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Metformin

Metformin is used to treat a type of diabetes mellitus (sugar diabetes) called type 2 diabetes. With this type of diabetes, insulin produced by the pancreas is not able to get sugar into the cells of the body where it can work properly. Using metformin will help to lower blood sugar when it is too high and help restore the way you use food to make energy. Metformin does not help patients who have insulin-dependent or type 1 diabetes because they cannot produce insulin from their pancreas gland. Their blood glucose is best controlled by insulin injections.

Metformin drug also known as N,N-dimethylimidodicarbonimidic diamide hydrochloride from the class biguanide is an oral anti-diabetic drug. It is first line drug for the treatment of type 2 diabetes especially for obese people and it is also suggested as the best medicine for the patients with heart failure.

It contains metformin hydrochloride as an active ingredient and sodium carboxymethyl cellulose, hypromellose, microcrystalline cellulose, magnesium stearate as inactive ingredient.
Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether and chloroform.

Medicinal Use::
The biguanide originating from a plant french lilac also includes the withdrawn agents phenformin and buformin. Metformin is the only anti-diabetic drug that has been proven to protect against the cardiovascular complications of diabetes, this was first shown in the United Kingdom Prospective Diabetes Study which was done on large number of overweight patients with diabetes. It also helps in reducing LDL cholesterol and triglyceride levels, and weight loss. When metformin prescribed as per the requirement causes adverse effect of gastrointestinal upset.
As off label medication, it is used in polycystic ovary syndrome, non-alcoholic fatty liver disease and premature puberty.

Metformin Investigations::
As per the research undertaken at M.D. Anderson Cancer Center suggests the use of metformin against pancreatic cancer. The risk of pancreatic cancer in research participants who took metformin was found to be 62% lower than in participants who had never taken it, whereas participants who had used insulin or secretagogues (such as the sulfonylureas) were found to have a 5-fold and 2.5-fold higher risk of pancreatic cancer respectively, compared to participants that had been treated with neither.

Pharmacokinetics And Mechanism Of Action::
Metformin having an oral bioavaibility of 50-60% in fasting condition is absorbed slowly. It is distributed to red blood cells with a much longer elimination half-life of 17.6 hours. Metformin improves hyperglycemia primarily through its suppression of hepatic glucose production. It activates AMP i.e. activated protein kinase which is a liver enzyme that plays an important role in insulin signaling. Research published in later years further suggests that activation of AMPK is required for an increase in the expression of SHP which in turn inhibits the expression of the hepatic gluconeogenic genes PEPCK and Glc-6-Pase. In addition metformin also increases insulin sensitivity, enhances peripheral glucose uptake, increases fatty acid oxidation and decreases absorption of glucose from the gastrointestinal tract. AMPK is known to cause GLUT4 translocation resulting in insulin-independent glucose uptake. Study conducted in 2008 shows that the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK- and PKC-dependent mechanisms.

Clinical Trials::
With concomitant metmorfin and sulfonylurea therapy, the desired control of blood glucose is obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on metformin 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg, or 2500/20 mg of metformin and glyburide respectively, to reach the goal of glycemic control and plasma glucose response.
In a single-dose interaction study in type 2 diabetes patients, coadministration of metformin and glyburide did not result in any changes in metformin pharmacodynamics. Decrease in glyburide AUC and Cmax were observed, but were highly variable.

A single-dose metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance.

In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.

A 16-week, double-blind, placebo-controlled, dose-response study of metformin, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA1c 7.0%-11.0%, FPG 126-280 mg/dL). Compared with placebo, improvement in glycemic control was seen at all dose levels of metformin hydrochloride.

Vitamin B12 Levels And Geriatrics::
In controlled clinical trials of metformin of 29 weeks duration a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex is however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects.

Nursing Mothers::
Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.