Metformin is associated with reduced COVID-19 severity in patients with prediabetes

Chan, Lauren; Casiraghi, E.; Laraway, Bryan; Coleman, Benjamin; Blau, Hannah; Zaman, Adnin; Harris, Nomi L.; Wilkins, Kenneth J.; Antony, Blessy; Gargano, Michael; Valentini, Giorgio; Sahner, David; Haendel, Melissa; Robinson, Peter N.; Bramante, Carolyn; Reese, Justin

doi:10.1016/j.diabres.2022.110157

Cited by 15 publications

(6 citation statements)

References 62 publications

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“…However, these data do suggest that addressing microbial dysbiosis in the gut and oral microbiomes may be targets for intervention to improve health in COVID-19 disease. Supporting this, Metformin treatment, which has been shown to be beneficial to gut health and microbial balance, is a highly effective treatment in COVID-19 patients [94][95][96][97][98][99] . Thus, future studies to assess treatments such as Metformin and the potential role in microbiome health and fatty acid production will be critical to determine optimal treatment interventions for COVID-19, that best target mucosal and microbial health.…”

Section: Discussionmentioning

confidence: 93%

SARS-CoV-2 infection is associated with intestinal permeability, systemic inflammation, and microbial dysbiosis in hospitalized COVID-19 patients

Basting,

Langat,

Broedlow

et al. 2023

Preprint

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Coronavirus disease 2019 (COVID-19) and associated severity has been linked to uncontrolled inflammation and may be associated with changes in the microbiome of mucosal sites including the gastrointestinal tract and oral cavity. These sites play an important role in host-microbe homeostasis and disruption of epithelial barrier integrity during COVID-19 may potentially lead to exacerbated inflammation and immune dysfunction. Outcomes in COVID-19 are highly disparate, ranging from asymptomatic to fatal, and the impact of microbial dysbiosis on disease severity is unclear. Here, we obtained plasma, rectal swabs, oropharyngeal swabs, and nasal swabs from 86 patients hospitalized with COVID-19 and 12 healthy volunteers. We performed 16S rRNA sequencing to characterize the microbial communities in the mucosal swabs and measured circulating cytokines, markers of gut barrier integrity, and fatty acids in the plasma samples. We compared these plasma concentrations and microbiomes between healthy volunteers and the COVID-19 patients who had survived or unfortunately died by the end of study enrollment, and between severe disease and healthy controls, as well as performed a correlation analysis between plasma variables and bacterial abundances. The rectal swabs of COVID-19 patients had reduced abundances of several commensal bacteria includingFaecalibacterium prausnitsii, and an increased abundance of the opportunistic pathogensEggerthella lentaandHungatella hathewayi. Furthermore, the oral pathogenScardovia wiggsiaewas more abundant in the oropharyngeal swabs of COVID-19 patients who died. The abundance of bothH. hathewayiandS. wiggsiaecorrelated with circulating inflammatory markers including IL-6, highlighting the possible role of the microbiome in COVID-19 severity, and providing potential therapeutic targets for managing COVID-19.

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Section: Discussionmentioning

confidence: 93%

SARS-CoV-2 infection is associated with intestinal permeability, systemic inflammation, and microbial dysbiosis in hospitalized COVID-19 patients

Basting,

Langat,

Broedlow

et al. 2023

Preprint

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“…Separate trials found that COVID-19 outcomes were improved by initiation of metformin, beginning shortly after infection: … “Metformin had a 42% reduction in ER visits/hospitalizations/death through 14 days; a 58% reduction in hospitalizations/death through 28 days, and a 42% reduction in Long COVID through 10 months”… (Bramonte et al 2023 ; Erickson 2023 ; Boulware 2023 ). Many retrospective studies had previously indicated that pre-infection administration of metformin improved COVID-19 outcomes in diabetic individuals (Ibrahim 2021 ; Lalau et al 2021 ; Chan et al 2022 ; Wiernsperger et al 2022 ; Ma et al 2023 ; Pedrosa et al 2023 ; Yen et al 2023 and others). Prior metformin administration also improved COVID-19 in non-diabetics taking it for polycystic ovary syndrome, and pre-diabetics taking it for preventive risk reduction (Chan et al 2022 ).…”

Section: Separate Human Trials Reveal That Covid-19 Outcomes Can Be I...mentioning

confidence: 99%

Coordination chemistry suggests that independently observed benefits of metformin and Zn2+ against COVID-19 are not independent

Lockwood

2024

Biometals

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Independent trials indicate that either oral Zn2+ or metformin can separately improve COVID-19 outcomes by approximately 40%. Coordination chemistry predicts a mechanistic relationship and therapeutic synergy. Zn2+ deficit is a known risk factor for both COVID-19 and non-infectious inflammation. Most dietary Zn2+ is not absorbed. Metformin is a naked ligand that presumably increases intestinal Zn2+ bioavailability and active absorption by cation transporters known to transport metformin. Intracellular Zn2+ provides a natural buffer of many protease reactions; the variable “set point” is determined by Zn2+ regulation or availability. A Zn2+-interactive protease network is suggested here. The two viral cysteine proteases are therapeutic targets against COVID-19. Viral and many host proteases are submaximally inhibited by exchangeable cell Zn2+. Inhibition of cysteine proteases can improve COVID-19 outcomes and non-infectious inflammation. Metformin reportedly enhances the natural moderating effect of Zn2+ on bioassayed proteome degradation. Firstly, the dissociable metformin–Zn2+ complex could be actively transported by intestinal cation transporters; thereby creating artificial pathways of absorption and increased body Zn2+ content. Secondly, metformin Zn2+ coordination can create a non-natural protease inhibitor independent of cell Zn2+ content. Moderation of peptidolytic reactions by either or both mechanisms could slow (a) viral multiplication (b) viral invasion and (c) the pathogenic host inflammatory response. These combined actions could allow development of acquired immunity to clear the infection before life-threatening inflammation. Nirmatrelvir (Paxlovid®) opposes COVID-19 by selective inhibition the viral main protease by a Zn2+-independent mechanism. Pending safety evaluation, predictable synergistic benefits of metformin and Zn2+, and perhaps metformin/Zn2+/Paxlovid® co-administration should be investigated.

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“…One of the commonly administered drugs for COVID-19 patients is Metformin, which helps regulate insulin resistance and moderate BMI and androgen excess. 44 Fortunately, Metformin could help reduce COVID-19 severity in patients, due to its anti-viral and anti-inflammatory effects, as shown in a study conducted by Chan et al 45 An interesting study by Jerzak and Szafarowska investigated personalized therapy protocols for pregnant PCOS patients positive for COVID-19. 46 Due to the complexity of cases, individualized modalities have been applied, with main components of anti-coagulants as Aspirin and Low Molecular Weight Heparin (LMWH), anti-inflammatory drugs as N-acetylcysteine (NAC), and Metformin.…”

Section: Comparison With Existing Literaturementioning

confidence: 99%

COVID-19 and the need for special care for women with polycystic ovary syndrome: A systematic review

Alrubasy,

Sameer,

Taha

et al. 2024

F1000Res

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Objective The study investigates the association between coronavirus disease 2019 (COVID-19) and polycystic ovary syndrome (PCOS) and assess whether women with PCOS are at a higher susceptibility and risk for COVID-19 complications. Methods This review analyzes articles indexed in PubMed, Scopus, Google Scholar, and the Cochrane Library, focusing on the onset of the COVID-19 pandemic in December 1, 2019, until November 1, 2022. The quality of the evidence was assessed using the NIH quality assessment tool. The study was registered on PROSPERO (CRD42023371956) on January 12, 2023. Results A total of 11 observational studies were identified, totaling 22,155 PCOS patients. Despite the heterogeneity of the included studies, the findings of most of the studies were similar in terms of increased susceptibility and severity of COVID-19 infection in PCOS patients. PCOS patients were reported to have a 51% higher risk of COVID-19 infection than non-PCOS women (HR =1.51). Many causes have been identified to play a role, most notably the overactivation of the renin-angiotensin system (RAS) and elevated levels of RAS-associated proteins, decreased serum levels of neuropilin-1 (sNRP1), elevated serum biomarkers such as platelet degranulation and coagulation cascade markers increased acute phase response, and lower levels of vitamin D could render PCOS patients susceptible to a chronic inflammatory state, which can also lead to difficulties and severe consequences, when impacted by COVID-19. Furthermore, the COVID-19 pandemic also influenced psychological well-being, with an increase in the incidence and severity of depression and anxiety among PCOS patients in the COVID-19 pandemic era compared to healthy individuals. Conclusions Patients with PCOS are more likely to get infected with COVID-19 and display a higher affinity to severe infections and complications due to overlapping and confounding factors. These findings suggest that PCOS patients may need more medical attention when infected with COVID-19.

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Metformin is associated with reduced COVID-19 severity in patients with prediabetes

Cited by 15 publications

References 62 publications

SARS-CoV-2 infection is associated with intestinal permeability, systemic inflammation, and microbial dysbiosis in hospitalized COVID-19 patients

SARS-CoV-2 infection is associated with intestinal permeability, systemic inflammation, and microbial dysbiosis in hospitalized COVID-19 patients

Coordination chemistry suggests that independently observed benefits of metformin and Zn2+ against COVID-19 are not independent

COVID-19 and the need for special care for women with polycystic ovary syndrome: A systematic review

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