Could venlafaxine cause hyperglycaemia?/nBackground: A 55-year-old male patient with type II-diabet

Fråga: Could venlafaxine cause hyperglycaemia?

Background: A 55-year-old male patient with type II-diabetes, treated with insulin and glibenclamide, has noted an increase in morning blood glucose levels from around 6 to 10 mmol/l since the start of venlafaxine (Efexor)-treatment a few weeks ago. The patient has tried to compensate for this by reduced intake of carbohydrates. The current dose of venlafaxine is 75 mg twice daily, but an increase to 75 mg three times daily is being considered. At present, the patient also takes digoxin, flupentixol, and erythromycin.

Sammanfattning: In summary, only one previous Swedish case of hyperglycaemia possibly related to venlafaxine was found, otherwise documentation on the topic is very limited. The present case concerns relatively mild hyperglycaemia in type II-diabetes, which has already progressed to insulin treatment. A further decrease in insulin sensitivity, as part of disease progression, appears to be a more likely explanation to the impaired glucose control than venlafaxine treatment.

Svar: Venlafaxine is a novel antidepressant, with a serotoninergic and noradrenergic action. Despite a thorough literature search, we have not found any information about venlafaxine-induced hyperglycaemia.

However, in the Swedish Drug Information System (Swedis), there is one report of hyperglycaemia associated with venlafaxine treatment (1). In brief, it describes a 76-year-old woman treated with prednisolone for polymyalgia rheumatica, and who also suffered from Alzheimer´s disease. Furthermore, she was on antidepressive treatment with fluoxetine, but switched to venlafaxine, as depressive symptoms worsened. The patient was not diabetic. One week later, severe hyperglycaemia (40 mmol/l) and low blood pressure developed, which reversed completely after admission to the hospital, a few days insulin treatment and cessation of venlafaxine (1).

In the above Swedish case, the causality between venlafaxine and hyperglycaemia was considered possible. In the WHO-database (2), 10 cases of hyperglycaemia associated with venlafaxine were found, however without any further clinical details or causality assessment. Considering that venlafaxine is a relatively new drug, we recommend the present case be reported to SADRAC (The Swedish Adverse Reaction Advisory Committee).

Interestingly, a case report describing hyperglycaemia during morning hours induced by mianserin, another antidepressant was located (3). Otherwise, no documentation was found on hyperglycaemia or diabetes associated with mirtazapine, an antidepressant with a similar type-of-action to venlafaxine, or reboxetine, a potent noradrenaline uptake inhibitor.

Concerning serotonin uptake inhibitors, it was proposed that fluoxetine and possibly other serotoninergic agents might induce hyperglycaemia in rats (4, 5). However, the doses used were high (20 mg/kg) and effects on blood glucose were transient, essentially normalising within an hour (4). In contrast, a multicenter study based on 82 patients with non-insulin-dependent diabetes, reported short-term beneficial effects of fluoxetine on metabolism, with a significant reduction of HbA1c-levels and triglycerides after 8 weeks of fluoxetine treatment, compared to the placebo group (6). The underlying mechanism was not clear, but frequent adverse effects of fluoxetine, such as nausea, diarrhoea and tremor, were reported to a much greater extent in the fluoxetine group.

Finally, there are no apparent interactions at the level of drug metabolism in the present case of mild hyperglycaemia, which could explain impaired glucose control, such as induction of glibenclamide metabolism. Venlafaxine is predominantly metabolised by CYP2D6 (7), erythromycin by CYP3A4 (7), and glibenclamide, like other structurally related oral antidiabetics, is probably metabolised by CYP2C9 (8). 1 Swedis (The Swedish Drug Information System) 2 Intdis (International Drug Information System): WHO:s adverse drug reactions database 3 Marley J, Rohan A: Mianserin-induced hyperglycaemia. Lancet 1993; 342: 1431 4 Yamada J, Sugimoto Y, Inoue K: Selective serotonin reuptake inhibitors fluoxetine and fluvoxamine induce hyperglycemia by different mechanisms. Eur J Pharmacol 1999; 382: 211-215 5 Erenmisoglu A, Ozdogan UK, Saraymen R, Tutus A: Effect of some antidepressants on glycaemia and insulin levels of normoglycaemic and alloxan-induced hyperglycaemic mice. J Pharm Pharmacol 1999; 51: 741-3 (Medline abstract) 6 Daubresse J-C, Kolanowski J, Krzentowski G, Kutnowski M, Scheen A, van Gaal L: Usefulness of fluoxetine in obese non-insulin-dependent diabetics: A multicenter study. Obes Res 1996; 4: 391-6 7 Riesenman C: Antidepressant drug interactions and the cytochrome P450 system: a crutucal appraisal. Pharmacotherapy 1995; 15: 84S-99S 8 Miners JO, Birkett DJ: Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998; 45: 525-538