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

• ClinicalTrials.gov Identifier: NCT03921242
• Recruitment Status: Active, not recruiting
• First Posted: April 19, 2019
• Last Update Posted: May 5, 2021
• Sponsor: Weill Medical College of Cornell University
• Collaborator: Patient-Centered Outcomes Research Institute
• Information provided by (Responsible Party): Weill Medical College of Cornell University

Study Description

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.

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.

Study Design

• 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: October 1, 2021
• Estimated Study Completion Date: October 1, 2021

Groups and Cohorts

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

Outcome Measures

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.

Eligibility Criteria

• 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

Contacts and Locations

Locations

United States, North Carolina

University of North Carolina

Chapel Hill, North Carolina, United States, 27599

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

Sponsors and Collaborators

Weill Medical College of Cornell University

Patient-Centered Outcomes Research Institute

Investigators

• Principal Investigator: Alvin Mushlin; Weill Cornell Medical College/Memorial Sloan Kettering Cancer Center

More Information

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT03921242
• Other Study ID Numbers: 1809019555
• First Posted: April 19, 2019
• Last Update Posted: May 5, 2021
• Last Verified: May 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

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; Hypoglycemic Agents; Physiological Effects of Drugs; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action