Cardiovascular Events, Type2 Diabetes, Renal Disease
Conditions
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).
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.
Interventions
DRUGSGLT2 inhibitor
Any SGLT2i dispensing claim
DRUGDPP-4 inhibitor
Any DPP-4 inhibitor claim
DRUGGLP-1RA
Any SGLT2i dispensing claim
DRUG2nd generation SU
Any 2nd generation SU claim
Sponsors
Patient-Centered Outcomes Research Institute
VA Boston Healthcare System
McGill University
Brigham and Women's Hospital
Study design
Observational model
COHORT
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame |
|---|---|
| All-cause mortality | through study completion, an average of 1 year |
| Myocardial Infarction (MI) | through study completion, an average of 1 year |
| Coronary revascularization | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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. |
| Acute pancreatitis | through study completion, an average of 1 year | exposure of interest - GLP1 RA, DPP4i |
| 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 | — |
Countries
United States
Outcome results
None listed