Web site: May 1999
Prescriber Update No.18:36-38
Medsafe Editorial Team
Hyperglycaemia, sometimes leading to ketoacidosis or glycosuria, has been reported in association with clozapine. In some cases the condition has been of new onset, and in others exacerbation of pre-existing diabetes mellitus has occurred. Hyperglycaemia appears to be of early onset (2 weeks to 3 months after initiation of clozapine) and to occur without predisposing factors. Clozapine-induced hyperglycaemia may be serious leading to coma, but it is reversible on discontinuation of clozapine. In some cases continuation of clozapine is possible by controlling serum glucose levels with the use of hypoglycaemic agents. This approach may be useful in refractory schizophrenia responsive to clozapine. In those with diabetes mellitus, glucose monitoring should be conducted in conjunction with the obligatory haematological monitoring. All patients should be advised to report altered consciousness, polyuria or increased thirst.
New onset hyperglycaemia may occur with
Glycaemic control may be possible with hypoglycaemic agents
Hyperglycaemia may be serious but it is reversible with clozapine withdrawal
Hyperglycaemia is unpredictable and of early onset
Monitor at-risk patients on initiation of clozapine
The Australian Adverse Drug Reactions Advisory Committee1 has now received more than 12 reports of hyperglycaemia, diabetes mellitus, ketoacidosis or glycosuria with clozapine. The reports include cases of new onset hyperglycaemia and cases of exacerbation of pre-existing diabetes. In some cases clozapine was continued with a change in the measures to maintain glucose control, such as use of insulin for the first time. In cases where clozapine was withdrawn, glucose control returned to the pre-treatment situation. The evidence is strongly suggestive of a causal connection between clozapine and hyperglycaemia.
Several case reports2-4 illustrating this adverse reaction have been published. In one case a 32-year-old man2 had a strong family history, but no personal history of diabetes mellitus. Eight weeks after starting clozapine 425 mg/day he was observed to be obtunded, dehydrated and hypotensive with a serum glucose level of 52 mmol/L, a pH of 7.22, moderate serum ketones and a urea concentration of 19 mmol/L. The patient was treated for diabetic ketoacidosis and given daily insulin. Clozapine was discontinued. Because of the lack of control of his symptoms of paranoid schizophrenia, clozapine was reinstated with a resulting considerable fluctuation in his insulin requirements. However, he subsequently achieved reasonable glycaemic control (glucose 5.7-17.9 mmol/L) on clozapine 450 mg/day with glibenclamide 2.5 mg/day. The patient’s blood sugar levels normalised whenever he stopped clozapine due to non-compliance with treatment.
A second patient, a 44-year-old man,2 had no personal or family history of diabetes mellitus, but he was obese (42% over ideal body weight). Five weeks after commencing clozapine 450 mg/day, mild hyperglycaemia (11 mmol/L) was observed. Glucose levels continued to increase despite restriction of sugar intake. Because of the refractory nature of the patient’s schizoaffective disorder, a decision was made to continue clozapine. He was stabilised on clozapine 675 mg/day and glibenclamide 30 mg/day.
A third patient, a 34-year-old woman,3 was admitted to intensive care in a comatose condition 6 weeks after initiation of clozapine 250 mg/day. The patient was also taking lithium carbonate and benztropine. On admission she had a serum glucose level of 68 mmol/L, a pH of 7.24 and an acetone/ketone ratio of 1:16. Glucose and ketones were found in the urine. She required ventilatory support and intravenous insulin for 5 days. After full recovery (glucose levels 4.4-6.7 mmol/L without insulin), clozapine was recommenced. Insulin was again required. The patient’s glucose levels gradually returned to normal without intervention after clozapine was withdrawn.
Glucose intolerance with clozapine is probably more likely to occur in those with existing diabetes or a family history of diabetes mellitus, but it also may occur in the absence of predisposing conditions or use of other agents causing hyperglycaemia. Clozapine-induced hyperglycaemia can be serious, but it is fully reversible on withdrawal of clozapine. The critical period appears to be the first 2 weeks to 3 months after initiation of clozapine.
Glycaemic control following initiation of clozapine should be monitored in diabetics and should be considered in those with a family history of diabetes mellitus or a personal history of hyperglycaemia (e.g. gestational or drug-induced). Glucose monitoring could be added to the patient’s obligatory haematological monitoring. Patients taking clozapine should be advised to report symptoms of hyperglycaemia such as altered consciousness, polyuria or increased thirst. In some patients it is possible to continue clozapine therapy by controlling serum glucose levels with the use of hypoglycaemic agents. This option may be important for those with refractory schizophrenia and related disorders who are responsive to clozapine. It may be worth reviewing patients on clozapine who have poor glucose control to ascertain whether clozapine may be the cause. Hyperglycaemia has also been observed with olanzapine.5