New study suggests metformin is associated with less severe COVID-19 across prediabetic individuals

In a recent study posted to the medRxiv* preprint server, researchers illustrated that metformin was associated with decreased coronavirus disease 2019 (COVID-19) severity among prediabetic patients.

Background 

Since the commencement of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), researchers and clinicians have strived for novel therapeutic prospects for managing COVID-19 patients. Present treatments, including immune-related and antiviral therapies, have decreased but not completely eradicated SARS-CoV-2-linked mortality and morbidity. The ongoing SARS-CoV-2 pandemic emphasizes the essentiality of finding drugs that enhance COVID-19 outcomes.

Drug repurposing is one method for finding new medicines, and it involves identifying priorly marketed drugs that might be useful in treating COVID-19. Evidence suggests that an oral antihyperglycemic agent, metformin, is related to less severe SARS-CoV-2 infection in diabetic patients relative to other antihyperglycemic drugs.

Interestingly, metformin is prescribed for off-label usage in some people who do not have diabetes, including those with prediabetes and polycystic ovary syndrome (PCOS). These patients also belong to high-risk populations for severe SARS-CoV-2 infection. Hence, these cohorts offer a chance to explore further the impact of metformin use before the development of COVID-19.

About the study

In the present retrospective observational analysis, the investigators hypothesized that reported metformin usage before COVID-19 will be linked to reduced severity of SARS-CoV-2 infection outcomes. In turn, metformin use before infection might be a cost-effective method for favorable COVID-19 outcomes for prediabetic patients through glycemic management or other mechanisms.

The researchers built groups of SARS-CoV-2-positive non-diabetic metformin users with either prediabetes or PCOS. They also constructed propensity-weighted 282 and 313 levothyroxine control users, a hypothyroidism medication not known to influence COVID-19 outcomes, with PCOS and prediabetes, respectively. The scientists accomplished this using harmonized electronic health record (EHR) information from 53 hospitals. In detail, they utilized clinical patient data from the National COVID Cohort Collaborative (N3C) in the United States (US).

Patients who tested positive for SARS-CoV-2 after 1 January 2020, using laboratory procedures such as polymerase chain reaction (PCR) or antigen screening, were included in the study. Further, COVID-19-positive patients were allocated to the PCOS and prediabetes patient cohorts.

The team explored the potential connection between metformin therapy and COVID-19 severity within each cohort. Moreover, the authors conducted inverse probability weighting to adjust further the residual covariate mismatch within the groups. The primary study outcome of interest was SARS-CoV-2 infection severity, classified as mild emergency department (mild ED), mild, severe, moderate, or hospice/mortality. 

Results 

Cumulatively, the scientists found a significant correlation between less severe COVID-19 and metformin use among the prediabetes group relative to levothyroxine use adopting a binary categorization. The study results demonstrated that metformin use was connected to a reduced rate of SARS-CoV-2 infections among the prediabetes cohort that were mild ED, mild or worse, and moderate or worse in severity. Hence, the study data confirmed the relationship between metformin use and less severe SARS-CoV-2 infection.

On the other hand, the authors did not discover any correlation between metformin use and COVID-19 severity among PCOS patients. However, the number of patients was relatively limited. This inference might indicate that either the metformin-mediated reduction in COVID-19 severity was not occurring in individuals with PCOS or that the power of the study was insufficient to identify the metformin-mediated improvement. 

Furthermore, point estimations of the odds ratio of metformin compared to levothyroxine were directionally constant in PCOS and prediabetic populations. However, these associations were not statistically significant.

Conclusions

Although there have been numerous studies to determine how metformin affects COVID-19 in people with type 2 diabetes, the authors claimed that the present research was the broadest study to look into its off-label use, including those with PCOS and prediabetes.

According to the study findings, metformin, like in other studies of people with diabetes, was linked to less severe SARS-CoV-2 infection in patients with prediabetes. This was a significant finding considering 19% to 38% of Americans have prediabetes, and COVID-19 is still a public health crisis.

The team mentioned that the small number of patients with the most severe SARS-CoV-2 disease or infection-linked mortality prevented them from determining how much metformin reduces the likelihood of COVID-19-associated death or mechanical ventilation in prediabetic individuals. Future studies employing prospective trials and possibly randomized investigations are required to define the connection between COVID-19 severity and metformin in people with prediabetes and to determine whether metformin is linked to better SARS-CoV-2 infection outcomes.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.