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).

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.

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

Optum and MarketScan databases are U.S. research claims databases that include adults with employer-based health plans, with nationwide coverage for over 60 million Americans, and meaningful numbers of patients ≥65 years from Medicare Advantage plans, employer-sponsored plans covering seniors, and Medicare supplemental insurance plans. Medicare FFS is a U.S. federal health insurance program providing coverage to individuals ≥65 years and to younger individuals with disabilities. The Partners RPDR captures longitudinal EHR data for all patients that receive care at 2 large health care provider networks in the Boston metro area. The VHA is the largest integrated national health system, serving over 12 million U.S. Veterans. The VHA database includes demographic, diagnostic and procedure information from inpatient/outpatient encounters. The CPRD is comprised of two large, computerized databases of longitudinal primary care records, GOLD and Aurum, for >50 million UK patients.