Oral Antidiabetic Agents - Luzimar Teixeira

390 Krentz & Bailey
recommended in the UK, can be usefully comple- nylureas with respect to the risks of weight gain and
mented by self measurement of capillary blood glu- hypoglycaemia. Compared with older sulphocose
in selected, empowered patients and in particu- nylureas, glimepiride is relatively expensive and
lar clinical scenarios, for example in patients in clinical outcome data are not available, as they are
whom iatrogenic hypoglycaemia is a concern. for the agents used in the UKPDS. The clinical
relevance of theoretical, but much debated, effects
1. Insulin Secretagogues
of glimepiride on ischaemic preconditioning –
whereby a brief episode of ischaemia protects the
myocardium against the detrimental effects of sub-
1.1 Sulphonylureas sequent and more severe interruption of perfusion –
remain uncertain. The issues of the importance of
Sulphonylureas have been extensively used for ischaemic preconditioning and the possible influthe
treatment of type 2 diabetes for nearly 50 years. ence of different sulphonylureas continue to be de-
They lower blood glucose concentrations primarily bated (see section 1.1.5). [14]
by stimulating insulin secretion from the β cells of
the pancreatic islets. By the 1960s several sulphonylureas
were available, including tolbutamide,
1.1.1 Mode of Action
acetohexamide, tolazamide and chlorpropamide, ofproducing
Sulphonylureas have direct effects on the insulin-
fering a range of pharmacokinetic options. Howsulphonylurea
islet β cells. The drugs bind to the β-cell
ever, doubts about safety were raised in the 1970s. A
receptor (SUR)-1, part of a transever,
large US multicentre trial of antidiabetic therapy, membrane complex with adenosine 5′-triphosphatethe
UGDP (University Group Diabetes Program) [11] sensitive Kir 6.2 potassium channels (KATP chan-
reported apparent detrimental cardiovascular effects nels). [14,15] Binding of the sulphonylurea closes these
of tolbutamide. The UGDP was heavily criticised KATP channels; this reduces cellular potassium ef-
for perceived methodological failings and its find- flux favouring membrane depolarisation. In turn,
ings were far from being universally accepted. Sub- depolarisation opens voltage-dependent calcium
sequent observational and randomised clinical stud- channels, resulting in an influx of calcium that actiies
using sulphonylureas have provided mixed evi- vates calcium-dependent proteins that control the
dence, but a review of the available literature release of insulin (figure 2). When sulphonylureas
provides little in the way of convincing evidence of interact with SUR1 in the β-cell plasma membrane
cardiovascular toxicity. [12] Indeed, some studies they cause prompt release of pre-formed insulin
have reported a decreased incidence of cardio- granules adjacent to the plasma membrane – the sovascular
events in subjects with lesser degrees of called ‘first phase’ of insulin release. [16] Sulphoglucose
intolerance who received sulphony- nylureas also increase the extended (‘second phase’)
lureas. [12] The UKPDS investigators did not find any of insulin release that begins approximately 10 minincrease
in risk of myocardial infarction among pa- utes later as insulin granules are translocated to the
tients treated with sulphonylureas compared with membrane from within the β cell. [17] The protracted
patients randomised to insulin as monotherapy. [1] stimulation of the ‘second phase’ of insulin release
The Steno-2 Study, [8] has already been mentioned. involves the secretion of newly formed insulin granules.
A succession of more potent so-called secondwhile
The increased release of insulin continues
generation sulphonylureas emerged in the 1970s and
there is ongoing drug stimulation, provided
1980s, for example glibenclamide (glyburide), the β cells are fully functional. Sulphonylureas can
gliclazide and glipizide. The latest, glimepiride, was cause hypoglycaemia since insulin release is initiat-
introduced in the late 1990s. [13] Glimepiride is a ed even when glucose concentrations are below the
once-daily drug for which claims have been made normal threshold for glucose-stimulated insulin re-
that it might offer advantages over other sulpho- lease (approximately 5 mmol/L).
© 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)