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NCT Number: NCT07566299

Early GLP-1 Receptor Agonist and SGLT2 Inhibitor Add-On Strategies in Adults With Obesity, Type 2 Diabetes, Cardiovascular-Kidney-Metabolic Syndrome Stage 2-3, and Metabolic Dysfunction-Associated Steatotic Liver Disease

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, cardiovascular-kidney-metabolic syndrome stage 2-3, and metabolic dysfunction-associated steatotic liver disease who initiate a GLP-1 receptor agonist or an SGLT2 inhibitor as background therapy. Within each background-therapy cohort, patients who added the complementary class within 90 days of initiation were compared against patients who did not, with prespecified comparisons against both the overall non-complementary cohort and the analytical subset who initiated usual-care add-on therapy (DPP-4 inhibitors, sulfonylureas, or insulin) within the same window. The primary outcome is all-cause mortality over 60 months, with major adverse cardiovascular, kidney, and liver outcomes also evaluated. Propensity-score matching is used to reduce bias from nonrandom treatment selection.

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Key information

Conditions

Obesity Type 2 Diabetes Mellitus Cardiovascular-kidney-metabolic Syndrome Metabolic Dysfunction-Associated Steatotic Liver Disease

Age range

18 year and older

Sex eligibility

All sexes

Study type

Observational

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Adults aged 18 years or older.
  • BMI ≥27 kg/m², or diagnosis codes consistent with obesity
  • Type 2 diabetes mellitus
  • Cardiovascular-kidney-metabolic syndrome stage 2-3
  • Metabolic dysfunction-associated steatotic liver disease
  • New initiation of GLP-1 receptor agonist therapy or SGLT2 inhibitor therapy during the study period as background therapy
  • No prescription of either GLP-1 receptor agonist or SGLT2 inhibitor within the 6-month washout window before background therapy initiation

Exclusion criteria

  • Type 1 diabetes mellitus, or other specified diabetes types that are not type 2 diabetes
  • Human immunodeficiency virus infection
  • Other chronic, alcohol-related, or secondary liver diseases
  • Prior bariatric surgery
  • Prior solid-organ transplantation
  • Hepatocellular carcinoma or liver transplant within 1 year before background therapy initiation
  • Major cardiovascular, kidney, or liver event within the 6-month window before background therapy initiation
  • Transplant-related complications

Treatment and study plan

Primary outcomes

  1. All-cause Mortality (Comparison 1)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    All-cause mortality from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 1, comparing adults with obesity, type 2 diabetes, CKM syndrome stage 2-3, and MASLD who initiated GLP-1 RA therapy with early SGLT2i add-on versus those who initiated GLP-1 RA therapy without early SGLT2i add-on (monotherapy).

  2. All-cause Mortality (Comparison 2)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    All-cause mortality from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 2, comparing adults with obesity, type 2 diabetes, CKM syndrome stage 2-3, and MASLD who initiated GLP-1 RA therapy with early SGLT2i add-on versus those who initiated GLP-1 RA therapy with usual care (DPP-4 inhibitor, sulfonylurea, or insulin add-on).

  3. All-cause Mortality (Comparison 3)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    All-cause mortality from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 3, comparing adults with obesity, type 2 diabetes, CKM syndrome stage 2-3, and MASLD who initiated SGLT2i therapy with early GLP-1 RA add-on versus those who initiated SGLT2i therapy without early GLP-1 RA add-on (monotherapy).

  4. All-cause Mortality (Comparison 4)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    All-cause mortality from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 4, comparing adults with obesity, type 2 diabetes, CKM syndrome stage 2-3, and MASLD who initiated SGLT2i therapy with early GLP-1 RA add-on versus those who initiated SGLT2i therapy with usual care (DPP-4 inhibitor, sulfonylurea, or insulin add-on).

Secondary outcomes

  1. Major Adverse Cardiovascular Events (Comparison 1)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    Composite of acute myocardial infarction, cardiac arrest, intracerebral or intracranial hemorrhage, and cerebral infarction from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 1, comparing GLP-1 RA with early SGLT2i add-on versus GLP-1 RA monotherapy.

  2. Major Adverse Cardiovascular Events (Comparison 2)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    Composite of acute myocardial infarction, cardiac arrest, intracerebral or intracranial hemorrhage, and cerebral infarction from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 2, comparing GLP-1 RA with early SGLT2i add-on versus GLP-1 RA with usual care.

  3. Major Adverse Cardiovascular Events (Comparison 3)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    Composite of acute myocardial infarction, cardiac arrest, intracerebral or intracranial hemorrhage, and cerebral infarction from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 3, comparing SGLT2i with early GLP-1 RA add-on versus SGLT2i monotherapy.

  4. Major Adverse Cardiovascular Events (Comparison 4)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    Composite of acute myocardial infarction, cardiac arrest, intracerebral or intracranial hemorrhage, and cerebral infarction from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 4, comparing SGLT2i with early GLP-1 RA add-on versus SGLT2i with usual care.

  5. Major Adverse Kidney Events (Comparison 1)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    Composite of end-stage kidney disease, dialysis dependence or initiation, kidney failure, and dialysis-related procedures from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 1, comparing GLP-1 RA with early SGLT2i add-on versus GLP-1 RA monotherapy.

  6. Major Adverse Kidney Events (Comparison 2)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    Composite of end-stage kidney disease, dialysis dependence or initiation, kidney failure, and dialysis-related procedures from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 2, comparing GLP-1 RA with early SGLT2i add-on versus GLP-1 RA with usual care.

  7. Major Adverse Kidney Events (Comparison 3)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    Composite of end-stage kidney disease, dialysis dependence or initiation, kidney failure, and dialysis-related procedures from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 3, comparing SGLT2i with early GLP-1 RA add-on versus SGLT2i monotherapy.

  8. Major Adverse Kidney Events (Comparison 4)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    Composite of end-stage kidney disease, dialysis dependence or initiation, kidney failure, and dialysis-related procedures from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 4, comparing SGLT2i with early GLP-1 RA add-on versus SGLT2i with usual care.

  9. Major Adverse Liver Outcomes (Comparison 1)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    Composite of hepatic decompensation (ascites, hepatic encephalopathy, variceal bleeding, spontaneous bacterial peritonitis, hepatic failure, hepatorenal syndrome), hepatocellular carcinoma, and liver transplantation from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 1, comparing GLP-1 RA with early SGLT2i add-on versus GLP-1 RA monotherapy.

  10. Major Adverse Liver Outcomes (Comparison 2)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    Composite of hepatic decompensation, hepatocellular carcinoma, and liver transplantation from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 2, comparing GLP-1 RA with early SGLT2i add-on versus GLP-1 RA with usual care.

  11. Major Adverse Liver Outcomes (Comparison 3)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    Composite of hepatic decompensation, hepatocellular carcinoma, and liver transplantation from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 3, comparing SGLT2i with early GLP-1 RA add-on versus SGLT2i monotherapy.

  12. Major Adverse Liver Outcomes (Comparison 4)

    Time frame: From 90 days after treatment initiation through up to 60 months of follow-up

    Composite of hepatic decompensation, hepatocellular carcinoma, and liver transplantation from the 90-day landmark date through up to 60 months of follow-up in the propensity score-matched cohort for Comparison 4, comparing SGLT2i with early GLP-1 RA add-on versus SGLT2i with usual care.

Sponsors and collaborators

Lead sponsor

Chung Shan Medical University

Other

Collaborators

  • National Science and Technology Council, Taiwan

Registry information

Official study title

Early GLP-1 Receptor Agonist and SGLT2 Inhibitor Add-On Strategies in Adults With Obesity, Type 2 Diabetes, Cardiovascular-Kidney-Metabolic Syndrome Stage 2-3, and Metabolic Dysfunction-Associated Steatotic Liver Disease: A Target Trial Emulation

Important dates

Study start
2017
Primary completion
2026
Study completion
2026
First posted
May 5, 2026
Registry last updated
Jun 25, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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