Cardiovascular Disease Risk Factor, Cardiovascular-kidney-metabolic Syndrome, Kidney Disease, Obesity & Overweight, Type 2 Diabetes
Conditions
Keywords
GLP-1 RA, SGLT2i, Target trial emulation, TriNetX, Cardiovascular-Kidney-Metabolic Syndrome, Obesity, T2D
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.
Interventions
DRUGGLP-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.
DRUGSGLT2 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.
Sponsors
Chung Shan Medical University
National Science and Technology Council, Taiwan
Study design
Observational model
COHORT
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
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 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality (Comparison 1) | 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) | 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) | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Adverse Cardiovascular Events (MACE) (Comparison 1) | 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. |
| Major Adverse Cardiovascular Events (MACE) (Comparison 2) | 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. |
| Major Adverse Cardiovascular Events (MACE) (Comparison 3) | 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. |
| Major Adverse Cardiovascular Events (MACE) (Comparison 4) | 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. |
| Major Adverse Kidney Events (MAKE) (Comparison 1) | 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. |
| Major Adverse Kidney Events (MAKE) (Comparison 2) | 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. |
| Major Adverse Kidney Events (MAKE) (Comparison 3) | 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. |
| Major Adverse Kidney Events (MAKE) (Comparison 4) | 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. |
Participant flow
Recruitment details
Participants were identified retrospectively from the TriNetX US Collaborative Network electronic health record database during the prespecified study period. Eligible adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiated background therapy were assessed for inclusion in the study cohort.
Pre-assignment details
Eligibility criteria were applied at cohort identification. The index date (T0) was the first qualifying base-therapy prescription (GLP-1 RA or SGLT2i) after the 6-month washout; each participant was therefore assigned to a single base-therapy arm, and participants are unique across the two arms. Treatment strategies within each arm were classified by first add-on within 90 days of T0. Total Started reflects the unique number enrolled.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized 20-44 years (Comparison 1) | 0 Participants |
| Age, Customized 20-44 years (Comparison 2) | 11393 Participants |
| Age, Customized 20-44 years (Comparison 3) | 0 Participants |
| Age, Customized 20-44 years (Comparison 4) | 4575 Participants |
| Age, Customized 45-64 years (Comparison 1) | 17839 Participants |
| Age, Customized 45-64 years (Comparison 2) | 0 Participants |
| Age, Customized 45-64 years (Comparison 3) | 0 Participants |
| Age, Customized 45-64 years (Comparison 4) | 0 Participants |
| Age, Customized 65-74 years (Comparison 1) | 4306 Participants |
| Age, Customized 65-74 years (Comparison 2) | 0 Participants |
| Age, Customized 65-74 years (Comparison 3) | 0 Participants |
| Age, Customized 65-74 years (Comparison 4) | 0 Participants |
| Age, Customized ≥75 years (Comparison 1) | 1499 Participants |
| Age, Customized ≥75 years (Comparison 2) | 5444 Participants |
| Age, Customized ≥75 years (Comparison 3) | 0 Participants |
| Age, Customized ≥75 years (Comparison 4) | 5135 Participants |
| Age, Customized Other age category (Comparison 1) | 12 Participants |
| Age, Customized Other age category (Comparison 2) | 0 Participants |
| Age, Customized Other age category (Comparison 3) | 6 Participants |
| Age, Customized Other age category (Comparison 4) | 59 Participants |
| BMI ≥30 kg/m2 BMI ≥30 kg/m2 (Comparison 1) | 0 Participants |
| BMI ≥30 kg/m2 BMI ≥30 kg/m2 (Comparison 2) | 0 Participants |
| BMI ≥30 kg/m2 BMI ≥30 kg/m2 (Comparison 3) | 0 Participants |
| BMI ≥30 kg/m2 BMI ≥30 kg/m2 (Comparison 4) | 23009 Participants |
| CKD CKD (Comparison 1) | 1519 Participants |
| CKD CKD (Comparison 2) | 8532 Participants |
| CKD CKD (Comparison 3) | 2099 Participants |
| CKD CKD (Comparison 4) | 0 Participants |
| Dyslipidemia Dyslipidemia (Comparison 1) | 0 Participants |
| Dyslipidemia Dyslipidemia (Comparison 2) | 0 Participants |
| Dyslipidemia Dyslipidemia (Comparison 3) | 11676 Participants |
| Dyslipidemia Dyslipidemia (Comparison 4) | 0 Participants |
| Ethnicity (NIH/OMB) Comparison 1 Hispanic or Latino | 0 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 | 4505 Participants |
| Ethnicity (NIH/OMB) Comparison 2 Not Hispanic or Latino | 57712 Participants |
| Ethnicity (NIH/OMB) Comparison 2 Unknown or Not Reported | 6771 Participants |
| Ethnicity (NIH/OMB) Comparison 3 Hispanic or Latino | 3742 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 | 50701 Participants |
| Ethnicity (NIH/OMB) Comparison 4 Unknown or Not Reported | 0 Participants |
| HbA1c ≥7% HbA1c ≥7% (Comparison 1) | 0 Participants |
| HbA1c ≥7% HbA1c ≥7% (Comparison 2) | 22018 Participants |
| HbA1c ≥7% HbA1c ≥7% (Comparison 3) | 10327 Participants |
| HbA1c ≥7% HbA1c ≥7% (Comparison 4) | 18758 Participants |
| Hypertension Hypertension (Comparison 1) | 11197 Participants |
| Hypertension Hypertension (Comparison 2) | 53767 Participants |
| Hypertension Hypertension (Comparison 3) | 0 Participants |
| Hypertension Hypertension (Comparison 4) | 0 Participants |
| Race/Ethnicity, Customized Asian (Comparison 1) | 448 Participants |
| Race/Ethnicity, Customized Asian (Comparison 2) | 0 Participants |
| Race/Ethnicity, Customized Asian (Comparison 3) | 0 Participants |
| Race/Ethnicity, Customized Asian (Comparison 4) | 3077 Participants |
| Race/Ethnicity, Customized Black or African American (Comparison 1) | 3218 Participants |
| Race/Ethnicity, Customized Black or African American (Comparison 2) | 0 Participants |
| Race/Ethnicity, Customized Black or African American (Comparison 3) | 0 Participants |
| Race/Ethnicity, Customized Black or African American (Comparison 4) | 0 Participants |
| Race/Ethnicity, Customized Other Races (Comparison 1) | 0 Participants |
| Race/Ethnicity, Customized Other Races (Comparison 2) | 1328 Participants |
| Race/Ethnicity, Customized Other Races (Comparison 3) | 0 Participants |
| Race/Ethnicity, Customized Other Races (Comparison 4) | 0 Participants |
| Race/Ethnicity, Customized Other, Unknown, or Not Reported (Comparison 1) | 0 Participants |
| Race/Ethnicity, Customized Other, Unknown, or Not Reported (Comparison 2) | 0 Participants |
| Race/Ethnicity, Customized Other, Unknown, or Not Reported (Comparison 3) | 1531 Participants |
| Race/Ethnicity, Customized Other, Unknown, or Not Reported (Comparison 4) | 6243 Participants |
| Race/Ethnicity, Customized White (Comparison 1) | 11684 Participants |
| Race/Ethnicity, Customized White (Comparison 2) | 53392 Participants |
| Race/Ethnicity, Customized White (Comparison 3) | 25895 Participants |
| Race/Ethnicity, Customized White (Comparison 4) | 23707 Participants |
| SBP ≥140 mmHg SBP ≥140 mmHg (Comparison 1) | 8065 Participants |
| SBP ≥140 mmHg SBP ≥140 mmHg (Comparison 2) | 35375 Participants |
| SBP ≥140 mmHg SBP ≥140 mmHg (Comparison 3) | 0 Participants |
| SBP ≥140 mmHg SBP ≥140 mmHg (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) | 19156 Participants |
| Sex/Gender, Customized Male (Comparison 1) | 0 Participants |
| Sex/Gender, Customized Male (Comparison 2) | 19898 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) | 37 Participants |
| Sex/Gender, Customized Unknown or Not Reported (Comparison 2) | 0 Participants |
| Sex/Gender, Customized Unknown or Not Reported (Comparison 3) | 60 Participants |
| Sex/Gender, Customized Unknown or Not Reported (Comparison 4) | 0 Participants |
| Tobacco Use Tobacco Use (Comparison 1) | 451 Participants |
| Tobacco Use Tobacco Use (Comparison 2) | 0 Participants |
| Tobacco Use Tobacco Use (Comparison 3) | 0 Participants |
| Tobacco Use Tobacco Use (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 | 291 / 16,864 | 444 / 16,827 | 674 / 39,552 | 877 / 39,518 | 352 / 18,850 | 562 / 18,941 | 593 / 34,963 | 770 / 34,987 |
| 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 | 754 / 16,796 | 983 / 16,734 | 1,862 / 39,392 | 2,073 / 39,243 | 854 / 18,771 | 1,223 / 18,868 | 1,495 / 34,819 | 1,727 / 34,827 |
Outcome results
None listed