Metformin

Discovery

Metformin, first discovered by Emil Werner and James Bell in 1922, was originally one of several biguanides being tested. Metformin (dimethylbiguanide) has become the preferred first-line oral blood glucose-lowering agent to manage type 2 diabetes. Its history is linked to Galega officinalis (also known as goat’s rue), a traditional herbal medicine in Europe, found to be rich in guanidine, which, in 1918, was shown to lower blood glucose. Sixty years after its introduction in diabetes treatment, metformin has become the most prescribed glucose-lowering medicine worldwide with the potential for further therapeutic applications.

Description

The study of metformin and its hypoglycemic effects originated from the study of goat’s rue plants, also known as Galega officinalis(French lilac). Goat’s rues are native plants in the Middle East and introduced to Europe later and have been used as forage and ornamental plants throughout the world, including China. As early as in the Middle Ages in Europe, it was found that goat’s rues could ease polyuria, which is one of the typical symptoms of diabetes. While goat’s rues were used to treat a variety of other diseases in the Middle Ages, it was found to cause poisoning symptoms in livestock. Goat’s rues are still used as medical plants at present, mainly for diabetes, diuretic, hepatoprotection, aiding in digestion and promoting lactation, etc. In China, goat’s rues were recorded first in the dictionary of Chinese seed plants and mainly used for the treatment of diabetes. However, because of high toxicity, it is rarely used in traditional Chinese medicines at present.

Physical properties

Appearance: white crystalline or crystalline powder, odorless. Solubility: freely soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform or ether. Melting point: 223–226°C.

Originator

Diabetex ,Germania

History

Metformin is a biguanide compound which originated from the extraction of goat’s rue plants. The structure of metformin was identified by British scholars in the early 1920s. In 1922, Werner and Bell etal. first synthesized metformin in 31 institutes in Dublin, Ireland. In 1929, Slotta and Tschesche found metformin’s hypoglycemic action. However, because of other potent antidiabetic drugs such as insulin which were widely used in clinical practice, the pharmacological effects of metformin didn’t receive much attention.
Until the 1950s, a French diabetic scientist Jean Sterne found the hypoglycemic effect of metformin through the study of galegine. Then the drug was used in diabetic patients for the first time, and the results were published in 1957. UKPDS, which began from 1977 and ended in 1997 and was then followed up for 10years, is the longest in the history of clinical trials and has a significant impact on practice and guidelines for prevention and treatment of diabetes mellitus. In this trial, metformin was found to reduce the risk of diabetic complications by 32%. In addition, it was proved for the first time that metformin can reduce blood glucose and protect against cardiovascular function, especially in obese patients. In 1994, metformin was approved by the US FDA for type 2 diabetes treatment. Currently, metformin has become the world’s most widely used antidiabetic drug.
Aiming at improving the stability of the absorption of metformin, chemists have also carried out a series of structural renovation and modification. Metformin activates with carbonyl, esters, chlorides, and aldehydes to form triazine compounds, with 1,3-diketone to produce pyrimidine compounds, and with disulfides to produce C-S coupling products, etc.

Uses

non-insulin dependent diabetes mellitus

Indications

Metformin (Glucophage) was used in Europe for many years before it was approved for use in the United States in 1995. Metformin is the only approved biguanide for the treatment of patients with NIDDM that are refractory to dietary management alone. Metformin does not affect insulin secretion but requires the presence of insulin to be effective. The exact mechanism of metformin’s action is not clear, but it does decrease hepatic glucose production and increase peripheral glucose uptake. When used as monotherapy, metformin rarely causes hypoglycemia.

Definition

ChEBI: Metformin is a member of the class of guanidines that is biguanide the carrying two methyl substituents at position 1. It has a role as a hypoglycemic agent, a xenobiotic, an environmental contaminant and a geroprotector. It is functionally related to a biguanide. It is a conjugate base of a metformin(1+).

Manufacturing Process

The boiling mixture of 1,000 L xylene, 450 kg dimethylamine and 840 kg dicyanamide was added 365 kg hydrogene chloride. Yield of biguanide, 1,1- dimethyl-, hydrochloride 1,588 kg (96%). Biguanide, 1,1-dimethyl-, hydrochloride may be recrystallysed from methanol.

Therapeutic Function

Oral hypoglycemic

Biological Functions

Metformin can lower free fatty acid concentrations by 10 to 30%. This antilipolytic effect may help to explain the reduction in gluconeogenesis through reduced levels of available substrate (65). When given as a monotherapy, metformin treatment does not lead to hypoglycemia, so it is better described as an antihyperglycemic agent rather than a hypoglycemic agent.

General Description

Metformin, N,N-dimethylimidodicarbonimidicdiamide hydrochloride (Glucophage), is a bisguanidine.This class of agents is capable of reducing sugar absorptionfrom the gastrointestinal tract. Also, they can decrease gluconeogenesiswhile increasing glucose uptake by muscles andfat cells. These effects, in turn, lead to lower blood glucoselevels. Unlike the sulfonylureas, these are not hypoglycemicagents but rather can act as antihyperglycemics. This differencein nomenclature is caused by the inability of these agentsto stimulate the release of insulin from the pancreas. Often,metformin is coadministered with the nonsulfonylureas to improvethe efficacy of those agents.

Mechanism of action

The mechanism of action of biguanides is still not fully understood. Three major tissues have been identified as pharmacological sites of action: (1) the small intestinal wall, (2) the liver, and (3) peripheral tissues, mainly the skeletal muscle: 1. For the small intestine an inhibition of glucose absorption was described, however, this is, at least for metformin, of minor significance and not important for the blood glucose lowering effect. However, the intestinal glucose metabolization to lactate is stimulated and reduces the postprandial uptake of glucose by the liver. 2. Numerous studies have shown that biguanides inhibit hepatic gluconeogenesis and this may contribute to the blood glucose lowering effect, particularly in the fasting state. Again, metformin has probably less impact on  gluconeogenesis than phenformin and buformin. 3. In the peripheral tissues, metformin increases the glucose disposal and utilization particularly in the skeletal muscle, which is probably the major contribution to the blood glucose lowering activity. In vitro studies using cell cultures have shown that metformin potentiates insulin action. In vivo studies in animals and diabetic patients have demonstrated that metformin reduces insulin resistance, at least in obese individuals.

Pharmacology

As a traditional antidiabetic drug, metformin can reduce the levels of blood glucose and lipid, as well as regulating cell growth, anti-inflammation, antiaging, etc. The main pharmacological mechanisms are inhibition of hepatic gluconeogenesis, the activation of AMP-activated protein kinase (AMPK), and the regulation of mitochondrial function.
Improvement of Insulin Resistance and Decrease of Blood Glucose Levels
The main pharmacological effects of biguanide drugs are to reduce blood glucose output and improve peripheral insulin resistance. Metformin inhibits hyperglycemia mainly by inhibiting hepatic glucose production (hepatic gluconeogenesis), increasing muscle glucose uptake.
Regulation of Lipid Metabolism and Reducing Body Weight Metformin can reduce the blood triglycerides in circulation, improve liver steatosis, promote the oxidation of brown adipose tissue and VLDL-fatty acid triglyceride uptake, and inhibit fat formation; the process may be related with the activation of AMPK. AMPK can phosphorylate acetyl coenzyme A carboxylase (ACC) and inhibit the conversion of acetyl coenzyme A into malonyl-CoA. Malonyl-CoA is a precursor of fatty acid production and is an allosteric inhibitor of fatty acid transporting to mitochondria.
Prevention and Treatment of Tumors
Epidemiological studies have shown that metformin reduced the risk of multiple types of tumors in type 2 diabetes and nondiabetes patients and reduced tumor-related mortality. Metformin also has a therapeutic effect on various tumors. The antitumor effect of metformin may be through the reduction of serum insulin and insulin-like growth factor-1 (IGF-1) levels or activation of LKB1/AMPK, thereby blocking the mammalian target of rapamycin-sensitive complex 1 (mTORC1) signaling pathway.
Antiaging Antiaging effect is a major discovery in the new role of metformin. FDA approved the phase 4 of clinical trial of metformin for antiaging effect, and the trial is ongoing. The study suggests that the antiaging effect of metformin is closely related to the mitochondria, through the regulation of mitochondrial function to activate AMPK and inhibit mTOR, thereby reducing energy consumption. Furthermore, metformin can regulate oxidative stress, reduce tissue inflammation, and reduce the growth factor level and cell proliferation. The above effects and the combinational effect result in the improvement of health and achieving longevity.
Other Effects Studies have shown that metformin helps to prevent type 2 diabetes. For young people with a high body mass index, metformin is more effective than lifestyle control.
In addition, metformin can improve and prevent vascular disease, improve mitochondrial function, and serve as anti-inflammatory agent and antioxidant. Metformin is hydrophilic and distributed in tissues in an active manner. After oral administration, metformin is absorbed quickly and rapidly distributed into various tissues, mainly in the liver, gastrointestinal tract, and kidney.

Clinical Use

Metformin works best in patients with significant hyperglycemia and is often considered first-line therapy in the treatment of mild to moderate type II overweight diabetics who demonstrate insulin resistance. The United Kingdom Prospective Diabetes Study demonstrated a marked reduction in cardiovascular comorbidities and diabetic complications in metformintreated individuals. Metformin has also been used to treat hirsutism in individuals with polycystic ovarian syndrome and may enhance fertility in these women, perhaps by decreasing androgen levels and enhancing insulin sensitivity.

Safety Profile

Poison by subcutaneous and intraperitoneal routes. Mildly toxic by parenteral route. Experimental teratogenic effects. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx

Metabolism

Metformin is quickly absorbed from the small intestine. Bioavailability is from 50 to 60%, and the drug is not protein bound. Peak plasma concentrations occur at approximately 2 hours. The drug is widely distributed in the body and accumulates in the wall of the small intestine. This depot of drug serves to maintain plasma concentrations. Metformin is excreted in the urine, via tubular excretion, as unmetabolized drug with a half-life of approximately 2 to 5 hours; therefore, renal impairment as well as hepatic disease are contraindications for the drug.