BESTMED: Observational Evaluation of Second Line Therapy Medications in Diabetes (BESTMED)

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

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: DPP4; Drug: GLP-1 receptor agonist; Drug: Basal Insulin; Drug: SLGT2; Drug: SU

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 550000

Contacts and Locations

• Study Contact: Name: Emma Hegermiller, MS; Phone Number: 617-732-5661; Email: emma@bestmed.org
• Study Contact Backup: Name: Alexander Turchin, MD, MS; Phone Number: 617-732-5661; Email: aturchin@bwh.harvard.edu

Study Locations

• United States
  • Delaware
    • Wilmington, Delaware, United States, 19801
      • Recruiting
      • HealthCore, Inc.
      • Contact: Vincent Willey, PharmD
  • Kentucky
    • Lexington, Kentucky, United States, 40512-4611
      • Recruiting
      • Humana
      • Contact: Vinit Nair, MS, RPh
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Alexander Turchin, MD, MS
  • Ohio
    • Beachwood, Ohio, United States, 44122
      • Recruiting
      • Greater Plains Collaborative
      • Contact: Ryan Carnahan, PhD
  • Texas
    • Dallas, Texas, United States, 75246
      • Recruiting
      • Baylor Scott & White
      • Contact: Heather Kitzman Carmichael, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population is adults aged 30 or older who have type 2 diabetes and are at moderate risk of Atherosclerotic Cardiovascular Disease (ASCVD), and who are starting a second diabetes medication (after metformin). Patients from collaborating institutions will be included in the analysis based on study population inclusion and exclusion criteria.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
DPP4; Patients receiving second line diabetes treatment with dipeptidyl peptidase-4 inhibitors (DPP4) following metformin	Drug: DPP4; Dipeptidyl peptidase-4 inhibitors (DPP4) including alogliptin, linagliptin, sitagliptin, and saxagliptin
GLP1-RA; Patients receiving second line diabetes treatment with glucagon-like peptide-1 receptor agonists (GLP1-RA) following metformin	Drug: GLP-1 receptor agonist; Glucagon-like peptide-1 receptor agonists (GLP1-RA) including dulaglutide, exenatide, liraglutide and semaglutide
Basal insulin; Patients receiving second line diabetes treatment with basal insulin following metformin	Drug: Basal Insulin; degludec, detemir, glargine and NPH
SLGT2; Patients receiving second line diabetes treatment with sodium-glucose cotransporter-2 inhibitors (SLGT2) following metformin	Drug: SLGT2; Sodium-glucose cotransporter-2 inhibitors (SLGT2) including canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin
SU; Patients receiving second line diabetes treatment with sulfonylureas (SU) following metformin	Drug: SU; Sulfonylurea (SU) including glimepiride, glipizide, and glyburide

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Patient-Centered Outcomes Research Institute; Massachusetts General Hospital; University of Missouri-Columbia; Baylor College of Medicine; University of Iowa; The Cleveland Clinic; Medical College of Wisconsin; University of Utah; Intermountain Health Care, Inc.; HealthCore, Inc.; Humana Inc.; Allina Health; Marshfield Clinic; Baylor Scott and White Research Institute; Medical Outcomes Management
• Investigators: Principal Investigator: Alexander Turchin, MD, MS, Brigham and Women's Hospital

Publications and helpful links

General Publications

• Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998 May 12;97(18):1837-47. doi: 10.1161/01.cir.97.18.1837.
• D'Agostino RB, Wolf PA, Belanger AJ, Kannel WB. Stroke risk profile: adjustment for antihypertensive medication. The Framingham Study. Stroke. 1994 Jan;25(1):40-3. doi: 10.1161/01.str.25.1.40.
• Kannel WB, D'Agostino RB, Silbershatz H, Belanger AJ, Wilson PW, Levy D. Profile for estimating risk of heart failure. Arch Intern Med. 1999 Jun 14;159(11):1197-204. doi: 10.1001/archinte.159.11.1197.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2021
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: November 23, 2021
• First Submitted That Met QC Criteria: December 3, 2021
• First Posted (Actual): December 17, 2021

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 16, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin
• Other Study ID Numbers: 2021P001171

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No