CER-4-T2D: Comparative Effectiveness and Safety of Four Second Line Pharmacological Strategies in Type 2 Diabetes Study
Study Details
Study Description
Brief Summary
To perform an observational analysis to emulate a target trial (i.e., a hypothetical pragmatic trial that would have answered the causal question of interest) comparing the effectiveness and safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP-4i), and sulfonylureas (SU), at the class and individual agent level, in head-to-head comparisons in patients with type 2 diabetes (T2D).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Detailed Description
Aim 1: (1a.) To evaluate the effectiveness of sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP-4i), and sulfonylureas (SU), at the class and individual agent level, in head-to-head comparisons with respect to cardiovascular (CV) events, mortality, renal events, and other patient-centered outcomes (e.g., time spent at home), in patients with T2D and moderate baseline CV risk (event rate ≤3%/year). (1b.) To examine heterogeneity in treatment effects by age, race/ethnicity, gender, levels of CV risk, including high (≥4%/year) and low risk (<2%/year), chronic kidney disease (CKD), frailty, and multimorbidity.
Aim 2: (2a.) To monitor and quantify the association of the initiation of SGLT2i, GLP-1RA, DPP-4i, or SU, at the class and individual agent level, with previously reported drug-related harms (e.g., diabetic ketoacidosis (DKA), fractures, amputations, pancreatitis, severe hypoglycemia). (2b.) To scan study data sources for signals of potential serious unanticipated drug-related adverse events, using a data-mining approach (tree-based scan statistics). (2c.) By using data generated in Aims 2a and 2b, to build treatment-specific outcome prediction models to identify individual patients' likelihood of drug-related harms, based on specific combinations of patient features.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| SGLT-2i (Comparison 1) For SGLT-2i vs. DPP4i SGLT-2i - exposure group DPP4i - referent group |
Drug: SGLT2 inhibitor
Any SGLT2i dispensing claim
Other Names:
|
| DPP-4i (Comparison 1) For SGLT-2i vs. DPP4i SGLT-2i - exposure group DPP-4i - referent group |
Drug: DPP-4 inhibitor
Any DPP-4 inhibitor claim
Other Names:
|
| SGLT-2i (Comparison 2) For SGLT-2i vs GLP-1 RA SGLT-2i - exposure group GLP-1 RA - referent group |
Drug: SGLT2 inhibitor
Any SGLT2i dispensing claim
Other Names:
|
| GLP-1 RA (Comparison 2) For SGLT-2i vs GLP-1 RA SGLT-2i - exposure group GLP-1 RA - referent group |
Drug: GLP-1RA
Any SGLT2i dispensing claim
Other Names:
|
| GLP-1 RA (Comparison 3) For GLP-1 RA vs DPP-4i GLP-1 RA - exposure group DPP-4i - referent group |
Drug: GLP-1RA
Any SGLT2i dispensing claim
Other Names:
|
| DPP-4i (Comparison 3) For GLP-1 RA vs DPP-4i GLP-1 RA - exposure group DPP-4i - referent group |
Drug: DPP-4 inhibitor
Any DPP-4 inhibitor claim
Other Names:
|
| SGLT-2i (Comparison 4) For SGLT-2i vs SU SGLT-2i - exposure group SU - referent group |
Drug: SGLT2 inhibitor
Any SGLT2i dispensing claim
Other Names:
|
| SU (Comparison 4) For SGLT-2i vs SU SGLT-2i - exposure group SU - referent group |
Drug: 2nd generation SU
Any 2nd generation SU claim
Other Names:
|
| GLP-1 RA (Comparison 5) For GLP-1 RA vs SU GLP-1 RA - exposure group SU - referent group |
Drug: GLP-1RA
Any SGLT2i dispensing claim
Other Names:
|
| SU (Comparison 5) For GLP-1 RA vs SU GLP-1 RA - exposure group SU - referent group |
Drug: 2nd generation SU
Any 2nd generation SU claim
Other Names:
|
| DPP-4i (Comparison 6) For DPP-4i vs SU DPP-4i - exposure group SU - referent group |
Drug: DPP-4 inhibitor
Any DPP-4 inhibitor claim
Other Names:
|
| SU (Comparison 6) For DPP-4i vs SU DPP-4i - exposure group SU - referent group |
Drug: 2nd generation SU
Any 2nd generation SU claim
Other Names:
|
| SGLT2i (Comparison 7) For SGLT2i vs. GLP-1RA vs. DPP-4i vs. SU (4-way comparison) SGLT2i, GLP-1 RA, and SU - exposure groups DPP-4i - referent group |
Drug: SGLT2 inhibitor
Any SGLT2i dispensing claim
Other Names:
|
| GLP-1 RA (Comparison 7) For SGLT2i vs. GLP-1RA vs. DPP-4i vs. SU (4-way comparison) SGLT2i, GLP-1 RA, and SU - exposure groups DPP-4i - referent group |
Drug: GLP-1RA
Any SGLT2i dispensing claim
Other Names:
|
| DPP-4i (Comparison 7) For SGLT2i vs. GLP-1RA vs. DPP-4i vs. SU (4-way comparison) SGLT2i, GLP-1 RA, and SU - exposure groups DPP-4i - referent group |
Drug: DPP-4 inhibitor
Any DPP-4 inhibitor claim
Other Names:
|
| SU (Comparison 7) For SGLT2i vs. GLP-1RA vs. DPP-4i vs. SU (4-way comparison) SGLT2i, GLP-1 RA, and SU - exposure groups DPP-4i - referent group |
Drug: 2nd generation SU
Any 2nd generation SU claim
Other Names:
|
| SGLT2i (Comparison 8) For SGLT2i vs. GLP-1RA vs. DPP-4i (3-way comparison) SGLT2i and GLP-1 RA - exposure groups DPP-4i - referent group |
Drug: SGLT2 inhibitor
Any SGLT2i dispensing claim
Other Names:
|
| GLP-1 RA (Comparison 8) For SGLT2i vs. GLP-1RA vs. DPP-4i (3-way comparison) SGLT2i and GLP-1 RA - exposure groups DPP-4i - referent group |
Drug: GLP-1RA
Any SGLT2i dispensing claim
Other Names:
|
| DPP-4i (Comparison 8) For SGLT2i vs. GLP-1RA vs. DPP-4i (3-way comparison) SGLT2i and GLP-1 RA - exposure groups DPP-4i - referent group |
Drug: DPP-4 inhibitor
Any DPP-4 inhibitor claim
Other Names:
|
Outcome Measures
Primary Outcome Measures
- MACE [through study completion, an average of 1 year]
Myocardial Infarction, Ischemic Stroke, Cardiovascular mortality
- Modified MACE [through study completion, an average of 1 year]
Myocardial Infarction, Ischemic Stroke, All-Cause mortality
- Hospitalization for Heart Failure (HHF) Hospitalization for Heart Failure (HHF) [through study completion, an average of 1 year]
Secondary Outcome Measures
- Myocardial Infarction (MI) [through study completion, an average of 1 year]
- Stroke [through study completion, an average of 1 year]
- Cardiovascular Mortality [through study completion, an average of 1 year]
- All-cause mortality [through study completion, an average of 1 year]
- Coronary revascularization [through study completion, an average of 1 year]
Other Outcome Measures
- CKD progression [through study completion, an average of 1 year]
Sustained decrease in eGFR, KRT (maintenance dialysis and kidney transplantation), kidney death * exploratory outcome, since no validated claim-based outcome definition is currently available
- Sustained decrease in eGFR [through study completion, an average of 1 year]
* exploratory outcome, since no validated claim-based outcome definition is currently available
- Kidney replacement therapy (KRT) [through study completion, an average of 1 year]
* exploratory outcome, since no validated claim-based outcome definition is currently available
- Kidney death [through study completion, an average of 1 year]
* exploratory outcome, since no validated claim-based outcome definition is currently available
- Kidney failure [through study completion, an average of 1 year]
(sustained eGFR <15 ml/min/1.73m2, maintenance dialysis and kidney transplant) * exploratory outcome, since no validated claim-based outcome definition is currently available
- Early kidney disease [through study completion, an average of 1 year]
Defined by change in eGFR in patients with baseline eGFR > 60 * exploratory outcome, since no validated claim-based outcome definition is currently available
- Glycemic control [through study completion, an average of 1 year]
Defined by HbA1c change in patients with available baseline HbA1c
- Insulin initiation [through study completion, an average of 1 year]
- Weight loss or gain [through study completion, an average of 1 year]
Defined by weight change in patients with available baseline weight * exploratory outcome, since no validated claim-based outcome definition is currently available
- Diabetic ketoacidosis [through study completion, an average of 1 year]
exposure of interest - SGLT-2i
- Bone fractures [through study completion, an average of 1 year]
exposure of interest - SGLT-2i
- Lower-limb amputations [through study completion, an average of 1 year]
exposure of interest - SGLT-2i
- Acute kidney injury [through study completion, an average of 1 year]
exposure of interest - all drug classes
- Urinary infections [through study completion, an average of 1 year]
exposure of interest - SGLT-2i
- Genital infections [through study completion, an average of 1 year]
exposure of interest - SGLT-2i
- Acute pancreatitis [through study completion, an average of 1 year]
exposure of interest - GLP1 RA, DPP4i
- Biliary events [through study completion, an average of 1 year]
exposure of interest - GLP1 RA, DPP4i
- Severe hypoglycemia [through study completion, an average of 1 year]
exposure of interest - SU
- Short-term retinopathy progression [through study completion, an average of 1 year]
exposure of interest - GLP1 RA * exploratory outcomes, since no validated outcome definition is currently available
- Home time [through study completion, an average of 1 year]
Time spent out of hospital and skilled nursing facility, Time to Nursing Home Placement
- Medication persistence [through study completion, an average of 1 year]
Time to discontinuation
- Switching patterns [through study completion, an average of 1 year]
Treatment trajectories: patterns of use following initiation of treatment under study. To be illustrated using concentric circle diagrams or Sankey diagrams as appropriate.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Age ≥ 18 years for Optum Cliniformatics, IBM Marketscan, CPRD, and VHA, and ≥ 65 years for Medicare FFS at cohort entry
-
At least 12 months of continuous health plan enrollment (only claims) or registration with a general practitioner (CPRD) before and including cohort entry
-
Diagnosis of T2D within 12 months before (or ever before in CPRD) and including cohort entry
-
Low or moderate cardiovascular (CV) risk (≤3% risk of CV events/year) at cohort entry
- Metformin maintenance therapy, defined as 2 fills (or prescriptions in CPRD) of metformin monotherapy recorded within 6 months before and including cohort entry
Exclusion Criteria:
-
Missing age or gender information
-
Nursing care admission within 12 months before and including cohort entry (criteria ignored in CPRD)
-
Diagnosis of type 1 diabetes within 12 months before and including cohort entry
-
Diagnosis of secondary or gestational diabetes within 12 months before and including cohort entry
-
Any insulin fill or prescription within 12 months before and including cohort entry
-
Diagnosis of end stage renal disease (stage ≥ 5) within 12 months before and including cohort entry
-
Diagnosis of acute or chronic pancreatitis within 12 months before and including cohort entry
-
Diagnosis of cirrhosis or acute hepatitis within 12 months before and including cohort entry
-
Diagnosis of MEN-2 within 12 months before and including cohort entry
-
Recorded solid organ transplant code within 12 months before and including cohort entry
-
Patients with recorded initiation of more than one agent within a comparator class at cohort entry
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Brigham and Women's Hospital | Boston | Massachusetts | United States | 02120 |
Sponsors and Collaborators
- Brigham and Women's Hospital
- Patient-Centered Outcomes Research Institute
- VA Boston Healthcare System
- McGill University
Investigators
- Principal Investigator: Elisabetta Patorno, MD, DrPH, Brigham and Women's Hospital
Study Documents (Full-Text)
More Information
Publications
None provided.- 2021P001784