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. 2020 Aug;31(8):1847-1858.
doi: 10.1681/ASN.2019101119. Epub 2020 Jul 13.

The FDA Metformin Label Change and Racial and Sex Disparities in Metformin Prescription among Patients with CKD

Jung-Im Shin  1 , Yingying Sang  2   3 , Alex R Chang  4 , Stephan C Dunning  5 , Josef Coresh  2   6 , Lesley A Inker  7 , Elizabeth Selvin  2   6 , Shoshana H Ballew  2 , Morgan E Grams  2   6
Affiliations

The FDA Metformin Label Change and Racial and Sex Disparities in Metformin Prescription among Patients with CKD

Jung-Im Shin et al. J Am Soc Nephrol. 2020 Aug.

Abstract

Background: In 2016, the Food and Drug Administration (FDA) changed labeling regarding metformin contraindications in patients with diabetes and CKD from using serum creatinine-based thresholds to using eGFR-based thresholds. Because race and sex affect serum creatinine levels independently of GFR, the earlier creatinine-based contraindication may have inadvertently caused racial and sex disparities in metformin prescription among patients with low eGFR.

Methods: In an analysis of 15,946 Black and White primary care patients with diabetes and eGFR≥30 ml/min per 1.73 m2 in a large health system (the primary cohort), we assessed the association of race and sex with metformin prescription across eGFR level before and after the FDA label change. For a replication cohort, we meta-analyzed data from 36 cohorts with 1,051,723 patients from OptumLabs Data Warehouse.

Results: In the primary cohort, before the label change, Black patients with eGFR of 30-44 ml/min per 1.73 m2 were prescribed metformin less often than White counterparts (adjusted prevalence ratio [aPR], 0.65; 95% confidence interval [95% CI], 0.52 to 0.82); this disparity was significantly attenuated after the label change (aPR, 0.90; 95% CI, 0.74 to 1.09; P value for interaction by period =0.04). Results were consistent in the replication cohorts. Men with eGFR of 30-44 ml/min per 1.73 m2 received metformin prescriptions less often than women counterparts before the label change; this was nonsignificantly attenuated after the label change, but we found significant attenuation in the replication cohorts (aPRpre-label change, 0.76; 95% CI, 0.73 to 0.79; aPRpost-label change, 0.85; 95% CI, 0.83 to 0.88; P value for interaction by period <0.001).

Conclusions: The metformin label change to an eGFR-based contraindication may have reduced racial and sex disparities in metformin prescription in moderate kidney dysfunction.

Keywords: FDA drug label; chronic kidney disease; clinical epidemiology; creatinine; disparities; estimated glomerular filtration rate; glomerular filtration rate; metformin.

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Figures

Figure 1.
Figure 1.
Under the FDA’s serum creatinine-based metformin label, there was a steeper reduction in metformin prescription at eGFR<60 ml/min per 1.73 m2 in Black patients than in White patients. After FDA’s revision to an eGFR-based label, there was a significant increase in metformin prescription only in Black patients with eGFR of 30-44 ml/min per 1.73 m2 (A). There was no difference in sulfonylurea prescription (the negative control outcome) by race, nor was there a change in sulfonylurea prescription after the label change in all eGFR categories (B).
Figure 2.
Figure 2.
Black patients with eGFR of 30–44 ml/min per 1.73 m2 and men in the same eGFR category were consistently underprescribed metformin compared with White and women counterparts in all five baseline comparison periods before the label change, respectively. These racial (A) and sex (C) disparities were only attenuated after the label change. On the other hand, there were consistently no racial (B) or sex (D) differences in sulfonylurea prescription (the negative control outcome) for patients with eGFR of 30–44 ml/min per 1.73 m2 either before or after the label change. Prevalence ratios (PRs) were adjusted for age, sex (for association with race), race (for association with sex), eGFR, HbA1c, BMI, history of comorbidities (i.e., hypertension, myocardial infarction, congestive heart failure, liver disease, acidosis, hypoglycemia, and AKI), insulin use, and other glucose-lowering agent use in models using multiple imputation.
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