Antidiabetic drugs

Introduction

Diabetes mellitus (DM) is a chronic metabolic condition caused by an absolute (type I) or relative (type II) lack of insulin. In Australia, more than 1 million people have diabetes and 100,000 people are diagnosed every year with the condition. Indigenous and Māori populations in Australasia have some of the highest rates of type II diabetes in the world. For these reasons, antidiabetic medications are readily available and frequently taken in overdose both by diabetic and non-diabetic individuals.

The three major groups of antidiabetic medications are insulin, sulphonylureas and biguanides, all of which have been used for more than 50 years. Toxicity can result from intentional overdose, but also from decreased clearance of the medication at therapeutic dosing, due to underlying hepatic or renal disease.

A number of new agents for type II DM have been developed recently, including dipeptidyl peptidase-IV (DPP-IV) inhibitors, incretin mimetics, thiazolidinediones, alpha-glucosidase inhibitors, glinides and sodium–glucose cotransporter 2 (SGLT2) inhibitors. Overdose with these medications is less likely to cause significant clinical effects.

Insulin

Clinical features

The clinical features of insulin toxicity are the neuropsychiatric and autonomic manifestations of hypoglycaemia. Autonomic symptoms and signs include diaphoresis, tremor, nausea, palpitations and tachycardia; neuropsychiatric features are confusion, agitation, seizures, coma and focal neurological deficits. These manifestations are usually evident within hours of self-administration of an insulin overdose and the patient frequently presents in coma. The suspicion of deliberate overdose is entertained when recurrent profound hypoglycaemia occurs following an initial response to dextrose administration. If the history of deliberate overdose is known at the time of presentation, then profound, prolonged hypoglycaemia should be anticipated.

The reported dose of self-administered insulin should be compared to the daily therapeutic dose prescribed for the patient, if this is known or relevant. This will inform the risk assessment for the likely severity and duration of toxicity. Prolonged severe hypoglycaemia can cause permanent neurological sequelae or death.

Clinical investigations

Serial measurement of blood glucose concentrations, usually at the bedside, allows titration of dextrose administration. Serial measurements of electrolytes are necessary to monitor hypokalaemia and potassium replacement. Serum magnesium and phosphate levels may also be affected.

If surreptitious or malicious administration is suspected, assays of insulin and C-peptide levels can be useful to provide objective evidence of the presence of exogenous insulin, as endogenous insulin levels should always be suppressed in the presence of hypoglycaemia unless an insulinoma is present.

Treatment

Management of insulin overdose is essentially supportive and requires the administration of sufficient concentrated dextrose solution to maintain euglycaemia until all the insulin is absorbed from the depot site and its hypoglycaemic action terminated. After initial resuscitation to correct hypoglycaemia with 50% dextrose, a 10% dextrose infusion should be commenced at 100 mL/h and blood sugar levels followed closely. Further boluses of dextrose and titration of the infusion rate are implemented as necessary.

Very large doses of dextrose may be required, sometimes over days. Frequently, it is necessary to administer a 50% dextrose infusion to maintain euglycaemia, and this usually requires placement of a central venous or peripherally inserted central catheter (PICC) line, because concentrated dextrose solutions can cause sclerosing thrombophlebitis in peripheral veins. Oral feeding with complex carbohydrates is an important aspect of management in addition to intravenous therapy—this provides more physiological stabilization of blood sugar levels than parenteral administration of dextrose.

Hypokalaemia due to intracellular shifts should be anticipated and supplemental K ⁺ administered (e.g. 10 to 40 mmol/h IV in adults), guided by serial monitoring. Excessive K ⁺ administration should be avoided. Hyponatraemia and volume overload are other complications of hypertonic dextrose therapy.