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Coronavirus disease-2019 (COVID-19) caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is a growing global pandemic that has devastated Asia, Europe, and now the United States. Its increasing death toll has been linked to higher age and a number of comorbidities including hypertension, obesity, and diabetes (1, 2), but approaches to counteract this trend are still lacking. Being a new disease, the specific patient characteristics of these at risk populations are also only starting to emerge with studies reported from China (3–5), Europe (6, 7) and more recently New York (1, 2).

However, currently still very little is known about patient characteristics in the U.S., particularly in more diverse communities with a large proportion of Blacks/African-Americans such as in the South. This information is especially relevant as African-Americans have been disproportionally affected by this pandemic across the nation (8–10) and the prevalence of comorbidities including diabetes is very high in these communities (11). We therefore conducted a retrospective observational study of subjects diagnosed with COVID-19 at the University of Alabama at Birmingham (UAB) Hospital, a tertiary health care center in the South, aimed at identifying the patient characteristics and factors affecting mortality especially in the context of diabetes in this diverse cohort.

In summary, the findings of this study in a racially diverse population demonstrate that diabetes is an independent risk factor associated with increased mortality in individuals with COVID-19, whereas metformin treatment is associated with dramatically reduced mortality in subjects with T2D even after correcting for multiple covariates.

Most strikingly, we found that metformin use prior to the diagnosis of COVID-19 was associated with a ~3-fold decrease in mortality and significantly lower unadjusted and adjusted odds ratios in subjects with diabetes. Of note, this effect remained even after correcting for age, sex, race, obesity, and hypertension or chronic kidney disease and heart failure. Interestingly and in alignment with this finding, an early report from Wuhan, China also suggested that metformin was associated with decreased mortality in hospitalized COVID-19 patients with diabetes in (14). Metformin was also found to be associated with reduced risk of early death in the French CORONADO study (6) and most recently, it was suggested to be associated with decreased mortality in women with COVID-19 based on a UnitedHealth data analysis (12). The fact that such similar results were obtained in different populations from around the world suggests that the observed reduction in mortality risk, associated with metformin use in subjects with T2D and COVID-19, might be generalizable. In fact, a very recent meta-analysis of this collective work concluded that metformin has benefits in reducing the mortality rate from COVID-19 (15). Furthermore, these findings underline the importance of following general diabetes treatment and prevention guidelines and not delaying or discontinuing any metformin treatment. Especially during this pandemic that puts subjects with diabetes at particularly high risk, this treatment might not only help with diabetes management, but also reduce the risk of adverse outcome in case of a COVID-19 infection.

At this point, the mechanisms by which metformin might improve prognosis in the context of COVID-19 are not known. Our findings suggest that they go beyond any expected improvement in glycemic control or obesity as blood glucose, HbA1C, or BMI were not lower in COVID-19 survivors on metformin. Interestingly, metformin has previously been shown to also have anti-inflammatory (16, 17) and anti-thrombotic effects (18, 19) and excessive inflammatory responses, e.g., cytokine storm as well as disseminated thromboembolic events have been recognized as deadly complications of COVID-19 infection (20–22). It is therefore tempting to speculate that by exerting some of its anti-fibrinolytic activities (18) and inhibiting inflammatory cytokines such as tumor necrosis factor alpha or interleukin-6 (16, 17), suspected to play a role in the immune response to COVID-19 (12), metformin might improve outcome. In fact, even prior to the COVID-19 pandemic, preadmission metformin use was found to be associated with reduced mortality in medical and surgical intensive care patients with T2D (23).

While diabetes has been recognized universally as one of the major comorbidities adversely affecting COVID-19 outcome, the factors responsible for this phenomenon are not well understood. Of note, we found that the increased mortality risk of subjects with diabetes persisted even after correcting for covariates such as age, race, obesity, and hypertension, suggesting that while these factors might contribute to a worse outcome, they cannot fully account for it. In the CORONADO study higher glucose levels at admission were associated with a trend toward increased mortality (6) and in-hospital hyperglycemia contributed to worse prognosis in a large multicenter study of patients with COVID-19 from Wuhan (24). Consistently, we found in general slightly higher glucose levels in subjects who died. However, neither blood glucose levels at diagnosis nor during the illness were lower in metformin-users, making it very unlikely that better control of blood glucose was responsible for the improved outcome observed in subjects taking metformin. Also, long-term glycemic control as assessed by HbA1C did not affect mortality in our study, in alignment with previous reports (6). Similar to the issue with metformin, other factors such as diabetes-associated inflammation (25) and coagulopathy (26) may therefore play a more prominent role in this regard. In addition, a recent report also demonstrated that pancreatic beta cells can get infected and damaged by SARS-CoV-2 (27) providing a potential explanation for the extremely high insulin requirements seen in some subject with COVID-19 as well as the development of diabetic ketoacidosis and possibly new onset diabetes (28, 29).

Higher age and male sex were the other independent risk factors associated with increased mortality that we found consistently across subjects with and without diabetes. In fact, the mortality rate in males was more than two-fold higher than in females, which is in line with previous studies (30). Many theories have been proposed for why this might be, including the different concentrations of sex steroids, different fat distribution, different level of circulating pro-inflammatory cytokines, and different innate and adaptive immune response to viral infections (30, 31). In fact, due to this striking sexual dimorphism, studies using anti-androgens in COVID-19 positive men are currently ongoing. In any case, it is encouraging that the beneficial effects of metformin remained strong in the male subjects of our study.

In our cohort being African-American appeared to be primarily a risk factor for contracting COVID-19 rather than for mortality. These findings are supported by a recent study using an integrated-delivery health system cohort with similar demographics (~30% Blacks/African-American), which found that Black race was not associated with higher in-hospital mortality than White race. This suggests that any racial disparity observed may be more likely due to exposure risk and external, socioeconomic factors than to biological differences. The fact that other geographic areas (mostly with a smaller proportion of African-Americans), did see a difference in mortality (10), might be related to issues with healthcare access.

Limitations of the study include the size that did not allow for any separate analyses of additional subgroups such as T1D or subjects on other anti-diabetic drugs besides metformin. On the other hand, the diverse community comprising a large proportion of African-American men and women represents a unique feature of our study. Also, the fact that in our study metformin-users did not have lower blood glucose levels than non-users, suggested that better metabolic control was unlikely to be responsible for the improved outcome observed in these subjects.

Taken together, our study reaffirmed the role of the major comorbidities associated with COVID-19 in a more diverse population with a higher proportion of African-Americans, demonstrated the prominence of diabetes as an independent risk factor associated with higher mortality and revealed that metformin use prior to a diagnosis of COVID-19 was associated with a consistent and robust decrease in mortality in subjects with diabetes. Future studies will have to explore how metformin might confer these protective effects, provide a careful risk benefit assessment and determine whether the indications for metformin treatment should be broadened in the face of the ongoing COVID-19 pandemic.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by UAB Institutional Review Board. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

AC and TG were responsible for data acquisition and analysis. PL performed all the statistical analyses. MM and FO helped with the approach and interpretation. AS conceived the study and wrote the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.