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

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    Weill Medical College of Cornell University
Updated on 26 January 2021
chronic disease
type 2 diabetes mellitus
glomerular filtration rate
hemoglobin a1c
sglt2 inhibitor
antidiabetic agents
dipeptidyl peptidase-4 inhibitor


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.


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.

Condition chronic renal insufficiency, NIDDM, Diabetes Mellitus, Type 2, Diabetes Mellitus Type 2, type 2 diabetes mellitus, type 2 diabetes, type ii diabetes, noninsulin-dependent diabetes mellitus, diabetes type 2
Treatment Metformin, SGLT2 inhibitor, Sulfonylurea, DPP-4 inhibitor, GLP1 receptor agonist
Clinical Study IdentifierNCT03921242
SponsorWeill Medical College of Cornell University
Last Modified on26 January 2021


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Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: Diabetes Mellitus, Type 2 or Diabetes Mellitus Type 2 or NIDDM or chronic renal insufficiency?
Do you have any of these conditions: type ii diabetes or noninsulin-dependent diabetes mellitus or chronic renal insufficiency or Diabetes Mellitus, Type 2 or type 2 diabetes mellitus or ...?
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) value6.5% 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
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