Metformin is Associated with Reduced COVID-19 Severity in Patients with Prediabetes

Abstract

Background: With the continuing COVID-19 pandemic, identifying medications that improve COVID-19 outcomes is crucial. Studies suggest that use of metformin, an oral antihyperglycemic, is associated with reduced COVID-19 severity in individuals with diabetes compared to other antihyperglycemic medications. Some patients without diabetes, including those with polycystic ovary syndrome (PCOS) and prediabetes, are prescribed metformin for off-label use, which provides an opportunity to further investigate the effect of metformin on COVID-19.

Participants: In this observational, retrospective analysis, we leveraged the harmonized electronic health record data from 53 hospitals to construct cohorts of COVID-19 positive, metformin users without diabetes and propensity-weighted control users of levothyroxine (a medication for hypothyroidism that is not known to affect COVID-19 outcome) who had either PCOS (n = 282) or prediabetes (n = 3136). The primary outcome of interest was COVID-19 severity, which was classified as: mild, mild ED (emergency department), moderate, severe, or mortality/hospice.

Results: In the prediabetes cohort, metformin use was associated with a lower rate of COVID-19 with severity of mild ED or worse (OR: 0.630, 95% CI 0.450 - 0.882, p < 0.05) and a lower rate of COVID-19 with severity of moderate or worse (OR: 0.490, 95% CI 0.336 - 0.715, p < 0.001). In patients with PCOS, we found no significant association between metformin use and COVID-19 severity, although the number of patients was relatively small.

Conclusions: Metformin was associated with less severe COVID-19 in patients with prediabetes, as seen in previous studies of patients with diabetes. This is an important finding, since prediabetes affects between 19 and 38% of the US population, and COVID-19 is an ongoing public health emergency. Further observational and prospective studies will clarify the relationship between metformin and COVID-19 severity in patients with prediabetes, and whether metformin usage may reduce COVID-19 severity.

Figure 1.

Definition of prediabetes and PCOS cohorts. COVID-19 positive patients were filtered to remove any individuals with diabetes and then separated into PCOS (1A) and prediabetes (1B) cohorts. For both cohorts, we selected patients that had a recorded usage of either metformin or levothyroxine.

Figure 2.. Inverse probability weighting in PCOS and prediabetes cohorts.

Both PCOS (A) and prediabetes (B) cohorts were balanced using an inverse probability weighting approach. The standardized mean difference (x axis) is shown for each of 19 covariates (y axis) and the overall propensity score. Red triangles indicate the original covariate balance and blue circles indicate the covariate balance after weighting.

Figure 3.

Association between metformin usage and COVID-19 severity in PCOS and prediabetes cohorts. ✝For the PCOS cohort, insufficient patients with severe or worse disease and mortality/hospice were available for a logistic regression to be performed. All p-values are Bonferonni corrected.

Figure 4.. Forest Plots for Prediabetes.

A: Mild vs Mild ED and worse, B: Mild and mild ED vs moderate and worse (Forest plots for comparisons of Mild, mild ED, and moderate vs severe and worse, and for Mild, mild ED, moderate, and severe vs death with Covid-19 are reported in Supplementary Figure S2).

Figure 4.. Forest Plots for Prediabetes.

A: Mild vs Mild ED and worse, B: Mild and mild ED vs moderate and worse (Forest plots for comparisons of Mild, mild ED, and moderate vs severe and worse, and for Mild, mild ED, moderate, and severe vs death with Covid-19 are reported in Supplementary Figure S2).