Metformin Use in Diabetes Prior to Hospitalization: Effects on Mortality in Covid-19

Li, Jinghong; Wei, Qi; Li, Willis X.; McCowen, Karen C.; Xiong, Wei; Liu, Jiao; Jiang, Wenlijun; Marin, Traci; Thomas, Robert; He, Ming; Gongol, Brendan; Hepokoski, Mark; Yuan, Jason X.‐J.; Shyy, John Y.‐J.; Xiong, Nian; Malhotra, Atul

doi:10.4158/ep-2020-0466

Cited by 35 publications

(43 citation statements)

References 30 publications

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“…ARDS is associated with high mortality rates and is a serious and often fatal complication of COVID-19, although its manifestation in the latter differs from “typical” ARDS ( Fan et al., 2020 ; Han and Mallampalli, 2015 ; Li and Ma, 2020 ; Wu et al., 2020 ). Mortality and ARDS risk in SARS-CoV-2 infected individuals are increased by old age and comorbidities such as T2D, obesity and hypertension ( Gao et al., 2021 ; Guan et al., 2020 ; Richardson et al., 2020 ; Singh and Khan, 2020 ; Valencia et al., 2017 ), but are substantially reduced by long-term metformin usage ( Bramante et al., 2021 ; Crouse et al., 2021 ; Li et al., 2020 ; Luo et al., 2020 ). This protective effect is independent of glycemic control and is related to metformin’s anti-inflammatory properties ( Barzilai et al., 2016 ; Pollak, 2017 ; Valencia et al., 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…While dexamethasone is currently used in COVID-19 treatment, statins and metformin are only described to have a prophylactic effect. In particular, early studies from China have noted that long-term metformin usage decreased hospital mortality by 4-fold relative to other anti-diabetic drugs ( Li et al., 2020 ; Luo et al., 2020 ) and reduced COVID-19-associated heart failure and inflammation ( Cheng et al, 2020 ). In a US-based study, metformin reduces the odds ratio of COVID-19 death in African Americans with T2D by 10-fold ( Crouse et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation

et al. 2021

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Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1β production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation

et al. 2021

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“…The diabetes drug metformin indirectly inhibits NLRP3 by regulating mTOR, and its use is significantly associated with reduced mortality among patients with COVID-19 and type 2 diabetes. Metformin was also recently shown to inhibit NLRP3 activation and lung inflammation in SARS-CoV-2-infected mice 164 , 165 .…”

Section: Clinical Interventionsmentioning

confidence: 99%

Inflammasome activation at the crux of severe COVID-19

2021

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The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), results in life-threatening disease in a minority of patients, especially elderly people and those with co-morbidities such as obesity and diabetes. Severe disease is characterized by dysregulated cytokine release, pneumonia and acute lung injury, which can rapidly progress to acute respiratory distress syndrome, disseminated intravascular coagulation, multisystem failure and death. However, a mechanistic understanding of COVID-19 progression remains unclear. Here we review evidence that SARS-CoV-2 directly or indirectly activates inflammasomes, which are large multiprotein assemblies that are broadly responsive to pathogen-associated and stress-associated cellular insults, leading to secretion of the pleiotropic IL-1 family cytokines (IL-1β and IL-18), and pyroptosis, an inflammatory form of cell death. We further discuss potential mechanisms of inflammasome activation and clinical efforts currently under way to suppress inflammation to prevent or ameliorate severe COVID-19.

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“…Out of 946 potentially relevant articles, and following application of inclusion criteria, 32 studies were retained including a total of 44306 participants. The included studies were conducted in Austria [14], Belgium [15], China [16][17][18][19][20][21][22][23][24], France [25][26][27], Hong Kong [28], Iraq [29], Italy [30,31], Russia [32]which determines the high relevance of risk factor analysis for outcomes in DM patients to substantiate the strategy for this category of patients. AIM: To assess the effect of clinical and demographic parameters (age, gender, body mass index (BMI, South Korea [33,34], Spain [35,36], UK [37][38][39][40][41] and USA [42][43][44][45].…”

Section: Characteristics Of Included Studiesmentioning

confidence: 99%

Metformin therapy and severity and mortality of SARS-CoV-2 infection: a meta-analysis

Oscanoa

Amado

Vidal³

et al. 2021

Clinical Diabetology

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background. It has been postulated that metformin could have anti-SARS-CoV-2 action. this raises the hypothesis that people who take metformin may have lower SARS-CoV-2 severity and/or mortality. Objectives. to conduct a meta-analysis of the association between the use of Metformin and risk of severity and mortality in SARS-CoV-2 infection. Methods. We searched PubMed, EMbASE, Google scholar, the Cochrane Database of Systematic Reviews and preprint servers (medRxiv and Research Square) for studies published between December 2019 and January 2021. Data was extracted on study location, year of publication, design, number of participants, sex, age at baseline, body mass index, and exposure and outcome definition. Effect statistics were pooled using random effects models with 95% confidence intervals (CI). the quality of included studies was assessed with the Newcastle-Ottawa Scale (NOS). Results. thirty-two observational studies were included, combining to a total sample of 44306 participants. the mean NOS score of included studies was 7.9. Results suggested that metformin use was associated with a reduced risk of SARS-CoV-2 mortality (OR = 0.56, 95% CI: 0.46-0.68, P < 0.001; 22 studies) but not with disease severity (OR = 0.85, 95% CI: 0.71-1.02, P = 0.077; 15 studies). In the subgroup analysis, metformin reduces the risk of mortality (OR = 0.69, 95% CI: 0.55-0.88; P = 0.002) and severity (OR = 0.83, 95% CI: 0.70-0.97, P = 0.023) in patients aged 70 and above. Conclusions. the use of metformin was associated to lower risk of mortality from SARS-CoV-2 infection. this association does not imply causation and further research is required to clarify potential mechanisms.

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Metformin Use in Diabetes Prior to Hospitalization: Effects on Mortality in Covid-19

Cited by 35 publications

References 30 publications

Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation

Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation

Inflammasome activation at the crux of severe COVID-19

Metformin therapy and severity and mortality of SARS-CoV-2 infection: a meta-analysis

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