Comparative Effectiveness and Safety of Four Second Line Pharmacological Strategies in Type 2 Diabetes Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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Comparative Effectiveness and Safety of Four Second Line Pharmacological Strategies in Type 2 Diabetes Study

Conditions
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Cardiovascular Events, Type2 Diabetes, Renal Disease

Intervention / Treatment
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* Drug: SGLT2 inhibitor
* Drug: DPP-4 inhibitor
* Drug: GLP-1RA
* Drug: 2nd generation SU


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| SGLT-2i (Comparison 1)<br>For SGLT-2i vs. DPP4i SGLT-2i - exposure group DPP4i - referent group | Drug: SGLT2 inhibitor<br>* Any SGLT2i dispensing claim<br>* Other names: ERTUGLIFLOZIN PIDOLATE/SITAGLIPTIN PHOSPHATE;|
| DPP-4i (Comparison 1)<br>For SGLT-2i vs. DPP4i SGLT-2i - exposure group DPP-4i - referent group | Drug: DPP-4 inhibitor<br>* Any DPP-4 inhibitor claim<br>* Other names: ERTUGLIFLOZIN PIDOLATE/SITAGLIPTIN PHOSPHATE;|
| SGLT-2i (Comparison 2)<br>For SGLT-2i vs GLP-1 RA SGLT-2i - exposure group GLP-1 RA - referent group | Drug: SGLT2 inhibitor<br>* Any SGLT2i dispensing claim<br>* Other names: ERTUGLIFLOZIN PIDOLATE/SITAGLIPTIN PHOSPHATE;|
| GLP-1 RA (Comparison 2)<br>For SGLT-2i vs GLP-1 RA SGLT-2i - exposure group GLP-1 RA - referent group | Drug: GLP-1RA<br>* Any SGLT2i dispensing claim<br>* Other names: EXENATIDE;|
| GLP-1 RA (Comparison 3)<br>For GLP-1 RA vs DPP-4i GLP-1 RA - exposure group DPP-4i - referent group | Drug: GLP-1RA<br>* Any SGLT2i dispensing claim<br>* Other names: EXENATIDE;|
| DPP-4i (Comparison 3)<br>For GLP-1 RA vs DPP-4i GLP-1 RA - exposure group DPP-4i - referent group | Drug: DPP-4 inhibitor<br>* Any DPP-4 inhibitor claim<br>* Other names: ERTUGLIFLOZIN PIDOLATE/SITAGLIPTIN PHOSPHATE;|
| SGLT-2i (Comparison 4)<br>For SGLT-2i vs SU SGLT-2i - exposure group SU - referent group | Drug: SGLT2 inhibitor<br>* Any SGLT2i dispensing claim<br>* Other names: ERTUGLIFLOZIN PIDOLATE/SITAGLIPTIN PHOSPHATE;|
| SU (Comparison 4)<br>For SGLT-2i vs SU SGLT-2i - exposure group SU - referent group | Drug: 2nd generation SU<br>* Any 2nd generation SU claim<br>* Other names: GLIPIZIDE;|
| GLP-1 RA (Comparison 5)<br>For GLP-1 RA vs SU GLP-1 RA - exposure group SU - referent group | Drug: GLP-1RA<br>* Any SGLT2i dispensing claim<br>* Other names: EXENATIDE;|
| SU (Comparison 5)<br>For GLP-1 RA vs SU GLP-1 RA - exposure group SU - referent group | Drug: 2nd generation SU<br>* Any 2nd generation SU claim<br>* Other names: GLIPIZIDE;|
| DPP-4i (Comparison 6)<br>For DPP-4i vs SU DPP-4i - exposure group SU - referent group | Drug: DPP-4 inhibitor<br>* Any DPP-4 inhibitor claim<br>* Other names: ERTUGLIFLOZIN PIDOLATE/SITAGLIPTIN PHOSPHATE;|
| SU (Comparison 6)<br>For DPP-4i vs SU DPP-4i - exposure group SU - referent group | Drug: 2nd generation SU<br>* Any 2nd generation SU claim<br>* Other names: GLIPIZIDE;|
| SGLT2i (Comparison 7)<br>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<br>* Any SGLT2i dispensing claim<br>* Other names: ERTUGLIFLOZIN PIDOLATE/SITAGLIPTIN PHOSPHATE;|
| GLP-1 RA (Comparison 7)<br>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<br>* Any SGLT2i dispensing claim<br>* Other names: EXENATIDE;|
| DPP-4i (Comparison 7)<br>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<br>* Any DPP-4 inhibitor claim<br>* Other names: ERTUGLIFLOZIN PIDOLATE/SITAGLIPTIN PHOSPHATE;|
| SU (Comparison 7)<br>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<br>* Any 2nd generation SU claim<br>* Other names: GLIPIZIDE;|
| SGLT2i (Comparison 8)<br>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<br>* Any SGLT2i dispensing claim<br>* Other names: ERTUGLIFLOZIN PIDOLATE/SITAGLIPTIN PHOSPHATE;|
| GLP-1 RA (Comparison 8)<br>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<br>* Any SGLT2i dispensing claim<br>* Other names: EXENATIDE;|
| DPP-4i (Comparison 8)<br>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<br>* Any DPP-4 inhibitor claim<br>* Other names: ERTUGLIFLOZIN PIDOLATE/SITAGLIPTIN PHOSPHATE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MACE | Myocardial Infarction, Ischemic Stroke, Cardiovascular mortality | through study completion, an average of 1 year | 
| Modified MACE | Myocardial Infarction, Ischemic Stroke, All-Cause mortality | through study completion, an average of 1 year | 
| Hospitalization for Heart Failure (HHF) Hospitalization for Heart Failure (HHF) |  | through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |