Early Add-On Combination of GLP-1 Receptor Agonist and SGLT2 Inhibitor in People With Cardiovascular-Kidney-Metabolic Stage 2-3 (GLP1-SGLT2-CKM)

May 24, 2026 updated by: Yu-Nan Huang, Chung Shan Medical University

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Observational

Enrollment (Actual)

451036

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Adults (≥20 years) with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 identified from routinely collected electronic health record data in the TriNetX US Collaborative Network. Participants initiated a GLP-1 receptor agonist or an SGLT2 inhibitor and were classified according to early add-on treatment strategies.

Description

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 m2.
  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
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.
Drug: GLP-1 receptor agonist
Use of a glucagon-like peptide-1 receptor agonist as background therapy or add-on therapy in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.
Drug: SGLT2 inhibitor
Use of a sodium-glucose cotransporter-2 inhibitor as background therapy or add-on therapy in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.
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.
Drug: GLP-1 receptor agonist
Use of a glucagon-like peptide-1 receptor agonist as background therapy or add-on therapy in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.
Drug: SGLT2 inhibitor
Use of a sodium-glucose cotransporter-2 inhibitor as background therapy or add-on therapy in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
From index through 36 months
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.
From index through 36 months
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.
From index through 36 months
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.
From index through 36 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Major Adverse Cardiovascular Events (MACE) (Comparison 1)
Time Frame: From index through 36 months
Major adverse cardiovascular events 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.
From index through 36 months
Major Adverse Cardiovascular Events (MACE) (Comparison 2)
Time Frame: From index through 36 months
Major adverse cardiovascular events 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.
From index through 36 months
Major Adverse Cardiovascular Events (MACE) (Comparison 3)
Time Frame: From index through 36 months
Major adverse cardiovascular events 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.
From index through 36 months
Major Adverse Cardiovascular Events (MACE) (Comparison 4)
Time Frame: From index through 36 months
Major adverse cardiovascular events 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.
From index through 36 months
Major Adverse Kidney Events (MAKE) (Comparison 1)
Time Frame: From index through 36 months
Major adverse kidney events 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.
From index through 36 months
Major Adverse Kidney Events (MAKE) (Comparison 2)
Time Frame: From index through 36 months
Major adverse kidney events 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.
From index through 36 months
Major Adverse Kidney Events (MAKE) (Comparison 3)
Time Frame: From index through 36 months
Major adverse kidney events 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.
From index through 36 months
Major Adverse Kidney Events (MAKE) (Comparison 4)
Time Frame: From index through 36 months
Major adverse kidney events 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.
From index through 36 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Chung Shan Medical University

Collaborators

National Science and Technology Council, Taiwan

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2017

Primary Completion (Actual)

January 31, 2026

Study Completion (Actual)

January 31, 2026

Study Registration Dates

First Submitted

March 8, 2026

First Submitted That Met QC Criteria

March 8, 2026

First Posted (Actual)

March 12, 2026

Study Record Updates

Last Update Posted (Actual)

June 22, 2026

Last Update Submitted That Met QC Criteria

May 24, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CS1-25149
  • NSTC 113-2314-B-040-026-MY2 (Other Grant/Funding Number: National Science and Technology Council, Taiwan)
  • NSTC 114-2622-B-040-001 (Other Grant/Funding Number: National Science and Technology Council, Taiwan)
  • CSH-2025-C-012 (Other Grant/Funding Number: Chung Shan Medical University Hospital)
  • CSH-2025-C-023 (Other Grant/Funding Number: Chung Shan Medical University Hospital)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Individual participant data will not be shared. This retrospective observational study uses electronic health record data from the TriNetX US Collaborative Network. Access to individual-level data is restricted by data use agreements, institutional policies, and participant privacy protections.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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