BESTMED: Observational Evaluation of Second Line Therapy Medications in Diabetes

Study Overview
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Brief Summary
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An observational study of electronic patient data to compare diabetes medications and to determine which ones offer the best balance of risks and benefits.

Detailed Description
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Type 2 diabetes is an increasingly common disease that affects more than 10 percent of adults in the United States. Multiple medications are available to treat this condition. However, many of these medications have never been directly compared against one another, which makes it unclear which medication is the best to use. Investigators will use a large database of electronic patient data to compare diabetes medications to determine which ones offer the best balance of risks and benefits. This database will draw from several large healthcare institutions and health insurance companies that collectively pull from a patient population of over 130 million across all major regions of the United States. Investigators will study adults aged 30 or older who have type 2 diabetes and are at moderate risk of heart attacks and strokes, and who are starting a second diabetes medication (after metformin). Investigators will use clinical trial emulation, a cutting-edge statistical technique, to compare the following classes of diabetes medications: (1) DPP4 inhibitors (alogliptin, linagliptin, sitagliptin, or saxagliptin); (2) GLP1 receptor agonists (dulaglutide, exenatide, liraglutide, or semaglutide); (3) basal insulin (degludec, detemir, glargine, or NPH); (4) SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin); and (5) sulfonylureas (glimepiride, glipizide, or glyburide). To determine which diabetes medications provide the greatest benefit to patients, investigators will compare how much they reduce the risks of the following \conditions: (1) heart attack; (2) heart failure; (3) stroke; (4) kidney disease; (5) eye disease; and (6) liver disease. To allow patients with diabetes and their doctors to make fully informed decisions about which diabetes medication to take, investigators will also compare these medications' risks of the following possible side effects: (1) low blood sugar; (2) kidney infection; (3) severe skin infections in the genital area; (4) foot/leg amputations; (5) broken bones; (6) pancreatitis (i.e., severe inflammation of the pancreas); (7) pancreatic cancer; (8) thyroid cancer; and (9) death from causes other than heart attacks or strokes. In order to minimize the risk of bias and confounding, the analysis will be conducted using causal inference techniques, by emulating a randomized clinical trial (including both intention-to-treat and per-protocol analyses), while incorporating rigorous data quality checks.

Official Title
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BESTMED: Observational Evaluation of Second Line Therapy Medications in Diabetes

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: DPP4
* Drug: GLP-1 receptor agonist
* Drug: Basal Insulin
* Drug: SLGT2
* Drug: SU


Participation Criteria
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Eligibility Criteria
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Individuals meeting the following criteria between January 1, 2015 and December 31, 2021: Diabetes mellitus (DM) type II HbA1c of 7-11% within the past year Monotherapy with metformin for at least 3 months No prior non-metformin outpatient diabetes therapy Aged ≥30y At moderate risk of ASCVD Men aged ≥35y and women aged ≥45y with no history* of stroke, myocardial infarction, revascularization, or heart failure hospitalization Men aged 30-34 and women aged 30-44 with history* of hypertension, hyperlipidemia, retinopathy, kidney disease or neuropathy estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73m2 within the past 3 years Not pregnant at time 0 No history* of institutionalization with a diagnosis of dementia, metastatic cancer, end stage lung disease, end stage liver disease, pancreatitis, medullary thyroid cancer or severe UTIs Engagement with the healthcare system: enrollment for at least 12 months and attendance of at least one outpatient encounter in the prior 12 months (*) History will be derived from at least 12 months of EHR and claims prior to time zero and will use all available EHR and claims data between January 1, 2014 and time zero

Ages Eligible for Study
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Minimum Age: 30 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 |
| --- | --- |
| DPP4<br>Patients receiving second line diabetes treatment with dipeptidyl peptidase-4 inhibitors (DPP4) following metformin | Drug: DPP4<br>* Dipeptidyl peptidase-4 inhibitors (DPP4) including alogliptin, linagliptin, sitagliptin, and saxagliptin<br>|
| GLP1-RA<br>Patients receiving second line diabetes treatment with glucagon-like peptide-1 receptor agonists (GLP1-RA) following metformin | Drug: GLP-1 receptor agonist<br>* Glucagon-like peptide-1 receptor agonists (GLP1-RA) including dulaglutide, exenatide, liraglutide and semaglutide<br>|
| Basal insulin<br>Patients receiving second line diabetes treatment with basal insulin following metformin | Drug: Basal Insulin<br>* degludec, detemir, glargine and NPH<br>|
| SLGT2<br>Patients receiving second line diabetes treatment with sodium-glucose cotransporter-2 inhibitors (SLGT2) following metformin | Drug: SLGT2<br>* Sodium-glucose cotransporter-2 inhibitors (SLGT2) including canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin<br>|
| SU<br>Patients receiving second line diabetes treatment with sulfonylureas (SU) following metformin | Drug: SU<br>* Sulfonylurea (SU) including glimepiride, glipizide, and glyburide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 4-point major adverse cardiac events (MACE) | Includes: a) death from cardiovascular causes b) non-fatal myocardial infarction (MI) c) non-fatal stroke and d) hospitalization for heart failure (HF) | Follow-up begins 30 days after enrollment and ends at the earliest of a) the first study outcome; b) study end or c) loss to follow-up. Maximum duration of follow-up will be 10.5 years. | 
| 3-point major adverse cardiac events (MACE) | Includes: a) death from cardiovascular causes as reported in the National Death Index b) non-fatal MI and c) non-fatal stroke | Follow-up begins 30 days after enrollment and ends at the earliest of a) the first study outcome; b) study end or c) loss to follow-up. Maximum duration of follow-up will be 10.5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse outcomes | Includes a) severe hypoglycemia b) severe urinary tract infection (UTI) c) Fournier's gangrene d) lower extremity amputation e) bone fracture f) diabetic ketoacidosis (DKA) g) pancreatitis h) pancreatic cancer i) medullary thyroid cancer j) non-cardiovascular death | Follow-up begins 30 days after enrollment and ends at the earliest of a) the first study outcome; b) study end or c) loss to follow-up. Maximum duration of follow-up will be 10.5 years. | 
| Severe clinical outcomes | Includes: a) hospitalization for >= 30 days with any of the primary or secondary outcome endpoints as the primary or admitting diagnosis b) ICU admission with any of the primary or secondary outcome endpoints as the primary or admitting diagnosis or c) death from any cause | Follow-up begins 30 days after enrollment and ends at the earliest of a) the first study outcome; b) study end or c) loss to follow-up. Maximum duration of follow-up will be 10.5 years. | 
| Non-cardiovascular outcomes | Includes a) nephropathy b) diabetic retinopathy requiring treatment c) non-alcoholic fatty liver disease (NAFLD) with advanced fibrosis / nonalcoholic steatohepatitis (NASH) | Follow-up begins 30 days after enrollment and ends at the earliest of a) the first study outcome; b) study end or c) loss to follow-up. Maximum duration of follow-up will be 10.5 years. |