Comparative Effectiveness and Safety of Four Second Line Pharmacological Strategies in Type 2 Diabetes Study (CER-4-T2D)
May 14, 2026 updated by: Elisabetta Patorno, Brigham and Women's Hospital
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).
Study Overview
Status
Active, not recruiting
Conditions
Intervention / Treatment
Detailed Description
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.
Study Type
Observational
Enrollment (Estimated)
781430
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
Massachusetts
-
Boston, Massachusetts, United States, 02120
- Brigham and Women's Hospital
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Sampling Method
Non-Probability Sample
Study Population
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.
Description
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
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Observational Models: Cohort
- Time Perspectives: Retrospective
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
|---|---|
|
SGLT-2i (Comparison 1)
For SGLT-2i vs. DPP4i SGLT-2i - exposure group DPP4i - referent group
|
Any SGLT2i dispensing claim
Other Names:
|
|
DPP-4i (Comparison 1)
For SGLT-2i vs. DPP4i SGLT-2i - exposure group DPP-4i - referent group
|
Any DPP-4 inhibitor claim
Other Names:
|
|
SGLT-2i (Comparison 2)
For SGLT-2i vs GLP-1 RA SGLT-2i - exposure group GLP-1 RA - referent group
|
Any SGLT2i dispensing claim
Other Names:
|
|
GLP-1 RA (Comparison 2)
For SGLT-2i vs GLP-1 RA SGLT-2i - exposure group GLP-1 RA - referent group
|
Any SGLT2i dispensing claim
Other Names:
|
|
GLP-1 RA (Comparison 3)
For GLP-1 RA vs DPP-4i GLP-1 RA - exposure group DPP-4i - referent group
|
Any SGLT2i dispensing claim
Other Names:
|
|
DPP-4i (Comparison 3)
For GLP-1 RA vs DPP-4i GLP-1 RA - exposure group DPP-4i - referent group
|
Any DPP-4 inhibitor claim
Other Names:
|
|
SGLT-2i (Comparison 4)
For SGLT-2i vs SU SGLT-2i - exposure group SU - referent group
|
Any SGLT2i dispensing claim
Other Names:
|
|
SU (Comparison 4)
For SGLT-2i vs SU SGLT-2i - exposure group SU - referent group
|
Any 2nd generation SU claim
Other Names:
|
|
GLP-1 RA (Comparison 5)
For GLP-1 RA vs SU GLP-1 RA - exposure group SU - referent group
|
Any SGLT2i dispensing claim
Other Names:
|
|
SU (Comparison 5)
For GLP-1 RA vs SU GLP-1 RA - exposure group SU - referent group
|
Any 2nd generation SU claim
Other Names:
|
|
DPP-4i (Comparison 6)
For DPP-4i vs SU DPP-4i - exposure group SU - referent group
|
Any DPP-4 inhibitor claim
Other Names:
|
|
SU (Comparison 6)
For DPP-4i vs SU DPP-4i - exposure group SU - referent group
|
Any 2nd generation SU claim
Other Names:
|
|
SGLT2i (Comparison 7)
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
|
Any SGLT2i dispensing claim
Other Names:
|
|
GLP-1 RA (Comparison 7)
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
|
Any SGLT2i dispensing claim
Other Names:
|
|
DPP-4i (Comparison 7)
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
|
Any DPP-4 inhibitor claim
Other Names:
|
|
SU (Comparison 7)
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
|
Any 2nd generation SU claim
Other Names:
|
|
SGLT2i (Comparison 8)
For SGLT2i vs. GLP-1RA vs. DPP-4i (3-way comparison) SGLT2i and GLP-1 RA - exposure groups DPP-4i - referent group
|
Any SGLT2i dispensing claim
Other Names:
|
|
GLP-1 RA (Comparison 8)
For SGLT2i vs. GLP-1RA vs. DPP-4i (3-way comparison) SGLT2i and GLP-1 RA - exposure groups DPP-4i - referent group
|
Any SGLT2i dispensing claim
Other Names:
|
|
DPP-4i (Comparison 8)
For SGLT2i vs. GLP-1RA vs. DPP-4i (3-way comparison) SGLT2i and GLP-1 RA - exposure groups DPP-4i - referent group
|
Any DPP-4 inhibitor claim
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
MACE
Time Frame: through study completion, an average of 1 year
|
Myocardial Infarction, Ischemic Stroke, Cardiovascular mortality
|
through study completion, an average of 1 year
|
|
Modified MACE
Time Frame: through study completion, an average of 1 year
|
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)
Time Frame: through study completion, an average of 1 year
|
through study completion, an average of 1 year
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
|---|---|
|
Myocardial Infarction (MI)
Time Frame: through study completion, an average of 1 year
|
through study completion, an average of 1 year
|
|
Stroke
Time Frame: through study completion, an average of 1 year
|
through study completion, an average of 1 year
|
|
Cardiovascular Mortality
Time Frame: through study completion, an average of 1 year
|
through study completion, an average of 1 year
|
|
All-cause mortality
Time Frame: through study completion, an average of 1 year
|
through study completion, an average of 1 year
|
|
Coronary revascularization
Time Frame: through study completion, an average of 1 year
|
through study completion, an average of 1 year
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
CKD progression
Time Frame: through study completion, an average of 1 year
|
Sustained decrease in eGFR, KRT (maintenance dialysis and kidney transplantation), kidney death * exploratory outcome, since no validated claim-based outcome definition is currently available |
through study completion, an average of 1 year
|
|
Sustained decrease in eGFR
Time Frame: through study completion, an average of 1 year
|
* exploratory outcome, since no validated claim-based outcome definition is currently available
|
through study completion, an average of 1 year
|
|
Kidney replacement therapy (KRT)
Time Frame: through study completion, an average of 1 year
|
* exploratory outcome, since no validated claim-based outcome definition is currently available
|
through study completion, an average of 1 year
|
|
Kidney death
Time Frame: through study completion, an average of 1 year
|
* exploratory outcome, since no validated claim-based outcome definition is currently available
|
through study completion, an average of 1 year
|
|
Kidney failure
Time Frame: through study completion, an average of 1 year
|
(sustained eGFR <15 ml/min/1.73m2, maintenance dialysis and kidney transplant) * exploratory outcome, since no validated claim-based outcome definition is currently available |
through study completion, an average of 1 year
|
|
Early kidney disease
Time Frame: through study completion, an average of 1 year
|
Defined by change in eGFR in patients with baseline eGFR > 60 * exploratory outcome, since no validated claim-based outcome definition is currently available |
through study completion, an average of 1 year
|
|
Glycemic control
Time Frame: through study completion, an average of 1 year
|
Defined by HbA1c change in patients with available baseline HbA1c
|
through study completion, an average of 1 year
|
|
Insulin initiation
Time Frame: through study completion, an average of 1 year
|
through study completion, an average of 1 year
|
|
|
Weight loss or gain
Time Frame: through study completion, an average of 1 year
|
Defined by weight change in patients with available baseline weight * exploratory outcome, since no validated claim-based outcome definition is currently available |
through study completion, an average of 1 year
|
|
Diabetic ketoacidosis
Time Frame: through study completion, an average of 1 year
|
exposure of interest - SGLT-2i
|
through study completion, an average of 1 year
|
|
Bone fractures
Time Frame: through study completion, an average of 1 year
|
exposure of interest - SGLT-2i
|
through study completion, an average of 1 year
|
|
Lower-limb amputations
Time Frame: through study completion, an average of 1 year
|
exposure of interest - SGLT-2i
|
through study completion, an average of 1 year
|
|
Acute kidney injury
Time Frame: through study completion, an average of 1 year
|
exposure of interest - all drug classes
|
through study completion, an average of 1 year
|
|
Urinary infections
Time Frame: through study completion, an average of 1 year
|
exposure of interest - SGLT-2i
|
through study completion, an average of 1 year
|
|
Genital infections
Time Frame: through study completion, an average of 1 year
|
exposure of interest - SGLT-2i
|
through study completion, an average of 1 year
|
|
Acute pancreatitis
Time Frame: through study completion, an average of 1 year
|
exposure of interest - GLP1 RA, DPP4i
|
through study completion, an average of 1 year
|
|
Biliary events
Time Frame: through study completion, an average of 1 year
|
exposure of interest - GLP1 RA, DPP4i
|
through study completion, an average of 1 year
|
|
Severe hypoglycemia
Time Frame: through study completion, an average of 1 year
|
exposure of interest - SU
|
through study completion, an average of 1 year
|
|
Short-term retinopathy progression
Time Frame: through study completion, an average of 1 year
|
exposure of interest - GLP1 RA * exploratory outcomes, since no validated outcome definition is currently available |
through study completion, an average of 1 year
|
|
Home time
Time Frame: through study completion, an average of 1 year
|
Time spent out of hospital and skilled nursing facility, Time to Nursing Home Placement
|
through study completion, an average of 1 year
|
|
Medication persistence
Time Frame: through study completion, an average of 1 year
|
Time to discontinuation
|
through study completion, an average of 1 year
|
|
Switching patterns
Time Frame: through study completion, an average of 1 year
|
Treatment trajectories: patterns of use following initiation of treatment under study.
To be illustrated using concentric circle diagrams or Sankey diagrams as appropriate.
|
through study completion, an average of 1 year
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Principal Investigator: Elisabetta Patorno, MD, DrPH, Brigham and Women's Hospital
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
August 1, 2021
Primary Completion (Estimated)
May 31, 2026
Study Completion (Estimated)
September 30, 2027
Study Registration Dates
First Submitted
December 22, 2021
First Submitted That Met QC Criteria
January 21, 2022
First Posted (Actual)
February 2, 2022
Study Record Updates
Last Update Posted (Actual)
May 15, 2026
Last Update Submitted That Met QC Criteria
May 14, 2026
Last Verified
May 1, 2026
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Urogenital Diseases
- Male Urogenital Diseases
- Urologic Diseases
- Female Urogenital Diseases
- Female Urogenital Diseases and Pregnancy Complications
- Kidney Diseases
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Hypoglycemic Agents
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Protease Inhibitors
- Enzyme Inhibitors
- Peptide Hormones
- Peptides
- Amino Acids, Peptides, and Proteins
- Sulfur Compounds
- Organic Chemicals
- Heterocyclic Compounds, 1-Ring
- Heterocyclic Compounds
- Heterocyclic Compounds, 2-Ring
- Heterocyclic Compounds, Fused-Ring
- Thiazoles
- Azoles
- Pharmacologic Actions
- Chemical Actions and Uses
- Hydrocarbons
- Hydrocarbons, Cyclic
- Biological Factors
- Carbohydrates
- Naphthalenes
- Polycyclic Aromatic Hydrocarbons
- Hydrocarbons, Aromatic
- Polycyclic Compounds
- Glucosides
- Glycosides
- Amides
- Purines
- Complex Mixtures
- Pyrazines
- Biguanides
- Guanidines
- Amidines
- Sulfones
- Insulin, Long-Acting
- Insulins
- Pancreatic Hormones
- Thiophenes
- Quinazolines
- Toxins, Biological
- Triazoles
- Thiazolidinediones
- Urea
- Gastrointestinal Hormones
- Sulfonylurea Compounds
- Glucagon-Like Peptides
- Proglucagon
- Glucagon-Like Peptide 1
- Lovastatin
- Venoms
- Liraglutide
- Insulin Glargine
- Pioglitazone
- Rosiglitazone
- Linagliptin
- Sitagliptin Phosphate
- Exenatide
- Sodium-Glucose Transporter 2 Inhibitors
- Canagliflozin
- Metformin
- Glipizide
- Simvastatin
- Dipeptidyl-Peptidase IV Inhibitors
- Glyburide
- semaglutide
- empagliflozin
- dulaglutide
- dapagliflozin
- lixisenatide
- glimepiride
- IDegLira
- rGLP-1 protein
Other Study ID Numbers
- 2021P001784
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
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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