key: cord-0806511-nigru1o8
authors: Lally, Michelle; Tsoukas, Philip; Halladay, Christopher; O’Neill, Emily; Gravenstein, Stefan; Rudolph, James L.
title: Metformin is associated with Decreased 30-day Mortality among Nursing Home Residents Infected with SARS-CoV2
date: 2020-10-26
journal: J Am Med Dir Assoc
DOI: 10.1016/j.jamda.2020.10.031
sha: 59b68bdc3fda4e7e99205ba0ca9425b9df085b9f
doc_id: 806511
cord_uid: nigru1o8

Objectives The COVID-19 pandemic presents an urgent need to investigate whether existing drugs can enhance or even worsen prognosis; metformin, a known mammalian target of rapamycin (m-TOR) inhibitor, has been identified as a potential agent. We sought to evaluate mortality benefit among older persons infected with SARS-CoV-2 who were taking metformin as compared to those who were not. Design Retrospective cohort study Setting and Participants: 775 nursing home residents infected with SARS-CoV-2 who resided in one of the 134 Community Living Centers (CLC) of the Veterans Health Administration (VHA) during March 1, 2020 to May 13, 2020 were included. Methods Using a window of 14 days prior to SARS-CoV-2 testing, bar coded medication administration records were examined for dispensing of medications for diabetes. The COVID-19 infected residents were divided into groups: 1) residents administered metformin alone or in combination with other medications, 2) residents who used long acting or daily insulin, 3) residents administered other diabetes medications, and 4) residents not administered diabetes medication, including non-diabetics and untreated diabetics. Proportional hazard models adjusted for demographics, hemoglobin A1c, body mass index, and renal function. Results Relative to those not receiving diabetes medications, residents taking metformin were at significantly reduced hazard of death (adjusted HR 0.48, 95%CI 0.28, 0.84) over the subsequent 30 days from COVID-19 diagnosis. There was no association with insulin (adjusted HR 0.99, 95% 0.60, 1.64) or other diabetes medications (adjusted HR 0.71, 95% CI 0.38, 1.32). Conclusions and Implications Our data suggests a reduction in 30-day mortality following SARS-CoV-2 infection in residents who were on metformin-containing diabetes regimens. These findings suggest a relative survival benefit in nursing home residents on metformin, potentially through its mTOR inhibition effects. A prospective study should investigate the therapeutic benefits of metformin among persons with COVID-19.

Type II diabetes mellitus (T2DM) ranks highly among the multiple morbidities that affect 39 older nursing home residents. Diabetics typically fare worse with infections than non-diabetics. 40 Metformin, among the most common T2DM medications, could play an important role for 41 diabetics infected with SARS-CoV-2. A recent focus on potential treatment for SARS-CoV-2 42 infection includes a pathway not usually considered for its "antiviral" property, the mammalian 43 target of rapamycin (mTOR) pathway. 5 mTOR complexes are critical in many cell functions 44 including senescence and apoptosis, and they also play a role in viral protein production, 45 processing, and assembly. mTOR and its protein complexes, mTOR complex 1 (mTORC1) and 46 mTOR complex 2 (mTORC2), are functionally intertwined with the adenosine monophosphate (AMP)-associated protein kinase (AMPK) pathway and both biological cascades appear to be 48 plausible targets for COVID-19 therapy. 5

Metformin's immunomodulatory effects on mTOR inhibition have sparked interest as a 50 potential cancer and antiviral therapeutic. In a study by Sahra and colleagues, the expression of 51 the protein REDD1 (regulated in development and DNA damage responses 1), a known negative 52 regulator of mTOR, rapidly increased following metformin treatment in prostate, breast, and 53 lung cancer cells. 6 Metformin may also boast additional anti-inflammatory benefits via 54 alterations of the gut microbiota through carbohydrate metabolism 7 and/or antiseptic properties. 8

Metformin's potential anti-inflammatory and immunomodulatory effects are not thoroughly 56 understood, but increased interest in the utility of metformin in inflammatory diseases outside of 57 T2DM, such as human-immunodeficiency virus, 9 multiple sclerosis, 10 and systemic lupus, 11 is 58 growing. Metformin historically has shown a modest benefit in treating influenza. 12 Influenza A 59 virus has been shown to exploit host signaling molecules, including mTORC1 and mTORC2 60 protein complexes, to increase viral replication. 13 Metformin's potential antiviral mechanism of 61 action could be due to increased REDD1 which would lead to subsequent mTOR regulation. 6

A recent study demonstrated that diabetics with confirmed COVID-19 infection had 63 elevated risk of severe pneumonia, hyperinflammatory state, and hypercoagulability compared to 64 a similar cohort of non-diabetics. 14 In both diabetics and non-diabetics, the potential role for

The cohort included all residents of the 134 Community Living Centers (CLC) operated 74 by the Veterans Health Administration (VHA). CLCs are nursing homes that the VHA operates 75 directly. We evaluated the subset with laboratory confirmed evidence of SARS-CoV-2 tested 76 during the interval of March 1, 2020 and May 13, 2020, following the VHA directive that all 77 residents be tested. Demographic variables collected from VA administrative records included age, sex, and 92 race. Comorbidities were collected to complete the Elixhauser comorbidity index. 16 We collected additional variables which would be related to diabetes and metformin utilization. The proportional hazard assumption was satisfied for each of the outcomes. Multivariable 108 regression included variables which were significantly disparate among the groups.

Characteristics of the 775 residents with SARS-CoV2 infection are displayed in Table 1 variables. Our data additionally was unable to shed light on the rationale for their specific 209 diabetic regimen, as well as reason for hospitalization. As a retrospective study that did not include 210 clinical record review, we are unable to determine the appropriateness of metformin utilization. 211

Additionally, our study was designed to look at population outcomes rather than the 

World Health Organization. Disease Outbreak News: Pneumonia of unknown cause -247

First Case of 2019 Novel Coronavirus in the