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Comparative Effectiveness of Metformin for Type 2 Diabetes With Chronic Kidney Disease

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ClinicalTrials.gov Identifier: NCT03921242
Recruitment Status : Recruiting
First Posted : April 19, 2019
Last Update Posted : September 26, 2019
Sponsor:
Collaborator:
Patient-Centered Outcomes Research Institute
Information provided by (Responsible Party):
Weill Medical College of Cornell University

Brief Summary:
This is a proposal for a retrospective observational study of the safety of metformin use in patients with chronic kidney disease, compared to other commonly used diabetes drugs. It will be conducted using retrospective data from the New York City CDRN, Medicare administrate files, and New York State Medicaid administrative files, which will be linked and then deidentified prior to analysis.

Condition or disease Intervention/treatment
Diabetes Mellitus, Type 2 Renal Insufficiency, Chronic Drug: Metformin Drug: Sulfonylurea Drug: DPP-4 inhibitor Drug: SGLT2 inhibitor Drug: GLP1 receptor agonist

Detailed Description:

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.


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Study Type : Observational
Estimated Enrollment : 16000 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Comparative Effectiveness of Metformin for Type 2 Diabetes With Chronic Kidney Disease
Actual Study Start Date : August 1, 2019
Estimated Primary Completion Date : March 1, 2021
Estimated Study Completion Date : March 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases

Group/Cohort Intervention/treatment
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.
Drug: Metformin
Newly Initiated and regular metformin dosage as prescribed by each patient's medical care provider

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.
Drug: Sulfonylurea
Newly initiated and regular sulfonylurea dosage as prescribed by each patient's medical care provider

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.
Drug: DPP-4 inhibitor
Newly initiated and regular DPP-4 inhibitor dosage as prescribed by each patient's medical care provider

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.
Drug: SGLT2 inhibitor
Newly initiated and regular SGLT2 inhibitor dosage as prescribed by each patient's medical care provider

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.
Drug: GLP1 receptor agonist
Newly initiated and regular GLP1 receptor agonist dosage as prescribed by each patient's medical care provider




Primary Outcome Measures :
  1. 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

  2. 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.

  3. 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.


Secondary Outcome Measures :
  1. 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

  2. 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.

  3. 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.

  4. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
EHR data from two data sources (NYC and Mid-South CDRN's) will be linked to insurance claims data to identify adult patients (age > 18) with T2DM and CKD, who are initiating metformin or one of the comparator drugs. Also, participants will further be required to have at least one prescription for metformin, sulfonylurea, or DPP-4 inhibitor; at least 6 months preceding that prescription in which none of those drugs are used; and an eGFR within 1 month prior to the index date (the date on which the drug of interest is started) of < 60 mL/min
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03921242


Contacts
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Contact: Jeremy Orloff 646.962.9409 jeo2018@med.cornell.edu
Contact: James Flory floryj@mskcc.org

Locations
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United States, North Carolina
University of North Carolina Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Michele Jonsson-Funk    919-843-0384      
United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Rosette Chakkalakal    615-936-2187      
Sponsors and Collaborators
Weill Medical College of Cornell University
Patient-Centered Outcomes Research Institute
Investigators
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Principal Investigator: Alvin Mushlin Weill Cornell Medical College/Memorial Sloan Kettering Cancer Center

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Responsible Party: Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT03921242     History of Changes
Other Study ID Numbers: 1809019555
First Posted: April 19, 2019    Key Record Dates
Last Update Posted: September 26, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Renal Insufficiency
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Urologic Diseases
Metformin
Dipeptidyl-Peptidase IV Inhibitors
Sodium-Glucose Transporter 2 Inhibitors
Glucagon-Like Peptide 1
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action