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

March 8, 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 observational target-trial emulation study uses routinely collected electronic health record data from the TriNetX US Collaborative Network to compare early add-on treatment strategies in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3. The study evaluates outcomes among people who start a GLP-1 receptor agonist or an SGLT2 inhibitor and then, within 90 days, either add the alternate therapy, add a DPP-4 inhibitor or sulfonylurea, or do not receive early add-on treatment. The primary outcome is all-cause mortality within 36 months. Secondary outcomes include major adverse cardiovascular events and major adverse kidney events. Nonrandom treatment selection is addressed using propensity-score matching to estimate comparative risks and treatment effects.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This is a retrospective observational study designed as a target-trial emulation using routinely collected electronic health record data from the TriNetX US Collaborative Network. The study aims to compare 36-month risks of all-cause mortality and major cardiorenal outcomes among adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiate a GLP-1 receptor agonist or an SGLT2 inhibitor and subsequently follow different early treatment intensification strategies. Primary estimands are relative hazards and absolute risk differences at 36 months.

Eligible participants are adults aged 20 years or older with obesity and type 2 diabetes who meet cardiovascular-kidney-metabolic stage 2-3 criteria. Eligibility, exposures, and outcomes are operationalized using TriNetX electronic health record data, including ICD-10-CM diagnosis codes, body mass index of at least 27 kg/m2, hemoglobin A1c of at least 6.5%, and medication dispensing records. Exclusion criteria include prior use of relevant drug classes within 6 months, major cardiovascular disease or advanced kidney disease within 12 months, major cardiovascular or renal events within 6 months, and any history of non-type 2 diabetes, HIV, bariatric surgery, or solid-organ transplantation.

Three mutually exclusive early treatment intensification strategies are compared: early add-on SGLT2 inhibitor therapy, early add-on DPP-4 inhibitor or sulfonylurea therapy, and no early add-on therapy. For add-on strategies, the index date is the date of add-on initiation within 90 days after background therapy initiation. For the no early add-on strategy, the index date is the 90-day landmark after background therapy initiation.

Because treatment assignment is not randomized, nonrandom treatment selection is addressed using multinomial propensity-score matching with 1:1 nearest-neighbor matching without replacement and a caliper of 0.2 times the standard deviation of the logit propensity score. Post-match covariate balance is evaluated using standardized mean differences, and any residual imbalance is further adjusted for in the outcome models. Follow-up begins at the index date and continues until the earliest of the outcome of interest, death, last recorded encounter, or January 31, 2026, with intention-to-treat and per-protocol analyses performed.

The primary outcome is all-cause mortality within 36 months. Secondary outcomes include major adverse cardiovascular events, defined as cardiovascular arrest, myocardial infarction, or stroke, and major adverse kidney events, defined as end-stage kidney disease, dialysis dependence or initiation, kidney failure, or death. Comparative effects are estimated over 36 months for pairwise early add-on comparisons, with prespecified subgroup analyses by cardiovascular-kidney-metabolic stage, obesity severity, baseline kidney function, and baseline cardiovascular comorbidity.

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 with SGLT2i Add-On
Adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiated a GLP-1 receptor agonist as background therapy and added an SGLT2 inhibitor within 90 days as an early treatment intensification strategy. The index date was the date of SGLT2 inhibitor add-on initiation.
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.
GLP-1 RA with DPP-4i/SU Add-On
Adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiated a GLP-1 receptor agonist as background therapy and added a DPP-4 inhibitor or sulfonylurea within 90 days as an early treatment intensification strategy. The index date was the date of DPP-4 inhibitor or sulfonylurea add-on initiation.
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.
GLP-1 RA Only
Adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiated an GLP-1 receptor agonist as background therapy and did not receive early add-on treatment within 90 days. The index date was the 90-day landmark after background therapy initiation.
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.
SGLT2i with GLP-1 RA Add-On
Adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiated an SGLT2 inhibitor as background therapy and added a GLP-1 receptor agonist within 90 days as an early treatment intensification strategy. The index date was the date of GLP-1 receptor agonist add-on initiation.
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 with DPP-4i/SU Add-On
Adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiated an SGLT2 inhibitor as background therapy and added a DPP-4 inhibitor or sulfonylurea within 90 days as an early treatment intensification strategy. The index date was the date of DPP-4 inhibitor or sulfonylurea add-on initiation.
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 Only
Adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiated an SGLT2 inhibitor as background therapy and did not receive early add-on treatment within 90 days. The index date was the 90-day landmark after background therapy initiation.
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
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.
From index through 36 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Major Adverse Cardiovascular Events (MACE)
Time Frame: From index through 36 months
Composite of cardiovascular arrest, myocardial infarction, or stroke, assessed after index. Event definitions are based on inpatient or emergency encounters.
From index through 36 months
Major Adverse Kidney Events (MAKE)
Time Frame: From index through 36 months
Composite of end-stage kidney disease, dialysis dependence or initiation, kidney failure, or death, assessed after index.
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)

March 12, 2026

Last Update Submitted That Met QC Criteria

March 8, 2026

Last Verified

March 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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