Disclosures: Shin reports no relevant financial disclosures.
November 04, 2020
4 min read

Study: FDA’s metformin label change likely mitigated race, sex disparities

Disclosures: Shin reports no relevant financial disclosures.
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Data show Black adults with type 2 diabetes and moderate chronic kidney disease were significantly less likely to receive a metformin prescription compared with white counterparts under an old FDA serum creatinine-based metformin label.

This disparity was also present in analyses with sex and improved after the introduction of an FDA estimated glomerular filtration rate-based metformin label in 2016, according to Jung-Im Shin, MD, PhD, assistant professor of epidemiology at Johns Hopkins Bloomberg School of Public Health. This study suggests that drug dosing recommendations solely on the basis of serum creatinine may inadvertently cause race and sex disparities in medication use.

Shin is an assistant professor of epidemiology at Johns Hopkins Bloomberg School of Public Health.

Healio spoke with Shin about the history behind the metformin label change, data showing metformin under-prescribing among Black adults with type 2 diabetes, and how the findings fit into the current discussion on race disparities in health care. Shin and colleagues’ study was published in the Journal of the American Society of Nephrology in August.

Why did the FDA change the labeling of metformin to include the eGFR threshold?

Shin: Metformin was approved in the U.S. in 1995. From that time, metformin was contraindicated for adults with a high serum creatinine level — for men, at or above 1.5 mg/dL, and for women, at or above 1.4 mg/dL, due to concerns of lactic acidosis risk.

Since then, researchers have studied the risk for lactic acidosis associated with metformin use. The findings suggested that metformin might be safely used, except for patients with severe kidney disease.

In 2012 and 2013, there were two citizen petitions to the FDA, asking the agency to relax the renal contraindications for metformin. In response to those petitions, the FDA reviewed the observational evidence and, in April 2016, issued a communication allowing metformin use in people with mild to moderate CKD, defined as an eGFR of 30 mL/min/1.73 m² to 60 mL/min/1.73 m², but not in those with an eGFR below 30 mL/min/1.73 m².

What led you and your colleagues to conduct this new analysis of metformin prescriptions? What raised questions for you?

Shin: In current clinical practice, eGFR calculated from serum creatinine is used to assess kidney function. Because serum creatinine levels are higher among Black adults compared with white adults and higher among men compared with women, independent of kidney function, we hypothesized that the previous serum creatinine-based metformin label may have inadvertently introduced race and sex disparities in metformin prescription among patients with CKD. We also wanted to know whether these disparities were mitigated after the 2016 label change.

Can you discuss the study design? How many patients were you looking at?

Shin: We analyzed 15,946 patients with type 2 diabetes from Johns Hopkins Medicine electronic health record data. To examine the change in metformin prescription before and after the FDA label change (April 8, 2016), we created two 9-month period prevalent cohorts. The pre-label change period prevalent cohort was selected between July 15, 2015 and April 8, 2016; the post-label change period prevalent cohort was selected between April 9, 2016 and Jan. 1, 2017. Each cohort contained Black and white adults with type 2 diabetes with at least one outpatient measurement of serum creatinine during the 9-month period. The outcome was metformin prescription in a given period. We estimated the prevalence ratio for metformin prescription comparing Black patients with white patients across the eGFR category before and after the label change, with the same analysis done for sex.

To ensure our findings were robust, we conducted replication analysis using OptumLabs Data Warehouse to analyze more than 1 million patients from 36 cohorts with longer follow-up after the label change — up to 3 years.

What did the findings suggest, and were the results what you expected?

Shin: What we found was after the label change, the race disparity was attenuated for those with an eGFR between 30 mL/min/1.73 m² and 44 mL/min/1.73 m², attributed to an increase in metformin prescriptions in Black patients in the Johns Hopkins data. This was consistent in the replication analysis.

In the replication cohorts, we also saw significant attenuation in sex disparities in metformin prescription among patients with mild to moderate CKD after the label change, with men with mild CKD achieving parity in the 3 years after the change to an eGFR-based label.

A previous study using National Health and Nutrition Examination Survey data suggested a larger impact by the use of eGFR rather than serum creatinine on expanding metformin indications in Black adults compared with white adults and in men compared with women, and we confirmed it with our real-world data analysis.

Where do you think this research fits into our current discussion about race disparities in health care?

Shin: The Institute of Medicine states that reducing race disparities is one of the top strategic priorities for U.S. health care. Our study highlights the potential benefits of an eGFR-based label for optimizing metformin prescriptions compared with the previous serum creatinine-based label. There exist some concerns regarding the use of race to estimate GFR. The potential benefit of removing race in creatinine-based eGFR computation should be balanced with potential harms, such as underdosing medications or falsely labeling a patient as having CKD.

There have been major advances in diabetes management, including new classes of medications such as SGLT2 inhibitors with cardiorenal protective benefits. These new medications are more expensive, and access to these medications might be more difficult in the disadvantaged population. Although we are very excited about these new, life-saving medications, disparities in health outcomes could even become larger if these medications are not used in an equitable way.

What further research would you like to see?

Shin: We showed the FDA policy change could affect race and sex disparities in metformin prescriptions. The identification and improvement of disparities in health care is a national priority. Equity is important. Access to insurance is the single most important factor to reduce disparities in care. I hope to see more research on how to make a difference with various strategies including individual, community and policy level interventions.

For more information:

Jung-Im Shin, MD, PhD, can be reached at jshin19@jhmi.edu.