key: cord-0934537-cvd2eeax
authors: Hariyanto, Timotius Ivan; Kurniawan, Andree
title: Metformin use is associated with reduced mortality rate from coronavirus disease 2019 (COVID-19) infection
date: 2020-08-18
journal: Obes Med
DOI: 10.1016/j.obmed.2020.100290
sha: 17e858b4857faec51ca0656f24acb00c639344ce
doc_id: 934537
cord_uid: cvd2eeax

BACKGROUND AND AIMS: The coronavirus disease 2019 (COVID-19) pandemic has caused a significant impact on all aspects of life. One of the comorbidities associated with severe outcome and mortality of COVID-19 is diabetes. Metformin is one of the drugs which is most commonly used for the treatment of diabetes patients. This study aims to analyze the potential benefit of metformin use in reducing the mortality rate from COVID-19 infection. METHODS: We systematically searched the Google Scholar database using specific keywords related to our aims until August 3(rd), 2020. All articles published on COVID-19 and metformin were retrieved. Statistical analysis was done using Review Manager 5.4 software. RESULTS: A total of 5 studies with a total of 6,937 patients were included in our analysis. Our meta-analysis showed that metformin use is associated with reduction in mortality rate from COVID-19 infections [RR 0.54 (95% CI 0.32 – 0.90), p = 0.02, I(2) = 54%, random-effect modelling]. CONCLUSION: Metformin has shown benefits in reducing the mortality rate from COVID-19 infections. Patients with diabetes should be advised to continue taking metformin drugs despite COVID-19 infection status.

The global pandemic disease declared by the World Health Organization (WHO), coronavirus disease 2019 (COVID-19), has been caused a significant burden in health and economic aspects around the world. Until now, the number of positive and death cases is still increasing. Therefore, identification of the factors that involve in the development of the severe disease is very important to enable stratification of risk, optimize the reallocation of hospital resources, and guide public health recommendations and interventions. Several comorbid conditions such as hypertension, diabetes, cardiovascular disease, dyslipidemia, and thyroid disease have been identified to be associated with the development of severe outcomes from COVID-19. [1] [2] [3] One of the drugs most commonly taken by diabetes patients is metformin. Metformin has demonstrated beneficial effects in lowering blood glucose in patients with diabetes. [4] However, the association between metformin use and COVID-19

has not yet been established. This study aims to analyze the potential association between metformin use and the mortality rate from COVID-19 infection.

We conducted a systematic search of the literature on Google scholar using the keywords "metformin" OR "biguanides" AND "coronavirus disease 2019" OR "COVID-19", until the present time (August 3 rd , 2020) with language restricted to English only. The title, abstract, and full text of all articles identified that matched the search criteria were assessed, and those reporting the rate of metformin use in COVID-19 patients with a clinically validated definition of "mortality" were included in this meta-analysis. The references of all identified studies were also analyzed (forward and backward citation tracking) to identify other potentially eligible articles.

A meta-analysis was performed using Review Manager 5.4 (Cochrane Collaboration) software. Dichotomous variables were calculated using the Mantel-Haenszel formula with random-effects models. We used the I 2 statistic to assess the heterogeneity, value of < 25%, 26-50%, and > 50% considered as low, moderate, and high degrees of heterogeneity, respectively. The effect estimate was reported as risk ratio (RR) along with its 95% confidence intervals (CIs) for dichotomous variables, respectively. P-value was two-tailed, and the statistical significance set at ≤0.05.

A total of 8,110 records were obtained through systematic electronic searches and other ways. After screening titles, abstracts, and full texts, 5 studies [4] [5] [6] [7] [8] with a total of 6,937 COVID-19 patients were included in the meta-analysis. The essential characteristics of the included studies are summarized in Table 1 , whilst the individual and pooled RRs for the association between metformin use and mortality rate from COVID-19 is shown in Figure 1 .

Our pooled analysis showed a significant association of metformin use with reduction of mortality rate from COVID-19 infection, with high heterogeneity [RR 0.54 (95% CI 0.32 -0.90), p = 0.02, I 2 = 54%, random-effect modelling].

Based on our meta-analysis of available data, metformin use seems to be associated These changes can lead to decreased binding between ACE2 receptor and SARS-CoV-2

Receptor Binding Domain (RBD) due to steric hindrance by the addition of a large sized PO 4 3molecule, thus reducing SARS-CoV-2 infectivity. [9, 10] Second, metformin inhibits the mammalian target of rapamycin (mTOR) signaling via liver kinase B1 (LKB1). It also indirectly attenuates AKT activation through phosphorylation of insulin receptor substrate 1 (IRS-1) that resulted in inhibition of the mTOR signaling cascade. The PI3K/AKT/mTOR pathway plays a major role in MERS-CoV infection, which may also be implicated in the pathogenesis of SARS-CoV-2 infection, given many similarities between these two viruses.

Therefore, inhibition of mTOR signaling by metformin may result in a reduction of SARS-CoV-2 infectivity and mortality from COVID-19 infection. [11] Finally, through activation of AMPK, metformin can inhibit the inflammatory response that could potentially contribute to mortality through mechanism such as cytokine storm and vascular damage. [10, 12] Therefore, metformin use will decrease the inflammatory response, reducing the incidence of cytokine give positive impact and benefit from its pharmacodynamics nature regardless of the dosage and duration of treatment. We hope that this study can still give early insight into the further treatment protocol for COVID-19 infections, especially in those with diabetes.

J o u r n a l P r e -p r o o f 

Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia -A systematic review, meta-analysis, and meta-regression

Thyroid disease is associated with severe coronavirus disease 2019 (COVID-19) infection

Dyslipidemia is associated with severe coronavirus disease 2019 (COVID-19) infection

Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with Covid-19

Clinical Characteristics and Outcomes of Patients With Diabetes and COVID-19 in Association With Glucose-Lowering Medication

Metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes

Metformin Treatment Was Associated with Decreased Mortality in COVID-19 Patients with Diabetes in a

A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward

COVID-19 and diabetes: Is metformin a friend or foe?

Diabetes in COVID-19: Prevalence, pathophysiology, prognosis and practical considerations

Metformin in COVID-19: A possible role beyond diabetes

Association of high level gene expression of ACE2 in adipose tissue with mortality of COVID-19 infection in obese patients