Results Summary

What was the research about?

Type 2 diabetes is a long-term health problem that causes blood sugar levels to rise. Some people with diabetes also have chronic kidney disease, or CKD. In CKD, the kidneys don’t work well to remove waste from the blood.

Metformin is a type of medicine used to treat diabetes. People once thought metformin could cause serious problems for people with CKD. But studies have shown that metformin is safe for patients with mild CKD. In this study, the research team wanted to learn if using metformin is safe and effective for patients with diabetes and moderate to severe CKD.

The research team first compared health records of patients starting metformin with patients starting four other types of diabetes medicines:

  • Sulfonylureas
  • DPP-4 inhibitors
  • GLP-1 receptor agonists
  • SGLT2 inhibitors

Because the study didn’t have enough complete data for patients with diabetes and moderate to severe CKD starting these medicines, the research team looked at health records of a larger group of patients with mild to moderate CKD currently using these medicines.

What were the results?

Because of the limited data for patients starting the medicines, the research team can’t say for sure if starting metformin was as safe as, or worked better than, the other types of medicines. Metformin appeared to be similar to sulfonylureas and better than DPP-4 inhibitors in reducing average blood sugar levels.

For the larger group of patients currently using these medicines, compared with metformin, sulfonylureas had an increased risk of severe low blood sugar levels. The other medicines didn’t have the increased risk.

While using metformin, patients didn’t have an increased risk of a hospital stay for acidosis. Acidosis is a serious problem that can happen when blood sugar is too high for too long.

What did the research team do?

The research team looked at health record and insurance claims data from 2012 to 2017 for patients with diabetes and CKD. All were ages 65 and older and had Medicare. Data were collected from New York, North Carolina, and Tennessee.

For the larger group of patients currently using the medicines, the research team compared:

  • 5,370 patients using metformin with 4,192 patients using sulfonylureas
  • 5,471 patients using metformin with 2,524 patients using DPP-4 inhibitors
  • 6,958 patients using metformin with 802 patients using GLP-1 receptor agonists
  • 6,602 patients using metformin with 255 patients using SGLT2 inhibitors

Patients with diabetes gave input on the study.

What were the limits of the study?

Fewer patients who used newer medicines such as GLP-1 receptor agonists and SGLT2 inhibitors had data available than the research team expected. As a result, the team had limited ability to compare metformin with these medicines. The team also couldn’t assign patients by chance to the medicines; factors other than the type of medicine, like patient traits such as age or health, may have affected the results.

Future research could use a study design that assigns patients by chance to the medicines.

How can people use the results?

Patients with diabetes and CKD and their doctors can use the results when considering metformin.

Final Research Report

View this project's final research report.

Peer-Review Summary

Peer review of PCORI-funded research helps make sure the report presents complete, balanced, and useful information about the research. It also assesses how the project addressed PCORI’s Methodology Standards. During peer review, experts read a draft report of the research and provide comments about the report. These experts may include a scientist focused on the research topic, a specialist in research methods, a patient or caregiver, and a healthcare professional. These reviewers cannot have conflicts of interest with the study.

The peer reviewers point out where the draft report may need revision. For example, they may suggest ways to improve descriptions of the conduct of the study or to clarify the connection between results and conclusions. Sometimes, awardees revise their draft reports twice or more to address all of the reviewers’ comments. 

Peer reviewers commented and the researchers made changes or provided responses. Those comments and responses included the following:

  • The reviewers questioned how the researchers modified the study design to improve study power, particularly regarding prevalent user design and intent-to-treat (ITT) analysis. The researchers explained that the ITT analysis was always planned for aim 1 sensitivity analysis, and that ITT was always planned as the primary analysis for aim 2. The prevalent user design as well as time-varying exposure designs were added early in the project not to improve study power but because the researchers were interested the long-term impact of hypoglycemia from sulfonylureas and in the effect of taking concomitant diabetes medication. They also articulated the specific limitations of prevalent user designs and time-varying approaches in the discussion section.
  • The reviewers suggested further that the researchers address their rationale for the study changes given the differences these changes caused for study interpretation. The researchers added a discussion about the rationale and potential for bias that changes to the study created, especially expansion of the study sample from only new users of the medication to including prevalent users. They noted that the two groups addressed very different questions.
  • The reviewers asked about the use of ‘time-varying covariates’ because it was not clear what these were or how they were analyzed. The researchers explained that this referred to exposures to antidiabetic drugs during the follow-up period so that these changes could be incorporated into the statistical model. To reduce confusion, the researchers replaced the term time-varying covariates with more descriptive language in the text.

Conflict of Interest Disclosures

Project Information

James Flory, MD, MSCE
Alvin Mushlin, MD, ScM
Joan and Sanford I. Weill Medical College of Cornell University
Comparative Effectiveness of Metformin for Type 2 Diabetes with Chronic Kidney Disease

Key Dates

August 2018
April 2023

Study Registration Information


Has Results
Health Conditions Health Conditions These are the broad terms we use to categorize our funded research studies; specific diseases or conditions are included within the appropriate larger category. Note: not all of our funded projects focus on a single disease or condition; some touch on multiple diseases or conditions, research methods, or broader health system interventions. Such projects won’t be listed by a primary disease/condition and so won’t appear if you use this filter tool to find them. View Glossary
Populations Populations PCORI is interested in research that seeks to better understand how different clinical and health system options work for different people. These populations are frequently studied in our portfolio or identified as being of interest by our stakeholders. View Glossary
Intervention Strategy Intervention Strategies PCORI funds comparative clinical effectiveness research (CER) studies that compare two or more options or approaches to health care, or that compare different ways of delivering or receiving care. View Glossary
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Last updated: March 14, 2024