| Drug ID: | D157 |
| Drug Name: | Glucophage |
| Synonyms: |
1,1-Dimethylbiguanide; Dimethylbiguanid; Metformin; Metformine
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| Type: | Chemical drug |
| DrugBank ID: |
DB00331
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| DrugBank Description: |
Metformin is an antihyperglycemic agent of the _biguanide_ class, used for the management of type II diabetes) . Currently, metformin is the first drug of choice for the management of type II diabetes and is prescribed to at least 120 million people worldwide .
Metformin is considered an antihyperglycemic drug because it lowers blood glucose concentrations in type II diabetes without causing hypoglycemia. Metformin is commonly described as an _insulin sensitizer_ leading to a decrease in insulin resistance and a clinically significant reduction of plasma fasting insulin levels . Another well-known benefit of this drug is modest weight loss. Metformin is the drug of choice for obese type II diabetes patients .
Metformin was first approved in Canada in 1972 , followed by 1995 in the USA . This drug is available in regular and extended-release forms .
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| PubChem ID: |
14219
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| CasNo: |
1115-70-4
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| Repositioning for NAFLD: |
Yes
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| SMILES: |
C(=N)(NC(=N)N)N(C)C.Cl
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| Structure: |
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| InChiKey: |
OETHQSJEHLVLGH-UHFFFAOYSA-N
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| Molecular Weight: |
165.628
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| DrugBank Targets: |
5'-AMP-activated protein kinase subunit beta-1 inducer&activator; Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial inhibitor; Glycerol-3-phosphate dehydrogenase [NAD(+)], cytoplasmic inhibitor
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| DrugBank MoA: |
Metformin's mechanisms of action are unique from other classes of oral antihyperglycemic drugs. Metformin decreases blood glucose levels by decreasing hepatic glucose production (gluconeogenesis), decreasing the intestinal absorption of glucose, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization . It is well established that metformin inhibits mitochondrial complex I activity, and it has since been generally postulated that its potent antidiabetic effects occur through this mechanism . The above processes lead to a decrease in blood glucose, managing type II diabetes and exerting positive effects on glycemic control.
After ingestion, the organic cation transporter-1 (OCT1) is responsible for the uptake of metformin into hepatocytes (liver cells). As this drug is positively charged, it accumulates in cells and in the mitochondria because of the membrane potentials across the plasma membrane as well as the mitochondrial inner membrane. Metformin inhibits mitochondrial complex I, preventing the production of mitochondrial ATP leading to increased cytoplasmic ADP:ATP and AMP:ATP ratios . These changes activate AMP-activated protein kinase (AMPK), an enzyme that plays an important role in the regulation of glucose metabolism . Aside from this mechanism, AMPK can be activated by a lysosomal mechanism involving other activators. Following this process, increases in AMP:ATP ratio also inhibit _fructose-1,6-bisphosphatase_ enzyme, resulting in the inhibition of gluconeogenesis, while also inhibiting _adenylate cyclase_ and decreasing the production of cyclic adenosine monophosphate (cAMP) , a derivative of ATP used for cell signaling . Activated AMPK phosphorylates two isoforms of acetyl-CoA carboxylase enzyme, thereby inhibiting fat synthesis and leading to fat oxidation, reducing hepatic lipid stores and increasing liver sensitivity to insulin .
In the intestines, metformin increases anaerobic glucose metabolism in enterocytes (intestinal cells), leading to reduced net glucose uptake and increased delivery of lactate to the liver. Recent studies have also implicated the gut as a primary site of action of metformin and suggest that the liver may not be as important for metformin action in patients with type 2 diabetes. Some of the ways metformin may play a role on the intestines is by promoting the metabolism of glucose by increasing glucagon-like peptide I (GLP-1) as well as increasing gut utilization of glucose .
In addition to the above pathway, the mechanism of action of metformin may be explained by other ways, and its exact mechanism of action has been under extensive study in recent years .
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| DrugBank Pharmacology: |
**General effects**
Insulin is an important hormone that regulates blood glucose levels . Type II diabetes is characterized by a decrease in sensitivity to insulin, resulting in eventual elevations in blood glucose when the pancreas can no longer compensate. In patients diagnosed with type 2 diabetes, insulin no longer exerts adequate effects on tissues and cells (called insulin resistance) and insulin deficiency may also be present .
Metformin reduces liver (hepatic) production of glucose, decreases the intestinal absorption of glucose, and enhances insulin sensitivity by increasing both peripheral glucose uptake and utilization. In contrast with drugs of the _sulfonylurea_ class, which lead to hyperinsulinemia, the secretion of insulin is unchanged with metformin use .
**Effect on fasting plasma glucose (FPG) and Glycosylated hemoglobin (HbA1c)**
HbA1c is an important periodic measure of glycemic control that is used to monitor diabetic patients. Fasting plasma glucose is also a useful and important measure of glycemic control. In a 29-week clinical trial of subjects diagnosed with type II diabetes, metformin decreased the fasting plasma glucose levels by an average of 59 mg/dL from baseline, compared to an average increase of 6.3 mg/dL from baseline in subjects taking a placebo . Glycosylated hemoglobin (HbA1c) was decreased by about 1.4% in subjects receiving metformin, and increased by 0.4% in subjects receiving placebo only .
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| DrugBank Indication: |
**Metformin tablet**
Metformin is indicated as an adjunct to diet and exercise to increase glycemic control in _adults and pediatric patients_ 10 years of age and older diagnosed with type 2 diabetes mellitus.
**Metformin extended-release tablet (XR)**
The extended-release form is indicated as an adjunct to diet and exercise to improve glycemic control in only _adults_ with type 2 diabetes mellitus. Safety in children has not been determined to this date.
An extended-release combination product containing empagliflozin, linagliptin, and metformin was approved by the FDA in January 2020 for the improvement of glycemic control in adults with type 2 diabetes mellitus when used adjunctively with diet and exercise.
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| Targets: |
--
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| Therapeutic Category: |
--
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| Clinical Trial Progress: |
Clinical trial on-going (EUCTR2011-001010-34-AT)
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| Latest Progress: |
Under clinical trials
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