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.

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.

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.

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.

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.

Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes.

BACKGROUND: Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 diabetes. The efficacy and safety of once-weekly tirzepatide as compared with semaglutide, a selective GLP-1 receptor agonist, are unknown. METHODS: In an open-label, 40-week, phase 3 trial, we randomly assigned 1879 patients, in a 1:1:1:1 ratio, to receive tirzepatide at a dose of 5 mg, 10 mg, or 15 mg or semaglutide at a dose of 1 mg. At baseline, the mean glycated hemoglobin level was 8.28%, the mean age 56.6 years, and the mean weight 93.7 kg. The primary end point was the change in the glycated hemoglobin level from baseline to 40 weeks. RESULTS: The estimated mean change from baseline in the glycated hemoglobin level was -2.01 percentage points, -2.24 percentage points, and -2.30 percentage points with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and -1.86 percentage points with semaglutide; the estimated differences between the 5-mg, 10-mg, and 15-mg tirzepatide groups and the semaglutide group were -0.15 percentage points (95% confidence interval [CI], -0.28 to -0.03; P = 0.02), -0.39 percentage points (95% CI, -0.51 to -0.26; P<0.001), and -0.45 percentage points (95% CI, -0.57 to -0.32; P<0.001), respectively. Tirzepatide at all doses was noninferior and superior to semaglutide. Reductions in body weight were greater with tirzepatide than with semaglutide (least-squares mean estimated treatment difference, -1.9 kg, -3.6 kg, and -5.5 kg, respectively; P<0.001 for all comparisons). The most common adverse events were gastrointestinal and were primarily mild to moderate in severity in the tirzepatide and semaglutide groups (nausea, 17 to 22% and 18%; diarrhea, 13 to 16% and 12%; and vomiting, 6 to 10% and 8%, respectively). Of the patients who received tirzepatide, hypoglycemia (blood glucose level, <54 mg per deciliter) was reported in 0.6% (5-mg group), 0.2% (10-mg group), and 1.7% (15-mg group); hypoglycemia was reported in 0.4% of those who received semaglutide. Serious adverse events were reported in 5 to 7% of the patients who received tirzepatide and in 3% of those who received semaglutide. CONCLUSIONS: In patients with type 2 diabetes, tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks. (Funded by Eli Lilly; SURPASS-2 ClinicalTrials.gov number, NCT03987919.).

Metformin use and mortality and length of stay among hospitalized patients with type 2 diabetes and COVID-19: A multiracial, multiethnic, urban observational study.

Introduction: Diabetes mellitus is a common comorbidity among patients with coronavirus disease 2019 (COVID-19). Diabetic patients with COVID-19 have a two-fold increased risk of death and tend to have more severe infection compared to the general population. Metformin, a first-line medication for diabetes management, has anti-inflammatory and immunomodulatory effects. Previous studies focusing on metformin and COVID-19 clinical outcomes have had mixed results, with some showing a mortality benefit or decreased complications with metformin use. To date, few studies have analyzed such outcomes among a diverse, multiracial community. Methods: This was a retrospective review of patients with Type 2 diabetes and a confirmed COVID-19 infection admitted to an urban academic medical center from January 1, 2020 to May 7, 2020. Baseline characteristics were collected. The primary outcomes of the study were in-hospital mortality and length of stay (LOS). Results: A total of 4462 patients with Type 2 diabetes and confirmed COVID-19 were identified. 41.3% were Black, and 41.5% were Hispanic. There were 1021 patients in the metformin group and 3441 in the non-metformin group. Of note, more participants in the metformin group had comorbid disease and/or advanced diabetes. We found no statistically significant differences between the metformin and non-metformin group in in-hospital mortality (28.1% vs 25.3%, P=0.08) or length of hospital stay in days (7.3 vs. 7.5, P=0.59), even after matching patients on various factors (29.3% vs. 29.6%, P=0.87; 7.7 vs. 8.1, P=0.23). Conclusion: While patients had more comorbid disease and advanced diabetes in the metformin group, there were no significant differences with regard to in-hospital mortality or length of stay due to COVID-19 compared to the non-metformin group. Prospective studies are needed to determine if there is clinical benefit for initiating, continuing, or re-initiating metformin in patients hospitalized with COVID-19.

Diabetes medications and associations with Covid-19 outcomes in the N3C database: A national retrospective cohort study.

BACKGROUND: While vaccination is the most important way to combat the SARS-CoV-2 pandemic, there may still be a need for early outpatient treatment that is safe, inexpensive, and currently widely available in parts of the world that do not have access to the vaccine. There are in-silico, in-vitro, and in-tissue data suggesting that metformin inhibits the viral life cycle, as well as observational data suggesting that metformin use before infection with SARS-CoV2 is associated with less severe COVID-19. Previous observational analyses from single-center cohorts have been limited by size. METHODS: Conducted a retrospective cohort analysis in adults with type 2 diabetes (T2DM) for associations between metformin use and COVID-19 outcomes with an active comparator design of prevalent users of therapeutically equivalent diabetes monotherapy: metformin versus dipeptidyl-peptidase-4-inhibitors (DPP4i) and sulfonylureas (SU). This took place in the National COVID Cohort Collaborative (N3C) longitudinal U.S. cohort of adults with +SARS-CoV-2 result between January 1 2020 to June 1 2021. Findings included hospitalization or ventilation or mortality from COVID-19. Back pain was assessed as a negative control outcome. RESULTS: 6,626 adults with T2DM and +SARS-CoV-2 from 36 sites. Mean age was 60.7 +/- 12.0 years; 48.7% male; 56.7% White, 21.9% Black, 3.5% Asian, and 16.7% Latinx. Mean BMI was 34.1 +/- 7.8kg/m2. Overall 14.5% of the sample was hospitalized; 1.5% received mechanical ventilation; and 1.8% died. In adjusted outcomes, compared to DPP4i, metformin had non-significant associations with reduced need for ventilation (RR 0.68, 0.32-1.44), and mortality (RR 0.82, 0.41-1.64). Compared to SU, metformin was associated with a lower risk of ventilation (RR 0.5, 95% CI 0.28-0.98, p = 0.044) and mortality (RR 0.56, 95%CI 0.33-0.97, p = 0.037). There was no difference in unadjusted or adjusted results of the negative control. CONCLUSIONS: There were clinically significant associations between metformin use and less severe COVID-19 compared to SU, but not compared to DPP4i. New-user studies and randomized trials are needed to assess early outpatient treatment and post-exposure prophylaxis with therapeutics that are safe in adults, children, pregnancy and available worldwide.

Targeting T cell (oxidative) metabolism to improve immunity to viral infection in the context of obesity.

Disorders of systemic metabolism can influence immunity. Individuals with obesity are known to have increased inflammation, increased risk to select autoimmune diseases, impaired response to several infections, and impaired vaccine response. For example, over the last decade, it has become clear that individuals with obesity have increased risk of morbidity and mortality from influenza infection. Unsurprisingly, this finding is also observed in the current COVID-19 pandemic: individuals with obesity, particularly severe obesity, have increased risk of poor outcomes from SARS-CoV-2 infection, including increased rates of hospitalization, ICU admission, mechanical ventilation, and death. Several studies have now demonstrated a critical role for T cells in the context of obesity-associated immune dysfunction in response to viral infection, and one mechanism for this may be altered T cell metabolism. Indeed, recent studies have shown that activated T cells from obese mice have an altered metabolic profile characterized by increased glucose oxidation, both in vitro and in vivo following viral infection. For that reason, treatments that target abnormal immune cell metabolism in obesity may improve outcomes to viral infection. To that end, several recent studies have shown that use of the metabolic drug, metformin, can reverse abnormal T cell metabolism and restore T cell immunity, as well as survival, in response to viral infection. These findings will be discussed in detail here.

COVID-19 and diabetic ketoacidosis: A case series at an urban district hospital in South Africa.

BACKGROUND:  Coronavirus disease 2019 (COVID-19) is associated with an increased prevalence and mortality from diabetic ketoacidosis (DKA) globally. With limited access to specialised care, most patients with DKA in South Africa are managed at district hospital level. This study describes the profile of patients admitted to a district hospital in South Africa with DKA and COVID-19 and examines associated risk factors encountered. METHODS:  This was a case series of all patients presenting to a district hospital with DKA and COVID-19 infection between July 2020 and July 2021. Data extracted included patients' demographic profiles, biochemical results, comorbidities and clinical outcomes. RESULTS:  The median age of the 10 patients admitted during the study period was 39 years old (±12), six of whom were male. The hemoglobin A1c (HbA1c) values on admission ranged from 9.7 to 13.8. Five of the patients had pre-existing type 2 diabetes mellitus (DM). Four of the known DM patients were on metformin only, and one was on biphasic insulin. Three patients had other pre-existing comorbidities, two patients with hypertension and one with human immunodeficiency virus (HIV). Three patients demised, two of whom were hypoxic on admission. CONCLUSION:  Diabetic ketoacidosis appears more commonly in COVID-19 infected patients with type 2 DM and at a young age. Suboptimal glycaemic control was associated with DKA, and hypoxia was a strong predictor for mortality. Treatment inertia was evident in the known DM group, who were on monotherapy despite persistent hyperglycaemia. Greater vigilance is required to detect ketosis in type 2 DM and intensify therapy to improve glycaemic control.