Associations of Early Add-On GLP-1 Receptor Agonist and SGLT2 Inhibitor Therapy With Mortality and Kidney Outcomes in Adults With Obesity and Type 2 Diabetes Across Cardiovascular-Kidney-Metabolic Stages 2-3: A Target-Trial Emulation
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Enrollment
- 451,036
- Primary Endpoint
- All-cause Mortality (Comparison 1)
Study Overview
Brief Summary
This retrospective observational target-trial emulation uses electronic health record data from the TriNetX US Collaborative Network to compare early treatment intensification strategies in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiate a GLP-1 receptor agonist or an SGLT2 inhibitor. The study compares patients who, within 90 days of starting background therapy, add the alternate agent, add a DPP-4 inhibitor or sulfonylurea, or do not receive early add-on therapy. The primary outcome is all-cause mortality over 36 months, with secondary cardiorenal outcomes also evaluated. Propensity-score methods are used to reduce bias from nonrandom treatment selection.
Detailed Description
This study is a retrospective observational target-trial emulation using electronic health record data from the TriNetX US Collaborative Network. It evaluates early treatment intensification strategies after initiation of a GLP-1 receptor agonist or an SGLT2 inhibitor in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.
Patients are grouped according to treatment changes made within 90 days after treatment initiation, including addition of the alternate drug class, addition of a DPP-4 inhibitor or sulfonylurea, or no early add-on treatment. Follow-up is aligned across comparison groups after this initial treatment assessment period.
The study uses routinely collected clinical data to assess the comparative effectiveness of these strategies on mortality and cardiorenal outcomes in real-world practice. Propensity-score-based methods are used to reduce confounding associated with nonrandom treatment selection.
Study Design
- Study Type
- Observational
- Observational Model
- Cohort
- Time Perspective
- Retrospective
Eligibility Criteria
- Ages
- 20 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Adults aged 20 years or older.
- •Obesity, defined by body mass index (BMI) 27 kg/m2 or greater.
- •Type 2 diabetes mellitus, defined using electronic health record data, including diagnosis codes and/or hemoglobin A1c 6.5% or greater.
- •Met cardiovascular-kidney-metabolic (CKM) stage 2-3 criteria at baseline.
- •Initiated a GLP-1 receptor agonist or an SGLT2 inhibitor as background therapy.
- •Had treatment strategy classification based on early add-on initiation within 90 days after background therapy initiation, or no early add-on with index at the 90-day landmark.
Exclusion Criteria
- •Prior use of GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, or sulfonylureas within 6 months before cohort entry.
- •Major cardiovascular disease or revascularization within 12 months before cohort entry.
- •Advanced kidney disease within 12 months before cohort entry, including end-stage kidney disease, dialysis, or estimated glomerular filtration rate less than 15 mL/min/1.73 m
- •Major cardiovascular or renal events within 6 months before index.
- •Any history of non-type 2 diabetes, HIV infection, bariatric surgery, or solid-organ transplantation.
- •Missing critical baseline covariates.
Arms & Interventions
GLP-1 RA Base Therapy
Adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiated a GLP-1 receptor agonist as base therapy after a 6-month washout from GLP-1 RA, SGLT2i, DPP-4i, and sulfonylureas. Within this cohort, participants were classified by the first add-on treatment within 90 days into three mutually exclusive strategies: SGLT2i add-on, DPP-4i or sulfonylurea add-on, or no early add-on.
Intervention: SGLT2 inhibitor (Drug)
SGLT2i Base Therapy
Adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiated an SGLT2 inhibitor as base therapy after a 6-month washout from GLP-1 RA, SGLT2i, DPP-4i, and sulfonylureas. Within this cohort, participants were classified by the first add-on treatment within 90 days into three mutually exclusive strategies: GLP-1 RA add-on, DPP-4i or sulfonylurea add-on, or no early add-on.
Intervention: GLP-1 receptor agonist (Drug)
SGLT2i Base Therapy
Adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiated an SGLT2 inhibitor as base therapy after a 6-month washout from GLP-1 RA, SGLT2i, DPP-4i, and sulfonylureas. Within this cohort, participants were classified by the first add-on treatment within 90 days into three mutually exclusive strategies: GLP-1 RA add-on, DPP-4i or sulfonylurea add-on, or no early add-on.
Intervention: SGLT2 inhibitor (Drug)
GLP-1 RA Base Therapy
Adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiated a GLP-1 receptor agonist as base therapy after a 6-month washout from GLP-1 RA, SGLT2i, DPP-4i, and sulfonylureas. Within this cohort, participants were classified by the first add-on treatment within 90 days into three mutually exclusive strategies: SGLT2i add-on, DPP-4i or sulfonylurea add-on, or no early add-on.
Intervention: GLP-1 receptor agonist (Drug)
Outcomes
Primary Outcomes
All-cause Mortality (Comparison 1)
Time Frame: From index through 36 months
All-cause mortality within 36 months in the propensity score-matched cohort for Comparison 1, comparing GLP-1 RA with SGLT2i add-on versus GLP-1 RA with DPP-4 inhibitor or sulfonylurea add-on in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.
All-cause Mortality (Comparison 2)
Time Frame: From index through 36 months
All-cause mortality within 36 months in the propensity score-matched cohort for Comparison 2, comparing GLP-1 RA with SGLT2i add-on versus GLP-1 RA without early add-on treatment in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.
All-cause Mortality (Comparison 3)
Time Frame: From index through 36 months
All-cause mortality within 36 months in the propensity score-matched cohort for Comparison 3, comparing SGLT2i with GLP-1 RA add-on versus SGLT2i with DPP-4 inhibitor or sulfonylurea add-on in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.
All-cause Mortality (Comparison 4)
Time Frame: From index through 36 months
All-cause mortality within 36 months in the propensity score-matched cohort for Comparison 4, comparing SGLT2i with GLP-1 RA add-on versus SGLT2i without early add-on treatment in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.
All-Cause Mortality
Time Frame: From index through 36 months
All-cause mortality within 36 months after index, comparing early add-on treatment strategies in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.
Secondary Outcomes
- Major Adverse Cardiovascular Events (MACE) (Comparison 1)(From index through 36 months)
- Major Adverse Cardiovascular Events (MACE) (Comparison 2)(From index through 36 months)
- Major Adverse Cardiovascular Events (MACE) (Comparison 3)(From index through 36 months)
- Major Adverse Cardiovascular Events (MACE) (Comparison 4)(From index through 36 months)
- Major Adverse Kidney Events (MAKE) (Comparison 1)(From index through 36 months)
- Major Adverse Kidney Events (MAKE) (Comparison 2)(From index through 36 months)
- Major Adverse Kidney Events (MAKE) (Comparison 3)(From index through 36 months)
- Major Adverse Kidney Events (MAKE) (Comparison 4)(From index through 36 months)
- Major Adverse Cardiovascular Events (MACE)(From index through 36 months)
- Major Adverse Kidney Events (MAKE)(From index through 36 months)
Investigators
Yu-Nan Huang
Assistant Professor/Research Fellow
Chung Shan Medical University