Metformin adverse effects

Metformin, a biguanide derivative, can lower excessive blood glucose levels, provided that insulin is present Metformin does not stimulate insulin release. Glucose release from the liver is decreased, while peripheral uptake is enhanced. The danger of hypoglycemia apparently is not increased. Frequent adverse effects include anorexia, nausea, and diarrhea Overproduction of lactic acid (lactate acidosis, lethality 50%) is a rare, potentially fatal reactioa Metformin is used in combination with sulfony-lureas or by itself. It is contraindicated in renal insufficiency and should therefore be avoided in elderly patients. 

Chiidren Safety and efficacy of metformin IR for the treatment of type 2 diabetes have been established in children 10 to 16 years of age who demonstrated a similar response in glycemic control to that seen in adults. Adverse effects were similar to those described in adults. A maximum daily dose of 2,000 mg is recommended. Safety and efficacy of metformin ER in children have not been established. 

Sitagliptin is a selective dipeptidylpeptidase 4 (DPP-4) inhibitor which increases the active form of GLP-1 (glucagon-like-peptide-1) and GIP (glucose-dependent insulinotropic peptide). This enzyme-inhibiting drug is to be used either alone or in combination with metformin or a thiazolidinedione for control of type 2 diabetes mellitus. Adverse effects were as common with sitagliptin (whether used alone or with metformin or pioglitazone) as they were with placebo, except for nausea and common cold-like symptoms. 

In a multicenter, double-blind, placebo-controlled study, 81 patients, in whom treatment with metformin was inadequate, received extra acarbose or placebo during 24 weeks after a 4-week run-in period to establish the optimal dose of acarbose (28). HbAic was reduced by 1.02% and fasting blood glucose by 1.13 mmol/1. Gastrointestinal adverse effects were more common in the acarbose group. 

Biguanides (1) and metformin (2-4) have been reviewed. Metformin (rINN) is the only biguanide commonly used buformin (rINN) and phenformin (rINN) have been withdrawn in many countries (SEDA-4, 306) because of dangerous adverse effects. However, they are still available in a few countries, and with increasing travel, adverse effects of drugs no longer available in one country can occur if the drug is obtained elsewhere. 

In a prospective, randomized, double-blind, placebo-con-trolled study for 24 weeks, 701 patients took nateglinide 120 mg before the three main meals, or metformin 500 mg tds, or the combination of the two, or placebo (20). The most frequent adverse effect was hypoglycemia, and it was most common in the combination group. There were no differences between those who took nateglinide only or metformin only and there were no episodes of serious hypoglycemia. Diarrhea was more frequent in those taking metformin or the combination, but infection, nausea, headache, and abdominal pain were comparable in the two groups. 

Of 82 patients insufficiently controlled by metformin, 27 continued to take metformin with placebo, 28 took titrated repaglinide with placebo, and 27 took metformin with titrated repaglinide for 4-5 months (21). There were no serious adverse effects. Nine patients taking metformin + repaglinide reported 30 hypoglycemic events and three patients taking repaglinide reported 9 events. 

There is no doubt from reports such as this in people who take overdoses that metformin can cause lactic acidosis. In a review of enquires to a poison center relating to metformin between 1995 and 2003 there were 109 enquires, of which 62 were for attempted suicide and 47 for adverse effects 14 patients had had lactic acidosis (57). Eight were taking metformin as regular therapy, of whom one died of six who had attempted suicide, three died. 

The gastrointestinal adverse effects of metformin can be reduced by giving the metformin during or immediately after meals, starting with a low dose and increasing it gradually (64). 

The use of metformin in polycystic ovarian syndrome, which is often accompanied by insulin resistance or other aspects of the metabolic syndrome, has been systematically reviewed (101). Metformin was therapeutically less effective than weight loss. Adverse effects were nausea, vomiting, and gastrointestinal disturbances. 

Adverse effects are more likely to occur with metformin at the start of therapy. In retrospective case note review comparison of modified-release and immediate-release metformin 9.2% of those newly started on modified-release metformin (n — 65) had gastrointestinal adverse effects compared with 20% of those who started on immediate-release metformin (n — 363) (126). The main gastrointestinal adverse effect was diarrhea. The mean doses were 1258 mg/day for modified-release metformin and 1282 mg/day for immediate-release metformin. 

Exenatide (synthetic exendin-4, from the saliva from a lizard), which has a 53% overlap with glucagon-like peptide-1 and which also binds to the glucagon-like peptide-1 receptor, has been investigated in a placebo-controlled study for 28 days in 116 patients with type 2 diabetes in addition to a sulfonylurea or metformin (1). The most common adverse effects were nausea (mostly only in the first week) and mild to moderate hypoglycemia, for which no treatment was needed. 

Pioglitazone, is indicated once daily in patients not controlled by metformin alone. It is contraindicated by cardiac or hepatic failure. Weight gain and oedema are the main adverse effects. 

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