Antidiabeticos biguanfdicos
Adverse Effects
Gastrointestinal adverse effects including anorexia, nausea, vomiting, and diarrhoea may occur with bigua-nides patients may experience taste disturbance and there may be weight loss. Absorption of various substances including vitamin B12 may be impaired. Skin reactions have been reported rarely. Hypoglycaemia is rare with a biguanide given alone, although it may occur if other contributing factors or drugs are present.
Lactic acidosis, sometimes fatal, has occurred with biguanides, primarily with phenformin. When it has occurred with metformin most cases have been in patients whose condition contra-indicated the use of the drug, particularly those with renal impairment. Phenformin has been implicated in the controversial reports of excessive cardiovascular mortality associated with oral hypoglycaemic therapy (see under Sulfonylureas, Effects on the Cardiovascular System).
Effects on the blood. Megaloblastic anaemia has occurred with biguanide therapy (see Malabsorption, under Effects on the Gastrointestinal Tract, below). A few cases of metformin-induced haemolysis resulting in hyperbilirubinaemia and jaundice have also been described.
Effects on the gastrointestinal tract. DIARRHOEA. In a retrospective survey, 30 of 265 diabetic patients reported diarrhoea or alternating diarrhoea and constipation, comprising: 11 of 54 taking metformin 9 of 45 taking metformin with a sulfonylurea 3 of 53 taking a sulfonylurea only 5 of 78 on insulin therapy 2 of 35 on diet alone. Among 150 nondiabetic controls 12 reported diarrhoea. Chronic diarrhoea described as watery, often explosive, and frequently causing faecal incontinence, has been reported as an adverse effect of late onset in patients receiving metformin. Some patients had been on stable metformin therapy for several years before the onset of diarrhoea. Symptoms ceased upon withdrawal of metformin, and recurred in cases of rechallenge.
MALABSORPTION. Megaloblastic anaemia due to vitamin B12 malabsorption in a 58-year-old woman was associated with long-term treatment with metformin.
In a survey of diabetic patients receiving biguanide therapy,malabsorption of vitamin B12 was observed in 14 of 46 diabetics taking metformin or phenformin metformin was more commonly to blame. Withdrawal of the drug resulted in normal absorption in only 7 of the 14. In a series of 10 patients with vitamin B12 deficiency associated with metformin, vitamin B12 concentrations and blood count abnormalities were reported to have been corrected within 3 months of starting treatment with intramuscular or oral cyanocobalamin 2 patients were transferred to treatment with other antidiabetic agents.
Effects on the liver. Severe cholestatic hepatitis attributed to metformin has been reported.
Effects on the pancreas. Acute pancreatitis is more commonly associated with phenformin. However, there have also been a few cases of pancreatitis associated with metformin, in which renal failure may have precipitated metformin toxicity.
Hypersensitivity. Vasculitis and pneumonitis in a 59-year-old woman was associated with use of metformin. Symptoms improved on withdrawal of metformin, but reappeared on its re-introduction. Cutaneous vasculitis in a 33-year-old woman also resolved on withdrawal of metformin and recurred with its re-introduction.
Hypoglycaemia. UK licensed product information for metformin states that hypoglycaemia does not occur with metformin alone, even in overdosage, although it may occur if given with alcohol or other hypoglycaemics. Interim results from the UK Prospective Diabetes Study, however, indicate that metformin therapy was associated with fewer hypoglycaemic episodes than sulfonylurea or insulin treatment, but more than with diet alone. One or more hypoglycaemic episodes were reported in 6% of the patients receiving the biguanide in this study, although only 1 patient had a severe episode.
Lactic acidosis. There is a small but definite risk of lactic acidosis associated with use of biguanide antidiabetics. Most early reports involved phenformin, which was consequently removed from the market in many countries although cases of phenformin-associated lactic acidosis still occur. There has therefore been concern about the risks of lactic acidosis with metformin, which is still in wide use. However, lactic acidosis with metformin appears to be much less common: a review suggested that the incidence was of the order of 3 cases per 100 000 patient years, which was 20 times less frequent than with phenformin. This concurs with the findings of the FDA after the introduction of metformin to the US market: in the year after the marketing of metformin in the USA, the FDA had received reports of metformin-associated lactic acidosis in 66 patients, the diagnosis being confirmed in 47. This represented a rate of about 5 cases per 100 000. Most patients who do develop lactic acidosis with metformin have one or more precipitating risk factors such as renal impairment, congestive heart failure, or other conditions predisposing to hypoxaemia or acute renal failure, including septicaemia, acute hepatic decompensation, alcohol abuse, acute myocardial infarction, and shock. A systematic review, which considered results comprising nearly 48 000 patient years of treatment with metformin, concluded that provided metformin was prescribed taking into account the proper contra-indications, there was no evidence of an increased risk of lactic acidosis. Nonetheless, there have been a few reports of lactic acidosis developing in metformin-treated patients without apparent risk factors.
Treatment of Adverse Effects
Acute poisoning with biguanides may lead to the development of lactic acidosis (see Metabolic Acidosis) and calls for intensive supportive therapy. Glucose or glucagon may be required for hypoglycaemia, the general management of which is outlined in Insulin.
Precautions
Biguanides are inappropriate for patients with diabetic coma and ketoacidosis, or for those with severe infection, trauma, or other severe conditions where the biguanide is unlikely to control the hyperglycaemia insulin should be used in such situations. Biguanides should not be given to patients with even mild renal impairment, as it may predispose patients to lactic acidosis, and renal function should be monitored throughout therapy. Dehydration may contribute to renal impairment. Conditions associated with hypoxia, such as acute heart failure, recent myocardial infarction, or shock, may increase the risk of lactic acidosis. Other conditions that may also predispose to lactic acidosis in a patient taking a biguanide include excessive alcohol intake and hepatic impairment. Biguanides should be temporarily stopped for examinations using contrast media (see under Interactions, below).
Insulin is preferred for the treatment of diabetes in pregnancy.
Owing to the possibility of decreased vitamin B12 absorption, annual monitoring of vitamin B12 concentrations is advisable during long-term treatment.
Driving. In the UK, patients with diabetes mellitus treated with insulin or oral hypoglycaemics are required to notify their condition to the Driver and Vehicle Licensing Agency, who then assess their fitness to drive. Patients treated with oral hypoglycaemics are generally allowed to retain standard driving licences those treated with insulin receive restricted licences which must be renewed (with appropriate checks) every 1 to 3 years. Patients should be warned of the dangers of hypoglycaemic attacks while driving, and should be counselled in appropriate management of the situation (stopping driving as soon as it is safe to do so, taking carbohydrate immediately, and quitting the driving seat and removing the ignition key from the car) should such an event occur. Patients who have lost hypoglycaemic awareness, or have frequent hypoglycaemic episodes, should not drive. In addition, eyesight must be adequate (field of vision of at least 120°) for a licence to be valid. Patients treated with diet or oral hypoglycaemics are normally allowed to hold vocational driving licences for heavy goods vehicles or passenger carrying vehicles those treated with insulin may not drive such vehicles, and are restricted in driving some other vehicles such as small lorries and minibuses.
Interactions
Use of a biguanide with other drugs that lower blood-glucose concentrations increases the risk of hypoglycaemia, while drugs that increase blood glucose may reduce the effect of biguanide therapy.
In general fewer drug interactions have been reported with biguanides than with sulfonylureas. Alcohol may increase the risk of lactic acidosis as well as of hypoglycaemia. Care should be taken if biguanides are given with drugs that may impair renal function.
Anticoagulants. For the effect of metformin on phenprocoumon activity, see Antidiabetics.
Antivirals. Fatal lactic acidosis has been reported in a patient given metformin with didanosine, stavuc&ne, and tenofovir.
Cimetidine. Cimetidine increased plasma-metformin concentrations in 7 healthy subjects. The renal clearance of metformin was reduced competition for proximal tubular secretion was considered responsible. A reduction in metformin dosage may be required in patients taking metformin and cimetidine, in order to reduce the risk of lactic acidosis.
Contrast media. Biguanides should be temporarily stopped for examinations using iodinated contrast media and withheld after the examination until normal renal function is confirmed, because of the risk of contrast media-induced renal impairment leading to biguanide toxicity and associated lactic acidosis. Licensed product information for some contrast media preparations warns that biguanides should be temporarily stopped 48 hours before the examination, and withheld for at least 48 hours after and until normal renal function is confirmed.
A number of guidelines on the use of iodinated contrast media give advice for the management of patients taking metformin. Some suggest that, in general, metformin can be stopped at the time of the examination. Others are more detailed, suggesting that if serum-creatinine is normal metformin may be stopped at the time of the examination, but that if it is raised metformin should be stopped 48 hours before giving the contrast medium.’They all agree that metformin should be withheld for 48 hours after the examination and until normal renal function is confirmed, although one suggests that no special precaution is needed for patients with normal serum-creatinine who are to be given a low volume of iodinated contrast medium (up to 100 mL).
Ketotifen. Platelet counts in 10 diabetic patients receiving biguanides fell (markedly in 3 patients) when they were also given ketotifen. Counts returned to normal a few days after the end of ketotifen therapy. However, the investigators did not consider the effect clinically significant.
Sulfonylureas. For reference to an apparent increase in mortality with an intensive regimen of metformin plus a sulfonylurea.
Uses and Administration
The biguanide antidiabetics are a class of oral antidiabetic drugs used in the treatment of type 2 diabetes mellitus. They are given to supplement treatment by diet modification when such modification has not proved effective on its own. In addition, because biguanides are not associated with weight gain they are preferred in obese patients. Although sulfonylureas may be preferred in non-obese patients, a biguanide is often added or given instead to patients who are not responding to a sulfonylurea. The mode of action of biguanides is not clear. They do not stimulate insulin release but require that some insulin be present in order to exert their antidiabetic effect. Possible mechanisms of action include delay in the absorption of glucose from the gastrointestinal tract, an increase in insulin sensitivity and glucose uptake into cells, and inhibition of hepatic gluconeogenesis. Biguanides do not usually lower blood-glucose concentrations in non-diabetic subjects.
Hyperlipidaemias. The effect of biguanides on lipid metabolism is unclear, although some studies have shown a beneficial effect on serum-lipid profiles in both obese and lean patients with type 2 diabetes, hypertension, and/or hyperlipidaemia. Reductions in concentrations of total cholesterol, low-density and very low-density-lipoprotein cholesterol have been reported, as well as modest increases in high-density-lipoprotein cholesterol. Some studies have also reported a reduction in serum-triglyceride levels. Such effects may be beneficial in the long-term treatment of type 2 diabetes mellitus with concomitant lipid disorders.
Polycystic ovary syndrome. For discussion of the potential of metformin in polycystic ovary syndrome.