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Metformin – boon or bane

posted on 8/20/2018 Facebook Facebook

Metformin is on the World Health Organization''s list of essential medicines and belongs to a class of drugs known as biguanides. It is an oral glucose-lowering agent and is the first drug of choice for the treatment of Type 2 Diabetes. Though the exact mechanism of metformin is not known it appears to act by improving the insulin sensitivity by increasing peripheral glucose uptake and utilization, decreasing the amount of glucose made by the liver, and intestinal absorption of glucose. The glucose-lowering effects of metformin are mediated by the activation of AMP-activated protein kinase (AMPK), a liver enzyme which plays an important role in insulin signaling, energy balance, and the metabolism of both glucose and lipids.

The drug is widely used because of its relatively low cost, efficacy, and safety (low risk of hypoglycemia, lack of weight gain). It is also increasingly being used in polycystic ovary syndrome (PCOS) due to the linkage between these two conditions. People at a prediabetic stage may decrease their chances of developing the disease with metformin treatment, although intensive physical exercise and dieting work significantly better for this purpose. Metformin has been found to be safe during pregnancy and women with gestational diabetes treated with metformin show less weight gain during pregnancy as against those treated with insulin. It has also been reported that babies born to women who were treated with metformin tend to have less visceral fat that may make them less prone to insulin resistance in later life.

Though well tolerated by majority of the population, there are instances of people (about 1 in 4) who are known to suffer from metformin-associated gastrointestinal (GI) side-effects (heartburn, stomach pain, nausea or vomiting, bloating, gas, diarrhea, constipation) and weight loss with approximately 5% unable to tolerate metformin at all. Gastrointestinal discomfort can be avoided in people by predicting the drug response using genetic testing. For eg. variation at a particular position in the intronic region of c11orf65 (chromosome 11 open reading frame 65) influences metformin treatment. Thus for patients where better response cannot be predicted, the treatment can begin with low dose or they can be administered slow- or extended-release preparations that may improve tolerability over a period of time. Another important gene for testing is the SLC22A1 or OCT1 gene that codes for polyspecific organic cation transporters in the liver, kidney, intestine. These transporters are important for elimination of organic cations, drugs and environmental toxins. Metformin being a cationic drug, the side effects that may be caused due to decreased clearance of metformin can be predicted based on the presence of nucleotide seen at a particular location in the OCT1 gene.

The most serious potential adverse effect seen is metformin-associated lactic acidosis (MALA), wherein the pH of blood which is normally around 7.4 is lowered upsetting the pH balance of the body and causing several complications. Though MALA is a rare condition, with an estimated prevalence of one to five cases per 100,000 population, it has a reported mortality of 30-50%. Metformin inhibits the uptake of lactate by hepatocytes for gluconeogenesis, leading to its excess build up. Impaired kidney function (a contraindication for metformin) leads to reduced clearance of both metformin and lactate, thereby increasing its levels which possibly account for MALA. Therefore any condition that may precipitate lactic acidosis is a contraindication like alcoholism (due to depletion of NAD+ stores), heart failure and respiratory disease (due to inadequate tissue oxygenation) and expectedly renal disease. Studies have suggested polymorphisms in the MATE1 (Multidrug and toxin extrusion protein 1) causing dysfunction of MATE1 as one of the risk factors for metformin induced lactic acidosis.

Thus taking into account the genetic testing findings, and paying attention to the contraindications can help in identifying patients who will respond better to metformin. This will save time and protect the patients from undesirable complications.


By Dr. Seema P. Todur, Ph.D., Sr. Scientific Officer, Positive Bioscience

Disclaimer:The opinions expressed in this blog are representative of the author and may not express the views of Positive Bioscience. This blog is intended for education and information for the general public. Before making any medical decisions a medical professional must be consulted. All rights reserved.

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