Metformin - a new approach.

Metformin is a widely used biguanide drug recommended as a first-line antidiabetic for type 2 diabetes. Currently, metformin is used not only in the treatment of diabetes but also in other diseases. Some studies have shown that metformin causes weight loss in insulin-sensitive and insulin-resistant overweight and obese patients. Metformin is an effective and safe option for women with gestational diabetes and type 2 diabetes in pregnancy, and it may also increase the ovulation rate in patients with polycystic ovary syndrome (PCOS). Longer survival times have been observed in cancer patients using metformin. Metformin has been shown to significantly correlate with lower mortality in obese or type 2 diabetic women hospitalized for COVID-19. It also has a protective effect on the development and progression of many types of cancer. The mechanisms of action of metformin are complex and still not fully understood. Metformin has been shown to act through both AMP-activated protein kinase (AMPK)-dependent mechanisms and AMPK-independent mechanisms. This paper presents the benefits of using metformin in the treatment of various diseases.

Metformin as a potential treatment for COVID-19.

INTRODUCTION: Early treatment for SARS-CoV-2 infection is essential to limit the clinical progression of COVID-19. However, limited therapeutic options are available for standard-risk patients, including those under age 50 who have received the primary series of COVID-19 vaccination as well as a bivalent booster. AREAS COVERED: Metformin is a widely used, inexpensive antihyperglycemic for the treatment of diabetes mellitus type 2 as well as polycystic ovarian syndrome, with a well-described safety profile. EXPERT OPINION: Although the mechanism of action has not been fully elucidated, metformin is known to alter glucose metabolism and is under investigation as an antiviral agent, demonstrating in vitro and in vivo activity against SARS-CoV-2. Recent work suggests metformin may also serve as a therapeutic option for patients with COVID-19 as well as those with post-acute sequelae of SARS-CoV-2 infection, known more commonly as 'long COVID-19.' This manuscript examines what is known about metformin for the treatment of COVID-19 and explores how this drug may be used in the future to address the SARS-CoV-2 pandemic.

Protocol for the Metformin Aneurysm Trial (MAT): a placebo-controlled randomised trial testing whether metformin reduces the risk of serious complications of abdominal aortic aneurysm.

BACKGROUND: Multiple observational studies have associated metformin prescription with reduced progression of abdominal aortic aneurysm (AAA). The Metformin Aneurysm Trial (MAT) will test whether metformin reduces the risk of AAA rupture-related mortality or requirement for AAA surgery (AAA events) in people with asymptomatic aneurysms. METHODS: MAT is an international, multi-centre, prospective, parallel-group, randomised, placebo-controlled trial. Participants must have an asymptomatic AAA measuring at least 35 mm in maximum diameter, no diabetes, no contraindication to metformin and no current plans for surgical repair. The double-blind period is preceded by a 6-week, single-blind, active run-in phase in which all potential participants receive metformin. Only patients tolerating metformin by taking at least 80% of allocated medication will enter the trial and be randomised to 1500 mg of metformin XR or an identical placebo. The primary outcome is the proportion of AAA events defined as rupture-related mortality or need for surgical repair. Secondary outcomes include AAA growth, major adverse cardiovascular events and health-related quality of life. In order to test if metformin reduced the risk of AAA events by at least 25%, 616 primary outcome events will be required (power 90%, alpha 0.05). DISCUSSION: Currently, there is no drug therapy for AAA. Past trials have found no convincing evidence of the benefit of multiple blood pressure lowering, antibiotics, a mast cell inhibitor, an anti-platelet drug and a lipid-lowering medication on AAA growth. MAT is one of a number of trials now ongoing testing metformin for AAA. MAT, unlike these other trials, is designed to test the effect of metformin on AAA events. The international collaboration needed for MAT will be challenging to achieve given the current COVID-19 pandemic. If this challenge can be overcome, MAT will represent a trial unique within the AAA field in its large size and design. TRIAL REGISTRATION: Australian Clinical Trials ACTRN12618001707257 . Registered on 16 October 2018.

The F/B ratio as a biomarker for inflammation in COVID-19 and T2D: Impact of metformin.

The pandemic of COVID-19 has highlighted the intricate relationship between gut microbiome and overall health. Recent studies have shown that the Firmicutes/Bacteroidetes ratio in the gut microbiome may be linked to various diseases including COVID-19 and type 2 diabetes (T2D). Understanding the link between gut microbiome and these diseases is essential for developing strategies for prevention and treatment. In this study, 115 participants were recruited and divided into three groups: 1st group: T2D patients and healthy controls, 2nd group: COVID-19 patients with and without T2D, 3rd group: T2D patients with COVID-19 treated with or without metformin. Gut microbial composition at the phylum level was assessed using qRT-PCR with universal primers targeting the bacterial 16 S rRNA gene and specific primers for Firmicutes and Bacteroidetes. Data was analyzed using one-way ANOVA, logistic regression, and Spearman's rank correlation coefficient. The study found that the ratio of Firmicutes to Bacteroidetes (F/B) was higher in patients with both T2D and COVID-19 compared to those with only T2D or COVID-19. Additionally, the F/B ratio was positively correlated with C-reactive protein (CRP) in T2D and COVID-19 patients. The study also suggests that metformin treatment may affect this correlation. Logistic regression analysis showed that the F/B ratio was significantly associated with CRP. These findings suggest that the F/B ratio may be a potential biomarker for inflammation in T2D and COVID-19 patients and metformin treatment may have an effect on the correlation between F/B and CRP levels.

Results From a Randomized, Open-Label, Crossover Study Evaluating the Effect of the Aldosterone Synthase Inhibitor Baxdrostat on the Pharmacokinetics of Metformin in Healthy Human Subjects.

BACKGROUND: Due to the high comorbidity of diabetes and hypertension, co-administration of metformin with anti-hypertensive drugs is likely. Baxdrostat is an aldosterone synthase inhibitor in development for the potential treatment of hypertension. In vitro data indicated that baxdrostat inhibits the multidrug and toxin extrusion 1 (MATE1) and MATE2-K renal transporters. Metformin is a MATE substrate, so this study assessed potential effects of baxdrostat on the pharmacokinetics of metformin. METHODS: Twenty-seven healthy volunteers received 1000 mg metformin alone and 1000 mg metformin in the presence of 10 mg baxdrostat in a randomized, crossover manner. Each treatment was separated by 10 or more days. Blood and urine samples were collected over a 3-day period after each treatment to measure plasma and urine concentrations of metformin. Safety was assessed by adverse events (AEs), physical examinations, electrocardiograms, vital signs, and clinical laboratory evaluations. RESULTS: There were no deaths, serious AEs, discontinuations due to treatment-emergent AEs, or noteworthy increases in AEs with either treatment, indicating that metformin and baxdrostat were well-tolerated when co-administered. Baxdrostat did not significantly affect plasma concentrations or renal clearance of metformin. CONCLUSION: The results of this study suggest that diabetic patients with hypertension receiving both metformin and baxdrostat are unlikely to require dose adjustment. REGISTRATION: ClinicalTrials.gov identifier no. NCT05526690.

Metformin: update on mechanisms of action and repurposing potential.

Currently, metformin is the first-line medication to treat type 2 diabetes mellitus (T2DM) in most guidelines and is used daily by >200 million patients. Surprisingly, the mechanisms underlying its therapeutic action are complex and are still not fully understood. Early evidence highlighted the liver as the major organ involved in the effect of metformin on reducing blood levels of glucose. However, increasing evidence points towards other sites of action that might also have an important role, including the gastrointestinal tract, the gut microbial communities and the tissue-resident immune cells. At the molecular level, it seems that the mechanisms of action vary depending on the dose of metformin used and duration of treatment. Initial studies have shown that metformin targets hepatic mitochondria; however, the identification of a novel target at low concentrations of metformin at the lysosome surface might reveal a new mechanism of action. Based on the efficacy and safety records in T2DM, attention has been given to the repurposing of metformin as part of adjunct therapy for the treatment of cancer, age-related diseases, inflammatory diseases and COVID-19. In this Review, we highlight the latest advances in our understanding of the mechanisms of action of metformin and discuss potential emerging novel therapeutic uses.

Metformin use before COVID-19 vaccination and the risks of COVID-19 incidence, medical utilization, and all-cause mortality in patients with type 2 diabetes mellitus.

AIMS: We designed this study to determine whether metformin use before COVID-19 vaccination influences the risk of COVID-19 infection, medical utilization, and mortality. METHODS: We used the US collaborative network of TriNetX to identify 123,709 patients with type 2 diabetes mellitus fully vaccinated against COVID-19 between January 1, 2020, and November 22, 2022. The study selected 20,894 pairs of metformin users and nonusers by propensity score matching. The Kaplan-Meier method and Cox proportional hazards models were used to compare the risks of COVID-19 infection, medical utilization, and mortality between the study and control groups. RESULTS: No significant difference was noted between metformin users and nonusers in the risk of COVID-19 incidence (aHR = 1.02, 95% CI = 0.94-1.10). Compared to the control cohort, the metformin cohort exhibited a significantly lower risk of hospitalization (aHR = 0.85, 95% CI = 0.81-0.89), critical care services (aHR = 0.81, 95% CI = 0.70-0.94), mechanical ventilation (aHR = 0.75, 95% CI = 0.60-0.95), and mortality (aHR = 0.75, 95% CI = 0.63-0.89). The subgroup analyses and sensitivity analysis showed similar results. CONCLUSION: The present study showed that metformin use before COVID-19 vaccination could not reduce COVID-19 incidence; however, it was associated with significantly lower risks of hospitalization, intensive care service, mechanical ventilation, and mortality in fully vaccinated type 2 diabetes mellitus patients.

Evaluation of Drug-Drug Interactions of Ensitrelvir, a SARS-CoV-2 3CL Protease Inhibitor, With Transporter Substrates Based on In Vitro and Clinical Studies.

Drug-drug interaction potentials of ensitrelvir, a novel oral inhibitor of 3C-like protease of severe acute respiratory syndrome coronavirus 2, for drug transporters were evaluated by in vitro and clinical studies. The target drug transporters assessed were P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, and multidrug and toxin extrusion 1 and 2K. In vitro study revealed that ensitrelvir is a substrate for P-gp and BCRP and inhibits P-gp, BCRP, OATP1B1, OATP1B3, OCT1, and OAT3. Based on these results, a clinical drug-drug interaction study to evaluate the effect of ensitrelvir on the pharmacokinetics of P-gp, BCRP, OATP1B1, OATP1B3, and OCT1 substrates was conducted with a cocktail approach using digoxin (P-gp substrate), rosuvastatin (BCRP, OATP1B1, and OATP1B3 substrate), and metformin (OCT1 substrate). The cocktail was administered first, and after the washout period, the cocktail was coadministered with 500 mg of ensitrelvir. No treatment-emergent adverse events were observed. Pharmacokinetic analyses demonstrated that the ratios (90% confidence intervals) of "cocktail with ensitrelvir" to "cocktail without ensitrelvir" for maximum plasma concentration and area under the plasma concentration-time curve were, respectively, 2.17 (1.72-2.73) and 1.31 (1.13-1.52) for digoxin, 1.97 (1.73-2.25) and 1.65 (1.47-1.84) for rosuvastatin, and 1.03 (0.91-1.16) and 1.02 (0.94-1.11) for metformin. The results indicate that the exposure levels of digoxin and rosuvastatin increased when coadministered with ensitrelvir, but those of metformin were not changed. In conclusion, ensitrelvir has an impact on the exposure levels of P-gp, BCRP, OATP1B1, and OATP1B3 substrates.

Metformin, a biological and synthetic overview.

Metformin is the most widely known anti-hyperglycemic, officially acquired by the USA government in 1995 and in 2001 it became the most prescribed treatment for type II diabetes. But how did it become the must-use drug for this disease in such a short period of time? it all started with traditional medicine, by using a plant known as "goat's rue" for the reduction of blood glucose levels. Its use arose in 1918 and evolved to the metformin synthesis in laboratories a couple of years later, using very rudimentary methods which involved melting and strong heating. Thus, a first synthetic route that allowed the preparation of the initial metformin derivates was established. Some of these resulted toxics, and others outperformed the metformin, reducing the blood glucose levels in such efficient way. Nevertheless, the risk and documented cases of lactic acidosis increased with metformin derivatives like buformin and phenformin. Recently, metformin has been widely studied, and it has been associated and tested in the treatment of type II diabetes, cancer, polycystic ovarian syndrome, cell differentiation to oligodendrocytes, reduction of oxidative stress in cells, weight reduction, as anti-inflammatory and even in the recent COVID-19 disease. Herein we briefly review and analyze the history, synthesis, and biological applications of metformin and its derivates.

Outpatient medications associated with protection from COVID-19 hospitalization.

The COVID-19 pandemic remains the pre-eminent global health problem, and yet after more than three years there is still no prophylactic agent against the disease aside from vaccines. The objective of this study was to evaluate whether pre-existing, outpatient medications approved by the US Food and Drug Administration (FDA) reduce the risk of hospitalization due to COVID-19. This was a retrospective cohort study of patients from across the United States infected with COVID-19 in the year 2020. The main outcome was adjusted odds of hospitalization for COVID-19 amongst those positive for the infection. Outcomes were adjusted for known risk factors for severe disease. 3,974,272 patients aged 18 or older with a diagnosis of COVID-19 in 2020 met our inclusion criteria and were included in the analysis. Mean age was 50.7 (SD 18). Of this group, 290,348 patients (7.3%) were hospitalized due to COVID-19, similar to the CDC's reported estimate (7.5%). Four drugs showed protective effects against COVID-19 hospitalization: rosuvastatin (aOR 0.91, p = 0.00000024), empagliflozin-metformin (aOR 0.69, p = 0.003), metformin (aOR 0.97, p = 0.017), and enoxaparin (aOR 0.88, p = 0.0048). Several pre-existing medications for outpatient use may reduce severity of disease and protect against COVID-19 hospitalization. Well-designed clinical trials are needed to assess the efficacy of these agents in a therapeutic or prophylactic setting.

Gut microbiota in patients with COVID-19 and type 2 diabetes: A culture-based method.

Background: The global pandemic of coronavirus disease 2019 (COVID-19) continues to affect people around the world, with one of the most frequent comorbidities being Type 2 Diabetes (T2D). Studies have suggested a link between disbalances in gut microbiota and these diseases, as well as with COVID-19, potentially due to inflammatory dysfunction. This study aims to analyze the changes in gut microbiota in COVID-19 patients with T2D using a culture-based method. Methods: The stool samples were taken from 128 patients with confirmed COVID-19. Changes in the composition of gut microbiota were analyzed by culture-based method. The study used chi-squared and t-test to find significant differences in gut bacteria between samples and non-parametric correlation analysis to examine relationship between gut bacteria abundance, C-reactive protein (CRP) levels and length of stay (LoS) in COVID-19 patients without T2D. Results: The gut microbiota of T2D patients with COVID-19 showed increased Clostridium spp., Candida spp., and decreased Bifidobacterium spp., Lactobacillus spp. Metformin-treated patients with T2D and COVID-19 without antibiotic treatment showed increased Bacteroides spp., Lactobacillus spp., and decreased Enterococcus, Clostridium compared to the same group with antibiotic treatment. The study also found a positive correlation between the abundance of certain gut microbiota genera, such as Klebsiella spp. and Enterococcus spp., and CRP levels and LoS in COVID-19 patients without and with T2D, while the abundance of other genera, such as Bifidobacterium spp. and Lactobacillus spp., was found to have a negative correlation. Conclusion: In conclusion, this study provides important insights into the gut microbiota composition of SARS-CoV-2-infected individuals with T2D and its potential impact on the course of the disease. The findings suggest that certain gut microbiota genera may be associated with increased CRP levels and longer hospital stays. The significance of this study lies in the fact that it highlights the potential role of gut microbiota in the progression of COVID-19 in patients with T2D, and may inform future research and treatment strategies for this patient population. The future impact of this study could include the development of targeted interventions to modulate gut microbiota in order to improve outcomes for COVID-19 patients with T2D.

Is metformin use associated with low mortality in patients with type 2 diabetes mellitus hospitalized for COVID-19? a multivariable and propensity score-adjusted meta-analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a new pandemic that the entire world is facing since December of 2019. Increasing evidence has shown that metformin is linked to favorable outcomes in patients with COVID-19. The aim of this study was to address whether outpatient or inpatient metformin therapy for type 2 diabetes mellitus is associated with low in-hospital mortality in patients hospitalized for COVID-19. METHODS: We searched studies published in PubMed, Embase, Google Scholar and Cochrane Library up to November 1, 2022. Raw event data extracted from individual study were pooled using the Mantel-Haenszel approach. Odds ratio (OR) or hazard ratio (HR) adjusted for covariates that potentially confound the association using multivariable regression or propensity score matching was pooled by the inverse-variance method. Random effect models were applied for meta-analysis due to variance among studies. RESULTS: Twenty-two retrospective observational studies were selected. The pooled unadjusted OR for outpatient metformin therapy and in-hospital mortality was 0.48 (95% CI, 0.37-0.62) and the pooled OR adjusted with multivariable regression or propensity score matching was 0.71 (95% CI, 0.50-0.99). The pooled unadjusted OR for inpatient metformin therapy and in-hospital mortality was 0.18 (95% CI, 0.10-0.31), whereas the pooled adjusted HR was 1.10 (95% CI, 0.38-3.15). CONCLUSIONS: Our results suggest that there is a significant association between the reduction of in-hospital mortality and outpatient metformin therapy for type 2 diabetes mellitus in patients hospitalized for COVID-19.

Noninsulin-based antihyperglycemic medications in patients with diabetes and COVID-19: A systematic review and meta-analysis.

BACKGROUND: Patients with diabetes are more likely to suffer COVID-19 complications. Using noninsulin antihyperglycemic medications (AGMs) during COVID-19 infection has proved challenging. In this study, we evaluate different noninsulin AGMs in patients with COVID-19. METHODS: We searched Medline, Embase, Web of Science, and Cochrane on 24 January 2022. We used the following keywords (COVID-19) AND (diabetes mellitus) AND (antihyperglycemic agent). The inclusion criteria were studies reporting one or more of the outcomes. We excluded non-English articles, case reports, and literature reviews. Study outcomes were mortality, hospitalization, and intensive care unit (ICU) admission. RESULTS: The use of metformin rather than other glucose-lowering medications was associated with statistically significant lower mortality (risk ratio [RR]: 0.60, 95% confidence interval [CI]: 0.47, 0.77, p < .001). Dipeptidyl peptidase-4 inhibitor (DPP-4i) use was associated with statistically significantly higher hospitalization risk (RR: 1.44, 95% CI: 1.23, 1.68, p < .001) and higher risk of ICU admissions and/or mechanical ventilation vs nonusers (RR: 1.24, 95% CI: 1.04, 1.48, p < .02). There was a statistically significant decrease in hospitalization for SGLT-2i users vs nonusers (RR: 0.89, 95% CI: 0.84-0.95, p < .001). Glucagon-like peptide-1 receptor agonist (GLP-1RA) use was associated with a statistically significant decrease in mortality (RR: 0.56, 95% CI: 0.42, 073, p < 0.001), ICU admission, and/or mechanical ventilation (RR: 0.79, 95% CI: 0.69-0.89, p < .001), and hospitalization (RR: 0.73, 95% CI: 0.54, 0.98, p = .04). CONCLUSIONS: AGM use was not associated with increased mortality. However, metformin and GLP-1RA use reduced mortality risk statistically significantly. DPP-4i use was associated with a statistically significant increase in the risk of hospitalization and admission to the ICU.

Effects of Metformin, Insulin on Hematological Parameters of COVID-19 Patients with Type 2 Diabetes.

Background: COVID-19 infection caused by SARS-COV-2 can result in multi-organ injuries and significant mortality in severe and critical patients, particularly those with type 2 diabetes as a comorbidity. Metformin and insulin are the main diabetes medications that affect the outcome of patients with COVID-19. Objective: The purpose of our study was to find out the features of the hematological indicators of patients with COVID-19 patients and type 2 diabetes. Methods: This is a retrospective study of the hospital confirmed COVID-19 patients between January to March 2022, who were admitted to Transcarpathian Regional Clinical Infectious Diseases Hospital (Uzhhorod, Ukraine). Results: The effect of type 2 diabetes, metformin, and insulin on COVID-19 were analyzed, respectively. Demographics and blood laboratory indices were collected. In patients who took metformin, the level of CRP was significantly lower than in patients who did not take metformin (24 mg/L [IQR 15 - 58] vs 52 mg/L, [IQR 22-121], P = 0.046). Conclusion: Our findings suggest that pre-admission metformin use may benefit COVID-19 patients with type 2 diabetes.

Metformin in SARS-CoV-2 infection: A hidden path - from altered inflammation to reduced mortality. A review from the literature.

SARS-CoV-2 infection has been a major threat to human health and a huge challenge to Medicine. In only two years, COVID-19 affected >350 million people, causing >5.6 million deaths. Chronic inflammatory states, such as diabetes or obesity, are known risk factors for COVID-19 poorest outcomes, with higher risk for disease severity and greater mortality. Metformin remains on the first line of the management of hyperglycemia in type 2 diabetes. Through its anti-inflammatory and immunomodulatory mechanisms, metformin appears as an opportunity to control the dysregulated cytokine storm secondary to SARS-CoV-2 infection. Recent studies point towards a potential protective role of metformin in the course of COVID-19, showing that current or previous treatment with metformin associates with better outcomes.