Posters
Insulin secretagogue therapy and hypoglycemic risk
A pharmacological and clinical comparison of the prandial glucose
regulator repaglinide with sulphonylureas
Jørgen Smedegaard Kristensen¹, Kirstine Brown
Frandsen¹, Thomas Bayer¹, Peter Müller², David R. Owens³, Gareth
Dunsheath³ and Stephen Luzio³
¹Novo Nordisk, Copenhagen, Denmark, ²Novo Nordisk, Princeton, New
Jersey, USA, ³Llandough Hospital, Cardiff, UK
Sulphonylureas are widely used in Type 2 diabetes, in which the
prandial insulin response is, characteristically, impaired. However,
sulphonylureas were designed for once- or twice-daily dosing and have
extended durations of action that can increase insulin secretion in the
late postprandial timeframe. Furthermore, the secretagogue action of
sulphonylureas is not nutrient-dependent in vitro. Consequently,
sulphonylureas may put patients at risk of hypoglycemia in the
interprandial period.
Repaglinide
Repaglinide is the first insulin secretagogue specifically designed
for use in mealtime regimens. It has a rapid onset of action (10–15
minutes after oral administration, with tmax occurring at approximately
1 hour) and fast elimination (t½, approximately 30 minutes). In vitro,
its insulinotropic action is glucose-dependent. These properties raise
expectations that prandial repaglinide will carry a low risk of
hypoglycemia compared with sulphonylurea regimens. Data from two studies
now strengthen this expectation.
Results
Twelve patients with Type 2 diabetes and 12 healthy volunteers
were given a standardized 500 kcal meal on three separate occasions
preceded by a single dose of either repaglinide (2 mg), glibenclamide (5
mg) or placebo. Each subject received each treatment, with blood samples
assayed over 4 hours. In patients and volunteers, the secretagogues
increased insulin output relative to placebo. There was no overall
between-treatment difference in insulin output, but early-phase
secretion (–15 to 30 minutes) was significantly greater with
repaglinide than glibenclamide (Table). The longer duration of action of
glibenclamide was evident in a greater late-phase insulin secretion (120–240
minutes), reaching statistical significance among the healthy volunteers
(Table II).
The relative frequency of major hypoglycaemic events was assessed in a
meta-analysis of four randomized, double-blind, comparative studies, in
which prandial repaglinide (0.5–4 mg) was compared with recommended
doses of glibenclamide, gliclazide and glipizide over 1-year periods in
patients with Type 2 diabetes. In line with sulphonylurea requirements,
patients followed a strict pattern of three daily meals, fixed mealtimes
and optional snacks. Patients (repaglinide n = 761, sulphonylurea n =
367) performed home blood glucose monitoring whenever hypoglycemia was
suspected. The rate of major hypoglycemic episodes (defined as blood
glucose < 2.5 mmol/l plus symptoms) associated with repaglinide and
sulphonylureas, respectively, was 1.31% and 3.27% (p < 0.03; Figure),
with
a relative risk of 2.8 for sulphonylurea-treated patients (p = 0.01).
Fifty-seven percent of sulphonylurea-related hypoglycaemic events were associated with
blood glucose < 3.33 mmol/l; with repaglinide 62% of events occurred
with blood glucose > 3.33 mmol/l. Most hypoglycaemic episodes
associated with repaglinide occurred between 8 am and midnight with
repaglinide, whereas with glibenclamide most episodes were nocturnal.
Figure: Major hypoglycemic reactions during
repaglinide treatment versus sylphonylure treatment
Conclusion
In conclusion, prandial repaglinide is characterized,
pharmacologically, by rapid, selective augmentation of early-phase
insulin secretion. In clinical practice, repaglinide incurs a lower risk
of major hypoglycemia than sulphonylureas, and there is evidence that
patients may preserve a greater awareness of falling blood glucose
concentrations and may incur a lower burden of nocturnal hypoglycemia.
