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Theranostics 2022Aging is a natural process, which plays a critical role in the pathogenesis of a variety of diseases, i.e., aging-related diseases, such as diabetes, osteoarthritis,... (Review)
Review
Aging is a natural process, which plays a critical role in the pathogenesis of a variety of diseases, i.e., aging-related diseases, such as diabetes, osteoarthritis, Alzheimer disease, cardiovascular diseases, cancers, obesity and other metabolic abnormalities. Metformin, the most widely used antidiabetic drug, has been reported to delay aging and display protective effect on attenuating progression of various aging-related diseases by impacting key hallmark events of aging, including dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, altered intercellular communication, telomere attrition, genomic instability, epigenetic alterations, stem cell exhaustion and cellular senescence. In this review, we provide updated information and knowledge on applications of metformin in prevention and treatment of aging and aging-related diseases. We focus our discussions on the roles and underlying mechanisms of metformin in modulating aging and treating aging-related diseases.
Topics: Aging; Cellular Senescence; Genomic Instability; Humans; Metformin; Telomere
PubMed: 35401820
DOI: 10.7150/thno.71360 -
Drugs Jul 2015People with elevated, non-diabetic, levels of blood glucose are at risk of progressing to clinical type 2 diabetes and are commonly termed 'prediabetic'. The term... (Review)
Review
People with elevated, non-diabetic, levels of blood glucose are at risk of progressing to clinical type 2 diabetes and are commonly termed 'prediabetic'. The term prediabetes usually refers to high-normal fasting plasma glucose (impaired fasting glucose) and/or plasma glucose 2 h following a 75 g oral glucose tolerance test (impaired glucose tolerance). Current US guidelines consider high-normal HbA1c to also represent a prediabetic state. Individuals with prediabetic levels of dysglycaemia are already at elevated risk of damage to the microvasculature and macrovasculature, resembling the long-term complications of diabetes. Halting or reversing the progressive decline in insulin sensitivity and β-cell function holds the key to achieving prevention of type 2 diabetes in at-risk subjects. Lifestyle interventions aimed at inducing weight loss, pharmacologic treatments (metformin, thiazolidinediones, acarbose, basal insulin and drugs for weight loss) and bariatric surgery have all been shown to reduce the risk of progression to type 2 diabetes in prediabetic subjects. However, lifestyle interventions are difficult for patients to maintain and the weight loss achieved tends to be regained over time. Metformin enhances the action of insulin in liver and skeletal muscle, and its efficacy for delaying or preventing the onset of diabetes has been proven in large, well-designed, randomised trials, such as the Diabetes Prevention Program and other studies. Decades of clinical use have demonstrated that metformin is generally well-tolerated and safe. We have reviewed in detail the evidence base supporting the therapeutic use of metformin for diabetes prevention.
Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Prediabetic State
PubMed: 26059289
DOI: 10.1007/s40265-015-0416-8 -
American Journal of Health-system... Apr 1997The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of metformin hydrochloride are reviewed.... (Review)
Review
The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of metformin hydrochloride are reviewed. Metformin is an antihyperglycemic agent; it lowers the blood glucose concentration without causing hypoglycemia. Proposed mechanisms of action include decreased intestinal absorption of glucose, increased glucose uptake from the blood into the tissues, decreased glucose production in the liver, and decreased insulin requirements for glucose disposal. Metformin is slowly absorbed from the small intestine and does not undergo hepatic metabolism. The half-life is about five hours. The major route of elimination is renal; the drug is contraindicated in patients with impaired renal function. In double-blind, placebo-controlled trials, metformin has shown efficacy in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). The drug is as effective as sulfonylureas in patients with diabetes who are nonobese or obese and whose diabetes is uncontrolled by diet alone. Metformin may be useful as addon therapy in obese patients with diabetes uncontrolled by sulfonylureas and diet. Lipid profiles may be favorably influenced. The most common adverse effects are gastrointestinal. A rare but potentially fatal adverse effect is lactic acidosis. Metformin has the potential to interact with cationic drugs eliminated by the renal tubular pathway. The usual effective dosage is 1.5-2.5 g/day orally in two or three divided doses. Metformin hydrochloride is an effective alternative to sulfonylureas in obese and non-obese patients with NIDDM in whom diet alone has not achieved glycemic control, and it may be useful as addon therapy in patients whose diabetes has not responded adequately to sulfonylureas plus dietary measures.
Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Interactions; Female; Glucose; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Metformin
PubMed: 9114921
DOI: 10.1093/ajhp/54.8.893 -
Expert Review of Endocrinology &... Mar 2019Combining antihyperglycemic agents in order to rapidly and safely achieve the best possible glycemic control is the standard of care today for the management of type 2... (Review)
Review
Combining antihyperglycemic agents in order to rapidly and safely achieve the best possible glycemic control is the standard of care today for the management of type 2 diabetes. Agents should ideally have mechanisms of actions that are complementary and that improve glycemic control without unacceptable gain in body weight or hypoglycemia. Areas covered: Ertugliflozin and metformin hydrochloride (ertugliflozin/metformin, SEGLUROMET) is a recently approved fixed-dose combination tablet containing the sodium-glucose co-transporter 2 (SGLT-2) inhibitor ertugliflozin and metformin. This review summarizes key characteristics of ertugliflozin and metformin, as well as the efficacy and safety results of co-administration of these agents in the ertugliflozin clinical development program. This information comes from the ertugliflozin/metformin prescribing information as well as published clinical trials obtained through a PubMed search. Expert commentary: SGLT-2 inhibitors are an important class of antihyperglycemic agents that are efficacious as monotherapy and in combination with other antihyperglycemic agents. Given their favorable effects on glycemia control as well as 'extra-glycemic' parameters such as body weight and blood pressure, they are ideal agents for appropriate patients with type 2 diabetes. The fixed-dose combination of ertugliflozin with metformin is an effective combination that is conveniently administered and may improve medication adherence and persistence.
Topics: Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Combinations; Humans; Hypoglycemic Agents; Metformin; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Treatment Outcome
PubMed: 30724637
DOI: 10.1080/17446651.2019.1571908 -
Pharmacological Research Mar 2022Metformin is the oldest and most commonly used first-line antidiabetic drug because of its good clinical efficacy, high safety, low cost and easy access. At the same... (Review)
Review
Metformin is the oldest and most commonly used first-line antidiabetic drug because of its good clinical efficacy, high safety, low cost and easy access. At the same time, in recent years, we have found that its role as a therapeutic drug is gradually expanding. A large number of basic studies have shown that metformin may become a promising attractive candidate for drug repurposing. Therefore, it is extremely beneficial to conduct an in-depth discussion on the main mechanism of metformin. As early as the year 1950, studies showed that metformin played a biological role by regulating mitochondria. Then, ground-breaking studies showed that metformin functions by inhibiting complex I in the mitochondrial respiratory chain. Although there are still many controversies about the key molecular targets of metformin, with the emergence of more and more evidence, it gradually came to be concluded that mitochondria play a central role in the application of metformin. Mitochondria are important fulcrums for cell functions. The exact mechanism of action in mitochondria of this pleiotropic anti-hyperglycaemic molecule is still unclear. This review article explores the core role of mitochondria in the pharmacological and toxicological effects of metformin, and summarises the mechanism of action if metformin in mitochondria. It also provides ideas and supporting evidence for the re-development and reuse of metformin as an old drug, as well as new insight into the treatment of human diseases.
Topics: Humans; Hypoglycemic Agents; Metformin; Mitochondria
PubMed: 35124206
DOI: 10.1016/j.phrs.2022.106114 -
Drug Delivery Oct 2016Metformin hydrochloride is a biguanide derivative widely used for the treatment of type 2 diabetes, prescribed nearly to 120 million people worldwide. Metformin has a... (Review)
Review
CONTEXT
Metformin hydrochloride is a biguanide derivative widely used for the treatment of type 2 diabetes, prescribed nearly to 120 million people worldwide. Metformin has a relatively low oral bioavailability (about 50-60%). Although the major effect of metformin is to decrease hepatic glucose output as an antihyperglycemic agent, its inhibitory effects on the proliferation of some cancer cells (e.g. prostate, breast, glioma cells) have been demonstrated in the cell culture studies. Development of novel formulation (e.g. microparticles, nanoparticles) strategies for metformin might be useful to improve its bioavailability, to reduce the dosing frequency, to decrease gastrointestinal side effects and toxicity and to be helpful for effective use of metformin in cancer treatment.
OBJECTIVE
The main aim of this review is to summarize metformin HCl-loaded micro- and nanoparticulate drug delivery systems.
METHOD
The literature was rewieved with regard to the physicochemical, pharmacological properties of metformin, and also its mechanism of action in type 2 diabetes and cancer. In addition, micro- and nanoparticulate drug delivery systems developed for metformin were gathered from the literature and the results were discussed.
CONCLUSION
Metformin is an oral antihyperglycemic agent and also has potential antitumorigenic effects. The repeated applications of high doses of metformin (as immediate release formulations) are needed for an effective treatment due to its low oral bioavailability and short biological half-life. Drug delivery systems are very useful systems to overcome the difficulties associated with conventional dosage forms of metformin and also for its effective use in cancer treatment.
Topics: Chemistry, Pharmaceutical; Diabetes Mellitus, Type 2; Drug Delivery Systems; Humans; Hypoglycemic Agents; Metformin; Nanoparticles
PubMed: 26394019
DOI: 10.3109/10717544.2015.1089957 -
Cell Metabolism Feb 2024Here, we summarize the current knowledge on eight promising drugs and natural compounds that have been tested in the clinic: metformin, NAD precursors, glucagon-like... (Review)
Review
Here, we summarize the current knowledge on eight promising drugs and natural compounds that have been tested in the clinic: metformin, NAD precursors, glucagon-like peptide-1 receptor agonists, TORC1 inhibitors, spermidine, senolytics, probiotics, and anti-inflammatories. Multiple clinical trials have commenced to evaluate the efficacy of such agents against age-associated diseases including diabetes, cardiovascular disease, cancer, and neurodegenerative diseases. There are reasonable expectations that drugs able to decelerate or reverse aging processes will also exert broad disease-preventing or -attenuating effects. Hence, the outcome of past, ongoing, and future disease-specific trials may pave the way to the development of new anti-aging medicines. Drugs approved for specific disease indications may subsequently be repurposed for the treatment of organism-wide aging consequences.
Topics: Humans; NAD; Aging; Metformin; Cardiovascular Diseases; Neoplasms
PubMed: 38181790
DOI: 10.1016/j.cmet.2023.12.007 -
Clinical Therapeutics Dec 2003Type 2 diabetes mellitus typically involves abnormal beta-cell function that results in relative insulin deficiency, insulin resistance accompanied by decreased glucose... (Review)
Review
BACKGROUND
Type 2 diabetes mellitus typically involves abnormal beta-cell function that results in relative insulin deficiency, insulin resistance accompanied by decreased glucose transport into muscle and fat cells, and increased hepatic glucose output, all of which contribute to hyperglycemia.
OBJECTIVE
This review examines the pharmacology, pharmacokinetics, drug-interaction potential, adverse effects, and dosing guidelines for metformin hydrochloride, a biguanide agent for the treatment of type 2 diabetes. Clinical trial data are reviewed, including efficacy and tolerability information, with a focus on studies of dual metformin therapy (metformin plus another oral agent or insulin) published from 1998 to the present. Pharmacoeconomic considerations are also discussed.
METHODS
Primary research and review articles were identified through a search of MEDLINE (1966-May 2003) and International Pharmaceutical Abstracts (1970-May 2003) using the terms metformin and/or Glucophage. Web of Science (1995-May 2003) was used to search for additional abstracts. The package inserts for metformin and metformin combination products were consulted. All identified articles and abstracts were assessed for relevance, and all relevant information was included. Priority was given to the primary medical literature and clinical trial reports.
RESULTS
Metformin is the only currently available oral antidiabetic/hypoglycemic agent that acts predominantly by inhibiting hepatic glucose release. Because patients with type 2 diabetes often have excess hepatic glucose output, use of metformin is effective in lowering glycosylated hemoglobin (HbA1c) by 1 to 2 percentage points when used as monotherapy or in combination with other blood glucose-lowering agents or insulin. Other metabolic variables (eg, dyslipidemia, fibrinolysis) may be improved with the use of metformin. Body weight is often maintained or slightly reduced from baseline. Metformin is well tolerated and is associated with few clinically deleterious adverse events. The most important and potentially life-threatening adverse event associated with its use is lactic acidosis, which occurs very rarely.
CONCLUSIONS
Metformin has multiple benefits in patients with type 2 diabetes. It can effectively lower HbA1c values, positively affect lipid profiles, and improve vascular and hemodynamic indices. Adverse effects are generally tolerable and self-limiting. The availability of products combining metformin with a sulfonylurea or rosiglitazone has expanded the array of therapies for the management of type 2 diabetes.
Topics: Clinical Trials as Topic; Contraindications; Diabetes Mellitus, Type 2; Drug Interactions; Drug Therapy, Combination; Glyburide; Humans; Hypoglycemic Agents; Metformin; Rosiglitazone; Sulfonylurea Compounds; Thiazolidinediones
PubMed: 14749143
DOI: 10.1016/s0149-2918(03)90089-0 -
Science Advances Sep 2022Ovarian fibrosis is a pathological condition associated with aging and is responsible for a variety of ovarian dysfunctions. Given the known contributions of tissue...
Ovarian fibrosis is a pathological condition associated with aging and is responsible for a variety of ovarian dysfunctions. Given the known contributions of tissue fibrosis to tumorigenesis, it is anticipated that ovarian fibrosis may contribute to ovarian cancer risk. We recently reported that diabetic postmenopausal women using metformin had ovarian collagen abundance and organization that were similar to premenopausal ovaries from nondiabetic women. In this study, we investigated the effects of aging and metformin on mouse ovarian fibrosis at a single-cell level. We discovered that metformin treatment prevented age-associated ovarian fibrosis by modulating the proportion of fibroblasts, myofibroblasts, and immune cells. Senescence-associated secretory phenotype (SASP)-producing fibroblasts increased in aged ovaries, and a unique metformin-responsive subpopulation of macrophages emerged in aged mice treated with metformin. The results demonstrate that metformin can modulate specific populations of immune cells and fibroblasts to prevent age-associated ovarian fibrosis and offers a new strategy to prevent ovarian fibrosis.
Topics: Animals; Female; Fibroblasts; Fibrosis; Humans; Metformin; Mice; Myofibroblasts; Ovary
PubMed: 36054356
DOI: 10.1126/sciadv.abq1475 -
Life Sciences Mar 2022Metformin hydrochloride is a highly hydrophilic molecule with low permeability. In the present study, to develop an effective drug to treat the metastatic breast cancer,...
AIMS
Metformin hydrochloride is a highly hydrophilic molecule with low permeability. In the present study, to develop an effective drug to treat the metastatic breast cancer, metformin caprylic acid was synthesized using metformin hydrochloride as a permeable agent.
MAIN METHODS
The cytotoxic effects of various concentrations of metformin caprylic acid and metformin hydrochloride (0 to 20 mM) on MCF-7 and MDA-MB-231 breast cancer cells and MCF-10A human mammary epithelial cell line were assessed by the MTT assay. Furthermore, Annexin V, PI staining, and cell flow cytometry assays were performed to evaluate the apoptotic effects. The invasion and migration ability of these cells were evaluated following treatment with equal concentration (3 mM) of the two compounds.
KEY FINDINGS
The treatment of tested cell lines with an equal concentration of two chemicals decreased cell viability in a time and dose-dependent manner, where in all cases, metformin caprylic acid caused significantly more apoptosis and invasion inhibition than that of metformin hydrochloride (*p < 0.05). Chemical structures of both compounds were confirmed by FTIR and H NMR, C NMR. Both chemicals inhibited the migration of MCF-7 and MCF-10A cells, but had no effect on MDA-MB-231 migration. All data are expressed as mean ± SD (n = 3).
SIGNIFICANCE
It seems that in an equal concentration, the similarity of the hydrophobic tail of caprylic acid to the cell membrane improves its entrance, while decreasing the drug excretion.
Topics: Breast Neoplasms; Caprylates; Cell Survival; Dose-Response Relationship, Drug; Female; Humans; MCF-7 Cells; Metformin
PubMed: 35016878
DOI: 10.1016/j.lfs.2022.120308