COVID-19 Drugs: University Of Alabama Study Shows That Metformin Decreases Mortality Rate In Type 2 Diabetes Patients Contracting COVID-19

COVID-19 Drugs: Researchers from the University of Alabama at Birmingham have found in a new study that metformin usage among patients with type 2 diabetes had decreased mortality rates when contracting the COVID-19 disease.

The COVID-19 disease is a growing pandemic with an increasing death toll that has been linked to various comorbidities as well as racial disparity. However, the specific characteristics of these at-risk populations are still not known and approaches to lower mortality are lacking.
 
The study team conducted a retrospective electronic health record data analysis of 25,326 subjects tested for COVID-19 between 2/25/20 and 6/22/20 at the University of Alabama at Birmingham Hospital, a tertiary health care center in the racially diverse Southern U.S. The primary outcome was mortality in COVID-19-positive subjects and the association with subject characteristics and comorbidities was analyzed using simple and multiple linear logistic regressions.
 
The study showed that the odds ratio of contracting COVID-19 was disproportionately high in Blacks/African-Americans (OR 2.6; 95% CI 2.19–3.10; p<0.0001) and in subjects with obesity (OR 1.93; 95% CI 1.64–2.28; p<0.0001), hypertension (OR 2.46; 95% CI 2.07–2.93; p<0.0001), and diabetes (OR 2.11; 95% CI 1.78–2.48; p<0.0001). Diabetes was also associated with a dramatic increase in mortality (OR 3.62; 95% CI 2.11–6.2; p<0.0001) and emerged as an independent risk factor in this diverse population even after correcting for age, race, sex, obesity, and hypertension.
 
Interestingly, the study team found that metformin treatment prior to diagnosis of COVID-19 was independently associated with a significant reduction in mortality in subjects with diabetes and COVID-19 (OR 0.33; 95% CI 0.13–0.84; p=0.0210).
 
Hence these study findings suggest that while diabetes is an independent risk factor for COVID-19-related mortality, this risk is dramatically reduced in subjects taking metformin prior to diagnosis of COVID-19, raising the possibility that metformin may provide a protective approach in this high risk population.
 
The study findings were published in the peer reviewed journal: Frontiers In Endocrinology. https://www.frontiersin.org/articles/10.3389/fendo.2020.600439/full
 
The racially diverse study findings showed that use of the diabetes drug metformin before a diagnosis of COVID-19 is associated with a threefold decrease in mortality in COVID-19 patients with Type 2 diabetes.
 
Diabetes is a significant comorbidity for COVID-19.
 
Dr Anath Shalev, M.D, Study Lead Author and Director of Comprehensive Diabetes Center, University of Alabama at Birmingham told Thailand Medical News, “This beneficial effect remained, even after correcting for age, sex, race, obesity, and hypertension or chronic kidney disease and heart failure."
 
Although 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, the study team 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 and in-hospital hyperglycemia contributed to worse prognosis in a large multicenter study of patients with COVID-19 from Wuhan. https://pubmed.ncbi.nlm.nih.gov/32472191/
https://pubmed.ncbi.nlm.nih.gov/32369736/
 
Consistently, the study team 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.
 
Similar to the issue with metformin, other factors such as diabetes-associated inflammation and coagulopathy may therefore play a more prominent role in this regard. https://pubmed.ncbi.nlm.nih.gov/20034371/
https://pubmed.ncbi.nlm.nih.gov/28122835/
 
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. https://pubmed.ncbi.nlm.nih.gov/32687793/
https://pubmed.ncbi.nlm.nih.gov/32314455/
 
Dr Shalev added, "Since similar results have now been obtained in different populations from around the world including China, France and a UnitedHealthcare analysis, this suggests that the observed reduction in mortality risk associated with metformin use in subjects with Type 2 diabetes and COVID-19 might be generalizable."
 
However how metformin improves prognosis in the context of COVID-19 is not known, Dr Shalev says.
 
The study  findings suggest that the mechanisms may go beyond any expected improvement in glycemic control or obesity, since neither body mass index, blood glucose nor hemoglobin A1C were lower in the metformin users who survived as compared to those who died.
 
Dr Shalev further added, "The mechanisms may involve metformin's previously described anti-inflammatory and anti-thrombotic effects."
 
The research included 25,326 patients tested for COVID-19 at the tertiary care UAB Hospital between Feb. 25 and June 22 of last year. Of the 604 patients found to be COVID-19-positive, 311 were African Americans.
 
The key primary outcome in the study was mortality in COVID-19-positive subjects, and the potential association with subject characteristics or comorbidities was analyzed.
 
The study team found that Blacks, who are only 26 percent of Alabama's population, were 52 percent of those who tested positive for COVID-19, and only 30 percent of those who tested negative. In contrast, only 36 percent of the COVID-19-positive subjects were white, while whites made up 56 percent of those who tested negative, further underlining the racial disparity. Once COVID-19-positive though, no significant racial difference in mortality was observed.
 
Dr Shalev added, "In our cohort being African American appeared to be primarily a risk factor for contracting COVID-19, rather than for mortality. This suggests that any racial disparity observed is likely due to exposure risk and external socioeconomic factors, including access to proper health care."
 
It was found that the overall mortality for COVID-19-positive patients was 11 percent. The study also found that 93 percent of deaths occurred in subjects over the age of 50, and being male or having high blood pressure was associated with a significantly elevated risk of death.
 
Significantly diabetes was associated with a dramatic increase in mortality, with an odds ratio of 3.62. Overall, 67 percent of deaths in the study occurred in subjects with diabetes.
 
The study team looked at the effects of diabetes treatment on adverse COVID-19 outcomes, focusing on insulin and metformin as the two most common medications for Type 2 diabetes. They found that prior insulin use did not affect mortality risk.
 
Interestingly however, prior metformin use was a different matter. Metformin use significantly reduced the odds of dying, and the 11 percent mortality for metformin users was not only comparable to that of the general COVID-19-positive population, it was dramatically lower than the 23 percent mortality for diabetes patients not on metformin.
 
Upon controlling for other covariates, age, sex and metformin use emerged as independent factors affecting COVID-19-related mortality. Interestingly, even after controlling for all these other covariates, death was significantly less likely with an odds ratio of 0.33  for type 2 diabetes subjects taking metformin, compared with those who did not take metformin.
 
Dr Shalev commented, "These study findings suggest that, while diabetes is an independent risk factor for COVID-19-related mortality, this risk is dramatically reduced in subjects taking metformin raising the possibility that metformin may provide a protective approach in this high-risk population."
 
The study team says future studies will need to explore how metformin is protective, as well as assess the risks and benefits of metformin treatment and the indications for its use in the face of the ongoing COVID-19 pandemic.
 
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