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1.
Biomed Pharmacother ; 144: 112230, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1517059

ABSTRACT

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has become a serious challenge for medicine and science. Analysis of the molecular mechanisms associated with the clinical manifestations and severity of COVID-19 has identified several key points of immune dysregulation observed in SARS-CoV-2 infection. For diabetic patients, factors including higher binding affinity and virus penetration, decreased virus clearance and decreased T cell function, increased susceptibility to hyperinflammation, and cytokine storm may make these patients susceptible to a more severe course of COVID-19 disease. Metabolic changes induced by diabetes, especially hyperglycemia, can directly affect the immunometabolism of lymphocytes in part by affecting the activity of the mTOR protein kinase signaling pathway. High mTOR activity can enhance the progression of diabetes due to the activation of effector proinflammatory subpopulations of lymphocytes and, conversely, low activity promotes the differentiation of T-regulatory cells. Interestingly, metformin, an extensively used antidiabetic drug, inhibits mTOR by affecting the activity of AMPK. Therefore, activation of AMPK and/or inhibition of the mTOR-mediated signaling pathway may be an important new target for drug therapy in COVID-19 cases mostly by reducing the level of pro-inflammatory signaling and cytokine storm. These suggestions have been partially confirmed by several retrospective analyzes of patients with diabetes mellitus hospitalized for severe COVID-19.


Subject(s)
COVID-19/drug therapy , Diabetes Mellitus/drug therapy , Hypoglycemic Agents/therapeutic use , Immunity, Cellular/drug effects , Metformin/therapeutic use , Severity of Illness Index , COVID-19/epidemiology , COVID-19/immunology , COVID-19/metabolism , Diabetes Mellitus/epidemiology , Diabetes Mellitus/immunology , Diabetes Mellitus/metabolism , Humans , Hypoglycemic Agents/pharmacology , Immunity, Cellular/physiology , Lymphocytes/drug effects , Lymphocytes/immunology , Lymphocytes/metabolism , Metformin/pharmacology , Mortality/trends , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/immunology , TOR Serine-Threonine Kinases/metabolism
2.
Geroscience ; 43(3): 1093-1112, 2021 06.
Article in English | MEDLINE | ID: covidwho-1499503

ABSTRACT

We are in the midst of the global pandemic. Though acute respiratory coronavirus (SARS-COV2) that leads to COVID-19 infects people of all ages, severe symptoms and mortality occur disproportionately in older adults. Geroscience interventions that target biological aging could decrease risk across multiple age-related diseases and improve outcomes in response to infectious disease. This offers hope for a new host-directed therapeutic approach that could (i) improve outcomes following exposure or shorten treatment regimens; (ii) reduce the chronic pathology associated with the infectious disease and subsequent comorbidity, frailty, and disability; and (iii) promote development of immunological memory that protects against relapse or improves response to vaccination. We review the possibility of this approach by examining available evidence in metformin: a generic drug with a proven safety record that will be used in a large-scale multicenter clinical trial. Though rigorous translational research and clinical trials are needed to test this empirically, metformin may improve host immune defenses and confer protection against long-term health consequences of infectious disease, age-related chronic diseases, and geriatric syndromes.


Subject(s)
COVID-19 , Communicable Diseases , Metformin , Aged , Communicable Diseases/drug therapy , Humans , Metformin/therapeutic use , Multicenter Studies as Topic , RNA, Viral , SARS-CoV-2
3.
Drug Saf ; 43(7): 657-660, 2020 07.
Article in English | MEDLINE | ID: covidwho-1482335

ABSTRACT

INTRODUCTION: Hydroxychloroquine was recently promoted in patients infected with COVID-19 infection. A recent experimental study has suggested an increased toxicity of hydroxychloroquine in association with metformin in mice. OBJECTIVE: The present study was undertaken to investigate the reality of this putative drug-drug interaction between hydroxychloroquine and metformin using pharmacovigilance data. METHODS: Using VigiBase®, the WHO pharmacovigilance database, we performed a disproportionality analysis (case/non-case study). Cases were reports of fatal outcomes with the drugs of interest and non-cases were all other reports for these drugs registered between 1 January 2000 and 31 December 2019. Data with hydroxychloroquine (or metformin) alone were compared with the association hydroxychloroquine + metformin. Results are reported as ROR (reporting odds ratio) with their 95% confidence interval. RESULTS: Of the 10,771 Individual Case Safety Reports (ICSR) involving hydroxychloroquine, 52 were recorded as 'fatal outcomes'. In comparison with hydroxychloroquine alone, hydroxychloroquine + metformin was associated with an ROR value of 57.7 (23.9-139.3). In comparison with metformin alone, hydroxychloroquine + metformin was associated with an ROR value of 6.0 (2.6-13.8). CONCLUSION: Our study identified a signal for the association hydroxychloroquine + metformin that appears to be more at risk of fatal outcomes (particularly by completed suicides) than one of the two drugs when given alone.


Subject(s)
Coronavirus Infections , Drug Interactions , Drug Therapy, Combination , Hydroxychloroquine , Metformin , Pandemics , Pneumonia, Viral , Adult , Adverse Drug Reaction Reporting Systems/statistics & numerical data , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Drug Therapy, Combination/adverse effects , Drug Therapy, Combination/mortality , Female , Humans , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/therapeutic use , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Male , Metformin/pharmacokinetics , Metformin/therapeutic use , Middle Aged , Pharmacovigilance , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , SARS-CoV-2
4.
BMJ Open ; 11(10): e052310, 2021 10 20.
Article in English | MEDLINE | ID: covidwho-1476607

ABSTRACT

OBJECTIVES: To investigate the association between baseline use of glucose-lowering drugs and serious clinical outcome among patients with type 2 diabetes. DESIGN: Territory-wide retrospective cohort of confirmed cases of COVID-19 between January 2020 and February 2021. SETTING: All public health facilities in Hong Kong. PARTICIPANTS: 1220 patients with diabetes who were admitted for confirmed COVID-19. PRIMARY AND SECONDARY OUTCOME MEASURES: Composite clinical endpoint of intensive care unit admission, requirement of invasive mechanical ventilation and/or in-hospital death. RESULTS: In this cohort (median age 65.3 years, 54.3% men), 737 (60.4%) patients were treated with metformin, 385 (31.6%) with sulphonylureas, 199 (16.3%) with dipeptidyl peptidase-4 (DPP-4) inhibitors and 273 (22.4%) with insulin prior to admission. In multivariate Cox regression, use of metformin and DPP-4 inhibitors was associated with reduced incidence of the composite endpoint relative to non-use, with respective HRs of 0.51 (95% CI 0.34 to 0.77, p=0.001) and 0.46 (95% CI 0.29 to 0.71, p<0.001), adjusted for age, sex, diabetes duration, glycated haemoglobin (HbA1c), smoking, comorbidities and drugs. Use of sulphonylureas (HR 1.55, 95% CI 1.07 to 2.24, p=0.022) and insulin (HR 6.34, 95% CI 3.72 to 10.78, p<0.001) were both associated with increased hazards of the composite endpoint. CONCLUSIONS: Users of metformin and DPP-4 inhibitors had fewer adverse outcomes from COVID-19 compared with non-users, whereas insulin and sulphonylurea might predict a worse prognosis.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Metformin , Pharmaceutical Preparations , Aged , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Female , Glucose , Hong Kong/epidemiology , Hospital Mortality , Humans , Hypoglycemic Agents/therapeutic use , Male , Metformin/therapeutic use , Retrospective Studies , SARS-CoV-2
5.
Pediatr Endocrinol Diabetes Metab ; 27(2): 134-140, 2021.
Article in English | MEDLINE | ID: covidwho-1405503

ABSTRACT

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.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Metformin , Diabetes Mellitus, Type 2/drug therapy , Female , Humans , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Pregnancy , SARS-CoV-2
6.
Sci Rep ; 11(1): 17968, 2021 09 09.
Article in English | MEDLINE | ID: covidwho-1402115

ABSTRACT

The impact of overlapping risk factors on coronavirus disease (COVID-19) severity is unclear. To evaluate the impact of type 2 diabetes (T2D) and obesity on COVID-19 severity, we conducted a cohort study with 28,095 anonymized COVID-19 patients using data from the COVID-19 Research Database from January 1, 2020 to November 30, 2020. The mean age was 50.8 ± 17.5 years, and 11,802 (42%) patients were male. Data on age, race, sex, T2D complications, antidiabetic medication prescription, and body mass index ≥ 30 kg/m2 (obesity) were analysed using Cox proportional hazard models, with hospitalization risk and critical care within 30 days of COVID-19 diagnosis as the main outcomes. The risk scores were 0-4 for age ≥ 65 years, male sex, T2D, and obesity. Among the participants, 11,294 (61.9%) had obesity, and 4445 (15.8%) had T2D. T2D, obesity, and male sex were significantly associated with COVID-19 hospitalization risk. Regarding hospitalization risk scores, compared with those for hospitalization risk score 0 and critical care risk score 0, hazard ratios [95% confidence intervals] were 19.034 [10.470-34.600] and 55.803 [12.761-244.015] (P < 0.001) (P < 0.001), respectively, for risk score 4. Complications from diabetes and obesity increased hospitalization and critical care risks for COVID-19 patients.


Subject(s)
COVID-19/pathology , Critical Care/statistics & numerical data , Diabetes Mellitus, Type 2/pathology , Obesity/pathology , Severity of Illness Index , Aged , Aging/pathology , COVID-19/drug therapy , Diabetes Complications/pathology , Female , Hospitalization/statistics & numerical data , Humans , Hypoglycemic Agents/therapeutic use , Intensive Care Units/statistics & numerical data , Male , Metformin/therapeutic use , Middle Aged , Risk Factors , SARS-CoV-2 , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , United States
8.
Front Endocrinol (Lausanne) ; 12: 587801, 2021.
Article in English | MEDLINE | ID: covidwho-1348470

ABSTRACT

Metformin is the first-line medication for type 2 diabetes, but it also has a long history of improved outcomes in infectious diseases, such as influenza, hepatitis C, and in-vitro assays of zika. In the current Covid-19 pandemic, which has rapidly spread throughout the world, 4 observational studies have been published showing reduced mortality among individuals with home metformin use. There are several potential overlapping mechanisms by which metformin may reduce mortality from Covid-19. Metformin's past anti-infectious benefits have been both against the infectious agent directly, as well as by improving the underlying health of the human host. It is unknown if the lower mortality suggested by observational studies in patients infected with Covid-19 who are on home metformin is due to direct activity against the virus itself, improved host substrate, or both.


Subject(s)
COVID-19/drug therapy , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Humans , Treatment Outcome
9.
Bioengineered ; 12(1): 4757-4767, 2021 12.
Article in English | MEDLINE | ID: covidwho-1337229

ABSTRACT

Metformin, a common clinical drug used to treat diabetes mellitus, is found with potential antiobese actions as reported in increasing evidences. However, the detailed mechanisms of metformin-antiobesity-related hypertension remain unrevealed. We have utilized the bioinformatics strategy, including network pharmacology and molecular docking analyses, to uncover pharmacological targets and molecular pathways of bioactive compounds against clinical disorders, such as cancers, coronavirus disease 2019. In this report, the in-silico approaches using network pharmacology and molecular docking was utilized to identify the core targets, pharmacological functions and mechanisms of metformin against obesity-related hypertension. The networking analysis identified 154 differentially expressed genes of obesity and hypertension, and 21 interaction genes, 6 core genes of metformin treating obesity-related hypertension. As results, molecular docking findings indicated the binding capability of metformin with key proteins, including interleukin 6 (IL-6) and chemokine (C-C motif) Ligand 2 (CCL2) expressed in obesity- and hypertension-dependent tissues. Metformin-exerted antihypertension/obesity actions involved in metabolic regulation, inflammatory suppression. And antihypertension/obesity mechanisms of metformin were revealed, including regulation of inflammatory and immunological signaling pathways for ameliorating microenvironmental homeostasis in targeting tissues. In conclusion, our current bioinformatics findings have uncovered all pharmacological targets, biological functions and signaling pathways of metformin treating obesity-related hypertension, thus promoting its clinical application in future.


Subject(s)
Hypertension/drug therapy , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Computational Biology , Humans , Molecular Docking Simulation , Signal Transduction
10.
Diabetes Res Clin Pract ; 178: 108977, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1322066

ABSTRACT

AIM: COVID-19 has spread globally with heavy impact on most countries and our therapeutic strategies in COVID-19 patients with diabetes are still limited. Recently, some new information was added to this field. We performed this updated meta-analysis to reveal the underlying effect of metformin on COVID-19 patients with diabetes. METHODS: We searched the PubMed, Embase and CNKI (China National Knowledge Infrastructure) databases for all articles. The odds ratio (OR) corresponding to the 95% confidence interval (95% CI) was used to assess the effect of metformin on COVID-19 patients with diabetes. The statistical heterogeneity among studies was assessed with the Q-test and I2 statistics. RESULTS: We collected 17 studies including 20,719 COVID-19 patients with diabetes. Our results found that metformin was associated with significantly decreased mortality and severity in COVID-19 patients with diabetes (OR = 0.64, 95% CI = 0.51-0.79 for mortality, and OR = 0.81, 95% CI = 0.66-0.99 for severity). CONCLUSIONS: Our meta-analysis indicated that following metformin treatment might benefit the patients with T2DM, both the mortality and severity. However, patients with severe COVID-19 should be monitored closely for the development of lactic acidosis, acidosis, and decreased kidney function.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Hypoglycemic Agents , Metformin , COVID-19/mortality , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Humans , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use
11.
Int J Mol Sci ; 22(14)2021 Jul 16.
Article in English | MEDLINE | ID: covidwho-1314668

ABSTRACT

COVID-19 infection poses an important clinical therapeutic problem, especially in patients with coexistent diseases such as type 2 diabetes. Potential pathogenetic links between COVID-19 and diabetes include inflammation, effects on glucose homeostasis, haemoglobin deoxygenation, altered immune status and activation of the renin-angiotensin-aldosterone system (RAAS). Moreover, drugs often used in the clinical care of diabetes (dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, metformin and insulin) may influence the course of SARS-CoV-2 infection, so it is very important to verify their effectiveness and safety. This review summarises the new advances in diabetes therapy and COVID-19 and provides clinical recommendations that are essential for medical doctors and for patients suffering from type 2 diabetes.


Subject(s)
COVID-19/therapy , Diabetes Mellitus, Type 2/therapy , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/complications , COVID-19/epidemiology , COVID-19/physiopathology , Diabetes Mellitus, Type 2/physiopathology , Diabetes Mellitus, Type 2/virology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Glucagon-Like Peptide-1 Receptor/agonists , Humans , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Metformin/therapeutic use , SARS-CoV-2/isolation & purification , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
12.
PLoS Pathog ; 17(6): e1009634, 2021 06.
Article in English | MEDLINE | ID: covidwho-1280641

ABSTRACT

Coronavirus Disease 2019 (COVID-19), caused by a new strain of coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), was declared a pandemic by WHO on March 11, 2020. Soon after its emergence in late December 2019, it was noticed that diabetic individuals were at an increased risk of COVID-19-associated complications, ICU admissions, and mortality. Maintaining proper blood glucose levels using insulin and/or other oral antidiabetic drugs (such as Metformin) reduced the detrimental effects of COVID-19. Interestingly, in diabetic COVID-19 patients, while insulin administration was associated with adverse outcomes, Metformin treatment was correlated with a significant reduction in disease severity and mortality rates among affected individuals. Metformin was extensively studied for its antioxidant, anti-inflammatory, immunomodulatory, and antiviral capabilities that would explain its ability to confer cardiopulmonary and vascular protection in COVID-19. Here, we describe the various possible molecular mechanisms that contribute to Metformin therapy's beneficial effects and lay out the scientific basis of repurposing Metformin for use in COVID-19 patients.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Diabetes Complications/drug therapy , Metformin/therapeutic use , Animals , COVID-19/complications , Drug Repositioning , Humans
13.
Immunity ; 54(7): 1463-1477.e11, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1263294

ABSTRACT

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)-1ß 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.


Subject(s)
Adenosine Triphosphate/metabolism , DNA, Mitochondrial/biosynthesis , Inflammasomes/drug effects , Metformin/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pneumonia/prevention & control , Animals , COVID-19/metabolism , COVID-19/prevention & control , Cytokines/genetics , Cytokines/metabolism , DNA, Mitochondrial/metabolism , Humans , Inflammasomes/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lipopolysaccharides/toxicity , Metformin/therapeutic use , Mice , Nucleoside-Phosphate Kinase/metabolism , Pneumonia/metabolism , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2/pathogenicity
14.
Immunopharmacol Immunotoxicol ; 43(3): 265-270, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1246577

ABSTRACT

Understanding the exact role of current drugs in Covid-19 disease is essential in the era of global pandemics. Metformin which prescribed as the first-line treatment of type 2 diabetes has beneficial effects on Sars-cov2 infection. These effects are including regulation of immune system, Renin-Angiotensin System and Dipeptidyl Peptidase 4 function in Covid-19 infection. It also activates ACE2, the main receptor of Sars-cov2, in the epithelial cells of respiratory tissue through AMPK signaling and subsequently decreases the rate of viral adhesion. Metformin also declines the adherence of Sars-cov2 to DPP4 (the other receptor of the virus) on T cells. Hence, regulatory effects of metformin on membranous ACE2, and DPP4 can modulate immune reaction against Sars-cov2. Also, immunometabolic effects of metformin on inflammatory cells impair hyper-reactive immune response against the virus through reduction of glycolysis and propagation of mitochondrial oxidation. Metformin also decreases platelet aggravation and risk of thrombosis. In this article, we argue that metformin has beneficial effects on Covid-19 infection in patients with type 2 diabetes and insulin resistance. This opinion should be investigated in future clinical trials.


Subject(s)
COVID-19/drug therapy , Diabetes Mellitus, Type 2 , Drug Repositioning , Insulin Resistance , Metformin/therapeutic use , SARS-CoV-2 , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Humans
15.
Front Endocrinol (Lausanne) ; 12: 645194, 2021.
Article in English | MEDLINE | ID: covidwho-1170080

ABSTRACT

Introduction: Diabetes mellitus (DM) is one of the most common comorbidities among patients with coronavirus disease 2019 (COVID-19) which may exacerbate complications of this new viral infection. Metformin is an anti-hyperglycemic agent with host-directed immune-modulatory effects, which relieve exaggerated inflammation and reduce lung tissue damage. The current systematic review aimed to summarize the available evidence on the potential mechanism of action and the efficacy of metformin in COVID-19 patients with DM. Methods: A systematic search was carried out in PubMed/Medline, EMBASE, the Cochrane Controlled Register of Trials (CENTRAL), and Web of Science up to July 30, 2020. The following keywords were used: "COVID-19", "SARS-CoV-2", "2019-nCoV", "metformin", and "antidiabetic drug". Results: Fourteen studies were included in our systematic review. Three of them were observational with 6,659 participants. Decreasing insulin resistance, reduction of some inflammatory cytokines like IL-6 and TNF-α, modulation of angiotensin-converting enzyme 2 (ACE2) receptor, and improving neutrophil to lymphocyte ratio are some of the potential mechanisms of metformin in COVID-19 patients with DM. Nine out of fourteen articles revealed the positive effect of metformin on the prognosis of COVID-19 in diabetic or even non-diabetic patients. Moreover, different studies have shown that metformin is more effective in women than men. Conclusions: The use of metformin may lead to improve the clinical outcomes of patients with mild to moderate SARS-CoV-2, especially in diabetic women. Further observational studies should be conducted to clarify the effects of metformin as a part of the treatment strategy of COVID-19.


Subject(s)
COVID-19/complications , COVID-19/drug therapy , Diabetes Mellitus/drug therapy , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Diabetes Complications/drug therapy , Humans
16.
Diabetes Metab Syndr ; 15(3): 777-782, 2021.
Article in English | MEDLINE | ID: covidwho-1163663

ABSTRACT

BACKGROUND AND AIMS: This study aims to synthesize evidence on dipeptidyl peptidase-4 (DPP-4) inhibitor and mortality in COVID-19 patients and factors affecting it. METHODS: We performed a systematic literature search from PubMed, Scopus, and Embase databases from inception of databases up until 7 March 2021. Studies that met all of the following criteria were included: 1) observational studies or randomized controlled trials that report COVID-19 patients, 2) reporting DPP-4 inhibitor use, 3) mortality, and 4) mortality based on DPP-4 inhibitor use. The exposure was DPP-4 inhibitor, defined as DPP-4 inhibitor use that started prior to COVID-19 hospitalization. The control group was patients with no exposure to DPP-4 inhibitor. The outcome was mortality. The pooled effect estimate was reported as risk ratio (RR). RESULTS: There were 4,477 patients from 9 studies in this systematic review and meta-analysis. 31% of (15%, 46%) the patients use DPP-4 inhibitor. Mortality occurs in 23% (15%, 31%) of the patients. DPP-4 inhibitor was associated with lower mortality in patients with COVID-19 (RR 0.76 [0.60, 0.97], p = 0.030, I2: 44.5%, p = 0.072). Meta-regression analysis showed that the association between DPP-4 inhibitor and mortality was significantly affected by metformin (RR 1.02 [1.00, 1.04], p = 0.048) and angiotensin converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) use (RR 1.04 [1.01, 1.07], p = 0.006), but not age (p = 0.759), sex (reference: male, p = 0.148), and hypertension (p = 0.218). CONCLUSION: DPP-4 inhibitor use was associated with lower mortality in COVID-19 patients, and the association was weaker in patients who were also taking metformin and/or ACE inhibitors.


Subject(s)
COVID-19/mortality , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/complications , COVID-19/epidemiology , Comorbidity , Diabetes Mellitus/drug therapy , Diabetes Mellitus/epidemiology , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Female , Humans , Hypertension/drug therapy , Hypertension/epidemiology , Male , Metformin/therapeutic use , Mortality , Regression Analysis , SARS-CoV-2/drug effects , SARS-CoV-2/physiology
17.
Life Sci ; 275: 119371, 2021 Jun 15.
Article in English | MEDLINE | ID: covidwho-1142119

ABSTRACT

AIMS: Type 2 diabetes is considered to be one of the essential risks of adverse outcomes in coronavirus disease 2019 (COVID-19).1 Metformin and insulin were suggested to affect the outcomes. However, divergent views are still expressed. We aim to gain further insight into metformin and insulin in both pre-admission and in-hospital usage in COVID-19 patients with pre-existed type 2 diabetes. MAIN METHODS: This is a multicentral retrospective study of the hospital confirmed COVID-19 patients between January 19 to April 09, 2020, who admitted to 3 main hospitals in Xiangyang city, China. The effect of type 2 diabetes, metformin, and insulin on COVID-19 were analyzed, respectively. Clinical characteristics, blood laboratory indices, clinical observational indices, and outcomes of these cases were collected. KEY FINDINGS: A total of 407 confirmed COVID-19 patients (including 50 pre-existed type 2 diabetes) were eligible in our study. COVID-19 patients with type 2 diabetes had more adverse outcomes than non-diabetes (OR2: mortality: 1.46 [95% CI3 1.11, 1.93]; P < 0.001). Pre-admission metformin usage showed a declined intensive care unit admission rate in a dose-dependent fashion (OR 0.04 [95% CI 0.00, 0.99]; adjust P = 0.049). While in-hospital insulin usage attempted to increase the invasive ventilation (8 [34.8%] vs. 1 [3.7%], adjust P = 0.043), independent of age and blood glucose. SIGNIFICANCE: Our study indicated that pre-admitted metformin usage may have beneficial effects on COVID-19 with pre-existed type 2 diabetes, insulin should be used sparingly in the hospital stay.


Subject(s)
COVID-19/complications , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Intensive Care Units/statistics & numerical data , Metformin/therapeutic use , SARS-CoV-2/isolation & purification , Adult , Blood Glucose , COVID-19/transmission , COVID-19/virology , China/epidemiology , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/virology , Female , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Retrospective Studies
18.
Eur J Pharmacol ; 898: 173934, 2021 May 05.
Article in English | MEDLINE | ID: covidwho-1086916

ABSTRACT

Metformin is the most commonly prescribed oral antidiabetic medication. Direct/indirect activation of Adenosine Monophosphate-activated protein kinase (AMPK) and non-AMPK pathways, amongst others, are deemed to explain the molecular mechanisms of action of metformin. Metformin is an established insulin receptor sensitising antihyperglycemic agent, is highly affordable, and has superior safety and efficacy profiles. Emerging experimental and clinical evidence suggests that metformin has pleiotropic non-glycemic effects. Metformin appears to have weight stabilising, renoprotective, neuroprotective, cardio-vascular protective, and antineoplastic effects and mitigates polycystic ovarian syndrome. Anti-inflammatory and antioxidant effects of metformin seem to qualify it as an adjunct therapy in treating infectious diseases such as tuberculosis, viral hepatitis, and the current novel Covid-19 infections. So far, metformin is the only prescription medicine relevant to the emerging field of senotherapeutics. Non-glycemic effects of metformin favourable to its repurposing in therapeutic use are hereby discussed.


Subject(s)
Anti-Infective Agents/therapeutic use , Antineoplastic Agents/therapeutic use , Hypoglycemic Agents/therapeutic use , Immunologic Factors/therapeutic use , Metformin/therapeutic use , Protective Agents/therapeutic use , Animals , Anti-Infective Agents/adverse effects , Antineoplastic Agents/adverse effects , COVID-19/drug therapy , COVID-19/epidemiology , Cardiovascular Diseases/prevention & control , Female , Humans , Hypoglycemic Agents/adverse effects , Immunologic Factors/adverse effects , Kidney Diseases/prevention & control , Metabolic Syndrome/drug therapy , Metformin/adverse effects , Obesity/drug therapy , Pandemics , Polycystic Ovary Syndrome/drug therapy , Protective Agents/adverse effects , SARS-CoV-2
19.
Diabetes Metab Syndr ; 15(2): 513-518, 2021.
Article in English | MEDLINE | ID: covidwho-1086908

ABSTRACT

BACKGROUND AND AIMS: Metformin has antiviral and anti-inflammatory effects and several cohort studies have shown that metformin lower mortality in the COVID population in a majority white population. There is no data documenting the effect of metformin taken as an outpatient on COVID-19 related hospitalizations. Our aim was to evaluate if metformin decreases hospitalization and severe COVID-19 among minority Medicare patients who acquired the SARS-CoV2 virus. METHODS: We conducted a retrospective cohort study including elderly minority Medicare COVID-19 patients across eight states. We collected data from the inpatient and outpatient electronic health records, demographic data, as well as clinical and echocardiographic data. We classified those using metformin as those patients who had a pharmacy claim for metformin and non-metformin users as those who were diabetics and did not use metformin as well as non-diabetic patients. Our primary outcome was hospitalization. Our secondary outcomes were mortality and acute respiratory distress syndrome (ARDS). RESULTS: We identified 1139 COVID-19 positive patients of whom 392 were metformin users. Metformin users had a higher comorbidity score than non-metformin users (p < 0.01). The adjusted relative hazard (RH) of those hospitalized for metformin users was 0.71; 95% CI 0.52-0.86. The RH of death for metformin users was 0.34; 95% CI 0.19-0.59. The RH of ARDS for metformin users was 0.32; 95% CI 0.22-0.45. Metformin users on 1000 mg daily had lower mortality, but similar hospitalization and ARDS rates when compared to those on 500-850 mg of metformin daily. CONCLUSIONS: Metformin is associated with lower hospitalization, mortality and ARDS among a minority COVID-19 population. Future randomized trials should confirm this finding and evaluate for a causative effect of the drug preventing disease.


Subject(s)
COVID-19/physiopathology , Diabetes Mellitus, Type 2/drug therapy , Hospitalization/statistics & numerical data , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Respiratory Distress Syndrome/epidemiology , African Americans , Aged , Aged, 80 and over , COVID-19/mortality , Cause of Death , Dose-Response Relationship, Drug , Female , Humans , Male , Medicare , Minority Groups , Proportional Hazards Models , Protective Factors , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , United States/epidemiology
20.
Acta Diabetol ; 58(6): 771-778, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1083192

ABSTRACT

AIMS: The relationship between metformin therapy and the risk of coronavirus disease (COVID-19) has not been reported among patients with type 2 diabetes mellitus (DM). We aimed to investigate whether metformin therapy was associated with the incidence of COVID-19 among type 2 DM patients in South Korea. METHODS: The National Health Insurance Service-COVID-19 cohort database, comprising COVID-19 patients from 1 January 2020 to 4 June 2020, was used for this study. Among them, adult patients with type 2 DM were included in this study. Metformin users were defined as those who had been prescribed continuous oral metformin for over a period of ≥ 90 days, and the control group was defined as all other patients. RESULTS: Overall, 27,493 patients with type 2 DM (7204, metformin user group; 20,289, control group) were included. After propensity score matching, 11,892 patients (5946 patients in each group) were included in the final analysis. In the logistic regression analysis, the odds of metformin users developing COVID-19 was 30% lower than that of the control group [odds ratio (OR): 0.70, 95% confidence interval (CI): 0.61-0.80; P < 0.001]. However, in the multivariate model, metformin use was not associated with hospital mortality when compared with that of the control group (OR: 1.26, 95% CI: 0.81-1.95; P = 0.301). CONCLUSIONS: Metformin therapy might have potential benefits for the prevention of COVID-19 among patients with type 2 DM in South Korea. However, it did not affect the hospital mortality of type 2 DM patients diagnosed with COVID-19.


Subject(s)
COVID-19/epidemiology , Databases, Factual/trends , Diabetes Mellitus, Type 2/epidemiology , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , National Health Programs/trends , Adult , Aged , COVID-19/chemically induced , COVID-19/prevention & control , Cohort Studies , Diabetes Mellitus, Type 2/drug therapy , Hospital Mortality/trends , Humans , Hypoglycemic Agents/adverse effects , Male , Metformin/adverse effects , Middle Aged , Republic of Korea/epidemiology , Risk Factors
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