• Incidence of Severe Hypoglycemia Assessed from EMR [ Time Frame: 18 Months ]
  Comparing the time-to event outcomes between metformin and other index exposures. Severe Hypoglycemic events are defined as events resulting in emergency room, observation, or inpatient visits where hypoglycemia is the primary diagnosis
• Difference in Glycosylated Hemoglobin (HbA1c) level (mmol/mol) [ Time Frame: 24 Months ]
  Comparing the change in HbA1c in the metformin-initiator cohort to the changes reported in the sulfonylurea- and DPP4-I-initiator cohorts at 3-9 months following baseline. HbA1c will be measured in mmol/mol.
• Heterogeneity of Treatment Effect Via Pre-specified Sub-Group Analyses [ Time Frame: 25 Months ]
  Determine the extent of heterogeneity in treatment effect through the stratification of the sample population by covariate subgroups (age, sex, BMI, race; baseline history of CVD, liver disease, and heart failure; specific sulfonylurea or DPP-4 inhibitor, and levels of renal function and metformin dose as time-varying covariates) and through the use of machine learning techniques.

• Incidence of acidosis, hospitalization for hyperglycemia, acute myocardial infarction, stroke, heart failure hospitalization, and heart failure emergency room visits [ Time Frame: 18 Months ]
  Comparing the time-to event outcomes between the metformin and other index exposure cohorts in terms of occurrences of acidosis, hospitalizations for hyperglycemia, acute myocardial infarction, stroke, heart failure hospitalizations, and heart failure emergency room visits
• Difference in Glycosylated Hemoglobin (HbA1c) level (mmol/mol) [ Time Frame: 24 Months ]
  Comparing the change in HbA1c in the metformin-initiator cohort to the changes reported in the sulfonylurea- and DPP4-I-initiator cohorts at 12-24 months following baseline. HbA1c will be measured in mmol/mol.
• Difference in Body-Mass Index Assessed From EMR (BMI) (kg/m2) [ Time Frame: 24 Months ]
  Comparing the change in body-mass index (BMI) in the metformin-initiator cohort to the changes reported in the sulfonylurea- and DPP4-I-initiator cohorts. BMI will be measured in kg/m2.
• Difference in Laboratory-Measured eGFR (mL/min) [ Time Frame: 24 Months ]
  Comparing the change in eGFR in the metformin-initiator cohort to the changes reported in the sulfonylurea- and DPP4-I-initiator cohorts. eGFR will be measured in mL/min.

Specific aims are as follows:

Aim 1. For patients with Type 2 Diabetes Mellitus(T2DM) and Chronic Kidney Disease (CKD), compare metformin to alternative non-insulin diabetes drugs (sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors)) with respect to the key safety outcome of severe hypoglycemia. The primary hypothesis is that metformin will be superior to sulfonylurea in terms of severe hypoglycemia rates, and non-inferior to DPP-4 inhibitors. Secondary outcomes will include hospitalization for acidosis, hospitalization for hyperglycemia, acute myocardial infarction, stroke, heart failure hospitalization, and heart failure emergency room visit.

Aim 2. For patients with T2DM and CKD, compare metformin to alternative non-insulin diabetes drugs with respect to HbA1c reduction. The primary hypothesis is that metformin will be superior to DPP-4 inhibitors and non-inferior to sulfonylureas for HbA1c reduction (i.e., improvement in blood sugar). Secondary outcomes will include change in body-mass index (BMI) and kidney function, non-persistence to treatment, and progression to insulin use.

Aim 3. Examine the heterogeneity of treatment effects on hypoglycemia risk and HbA1c response across patient subgroups. The primary hypothesis is that metformin's advantages will be more pronounced in more severe CKD.

Aim 4 (data completeness): Using the linked Medicare-CDRN dataset, assess completeness of CDRN data for drugs and hospitalization among Medicare recipients. Specifically, we will use Medicare data from 2013-2016 as a gold standard and assess the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of INSIGHT CDRN data from those years in identifying hospitalizations and prevalent diabetes drug use among Medicare patients with T2DM (type 2 diabetes mellitus), and develop and validate an algorithm to identify patients for whom NPV and PPV for hospitalizations and all major diabetes drug classes exceed 80%. We hypothesize that such an algorithm will identify a population of a quarter of eligible Medicare patients in the CDRN who meet or exceed these standards for completeness of data.

Aim 5. Conduct a cohort study to test the hypothesis that poorly controlled baseline HbA1c is not independently associated with the primary outcome (hospitalization with COVID). Primary analysis will be restricted to Medicare patients identified by aim 1 as likely to surpass 80% NPV and PPV for the primary outcome. A finding that HbA1c is not associated with worse outcomes would support relaxing glycemic targets during the pandemic when this allows patients to avoid unnecessary risks associated with aggressive treatment, monitoring, and exposure to the health care system.

Aim 6: Conduct a comparative cohort study to test the null hypothesis that metformin, SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1 receptor agonists, and sulfonylureas do not have class-specific effects on the primary outcome. Primary analysis will be restricted to Medicare patients identified by aim 1 as likely to surpass 80% NPV and PPV both for the primary outcome and exposure to the drug of interest. Two sub-hypotheses would be of special interest: if SGLT-2 inhibitors are associated with increased risk, this would support suggestions that they be temporarily stopped in high risk patients; if DPP-4 inhibitors are associated with decreased risk, this would argue for prospective research into this class as protective agents.

• Diabetes Mellitus, Type 2
• Renal Insufficiency, Chronic

• Drug: Metformin
  Newly Initiated and regular metformin dosage as prescribed by each patient's medical care provider
• Drug: Sulfonylurea
  Newly initiated and regular sulfonylurea dosage as prescribed by each patient's medical care provider
• Drug: DPP-4 inhibitor
  Newly initiated and regular DPP-4 inhibitor dosage as prescribed by each patient's medical care provider
• Drug: SGLT2 inhibitor
  Newly initiated and regular SGLT2 inhibitor dosage as prescribed by each patient's medical care provider
• Drug: GLP1 receptor agonist
  Newly initiated and regular GLP1 receptor agonist dosage as prescribed by each patient's medical care provider

• Metformin Cohort
  Group of study participants having both Type 2 Diabetes and Chronic Kidney disease and meeting the study's inclusion criteria for whom metformin was prescribed at baseline for this first time in each patient's medical history.
  Intervention: Drug: Metformin
• Sulfonylurea Cohort
  Group of study participants having both Type 2 Diabetes and Chronic Kidney disease and meeting the study's inclusion criteria for whom sulfonylurea was prescribed at baseline for this first time in each patient's medical history.
  Intervention: Drug: Sulfonylurea
• DPP4 Inhibitor Cohort
  Group of study participants having both Type 2 Diabetes and Chronic Kidney disease and meeting the study's inclusion criteria for whom a DPP4 Inhibitor was prescribed at baseline for this first time in each patient's medical history.
  Intervention: Drug: DPP-4 inhibitor
• SGLT2 Inhibitor Cohort
  Group of study participants having both Type 2 Diabetes and Chronic Kidney disease and meeting the study's inclusion criteria for whom an SGLT2 Inhibitor was prescribed at baseline for this first time in each patient's medical history.
  Intervention: Drug: SGLT2 inhibitor
• GLP1 Receptor Agonist Cohort
  Group of study participants having both Type 2 Diabetes and Chronic Kidney disease and meeting the study's inclusion criteria for whom a GLP1 receptor agonist was prescribed at baseline for this first time in each patient's medical history.
  Intervention: Drug: GLP1 receptor agonist

Inclusion Criteria:

• A coded inpatient or outpatient T2DM diagnosis (ICD9/ICD10) and an antidiabetic medication prescription within the 90 days following the diagnosis date (CP1); a coded T2DM diagnosis and an outpatient glycolated hemoglobin (HbA1C) value≥6.5% within 90 days before or after the diagnosis date (CP2); or any antidiabetic medication prescription within 90 days before or after an outpatient HbA1C value ≥6.5% (CP3).
• New use of a medication of interest (metformin, sulfonylurea, DPP4 inhibitor, SGLT2 inhibitor, or GLP1 receptor agonist
• Estimated glomerular filtration rate (eGFR) of less than 60 ml/min within the month prior to the new medication

Exclusion Criteria:

• Coded diagnoses of gestational diabetes
• Coded diagnoses of prediabetes
• Coded diagnoses of type 1 diabetes
• Evidence of a positive beta human chorionic gonadotropin test as a marker for pregnancy during the 90 days before or after the index date