Diabetes Oral Antidiabetic Drugs: Biguanides

The only drug in this group licensed for use in the UK is metformin (chemically known as dimethylbiguanide). The drug has a complex metabolic activity and works in a number of different ways, but it does not increase insulin secretion. Its principal effect is to inhibit gluconeogen-esis and so reduce the manufacture of glucose by the liver. In addition, it promotes the action of insulin so that more glucose is taken up from the circulation into muscles and tissues and its effects appear to be mainly within cells, beyond the receptor sites. Evidence suggests that metformin also lowers blood lipid levels (triglycerides and cholesterol) but this effect is variable. The combined effects of metformin are anti-hyperglycaemic, and it improves gly-caemic control in people with Type 2 diabetes. The drug is not associated with weight gain, and in fact there is a tendency for weight loss to occur, especially during the early course of treatment. Hence it is often recommended for those who are overweight, unless there are existing conditions which rule out its use.

Metformin has a half-life of two to three hours and it is absorbed into the blood from the small intestine. It is not metabolized by the liver but is excreted unchanged by the kidneys. This means that it is not suitable for those with any kidney impairment such as diabetic nephropathy, and people receiving metformin require occasional monitoring of their renal function. This involves checking for the presence of protein in the urine or raised creatine levels in the blood. (Creatine is a metabolic product normally excreted in urine.)

The main serious risk from treatment with metformin is the occurrence of an acute metabolic complication known as lactic acidosis, but this is very rare. Lactic acid is produced from glucose, most commonly by skeletal muscle but also in the brain, red blood cells and kidneys when oxygen is absent, in order to supply energy for vital functions. Lactic acid is composed of lactate and hydrogen ions, and usually lactate is extracted by the liver, heart and kidneys. However, in conditions of severe oxygen shortage, there can be an excessive build-up of lactic acid, resulting in lactic acidosis. This most commonly occurs when the tissues are starved of oxygen (tissue hypoxia) as a result of, for example, life-threatening shock or cardiac failure. However, it can also occur (very rarely) in diabetes and as a complication of metformin treatment because of the way the drug works metabolically. It is, however, considered to be a very small risk. It only occurs if the drug should happen to be used in the presence of some unsuspected underlying condition, especially kidney impairment. (The kidneys excrete metformin and impairment may lead to a build-up of the drug and hence an increased risk of lactic acidosis.) For this reason, people with any impairment of the kidneys, liver or heart or who might be at risk of tissue hypoxia, or who abuse alcohol, are not suitable for treatment with metformin. Those who are prescribed the drug are carefully monitored, especially for any development of impaired organ function.

A common side effect with metformin is gastrointestinal upset which can include nausea, vomiting, diarrhoea, wind and appetite loss. To avoid or minimize these problems, the tablets should either be taken with meals or immediately after eating. Quite often, the problem resolves as the person becomes accustomed to the drug but occasionally, symptoms persist or are unpleasant enough to necessitate a change of treatment. There may be a slight, metallic aftertaste in the mouth, and absorption of vitamin B₁₂ and folate (B₉) can also be affected, but not severely enough to cause problems. It is, however, sensible to eat plenty of foods containing these vitamins, if receiving metformin treatment and advice on this will be given by the clinical dietitian. Tablets are supplied in 500 mg and 850 mg dosages and the usual starting dose is 500 mg twice each day. The maximum dose is one 850 mg tablet twice daily or one 500 mg tablet three times a day. Tablets should always be taken at meal times. Metformin may also be combined with other oral antidiabetic drugs or, less commonly, with insulin therapy. Excretion of metformin is affected by cimetidine (a drug used to treat ulcers, acid stomach and pancreatitis) and a lower dose or a different medication is needed in people who are receiving this drug.

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