In a recent review published in the Journal of Diabetes and its complications, researchers reported the potential association between metformin usage and coronavirus disease 2019 (COVID-19) outcomes.
COVID-19 has led to an unprecedented increase in morbidities and deaths globally. Chronic inflammation conditions such as diabetes increase the risk of poor COVID-19 outcomes, including hospitalizations, intensive care unit (ICU) admissions, invasive mechanical ventilation (IMV) needs, and deaths.
Being approved by the ADA (American diabetes association) and the EASD (the European association for the study of diabetes) as a first-line agent for type 2 diabetes (T2D), metformin is widely used to lower blood glucose among individuals. Studies have reported on the probable protection conferred by metformin usage during SARS-CoV-2 infections.
About the review
In the present review, researchers presented reviewed existing literature on the impact of metformin use on SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection outcomes.
Mechanism of action of metformin in COVID-19
SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) to invade the host's cells. Metformin inhibits ATP (adenosine triphosphate) synthesis with a resultant increase in AMP (adenosine monophosphate) and ADP (adenosine diphosphate) expression with subsequent indirect AMPK (AMP-activated protein kinase) activation in liver cells.
Metformin may reduce SARS-CoV-2-ACE2 binding by inducing functional and conformational changes in ACE2 receptors via AMPK (adenosine monophosphate-activated protein kinase) activation. Further, the activation could inhibit the unadjusted inflammatory responses and reduce tumor necrosis factor-alpha (TNF-α) expression by upregulating interleukin-10 (IL-10) expression.
As a result, metformin could mitigate the COVID-19-associated cytokine storm, an effect reportedly greater among women than men. Furthermore, activated AMPK-induced mTOR or rapamycin inhibition could lower COVID-19 susceptibility and associated mortality.
Effects of metformin usage on COVID-19 outcomes
Studies conducted on humans and written in English were searched on the PubMed database, using keywords such as 'metformin' and 'SARS-CoV-2' or 'COVID-19' between January 1, 2020, and December 31, 2021, and data were updated on January 5, 2022. A total of 166 records were identified in the initial literature search, from which the team excluded systematic reviews, meta-analyses, literature reviews, commentaries, opinions, case reports, and letters. After reviewing the entire text of 61 papers, only 37 studies were considered for the final analysis.
Thirty-one records evaluated the association between the use of metformin and COVID-19-associated mortality risks, of which 22 studies reported a significant reduction of 13% to 19% in COVID-19-associated mortality. The protective effect was pronounced among high-risk COVID-19 individuals with higher HbA1c (glycated hemoglobin) values. Metformin usage before COVID-19 diagnosis, in the pre-hospitalization period, and continued during the hospitalization stay resulted in improved clinical status of patients.
Among older individuals, metformin usage reduced one-month in-hospital COVID-19-associated mortality and increased the chances of hospital discharge. The protective effects associated with metformin use were more prominent among obese female or T2D patients. Further, studies reported that the most optimum dose of metformin against COVID-19 was one to two grams daily.
Seven studies evaluated the impact of metformin usage on COVID-19-associated hospitalization, five of which reported significantly lower hospital admissions among metformin-treated individuals. Five studies (out of six) reported significant protection conferred by metformin against COVID-19-associated ICU admissions. Three studies evaluated the effects of metformin usage on IMV needs, all of which reported lower IMV needs among metformin-treated COVID-19 patients.
In addition, metformin use was also associated with lower ARDS (acute respiratory distress syndrome) incidence in the elderly, and the glucose-lowering agent lowered COVID-19 incidence among T2D patients, especially among women. Metformin usage led to lesser ALI (acute lung injury) (ALI), lower computed tomography (CT) scores for COVID-19 severity, and increased survival rates.
However, a few studies reported contradictory findings. Metformin use was also associated with a greater incidence of acidosis, especially lactic acidosis, among individuals with severe SARS-CoV-2 infections. Thus, clinicians must assess the risk-benefit ratios and patients' medical history before prescribing metformin therapy. The gender-based differences in metformin efficacy could be due to greater IL-10 expression and lower TNF-α expression among women than men.
Based on the present review findings, metformin appears to improve COVID-19 severity outcomes, from reducing COVID-19 susceptibility or incidence to hospitalization and ICU admissions, IMV requirements, or even lowering mortality risks. However, few studies showed contradictory findings, and therefore, further research must be conducted to validate the review findings, emphasizing the exposure timing, metformin treatment duration, dose, and mechanisms.
It is crucial to consider that hospitalization represents COVID-19 severity which could be translated into hepatic or renal impairments that are contraindications for metformin therapy, resulting in metformin withdrawal. Therefore, it can be assumed that COVID-19 severity resulted in greater mortality than the withdrawal of the drug. It is also important to consider that metformin usage might represent less severe diabetes and, thus, lower complication risks.