The effect of glibenclamide on insulin secretion at normal glucose concentrations

Abstract

Aims/hypothesis The aim of this study was to investigate the incremental and proportional effect of a sulfonylurea on insulin secretion rates at low, elevated and high blood glucose, using parallel groups with ascending or descending glucose steps to minimise potential biases of a single stepped clamp order. Methods Following 14 days on placebo or glibenclamide (2.5 mg) tablets twice daily, separated by 14 days washout, 19 type 2 diabetic patients had ascending or descending threestep hyperinsulinaemic glucose clamps at 4, 8 and 12 mmol/l. C-peptide secretion was estimated by two-compartment C-peptide deconvolution. Results Patients in the ascending glucose steps group (n=10) had mean (SD) age of 60.3 (6.5) years, BMI of 29.8 (4.9)kg/m 2 and fasting glucose on diet alone of 10.6 (2.9) mmol/l; while those in the descending glucose steps group (n=9) had mean age of 58.2 (8.0) years, BMI of 30.5 (5.4)kg/m 2 and fasting glucose on diet alone of 9.8 (2.2) mmol/l. The geometric means (95% CI) of C-peptide secretion rates on placebo for glucose at 4.0, 8.0 and 12.0 mmol/l were 63 (46, 86), 143 (105, 195) and 205 (149, 281)pmol/min, respectively. On glibenclamide, this increased by 140 (99, 181), 126 (85, 167) and 158 (117, 199) pmol/min, respectively ( p<0.001 vs placebo). The absolute increment was significant ( p<0.001) and independent of clamp glucose concentration ( p=0.54). The proportional increase was greater at 4 mmol/l: 2.8-fold (2.4, 3.2), compared with 1.8-fold (1.5, 2.0) and 1.7-fold (1.4, 1.9) at 8 and 12 mmol/l, respectively ( p<0.001). Conclusions/interpretation At low-normal glucose, glibenclamide exerted a disproportionate effect on insulin secretion. This study highlights the risks of hypoglycaemia when aiming for tight glucose control on this agent.

The KATP channel in migraine pathophysiology: a novel therapeutic target for migraine

“…The necessity of a subtype specific blocker is unavoidable because of occurrence of different subtypes in different tissues. Glibenclamide cannot be used due to its high affinity to the Kir6.2/SUR1 subtype of K ATP channels present in the pancreas with hypoglycemia as a side effect [ 80 ]. PNU-37883A is a Kir6.1 selective K ATP channel blocker that was originally developed as a diuretic drug [ 81 , 82 ].…”

Within-class differences of the sulfonylureas should be accounted for. Reply to Schrijnders D, Kleefstra N and Landman GWD [letter]

“…To the Editor: Schrijnders et al [1] express concern that the findings of our paper [2], highlighting the continued enhancement of insulin secretion by glibenclamide at near-normal glucose levels, may have been unduly extrapolated to other drugs in the sulfonylurea class. Whilst we emphasised (correctly in our view) in the discussion 'the need for cautious titration when using sulfonylureas as second-line agents after metformin when attempting to maintain tight glucose control', our abstract conclusion was specific to glibenclamide stating: 'This study highlights the risks of hypoglycaemia when aiming for tight glucose control on this agent.…”

Within-class differences of the sulfonylureas should be accounted for

“…In summary, in our opinion, Riefflin et al [1] should not have discussed their findings as applying to the sulfonylureas as a class, and we urge investigators and editors to bear in mind within-class differences.…”

“…In a recent issue of Diabetologia, Riefflin et al published the results of their investigation into the effects of glibenclamide (known as glyburide in the USA and Canada) on insulin secretion in patients at different levels of glucose control [1]. We acknowledge that these results provide further evidence for the unique side-effect profile of glibenclamide.…”