 Diabetes
Cardiac Disease

Interventions: Drug: Glucagon like peptide 1 receptor agonist
Drug: Sodium-glucose cotransporter 2 inhibitor
Drug: Dipeptidyl Peptidase 4 Inhibitor
Drug: Sulfonylurea

Registration Number: NCT05214573

Lead Sponsor: Mayo Clinic

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 386301

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: OBSERVATIONAL

Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Aims 1, 2B, and 3 Groups	Glucagon like peptide 1 receptor agonist	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.
Aims 1, 2B, and 3 Groups	Sodium-glucose cotransporter 2 inhibitor	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.
Aims 1, 2B, and 3 Groups	Dipeptidyl Peptidase 4 Inhibitor	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.
Aims 1, 2B, and 3 Groups	Sulfonylurea	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.

Primary Outcome Measures

Name	Time	Method
3-point Major Adverse Cardiovascular Event (MACE)	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.
Expanded Major Adverse Cardiovascular Events (MACE) and Its Components	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.
Patient Preferences for Second-line Type 2 Diabetes Medication Treatment Outcomes	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.

Secondary Outcome Measures

Name	Time	Method
Non-fatal Myocardial Infarction (MI)	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.
Non-fatal Stroke Events	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.
All-cause Mortality	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.
Severe Hypoglycemia	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.
Incident End-stage Kidney Disease	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.
Treatment for Diabetic Retinopathy or Macular Edema	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.
Lower Extremity Complications	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.