key: cord-0736967-nz09d36o
authors: Ganesh, Adithan; Randall, Michael D.
title: Does metformin affect outcomes in COVID‐19 patients with new or pre‐existing diabetes mellitus? A systematic review and meta‐analysis
date: 2022-02-23
journal: Br J Clin Pharmacol
DOI: 10.1111/bcp.15258
sha: 27461c7d10b0606045457c4adf319d3dd228ea60
doc_id: 736967
cord_uid: nz09d36o

AIMS: The COVID‐19 pandemic is a global public health emergency and patients with diabetes mellitus (DM) are disproportionately affected, exhibiting more severe outcomes. Recent studies have shown that metformin is associated with improved outcomes in patients with COVID‐19 and DM and may be a potential candidate for drug repurposing. We aimed to investigate the effects of metformin on outcomes in patients with COVID‐19 and DM. METHODS: Databases (PubMed, Scopus, Web of Science, EMBASE, Clinicaltrials.gov and Cochrane library) were searched up to 10 April 2021 for studies reporting data on metformin use in COVID‐19 patients with DM. The risk of bias was assessed using the Newcastle–Ottawa scale. Certainty of evidence was rated using the GRADE approach. The primary outcome was mortality reported as odds ratio (OR). A random‐effects meta‐analysis was carried out on both unadjusted and adjusted ORs. This study is registered with PROSPERO, CRD42020221842. RESULTS: In total, 2 916 231 patients from 32 cohort studies were included in the quantitative and qualitative synthesis. The meta‐analysis showed that metformin was significantly associated with lower mortality in COVID‐19 patients with DM in both unadjusted (OR 0.61 [95% confidence interval: 0.53–0.71], P < .00001, I (2) = 70%) and adjusted (OR 0.78 [95% confidence interval: 0.69–0.88], P < .00001, I (2) = 67%) models. CONCLUSION: Poor outcomes in COVID‐19 patients with DM can be attributed to inadequate glycaemic control and weakened immune responses. Metformin has multiple effects that can improve outcomes in patients with DM and our findings highlight a possible role of its use. However, robust randomised trials are needed to thoroughly assess its use.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID- 19) , has been associated with 141 400 973 total cases worldwide with 3 026 206 deaths and 18 283 297 active cases as of 18 April 2021. 1 While it is estimated that the overall case fatality ratio of the disease is 1.38% (95% confidence interval [Cl], 1.23-1.53), which is much lower than that of SARS-CoV and MERS-CoV with 15% and 35% respectively, the absolute number of deaths have been remarkably high due to its high transmission rate and increased risk of death with age and comorbidities. 2 Diabetes mellitus (DM) and hyperglycaemia have been identified as poor prognostic markers for pneumonia and observations from previous outbreaks have elucidated the damaging role of hyperglycaemia in infection. 3 It has been reported that a known history of diabetes (odds ratio [OR] 3.0; 95% CI, 1.4-6.3) and elevated fasting plasma glucose levels (OR 3.3; 95% CI, 1.4-7.7) are independent predictors of mortality in patients infected with SARS-CoV. 4 A retrospective cohort study of 144 patients admitted for SARS-CoV also showed that the DM as a comorbidity was independently associated with a 3-fold increase in poor outcomes (relative risk, 3.1; 95% CI, 1.4-7.2). 5 With regards to COVID-19, a retrospective, multicentre study of 7377 COVID -19 patients in China demonstrated that those with new or pre-existing diabetes and poor glycaemic control had higher all-cause mortality, higher progression to multiorgan failure and required more medical interventions (such as systemic corticosteroids, antibiotics, noninvasive and invasive ventilation) than patients without type 2 diabetes (T2D) or with well-controlled blood glucose. 6 Another report from China that analysed 174 COVID-19 patients demonstrated that patients with DM had a higher prevalence of CVD and were also at a higher risk of pneumonia, uncontrolled inflammatory responses and hypercoagulable states due to dysfunctional glucose metabolism. 7 In addition, they presented with increased lactate dehydrogenase, C-reactive protein and D-dimer, and more pronounced lung pathologies on CT scans, supporting the notion that diabetes is a risk factor for rapid progression of COVID-19. Lastly, a recent meta-analysis that included 16 003 patients found diabetes to be significantly associated with mortality from COVID-19 with an OR of 1.90 (95% Cl, 1.37-2.64) and a combined pooled OR of mortality or severity to be 2.16 (95% Cl, 1.74-2.68). 8 Acute and chronic hyperglycaemia can significantly impact the body's innate and adaptive immune responses towards infection and is associated with dysfunctional neutrophil chemotaxis, impaired macrophage function (via decreased superoxide formation) and dampened T-cell mediated responses. 9 In an in vivo mouse model investigating the effects of DM following MERS-CoV infection, more severe disease was observed in diabetic male mice, which was characterised by fewer inflammatory macrophages, CD4 + T cells and higher levels of interleukin (IL)-17a. 10 In another model, hyperglycaemic mice demonstrated higher rates of influenza infection and bacterial pneumonia due to decreased alveolar macrophage activation as well as lower levels of chemokines. 11 This dysfunctional immune system has been mirrored in patients with COVID-19 and poor glycaemic control as they exhibited lower peripheral counts of CD4 + and CD8 + T cells, NK cells, impaired macrophage activation and phagocytosis as well as higher levels of proinflammatory markers. 12 Lower serum levels of IL-10, an anti-inflammatory cytokine that inhibits the synthesis and release of proinflammatory cytokines such as IL-6, interferon-γ and tumour necrosis factor (TNF)-α, which are characteristic of the cytokine storm seen in COVID-19, have also been observed in patients with DM. 13 In terms of localised defence, insulin resistance and hyperglycaemia can lower levels of surfactant protein-D, a lung derived innate immune protein, as well as increase glucose concentrations in the airway surface liquid which consequently promotes lung pathogen overgrowth. 14 Therefore, patients with DM already exhibit a baseline level of low-grade inflammation due to hyperglycaemia and insulin resistance which predisposes them to an exaggerated immune response upon SARS-CoV-2 infection. This leads to a characteristic hyperinflammatory syndrome or cytokine storm responsible for the progression to severe disease ( Figure 1) .

Recent evidence has shown that metformin, an oral biguanide, is associated with reduced mortality and improved outcomes in patients with COVID-19 and DM with an OR of 0.77 (95% CI 0.73-0Á81) reported in 1 study. [15] [16] [17] [18] Alongside its glucose-lowering effects, metformin has immunomodulatory, anti-inflammatory, antitumour, antiageing and antiviral activity, which suggests the possibility of it to affect outcomes in critical illness. 19 Indeed, several studies have demonstrated the use of metformin being associated with reduced complications such as diabetic cardiomyopathy, myocardial infarction and hypertrophy. 20 Moreover, metformin has been found to be linked with lower mortality in other lung pathologies such as chronic obstructive pulmonary disorder and tuberculosis. 21, 22 It is thus important to examine whether the pleiotropic effects of metformin could be beneficial in COVID-19 patients with DM.

The aim of this study was to perform a systematic review and metaanalysis to investigate whether the use of metformin in COVID-19 patients with new or pre-existing diabetes mellitus affects outcomes such as mortality and severity of the disease.

This systematic review and meta-analysis are reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. 23 This study was also registered in the PROS-PERO, international prospective register of systematic reviews (ID: CRD42020221842) on 20 November 2020. The inclusion and exclusion criteria for the studies were as follows:

i. The studies should be published in English language in all databases.

ii. All participants should be adult patients (>18 y) diagnosed with COVID-19 and diabetes mellitus.

iii. Study design should be randomised controlled trials (RCTs) or observational studies (retrospective/prospective cohort, crosssectional and case-control) that looked at patients taking metformin vs. patients not taking metformin which reported at least 1 outcome (mortality or composite endpoint) and an OR, risk ratio or hazards ratio in either adjusted and/or nonadjusted forms.

iv. The studies should have at least 70 patients with COVID-19 and diabetes mellitus.

v. Case reports, conference abstracts, review articles, commentaries, editorials and nonhumane studies were excluded.

The authors searched each database and the titles and abstracts were reviewed to identify any potentially relevant articles. After identification of articles, the full texts were individually analysed according to the inclusion and exclusion criteria. Additionally, hand searches were performed to include any relevant studies that were not shown in the initial database search. The reference lists of included articles, review articles and meta-analyses were also screened to identify any other potential studies that could be utilised.

F I G U R E 1 Mechanisms contributing to worsened outcomes in patients with COVID-19 and diabetes mellitus (DM). Acute and chronic hyperglycaemia compromises the innate immune system through impaired neutrophil chemotaxis, decreased macrophage activity, dampened T-cell responses, decreased levels of anti-inflammatory cytokines (IL-10) and increased proinflammatory cytokines. The increased angiotensinconverting enzyme 2 (ACE2) expression in these patients favours more efficient SARS-CoV-2 entry into cells and potential damage to β islet cells of the pancreas. The presence of multiple comorbidities contributes to endothelial dysfunction and hypercoagulation. Lastly, vitamin D deficiency is a common finding which can further compromise the immune system 2.2 | Data extraction and quality assessment

The following data were extracted from each study and transferred to a spreadsheet: author(s), date of online publication, country, study design, number of patients with COVID-19 and diabetes mellitus, sex, patient age-range, primary outcomes (mainly mortality), and OR (unadjusted and/or adjusted forms). In studies that reported sufficient data on metformin use vs. nonmetformin use but did not report an OR, the OR was calculated separately on statistical software and put in the nonadjusted OR column.

The quality of the included studies and their risk of bias was assessed using the Newcastle-Ottawa Scale (NOS). The NOS has been developed to assess the quality of cohort studies used for a systematic review by using a star system where each study is judged on 3 broad domains: the selection of study groups; the comparison of cohorts and the establishment of the outcomes of interest in the cohort. 24 Each study was rated a maximum of 4 stars for selection, 2 stars for comparability and 3 stars for the outcome, with a total score of 9 and higher scores indicating better quality.

The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach 25 was used to evaluate the quality of evidence for outcomes. All included studies only reported mortality as an outcome, and thus the effect of metformin on mortality in COVID-19 patients with DM was tested. Only the studies that reported an adjusted OR was included in the analysis. The certainty of evidence was classified as very low, low, moderate or high using the GRADE criteria.

RCTs start as high-quality evidence and observational studies as lowquality evidence, which can subsequently be rated down based on 5 factors (risk of bias, inconsistency, indirectness, imprecision and publication bias), or rated up based on 3 factors (large magnitude of effect, doseresponse gradient and plausible biases reducing an apparent treatment effect). The GRADEpro software was used to rate evidence and present it in GRADE evidence profiles and summary of findings tables. 26 

To evaluate the association between metformin use and mortality, the ORs in nonadjusted and adjusted forms (with 95% CI) were taken as the effect size. A meta-analysis was then performed with the generic inverse variance method using a random-effects model to account for any significant heterogeneity between studies. To avoid any confounding effects, separate meta-analyses were carried out for unadjusted ORs and adjusted ORs that were reported/calculated from each study. Data including mortality in the metformin group, mortality in the nonmetformin group and total number of patients in each group were entered when calculating the nonadjusted ORs. Adjusted ORs were taken directly from the studies. Sensitivity analyses were carried out by excluding studies that could significantly influence the overall analysis, including those with large sample sizes or anomalous ORs. A P-value of <.05 was set to show a statistically significant association. Table 1 . 

In this meta-analysis the inverted funnel plot analysis from the adjusted studies showed a symmetrical distribution on the funnel plot, highlighted by the contour lines, indicating a low risk of publication bias ( Figure 5 ). The P-values for the Egger's and Begg's test were .061 and .064, respectively. Table 2 shows the GRADE evidence profile and summary of findings for the adjusted studies. Population comprised of COVID-19 patients with DM taking or not taking metformin. The outcome was mortality (reported in adjusted OR). The risk difference (95% CI) with metformin use was based on the assumed risk (i.e. risk with no metformin use, which was the mean control group risk across included studies) and the relative effect (95% CI) of the intervention. Overall certainty of evidence was rated as low quality, with the assessment of criteria shown in the table and the associated footnotes.

The findings of this extensive meta-analysis showed that the use of metformin in patients with COVID-19 and diabetes was significantly The presence of multiple comorbidities such as obesity, cardiovascular disease, hypertension and kidney damage in patients with DM is a common finding when admitted for COVID-19 and studies have confirmed that they are at an even higher risk of severe outcomes such as mortality. 56 Both hyperglycaemia and insulin resistance are associated with endothelial dysfunction and prothrombotic activity. 57 With COVID-19 also being linked to coagulation abnormalities in the latter stages of the disease, the presence of both hypercoagulation states puts these patients at an even higher risk of life- threatening thrombotic complications. 12 Additionally, the prevalence of obesity in patients with T2D is widely observed and a body mass index of >35 kg/m 2 is considered a risk factor for poor prognosis and associated with an increased requirement for invasive mechanical ventilation. 58 This is largely due to the conflicting comorbidities that compromise cardiometabolic health and obese patients being more prone to obstructive sleep apnoea and decreased pulmonary ventilation which predisposes them to poor outcomes when faced with respiratory tract infections. 59 Increased levels of angiotensin-converting enzyme 2 (ACE2) have been noted in the kidneys, lungs, heart and pancreas in murine models of DM and ACE2 is also overexpressed in chronic diseases in humans, which is thought to facilitate higher levels of SARS-CoV-2 entry into various organs and thus contribute to the poorer prognoses. A recent study showed that patients with DM or hypertension had reduced clearance and shedding of the SARS-CoV-2 virus which could be explained by the increased ACE2 expression. 60 The basis for the control risk is the mean control group risk across studies. Risk difference (and its 95% CI) is based on control risk and relative effect (converted to risk ratio) of the intervention (and its 95% CI). b

All studies were nonrandomised and assessed using the Newcastle-Ottawa Scale; while some studies had a higher risk of bias than others, no important difference was noted in sensitivity analyses excluding studies at higher risk of bias; hence we did not rate down for risk of bias.

c Although there was a high I 2 value (which can be exaggerated in observational studies), 25 most of the studies, especially those with larger sample sizes, reported a benefit with metformin use. Final decision not to rate down on inconsistency.

d Although there were some studies with high confidence intervals, these studies contributed to a small percentage of the weight of the meta-analysis. Furthermore, the study by Khunti et al., 18 which composed a significant proportion of our meta-analysis, showed a considerable beneficial effect, with a small confidence interval. Thus, the final decision was not to rate down.

e Visual inspection of the funnel plot as well as empirical examination of results showed no publication bias. *GRADE category of evidence: high certainty (we are very confident that the true effect lies close to that of the estimate of the effect); moderate certainty (we are moderately confident in the effect estimate;

the true effect is probably close to the estimate, but it is possibly substantially different); low certainty (our confidence in the effect estimate is limited; the true effect could be substantially different from the estimate of the effect); very low certainty (we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect).

OAS2 and MX1) while downregulating inflammatory mediators such as TNF-α. 67 Other mechanisms that metformin uses to improve outcomes in COVID-19 is through its ability to reduce the levels of proinflammatory cytokines such as IL-6 and TNF-α, which are characteristically seen in the systemic cytokine storm while boosting the levels of antiinflammatory cytokines, namely IL-10. 68 One study used in this metaanalysis found that metformin had sex-specific immunomodulatory actions in that the reduction in cytokines were more prominent in females than males. 16 Metformin also strengthens both the adaptive and innate immune system by promoting autophagy, which helps con- Metformin also activates 5-adenosine monophosphate-activated protein kinase (AMPK) which leads to decreased gluconeogenesis, increased insulin sensitivity, inhibition of PI3K/AKT/mTOR pathways and phosphorylation of angiotensin-converting enzyme 2 (ACE2) receptors, which impairs binding and subsequent entry of SARS-CoV-2 into cells its immunomodulatory, anti-inflammatory effects, antiviral effects ( Figure 6 ) as well as the results from this meta-analysis, suggests that metformin may be highly beneficial in attenuating the cytokine storm seen in patients with DM and COVID-19 while maintaining optimal glycaemic control and hence improve outcomes.

This systematic review has several limitations that need to be addressed in order to ascertain a clear picture with regards to metfor- The use of the GRADE approach provides valuable information regarding the certainty of evidence and sheds light into further research that may be warranted. Our review included the GRADE approach and used mortality as an outcome; however, it is likely that future studies, alongside RCTs will provide more data regarding metformin use in this population and we call for future reviews to use the GRADE approach to assess multiple outcomes (such as hospital admission, risk of deterioration, intubation and recovery) to thoroughly assess the potential clinical implications of metformin use.

With this in mind, more research is needed to confirm the role of metformin in COVID-19 through blinded RCTs. Given its promising nature, multiple trials are currently underway including the MET-Covid trial (ClinicalTrials.gov identifier: NCT04510194) and the DMMETCOVI9 trial (ClinicalTrials.gov identifier: NCT04626089), which are estimated to be completed by late 2021 to early 2022.

This systematic review evaluated whether the use of metformin affected outcomes in COVID-19 patients with DM and the results from this extensive meta-analysis showed that it was associated with lower mortality in both nonadjusted and adjusted ORs. Beyond its effects on glycaemic control, metformin could improve outcomes in these patients through multiple mechanisms, some of which lead to an attenuated cytokine storm, improved adaptive and 

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Does metformin affect outcomes in COVID-19 patients with new or pre-existing diabetes mellitus? A systematic review and metaanalysis

The creation of Figures 1 and 6 were done through BioRender (©Bio-Renderbiorender.com), which provides excellent tools for scientific drawing. We thank the library staff at the University of Nottingham for their assistance and input in devising the search strategies as well as the data extraction, quality assessment and analyses stages.This study was funded by the University of Nottingham.

None.

All data used in this manuscript including the search strategies, list of included and excluded studies, data extracted, quality assessment and assessment of publication bias are available upon reasonable request.

https://orcid.org/0000-0002-4772-5928