Cardiovascular-kidney-metabolic Syndrome, Metabolic Dysfunction-Associated Steatotic Liver Disease, Obesity Type 2 Diabetes Mellitus
Conditions
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, 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.
Interventions
None listed
Sponsors
Chung Shan Medical University
National Science and Technology Council, Taiwan
Study design
Observational model
COHORT
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality (Comparison 1) | 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). |
| All-cause Mortality (Comparison 2) | 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). |
| All-cause Mortality (Comparison 3) | 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). |
| All-cause Mortality (Comparison 4) | 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
| Measure | Time frame | Description |
|---|---|---|
| Major Adverse Cardiovascular Events (Comparison 1) | 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. |
| Major Adverse Cardiovascular Events (Comparison 2) | 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. |
| Major Adverse Cardiovascular Events (Comparison 3) | 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. |
| Major Adverse Cardiovascular Events (Comparison 4) | 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. |
| Major Adverse Kidney Events (Comparison 1) | 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. |
| Major Adverse Kidney Events (Comparison 2) | 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. |
| Major Adverse Kidney Events (Comparison 3) | 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. |
| Major Adverse Kidney Events (Comparison 4) | 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. |
| Major Adverse Liver Outcomes (Comparison 1) | 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. |
| Major Adverse Liver Outcomes (Comparison 2) | 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. |
| Major Adverse Liver Outcomes (Comparison 3) | 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. |
| Major Adverse Liver Outcomes (Comparison 4) | 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. |
Participant flow
Recruitment details
Participants were retrospectively identified from the TriNetX US Collaborative Network using de-identified electronic health records. Eligible adults with obesity, type 2 diabetes, cardiovascular-kidney-metabolic syndrome stage 2-3, and metabolic dysfunction-associated steatotic liver disease who newly initiated GLP-1 RA or SGLT2i therapy between January 1, 2017 and March 31, 2026 were included based on prespecified eligibility criteria.
Pre-assignment details
Enrollment and Participant Flow counts reflect unique participants in the overall study population, classified into four mutually exclusive treatment-strategy cohorts according to background therapy and 90-day add-on status. Participants were counted once in the Participant Flow module. Comparator-specific propensity score-matched cohorts were defined separately for prespecified pairwise outcome analyses and are reported in the Baseline Characteristics and Outcome Measures sections.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized 18-44 years (Comparison 1) | 4460 Participants |
| Age, Customized 18-44 years (Comparison 2) | 0 Participants |
| Age, Customized 18-44 years (Comparison 3) | 0 Participants |
| Age, Customized 18-44 years (Comparison 4) | 0 Participants |
| Age, Customized 45-64 years (Comparison 1) | 8299 Participants |
| Age, Customized 45-64 years (Comparison 2) | 14592 Participants |
| Age, Customized 45-64 years (Comparison 3) | 0 Participants |
| Age, Customized 45-64 years (Comparison 4) | 12153 Participants |
| Age, Customized ≥65 years (Comparison 1) | 7958 Participants |
| Age, Customized ≥65 years (Comparison 2) | 0 Participants |
| Age, Customized ≥65 years (Comparison 3) | 0 Participants |
| Age, Customized ≥65 years (Comparison 4) | 7765 Participants |
| BMI ≥30 kg/m² BMI ≥30 kg/m² (Comparison 1) | 21755 Participants |
| BMI ≥30 kg/m² BMI ≥30 kg/m² (Comparison 2) | 0 Participants |
| BMI ≥30 kg/m² BMI ≥30 kg/m² (Comparison 3) | 19729 Participants |
| BMI ≥30 kg/m² BMI ≥30 kg/m² (Comparison 4) | 16154 Participants |
| eGFR <60 mL/min/1.73 m² eGFR <60 mL/min/1.73 m² (Comparison 1) | 0 Participants |
| eGFR <60 mL/min/1.73 m² eGFR <60 mL/min/1.73 m² (Comparison 2) | 0 Participants |
| eGFR <60 mL/min/1.73 m² eGFR <60 mL/min/1.73 m² (Comparison 3) | 0 Participants |
| eGFR <60 mL/min/1.73 m² eGFR <60 mL/min/1.73 m² (Comparison 4) | 0 Participants |
| Ethnicity (NIH/OMB) Comparison 1 Hispanic or Latino | 1513 Participants |
| Ethnicity (NIH/OMB) Comparison 1 Not Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Comparison 1 Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Comparison 2 Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Comparison 2 Not Hispanic or Latino | 18506 Participants |
| Ethnicity (NIH/OMB) Comparison 2 Unknown or Not Reported | 4714 Participants |
| Ethnicity (NIH/OMB) Comparison 3 Hispanic or Latino | 3056 Participants |
| Ethnicity (NIH/OMB) Comparison 3 Not Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Comparison 3 Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Comparison 4 Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Comparison 4 Not Hispanic or Latino | 8019 Participants |
| Ethnicity (NIH/OMB) Comparison 4 Unknown or Not Reported | 0 Participants |
| HbA1c ≥7% HbA1c ≥7% (Comparison 1) | 10739 Participants |
| HbA1c ≥7% HbA1c ≥7% (Comparison 2) | 0 Participants |
| HbA1c ≥7% HbA1c ≥7% (Comparison 3) | 19696 Participants |
| HbA1c ≥7% HbA1c ≥7% (Comparison 4) | 0 Participants |
| Sex/Gender, Customized Female (Comparison 1) | 0 Participants |
| Sex/Gender, Customized Female (Comparison 2) | 0 Participants |
| Sex/Gender, Customized Female (Comparison 3) | 0 Participants |
| Sex/Gender, Customized Female (Comparison 4) | 5441 Participants |
| Sex/Gender, Customized Male (Comparison 1) | 0 Participants |
| Sex/Gender, Customized Male (Comparison 2) | 0 Participants |
| Sex/Gender, Customized Male (Comparison 3) | 0 Participants |
| Sex/Gender, Customized Male (Comparison 4) | 0 Participants |
| Sex/Gender, Customized Unknown or Not Reported (Comparison 1) | 0 Participants |
| Sex/Gender, Customized Unknown or Not Reported (Comparison 2) | 0 Participants |
| Sex/Gender, Customized Unknown or Not Reported (Comparison 3) | 0 Participants |
| Sex/Gender, Customized Unknown or Not Reported (Comparison 4) | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 278 / 14,358 | 396 / 14,389 | 248 / 12,897 | 425 / 12,865 | 290 / 13,359 | 418 / 13,345 | 270 / 11,034 | 402 / 10,974 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 608 / 14,303 | 715 / 14,276 | 574 / 12,848 | 754 / 12,798 | 548 / 13,297 | 667 / 13,302 | 484 / 10,977 | 613 / 10,949 |
Outcome results
None listed