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ADIS DRUG EVALUATION
Drugs 1998 Apr 55 (d): 563-584
0012-6667/98/C004.0563/S22.00/0
© Adis International Limited. All rights reserved.
Glimepiride
A Review of its Use in the Management of
Type 2 Diabetes Mellitus
Heather D. Langtry and Julia A. Balfour
Adis International Limited, Auckland, New Zealand
Various sections of the manuscript reviewed by:
J. Eckel, Diabetes-Forschunginstitut, Dusseldorf, Germany; L.C. Groop, Department of Endocrinology, Lund
University, Malmo General Hospital, Malmo, Sweden; A.D.B. Harrower, Department of Medicine,
Monklands Hospital, Airdrie, Scotland; R.J. Heine, Afdeling Endocrinologie, Academisch Ziekenhuis, Vrije
Universiteit, Amsterdam, The Netherlands; O.K. Matthews, Oxford Diabetes and Endocrinology Centre,
The Radcliffe Infirmary NHS Trust, Oxford, England; W. Waldhausl, Division of Endocrinology and
Metabolism, Department of Internal Medicine III, Allgemeines Krankenhaus der Stadt Wien, Vienna,
Austria.
Contents
Summary
...................................................................................................................................... 563
1. Introduction ...................................................................................................................................... 566
2. Pharmacodynamic Properties ......................................................................................................... 567
2.1 Pancreatic Effects ................................................................................................................... 567
2.1.1 Effects on Pancreatic -Cells .................. . ................................................................. 567
2.1.2 Effects on Blood Glucose Levels and Insulin Secretion .................................................. 567
2.2 ExtrapancreaticEffects ............................................ .. . . . . . . . ............................................. 569
2.3 Cardiovascular Effects ............................................................................................................. 570
3. Pharmacokinetic Properties and Drug Interactions .............. .......................................................... 571
3.1 Absorption and Distribution ..................................... .. . ........................................................•571
3.2 Metabolism and Excretion.................................................................................................... !572
3.3 Pharmacokinetics in Special Populations ............................................. ................................. 573
3.4 Drug Interactions ..................................................................................................................... 573
4. Clinical Efficacy ............................................................................................................................... 575
4.1 Dose-Ranging Studies and Comparisons with Placebo.......................................................... .:575
4.2 Comparisons with Other Sulphonylureas ................................................. ............................... 576
4.2.1 Comparisons with Glibenclamide (Glyburide) ........................................................... 576
4.2.2 Comparison with Gliclazide ........................................................................................... 577
4.2.3 Comparison with Glipizide ............................................................................................. 578
4.3 Combination with Insulin .......................................................................................................... 578
5. Tolerability ........................................................................................................................................ 579
6. Dosage and Administralion ............................................................................................................. 580
7. Place of Glimepiride in the Management of Type 2 Diabetes Mellitus ........................................... 581
Summary
Synopsis
Drugs 1998 Apr:; 55 (4)
Glimepiride is a sulphonylurea agent that Stimulates insulin release from pancreatic -cells and may act via extrapancreatic mechanisms. It is administered
once daily to patients with type 2 (non-insulin-dependent) diabetes mellilus in
whom glycaemia is not controlled by diet and exercise alone, and may be combined with insulin in patients with secondary sulphonylurea failure.
Langtry & Balfour
564
The greatest blood glucose lowering effects of glimepiride occur in the first 4
hours after the dose. Glimepiride has fewer and less severe effects on cardiovascular variables than glibenclamide (glyburide). Pharmacokinetics are mainly
unaltered in elderly patients or those with renal or liver disease. Few drug interactions with glimepiride have been documented.
In patients with type 2 diabetes, glimepiride has an effective dosage range of
0.5 to 8 mg/day, although there is little difference in efficacy between dosages of 4
and 8 mg/day. Glimepiride was similar in efficacy to glibenclamide and glipi-zide
in 1-year studies. However, glimepiride appears to reduce blood glucose more
rapidly than glipizide over the first few weeks of treatment. Glimepiride and
gliclazide were compared in patients with good glycaemic control at baseline in a
14-week study that noted no differences between their effects. Glimepiride plus
insulin was as effective as insulin plus placebo in helping patients with secondary
sulphonylurea failure to reach a fasting blood glucose target level of  7.8 mmol/L,
although lower insulin dosages and more rapid effects on glycaemia were seen with
glimepiride.
Although glimepiride monotherapy was generally well tolerated, hypoglycaemia occurred in 10 to 20% of patients treated for 1 year and 50% of patients
receiving concomitant insulin for 6 months. Pooled clinical trial data suggest
that glimepiride may have a lower incidence of hypoglycaemia than glibenclamide, particularly in the first month of treatment. Dosage is usually started at 1
mg/day, titrated to glycaemic control at 1- to 2-week intervals to a usual dosage
range of 1 to 4 mg/day (maximum 6 mg/day in the UK or 8 mg/day in the US).
Conclusions. Glimepiride is a conveniently administered alternative to other
sulphonylureus in patients with type 2 diabetes mellitus not well controlled by diet
alone. Its possible tolerability advantages and use in combination with other oral
antidiabetic drugs require further study. Glimepiride is also reported to reduce
exogenous insulin requirements in patients with secondary sulphonylurea failure
when administered in combination with insulin.
Pharmacodynamic
Properties
Glimepiride acts at ATP-sensitive potassium (KATP) channels on pancreatic -cells
to promote insulin release. It binds to 65kD protein on -cells, which appears to be a
part of the same sulphonylurea receptor that binds glibenclamide. Glimepiride
decreases gluco-/hexokinase binding to porin proteins and increases expression of
glucokinase mRNA and the glucose transporter GLUT2 in pancreatic cells in
vitro.
The maximum effects of glimepiride (relative to placebo) on blood glucose and
insulin levels in patients with type 2 (non-insulin-dependent) diabetes mel-litus
appear during the first 4 hours after the dose. Over this 4-hour period, greater
reductions in blood glucose occurred on the 4th day of treatment with glimepiride 2
mg/day than glibenclamide 10.5 mg/day (6.0 vs 5.1 mmol/L, p<0.05). A weak
relationship between blood glucose response and dosage was seen in patients with
type 2 diabetes receiving glimepiride 1 to 8 mg/day. Glimepiride increased or did
not change glucose utilisation rates in patients with type 2 diabetes in euglycae-mic
hyperinsulinaemic clamp studies. Glimepiride was also associated with greater
reductions in insulinaemia than glibenclamide during exercise, despite similar
reductions in blood glucose. Glimepiride may be given before or with breakfast,
with equivalent effect.
Effects of glimepiride on extrapancreatic mechanisms appear to be similar to
those of other sulphonylureas. The drug appears to act within peripheral cells at
© Adis International Limited. All rights reserved.
Drugs 1998 Apr; 55 (4)
Glimepiride: A Review
565
a point after insulin receptor interaction, increasing glucose transport and glucose
transporter expression (GLUT1 and GLUT4), lipogenesis and glyccgenesis.
Glimepiride also appeared to reduce insulin resistance and increase hepatic glucose disposal in animal models, but did not alter glucose utilisation in patients
with type 1 diabetes: these observations require further confirmation.
Unlike glibenclamide, glimepiride has few effects on cardiovascular variables,
with no effects on diazoxide-induced KATP channel opening in human volunteers. It
also has more modest effects on vasculature and heart function (ST segment
changes and blood pressure) in in vitro and animal studies than glibenclamide.
Pharmacokinetic
Properties and Drug
Interactions
Clinical Efficacy
After oral administration, glimepiride is completely absorbed, reaching peak
plasma concentrations (Cmax) of 103.2 and 550.8 g/L and areas under the plasma
concentration-time curve (AUC) of 326 and 2634 g/L • h after 1 and 8mg doses,
respectively. The time to Cmax (tmax) was 2.4 to 3.75 hours in patients with type 2
diabetes. Plasma protein binding was 99.4% and the volume of distribution was
8.8L. Accumulation does not occur after multiple doses. The drug is metabolised
mostly in the liver by CYP2C9 to the active MI (hydroxy) metabolite, with further
dehydrogenation to the inactive M2 (carboxy) metabolite. Ml has a tmax of 1.5
to 4.5 hours. 37 to 52% of a glimepiride dose is found in the urine as Ml or M2
within 48 hours. Clearance (CL) was 2.7 to 3.4 L/h for the parent drug and 8.6 to
10.2 L/h for Ml. Over 1 to 8mg doses, the terminal elimination half-life (t'/2 ) of
the parent drug increased from 3.2 to 8.8 hours, but the all-phase half-life was
1.2 to 1.5 hours. Pharmacokinetics are similar in elderly and younger patients.
Although CL tended to increase in patients with renal impairment as creatinine
clearance decreased from 3 to 0.6 L/h, the t'/2 was unaffected. The urinary excretion of Ml may be reduced, but no other pharmacokinetic changes are known
to occur during liver disease.
Glimepiride does not appear to have clinically significant interactions with
warfarin, cimetidine, ranitidine or propranolol. Although not specifically studied,
interactions may theoretically exist between glimepiride and other highly protein
bound drugs, -blockers, calcium channel blockers, estrogen, fibrates, statins,
nonsteroidal anti-inflammatory drugs, thyroid hormone or sulphonamides, warranting caution during concomitant use.
In dose-finding and placebo-controlled studies, the minimum effective dosage of
glimepiride (0.5 mg/day) had significantly greater effects than placebo on fasting
plasma glucose (FPG, -2.5 vs -1.0 mmol/L) and postprandial glucose (PPG, -4.9
vs -1.7 mmol/L) in patients with type 2 diabetes mellitus treated for 2 weeks.
Clear dose-response differences in FPG, PPG and glycosylated haemoglobin
(HbA1c) were seen between glimepiride 1 mg/day and 4 to 8 mg/day in a 14week study, but the differences were more modest between the latter 2 dosages.
However, in a 14-week study, glimepiride 16 mg/day was no more effective in
reducing FPG from baseline than 8 mg/day. Once-daily administration was as
effective as twice-daily use at dosages of 6 and 8 mg/day.
Glimepiride 1 to 8 mg/day was as effective after 1 year as glibenclamide 1.25
to 20 mg/day in reducing FPG, HbA1c or PPG. In 3 trials, differences in FPG and
HbA1c levels between glimepiride and glibenclamide were minor and inconsistent, and efficacy of these 2 agents was equivalent; however, lower fasting insulin
and C-peptide levels occurred with glimepiride. Long term extension of 2 of these
trials for up to 2.8 years showed no clinically significant differences in efficacy
between glimepiride and glibenclamide. Glimepiride 1 to 4 mg/day and gliclazide
© Adis International Limited. All rights reserved.
Drugs 1998 Apr: 55 (4)
566
Langtry & Balfour
80 to 320 mg/day had similar efficacy in patients with good glycaemic control at
baseline (FPG =6.3 mmol/L, HbA1c 5%); glimepiride 1 mg was generally equivalent
to gliclazide 80mg. However, the mild disease and short (14-week) duration of study
made differences between treatments more difficult to find; further comparisons
between glimepiride and gliclazide are needed. Glimepiride and glipizide were
equivalent in efficacy, decreasing FPG and HbA1c after 1 year's treatment;
however, glimepiride reduced FPG more rapidly during the first 10 weeks of study.
Insulin added to maximal dosages of glimepiride was compared with insulin plus
placebo in a 24-week study in obese patients with secondary sulphonylurea failure.
Patients in both groups achieved similar FPG and HbA1c levels at end-point (7.6
mmol/L and 7.6%). However, patients in the glimepiride plus insulin group
required lower insulin dosages (49 vs 78 U/day) and achieved more rapid lowering
of FPG after 2 and 4 weeks of treatment than the insulin/placebo group.
Tolerability
Dosage and
Administration
The most common treatment-emergent adverse events with glimepiride are dizziness, headache, asthenia and nausea; the drug is generally well tolerated. In
comparative trials, common adverse events appeared more often during treatment
with glimepiride than with placebo, occurred in similar proportions of glimepiride and
glipizide patients, and were less likely to occur with glimepiride than
glibenclamide, although these differences were not confirmed by statistical analysis.
Serious adverse events also followed this pattern, occurring in 8, 2, 8.8 and 12.4% of
glimepiride, placebo, glipizide and glibenclamide recipients, respectively. Serious
adverse events were usually not thought to be glimepiride related. In the US
comparative trials, hypoglycaemia symptoms occurred in more patients receiving
glimepiride than placebo (13.9 vs 2%), in similar percentages of glimepiride and
gliclazide recipients (21.2 vs 20.6%) and in fewer glimepiride than glibenclamide
patients (10 vs 16.3%). The incidence of hypoglycaemia was 1.7% with glimepiride
and 5.6% with glibenclamide during the first month of therapy. Mild hypoglycaemia
was more common during glimepiride plus insulin treatment (51%) than with
placebo plus insulin (37%) in a 6-month study, but moderate hypoglycaemia was
not ( 1 1 vs 15%).
Glimepiride is started at a dose of 1 to 2mg once daily with breakfast. Regular
blood glucose and HbA1c level monitoring is used to guide therapy. Dosages are
titrated every 1 to 2 weeks until glycaemic control or maximum dosages (8
mg/day in the US, 6 mg/day in the UK) are reached. Usual maintenance dosages are
1 to 4 mg/day. In the US, glimepiride 8 mg/day may be combined with insulin in
patients with secondary sulphonylurea failure. Patients receiving other sulphonylureas may be switched to glimepiride without a transition period.
Glimepiride may be used cautiously in elderly, malnourished or debilitated patients
and those with renal or hepatic insufficiency, but is not recommended for use in
children or in pregnant or breastfeeding women.
1. Introduction
Glimepiride (fig. 1) is a sulphonylurea antihyperglycaemic agent that may be given in a
single daily dose. It acts by stimulating insulin
release from pancreatic -cells and possibly
also via ex© Adis International Limited. All rights reserved.
trapancreatic mechanisms. This review
examines
its
pharmacodynamics,
pharmacokinetics and therapeutic use as
monotherapy in comparison with other
sulphonylureas or placebo in patients with type
2 (non-insulin-dependent) diabetes mellitus, as
well as its combination with exogenous insulin
Drugs 1998 Apr; 55 (4)
Glimepiride: A Review
567
Fig. 1. Chemical structure of glimepiride.
in type 2 diabetic patients with secondary
sul-phonylurea failure.
2. Pharmacodynamic Properties
2.1 Pancreatic Effects
2.1. 1 Effects on Pancreatic -Cells
The major site of activity of glimepiride is
thought to be membrane receptors on pancreatic
-cells, where it acts via ATP-regulated potassium
(KATP) channels, resulting in membrane depolarisation and release of insulin. [1] Glimepiride has a
2.5- to 3-fold higher rate of association, an 8- to
9-fold higher rate of dissociation and a 2.5- to 3fold lower binding affinity for rat -cell tumour
and insulinoma cells in vitro than glibenclamide
(glyburide).[2] Direct photoaffinity labelling studies in rat -cell tumour membranes in vitro show
that glimepiride binds to a 65kD protein and glibenclamide to a 140kD protein, both believed to be
part of the same sulphonylurea receptor since each
agent inhibits the binding of the other to these proteins.[3] Different binding affinities in rats have
been thought to result in differential effects of
these agents on insulin production. However, binding of glimepiride to mouse pancreatic islet cell
membranes was similar to that of glibenclamide,
as was the ability of glimepiride to inhibit KATP
channels in these cells.[4]
Glimepiride is also internalised into pancreatic
-cells, where it associates with secretory granules
in a manner similar to that of glibenclamide.[5] This
internalisation is thought to reflect insulinotropic
mechanisms of glimepiride other than at potassium
channels, as suggested by cationic flow studies in
rat islet cells.[6] Within -cells and adipocytcs, it
reduces gluco-/hexokinase binding to porin proteins, which is thought to play a role in
glucose
© Adis International Limited. All rights reserved.
sensing and oxidative phosphorylation.[7] Exposure
of insulinoma cells to glimepiride in vitro produced
dose-related increases in the expression of glucokinase mRNA and GLUT2 (a glucose transporter).[8]
Studies in isolated perfused rat pancreas[9,10]
show that glimepiride stimulates biphasic insulin
release, similar to that seen with glibenclamide,[10]
with a rapid initial peak followed by a slower, sus
tained second phase.[9,10] Glimepiride did not stim
ulate glucagon release in these 2 trials;[9,10] indeed,
one trial showed a modest inhibition of glucagon
secretion with both glimepiride and glibenclam
ide [9, 10]
2,1.2 Effects on Blood Glucose Levels and
Insulin Secretion
Compared with placebo, glimepiride decreases
blood glucose and increases blood insulin levels, with
maximum effects during the first 4 hours after the dose.
A 3-day crossover study [11] in 14 patients with type 2
diabetes found significantly greater peak reductions in
blood glucose (4.1 vs 1.9 nmol/ L) and increases in
plasma insulin (41 vs 28 mU/L) and C-peptide (1.8 vs
1.4 mg/L) with glimepiride 2 mg/day than placebo (p
< 0.05). The area under the curve (AUC) for blood
glucose versus time was significantly lower with
glimepiride than placebo over postdose hours 0 to 4
(reported as 9.0 vs 10.7 mmol/L) and hours 4 to 10
(reported as 7.9 vs 9.9 mmol/L). AUC values for
plasma insulin versus time (reported as 29 vs 19
mU/L) and C-peptide versus time (reported as 1.4 vs
1.1 mg/L) were significantly higher with glimepiride
over hours 0 to 4 but not over hours 4 to 10.[11] Effects
of the Ml (hydroxy) metabolite of glimepiride have
been studied only in healthy volunteers; Ml 1.5mg induced a 12% reduction in minimum serum glucose and
a 9% reduction in mean glucose concentrations
Drugs 1998 Apr; 55 (4)
565
Fig. 2. Effects of glimepiride on mean blood glucose levels in the 24 hours following administration. Blood glucose was evaluated in
86 patients with type 2 (non-insulin-dependent) diabetes mellitus on the 14th day of therapy with glimepiride 1, 2, 4 or 8mg once
daily, glibenclamide (glyburide) 10 mg/day or placebo. Mean changes in blood glucose levels from baseline, over the periods from
0 to 4, 4 to 8, 8 to 12, 12 to 24 and 0 to 24 hours after administration of study drugs, were calculated from areas under the blood
glucose-time curves.[14] All values for active treatment groups were statistically different from placebo (p < 0.05).
from 0 to 4 hours after administration compared
with placebo (no comparison was made will) the
parent drug).[12]
Glimepiride may also have greater immediate
effects on blood glucose levels than glibenclamide.
Significantly greater reductions in blood glucose
over 0 to 4 hours postdose occurred in 14 patients
with type 2 diabetes after 4 days of glimepiride 2
mg/day than after glibenclamide 10.5 mg/day.[13]
The peak decrease in blood glucose between breakfast and lunch was 6.0 mmol/L with glimepiride
and 5.1 mmol/L with glibenclamide (p < 0.05), and
the blood glucose AUC was reported as 8.5 versus
9.0 mmol/L (p < 0.05). No significant differences
were noted in blood glucose profiles between the
overlapping periods from 0 to 10 hours and 4 to 10
hours. [13]
® Adis International Limited. All rights reserved.
A 2-week unpublished dose-response study
(protocol 104) found at best a weak dose-response
relationship after glimepiride 1, 2, 4 or 8 mg/day
versus placebo or glibenclamide 10 mg/day in 86
type 2 diabetes patients.[14] Mean blood glucose
levels over all postdose periods from 0 to 24 hours
on day 14 were significantly different from placebo
in all active treatment groups (fig. 2). However, the
change in mean blood glucose over the whole period from 0 to 24 hours after the dose varied, reducing by 1.8, 1.3, 1.1 and 3.1 mmol/L in the
glimepiride 1, 2, 4 and 8 mg/day groups, respectively, and 2.5 mmol/L in the glibenclamide group,
compared with a 2.6 mmol/L increase in blood glucose in the placebo group.[14] See section 4.1 for
effects in studies of longer duration.
Hyperglycaemic and hyperinsulinaemic clamp
studies have been used to characterise the effects
Drugs 1998 Apr; 55 (4)
Glimepiride: A Review
of glimepiride on insulin secretion, but results of
different studies are equivocal. In 14 patients with
type 2 diabetes,[15] higher plasma insulin levels were
observed during a hyperglycaemic clamp on day 7
with glimepiride 5 mg/day treatment than with
placebo (AUC 377 vs 271 pmol/L • h, p < 0.005).
Blood glucose levels after termination of the clamp
decreased to 4.7 mmol/L with glimepiride and 6.2
mmol/L with placebo, but the greater decrease in
glucose with glimepiride did not promote a reduction
in insulin secretion.[15] A similar study in 15
nonobese patients[16] compared glimepiride l0mg,
glibenclamide l0mg or placebo during the clamp on
day 7, after 6 days at half these doses daily. The
increases in insulin from mean basal levels were
10.2, 12.8 and 5.7 mU/L with these 3 agents,
respectively (p < 0.02 between active treatments
and placebo). The same treatment protocol was
used in 9 nonobese patients who underwent a
euglycaemic hyperinsulinaemic clamp.[16] During
the clamp, blood glucose decreased with all
treatments (not statistically significant) and plasma
insulin increased by 35, 34.7 and 30.1 mU/L in
glimepiride, glibenclamide and placebo groups,
respectively, suggesting increased insulin secretion
with the active drugs compared with placebo (p <
0.01). Glimepiride and glibenclamide resulted in
more glucose metabolism per unit of insulin than
placebo (0.09 and 0.1 vs 0.03 kg • min per mU/L, p <
0.01), which may indicate greater tissue sensitivity
to insulin.[16] However, euglycaemic and
hyperglycaemic clamp studies indicated that neither
glucose utilisation nor insulin sensitivity increased
during 4 months' glimepiride therapy in 6 obese
patients with type 2 diabetes (reported in an
abstract).[17] It is not clear whether the differences in
results between this 4-month study and the 1-week
treatment[16] are a result of differences in duration of
treatment, patient body-weight or other factors.
The risk of exercise-induced hypoglycaemia
during glimepiride therapy was examined in 167
patients with type 2 diabetes.[18] Patients were
stabilised on glimepiride 3 mg/day or glibenclamide
10 mg/day for 2 to 4 weeks, then randomised to
exercise or no exercise groups. Exercise con-
569
sisted of 1 hour on a bicycle ergometer starting 1
hour after the dose on days 1 and 7. There were no
significant differences in blood glucose AUC between drugs in patients who exercised. However,
insulin AUC was reported to be significantly lower
with exercise than without exercise in giimepiride
recipients (reported as -59.4 pmol/L, p = 0.0001)
but less difference was seen in glibenclamide recipients (reported as -16.8 pmol/L, p = 0.023), or
for C-peptide AUCs (reported as -0.31 nmol/L, p
< 0.0001 for glimepiride and -0.01 nmol/L, p =
0.85 for glibenclamide). Hypoglycaemia occurred
in 3 of 45 glimepiride and 2 of 43 glibenclamide
recipients who exercised but not in patients who
did not exercise. Despite similar exercise-induced
reductions in blood glucose, glimepiride was associated with a greater exercise-induced reduction in
insulinaemia than glibenclamide. The investigators suggest that this may reduce the risk of hypoglycaemia during exercise (although it did not in
this trial). Further studies are needed to examine
whether exercise during glimepiride therapy produces sustained decreases in hyperinsulinaemia
with long term treatment and any reduction in
hypoglycaemia.
The effects of glimepiride 2 mg/day for 2 weeks
on blood glucose over the period from 0 to 4 hours
after breakfast were not significantly different
when the drug was given 30 minutes before break
fast or immediately before breakfast.[19] The results of this crossover study in 123 patients with
type 2 diabetes suggest that glimepiride may be
administered immediately before the first meal of
the day.
2.2 Extrapancreatic Effects
The evidence for potential extrapancreatic effects of glimepiride is inconclusive, but suggests
no major differences between this drug and other
agents of the sulphonylurea class.
In a euglycaemic clamp study in normal rats
receiving a low insulin infusion (6 mU/kg/min),
glimepiride 0.1 mg/kg/day increased the rate of
metabolic clearance of glucose (MCR), which
demonstrates an increase in insulin activity.[20] In
© Adis International Limited All rights reserved.
Drugs 1998 Apr; 55 (4)
570
contrast, glimepiride alone had no effects on MCR
at low or high (30 mU/kg/min) insulin infusion
rates in streptozotocin-diabetic rats, but when administered with insulin 5 U/day it substantially improved insulin response over that with insulin 5
U/day alone. The investigators suggest that glimepiride may contribute to overcoming insulin resistance.[20] The effects of the combination of
glimepiride and insulin on glucose utilisation appeared to be at least additive.
A euglycaemic clamp study in hepatic vein
catheterised dogs showed a doubling of hepatic
glucose disposal after 1 week of glimepiride 0.1
mg/kg/day.[21] However, the drug induced no
change in glucose utilisation in the liver or peripheral tissues in 5 patients with type I (insulindependent) diabetes mellilus.[21] which tends to
suggest a lack of extrapancreatic effects in humans.
Studies are now needed to determine the effects of
glimepiride on hepatic glucose disposal in patients
with type 2 diabetes.
Studies in dogs show that a lower ratio of total
plasma insulin increases to total blood glucose decreases occurred after oral glimepiride 90 g/kg
(0.03) than oral glibenclamide 90 g/kg (0.16),
gliclazide 1.8 mg/kg (0.11), or glipizide l80 g/kg
(0.7).[22] Investigators claimed that this low ratio
for glimepiride showed that the drug had greater
insulin-independent effects on blood glucose than
other sulphonylureas.[23] However, when in vitro
glycogenesis and lipogenesis are stimulated by either glimepiride [dose required to produce 50% of
maximal effect (ED5o) 1.7 and 0.4 mol/L, respectively] or glibenclamide (ED 50 2.9 and 0.8 mol/L)
in murine 3T3 adipocytes, peak responses were
similar between the 2 drugs.[24] Glucose transport
and GLUT4 tr anslocatio n wer e bo th
activated
by glimepiride and glibenclamide, which had
similar effects in insulin-resistant and non-insulinresistant adipocytes.[25] In rat cardiomyocytes, unlike
adipocytes, glimepiride had no acute effect on
glucose transport, but increased glucose uptake after chronic exposure,[26] probably through enhancement of expression of glucose transporters
GLUTl and GLUT4.[27]
© Adis International Limited. All rights reserved.
Langtry & Balfour
Glimepiride did not alter insulin binding to skeletal muscle insulin receptors in KK-Ay mice. In rat
fibroblasts overexpressing human insulin receptors
in vitro, both glimepiride and insulin altered glycerol incorporation into diacylglycerol, indicating
an effect at an intracellular stage occurring after
interaction with the insulin receptor.[28]
2.3 Cardiovascular Effects
KATP channels are thought to play a role in cardioprotective mechanisms that may be inhibited by
sulphonylureas. Although known to interact with
KATP channels in pancreatic islet cells (see section
2.1.1), glimepiride, unlike glibenclamide, is
thought to have no effects at cardiovascular KATP
channels in humans.[29] Healthy volunteers were
given an intravenous infusion of glimepiride,
glibenclamide or placebo before the start of an intra-arterial infusion of diazoxide, a specific KATP
channel opener that enhances forearm blood flow
(FBF).[29] Glibenclamide significantly inhibited
the stimulatory effects of diazoxide on FBF, but
neither placebo nor glimepiride had any effect on
this parameter. Furthermore, the ability of norepinephrine (noradrenaline), serotonin (5-hydroxytryptamine, 5-HT), potassium chloride and prostaglandin F2a to induce contractions in rat aorta in
vitro was inhibited by glimepiride.[30] In contrast,
glibenclamide attenuated responses to prostaglandin F2a, but not to norepinephrine, serotonin or potassium chloride.
Data from in vitro and in vivo studies.[31] in rats
(table I) and dogs are consistent with the previous
observations. They suggest that the modest effects
of glimepiride on KATP channels, blood vessels or
the heart were milder and affected fewer animals
compared with the same dosage of glibenclamide.
In open-chest anaesthetised dogs, glimepiride had
milder effects than glibenclamide or gliclazide in
inducing ST-segment elevation, increasing coronary resistance, myocardial oxygen extraction and
serum potassium levels, and reducing coronary
blood flow and the mechanical activity of the
heart.[31]
Drugs 1998 Apr: 55 (4)
Glimepiride: A Review
571
Table I. Effects of glimepiride (GLI), glibenclamide (glyburide, GLB) or placebo (PL) on in vitro and in vivo cardiovascular parameters in rats[31]
Abbreviations and symbols: IC5o = 50% inhibitory concentration; IV = intravenous; KATP channels = ATP-sensitive potassium channels;
MAP = mean arterial pressure; STZ = streptozotocin;  = increase;  = decrease; * p < 0.05 vs comparator. _________________________
The effects of glimepiride on electrical
activity of isolated rabbit heart muscle have been
examined in vitro.[32] Electrical threshold,
conduction time and effective refractory periods
were not substantially altered by either
glimepiride or chlorprop-amide, but increased
significantly (p < 0.01) with
glibenclamide in this mode l.
3. Pharmacokinefic Properties
and Drug Interactions
The pharmacokinetics of glimepiride and its
active Ml (hydroxy) and inactive M2 (carboxy)
metabolites have been determined using
HPLC[33] in patients with type 2 diabetes and
healthy volunteers. Major pharmacokinetic
variables are listed in table II.
3.1 Absorption and Distribution
A glimepiride 1 mg dose was completely
absorbed after oral administration.[34] In singledose studies in healthy volunteers, peak plasma
concentrations (Cmax) of glimepiride and the
area under
© Adis International Limited. All rights reserved.
the plasma concentration-time curve (AUG.)
were generally proportional to the dose. In 27
healthy volunteers, Cmax increased from 24.3 to
103.5 g/L after 0.25 to 1 mg doses,[37] and in 12
healthy volunteers it rose linearly from 103.2 to
550.8 g/L over 1 to 8mg doses.[36] AUC increased
from 72 to 339 g/L • h after 0.25 to 1 mg
doses[37] and from 326 to 2634 g/L • h after 1 to
8mg doses.[36] The glimepiride Cmax occurred 0.7
to 2.8 hours after administration of single doses of
the drug (tmax) to healthy volunteers and 2.4 to
3.75 hours after single or multiple doses in
patients with type 2 diabetes (table II). Plasma
protein binding of glimepiride is recorded as
99.4%[40] and the volume of distribution (Vd) as
8.8L.[41]
There were no major differences between Cmax,
tmax or AUC values after 1 day and those after 7
days of administration of glimepiride 0.5 or 1
mg once daily to 9 patients with type 2
diabetes.[35] Multiple doses did not result in
accumulation in 42 patients receiving
glimepiride 4, 8 or 16mg daily and
pharmacokinetics were generally linear over this
dosage range.[42]
Drugs 1998 Apr; 56 (4)
Langtry Balfour
572
Table II. Pharmacokinetics of glimepiride (GLI) and its M1 (hydroxy) metabolite after oral administration of the parent drug
Reference
Badian et al.[34]
Kaku et al.[35]
12 HV
SD1
GLI
Ml
GLI
88
2.7
449
3.1
20
3.9
134
3.3
29.6
2.4
75.9
GLI
27.6
2.6
73.0
GLI
M1
GLI
M1
89
3.75
303
23.3
4.5
5 NIDDM
SD 0 .5
4 NIDDM
MD 0.5 od x
7 days
SD1
12 HV
Ratheiser et
al.[38]
Rosenkranz[39]
27 HV
42 HV
11 LD +
(h)
AUC
(ug/L • h)
t1/2 (h)
Compound
CL(L/h)
[ml/min]
dose)
2.7 [45]
8.6 [143]
AeM1M2
(% of total
31.8
3.5
GLI
M1
103.2
2.3
326
24
2.8
133
SD2
GLI
176.8
2.4
668
42.1
2.8
210
SD4
M1
GLI
307.8
2.1
1297
M1
76.7
3.3
479
GLI
550.8
2.8
2634
M1
135.9
3.4
853
SD 0.25
SD 0.5
GLI
GLI
24.3
1.2
72
2.0
61 .2
0.7
125
1.0
36.6
38.1
SD1
GLI
103.5
1.3
339
1.5
44.9
34.5
2.6
164
2.7
SD 0.25-1.5
M1
GLI
M1
GLI
72-187
SD1
SD1
110.8
2
3.2
3.3 [55.3]
8.8 [146]
3.1
3.6
3.2 [53.5]
1.3
5.6
10.2 [170]
3.2 [53.6]
2.5
1.5
10.0 [166]
3.0
8.8
0.5-4
3.4 [56.5]
1.5
10.1 [169]
2.7
1.5-2
t1/2a
(h)
52
99.4
358.3
118.8
SD6
Nakashima et
al.[371]
tmax
Dose
(mg)
MD 1 od x
7 days
Malerczyk et
al.[36]
Cmax
Study
participants
3.2
=50
3-3.5
213-529
NIDDM
a Overall half-life of all phases.
Abbreviations: AeM1M2 = amount excreted into the urine as M1 and M2 (carboxy) metabolites; AUC = area under the plasma concentrationtime curve; CL = total body clearance; Cmax = peak plasma concentration; HV = healthy volunteers; LD = liver disease (periportal fibrosis,
mononuclear infiltration with connective tissue, fat metamorphosis with bridging necrosis, connective tissue infiltration); MD = multiple dose;
NIDDM = type 2 (non-insulin-dependent) diabetes mellitus; od = once daily; SD = single dose; tmax = time to Cmax; t1/2 = terminal
elimination half-life.
3.2 Metabolism and Excretion
Metabolism of glimepiride occurs primarily in
the liver; metabolic activity in rat kidneys is onethird that of hepatic metabolism.[43] The Ml metabolite appears to be formed by cytochrome P450
enzymes (involving CYP2C9)[41] in liver microsomes, whereas the further oxidation of M1 to the
M2 metabolite is effected by cytosolic alcohol and
aldehyde dehydrogenase enzymes.[43]
In healthy volunteers, the M1 metabolite appears rapidly after oral glimepiride administration,
with a tmax of 1.5 to 4.5 hours. The M2 metabolite
appears later than Ml, with its t, mx occurring 1.5
© Adis International Limited. All rights reserved.
hours after intravenous administration of Ml [12)
and 2.1 to 4.5 hours after administration of oral
glimepiride.
37 to 52% of an oral glimepiride dose is found
in the urine as the Ml and M2 metabolites within
24 to 48 hours (table II). The total body clearance
(CL) of glimepiride is not dose related, ranging
from 2.7 to 3.4 L/h after 1 to 8mg oral doses (table
II). CL of M1 after administration of oral glimepiride 1 to 8mg ranged from 8.6 to 10.2 L/h. The CL
of M2 (19.9 L/h) has been determined only after
intravenous administration of M1.[12] However, the
terminal elimination half-life (t1/2 ) of
glimepiride was variable after lower oral doses,
being 2 hours
Drugs 1998 Apr; 55 (4)
Glimepiride: A Review
after a 0.25mg dose, decreasing to 1 hour after a
0.5 mg dose and rising to 1.5 hours after a 1mg dose
in 27 healthy volunteers.[37] Furthermore, over a
range of doses from 1 to 8mg, the t'/2 of glimepiride increased from 3.2 to 8.8 hours in 12 healthy
volunteers, whereas the half-life of glimepiride
over all phases of elimination was within a narrower range (1.2 to 1.5 hours; table II). The halflife of the Ml metabolite was 2.7 to 3.5 hours (table
II) and that of the M2 metabolite was 4.1 to 5.6
hours after oral glimepiride doses of 0.25 to
1.5mg. [38]
3.3 Pharmacokinetics in Special Populations
There were no statistically significant differences in 24-hour AUC, CL and bodyweightadjusted clearance between elderly (65 years; n
= 50) and younger (n = 44) patients with type 2
diabetes receiving glimepiride 6mg once daily or
3mg twice daily in a 28-day study.[44]
16 patients with type 2 diabetes and
creatinine clearance (CLCR) values of 0.6 to 3
L/h (10 to 50 ml/min) received glimepiride 1 to
8mg once daily for 3 months.[45] CL was higher
in patients with CLCR <1.2 L/h (<20 ml/min), and
the investigators considered that this might be a
result of displacement of the drug from protein
binding. As CLCR decreased, CL and apparent
volume of distribution (Vd/F) of glimepiride
tended to increase and CL of the M1 and M2
metabolites tended to decrease. The t1/2 and mean
residence lime were unaffected by renal function.
Sulphonylureas are usually used with caution in
patients with severe liver disease.[39] Pharmacokinetics after a dose of glimepiride 1mg were studied
in 11 patients with type 2 diabetes and liver disease
of unspecified severity (reported in the review by
Rosenkranz[39]). No direct comparisons with pharmacokinetics in healthy individuals were conducted, but comparisons with results from other
studies[34,36] suggest that urinary excretion of the
M1 metabolite (51 to 443| g over 24 hours) may be
reduced by liver disease. However, pharmacokinetic variables were otherwise similar to those in
healthy volunteers (table II).
© Adis International Limited. All rights reserved.
3.4 Drug Interactions
There were no significant changes to pharmacokinetics of R- or S-warfarin (Cmax, CL, Vd, half-life or
protein binding,) after coadministration of a single
dose;of oral warfarin 25mg with glimepiride 4
mg/day in healthy; volunteers (number not specified).[46] The mean maximum prothrombin time
decreased from 16.2 to 14.6 seconds and the area
under the prothrombin time versus time curve decreased from 2198 to 2118 sec • h (decreases of 9.9
and 3.6%, respectively). The clinical significance
of these findings is thought to be minor[41] and the
effect of warfarin on glycaemic control was not
tested. Similarly, although a study in healthy volunteers found that concomitant aspirin reduced the
Cmax of glimepiride by 4% and increased its AUC
by 34%, pooled data from trials in diabetic patients
suggested no clinically significant interaction between these 2 agents.[47]
Concomitant administration of propranolol
with glimepiride at unspecified dosages to healthy
volunteers resulted in increases of 20% and 15%
in plasma glimepiride concentrations and t1/2 , respectively.[47] These changes occurred without
substantial alterations in pharmacodynamic effects
in healthy volunteers, and pooled data from clinical trials suggest no clinically significant interaction between glimepiride and -blockers.[47] However, caution is recommended when propranolol or
oilier -blockers are added to a pre-existing
glimepiride regimen. Studies addressing potential
interactions with calcium channel blockers, estrogen, fibrates, statins, nonsteroidal anti-inflammatory drugs, thyroid hormone and sulphonamides
have not been conducted. Pooled data from clinical
trials suggest that these drugs do not interfere significantly with the activity of glimepiride,[47] but
caution is recommended when they are coadministered with glimepiride.
Neither cimetidine 800mg once daily for 4 days
nor ranitidine 150mg twice daily for 4 days produced major changes in the AUC, Cmax, CL or Vd/F
of glimepiride in 18 healthy volunteers in a trial
reported as an abstract.[48]
Drugs 1998 Apr; 55 (4)
574
Langtry & Balfour
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Drugs 1998 Apr; 55 (4)
Glimepiride: A Review
The potential for interaction between sulphonylureas and highly protein bound drugs (e.g.
sulphonamides, nonsteroidal anti-inflammatory
drugs, etc.) suggests that patients receiving glimepiride should be monitored for hypoglycaemia or
loss of glycaemic control when these agents are
added or withdrawn.[41]
4. Clinical Efficacy
Glimepiride has been examined in placebo-controlled and dose-finding studies, comparisons with
other sulphonylureas and in combination with insulin in patients with type 2 diabetes. Disease severity has varied between patients, exemplified by
their status as having:
• loss of glycaemic control with diet and exercise
alone;
• previously stable glycaemic control on other
oral antidiabetic agents (mostly sulphonyl
ureas);
• loss of glycaemic control with other antidiabetic agents.
Major outcome measures used in most clinical
trials were fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c) and 2-hour postprandial plasma glucose (PPG) levels. Other outcome indicators included serum insulin, plasma
lipids and/or fasting C-peptide levels, blood pressure, bodyweight changes and insulin dosage.
Data for some trials evaluated in this review
were not clearly reported in the published literature
and some data were taken from unpublished trial
reports (listed in tables by their protocol numbers).
In addition, although dosages exceeding 8 mg/day
arc not currently recommended for use in patients
with type 2 diabetes (section 6), dosages of up to
16 mg/day were used in several clinical trials. Because of the way study data were reported, the results seen with the higher-than-recommended dosage cannot be easily separated from those recorded
for lower dosages (section 7).
© Adis International Limited. All rights reserved.
575
4.1 Dose-Ranging Studies and
Comparisons with Placebo
Glimepiride has significantly different effects
on glycaemia from placebo and is active at dosages
from 0.5 to 8 mg/day; once-daily regimens of up
to 8 mg/day are generally as effective as twicedaily regimens. Results of double-blind multicentre randomised placebo- or dosage-comparative trials examining the effects of glimepiride 0.25
to 16 mg/day are presented in table III. All studies
involving prior antihyperglycaemic therapy began
with a washout period of 1 to 3 weeks; baseline
values were measured at day 0 or day 1 before the
start of active treatment. These studies define minimum and maximum effective dosages of glimepiride and examine dose-response effects. Although
some patients had not received previous sulphonylurea therapy,[50-52] in most trials[49,53,54] patients
were previously responding to other sulphonylurea agents.
A 2-week Japanese trial[50] compared fixed
once-daily doses of glimepiride 0.25 and 0.5mg
with placebo in 93 patients and found 0.5mg to be
the minimum effective dose. Although all regimens resulted in reduced FPG and PPG, only
the 0.5 mg/day dosage produced reductions in FPG
(-2.5 mmol/L) or PPG (-4.9 mmol/L) that were
significantly different (p < 0.001) from those seen
with placebo (-1.0 and -1.7 mmol/L). Reductions
in HbA1c were similar across the 3 treatment arms
(-1.3 to -1.5%), but were unlikely to have been a
result of this short course of treatment.
Results from a 14-week study of fixed glimepiride dosages in a total of 304 patients[49] suggest that
responses to glimepiride continue to increase over
the 1 to 8 mg/day range (table III). Significantly
greater effects were seen on FPG and PPG with 4
and 8 mg/day than with 1 mg/day, and of patients
with baseline HbA1C of 8%, more had values of
<8% at end-point in the 8 mg/day group (14 of 31
patients, 45.2%) than the 4 mg/day group (5 of 29,
17.2%). Modest changes in body weight occurred
with 4 mg/day (+0.5kg) and 8 mg/day (+0.9kg);
there was no change with 1 mg/day and a loss of
1.82kg with placebo (p < 0.001 vs glimepiride). 81
Drugs 1998 Apr; 55 (4)
576
to 92% of glimepiride patients completed the study
versus 66% of placebo recipients.
Glimepiride 6mg once daily and 3mg twice
daily produced similar effects on FPG, PPG,
HbA1C, insulin and C-peptide levels in 98 patients
in a crossover study.[54] The only significant difference between dosage regimens was in mean 24hour glucose levels, which were lower after oncethan twice-daily administration (p < 0.05). In contrast, a 14-week study in 416 patients[53] found a
greater reduction (by 0.6 mmol/L) in FPG from
baseline when glimepiride was given as 2 daily
doses rather than as a single dose (p = 0.047). At
16 mg/day (but not at 8 mg/day) a twice-daily regimen resulted in a greater reduction in HbA1C (by
0.3%; p = 0.024) than a once-daily regimen. However, there were no significant differences in reductions in FPG from baseline to end-point between
groups receiving glimepiride 8 or 16mg total daily
doses. Thus, at total daily glimepiride doses of 16
and possibly 8mg there appears to be an advantage
in dividing the total dose in two; however, there is
no clear advantage to the use of total dosages of >8
mg/day.[53]
When glimepiride dosages were titrated between 1 and 8 mg/day to achieve FPG levels of 5
to 8.3 mmol/L, FPG was lower with glimepiride
than placebo after 2 weeks' treatment of a total of
249 patients.[51,52] 87% of the glimepiride group and
70% of the placebo group completed the study;
34% of glimepiride and 64% of placebo recipients
were receiving the highest dosages at end-point.
There was a clear correlation between baseline
FPG and the dosage of glimepiride at end-point.
After 10 weeks, glimepiride was superior to placebo (p < 0.001) in reducing FPG (-3.3 vs -0.7
mmol/L), HbA1c (-2.4 vs -1.0%) and PPG (-6.5
vs -1.7 mmol/L).
4.2 Comparisons with Other Sulphonylureas
Trials have compared glimepiride 1 to 16 mg/
day with glibenclamide 1.25 to 20 mg/day, glipizide 2.5 to 40 mg/day or gliclazide 80 to 320 mg/
day in >2300 patients with type 2 diabetes (table
IV). These randomised double-blind multicentre
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Langtry & Balfour
parallel-group trials involved initial titration of
dosages to achieve specific FPG goals (see table
IV). All but one[55] had a washout or pretreatment
period during which patients received no active
drug. Baseline findings between treatments were
measured at day 0 or day 1 at the start of active
treatment and in each study were similar between
groups.
Patients enrolled into 2 of the 3 comparisons
with glibenclamide had received previous glibenclamide therapy for 2 months and had FPG <l 3.9
mmol/L;[57,58]| in the third trial, patients were previously treated with diet (FPG < 16.7 mmol/L) or
sulphonylureas (FPG <11 mmol/L).[56] In the
gliclazide comparison,[55] patients were reported to be
previously well controlled on that drug, and in the
glipizide comparison,[51] patients were reported to
have no response to diet or to be previously treated
with sulphonylureas.
4.2.1 Comparisons with
Glibenclamide (Glyburide)
Dosage comparisons between agents are hampered by reporting methods, which were not consistent across trials. When glimepiride 1 to 8 mg/
day was compared with glibenclamide 1.75 to 14
mg/day,[58] distribution across the dosage ranges was
similar between groups: 47% of glimepiride
recipients required 8 mg/day and 47% of glibenclamide recipients required 14 mg/day. In another
trial, 51 % of glimepiride recipients required 8 mg/
day, whereas 42% of glibenclamide recipients required the maximum dosage of 20 mg/day.[57] A
third glibenclamide comparison reported only that
the majority of patients in each group required the
maximum dosage (glimepiride 16 mg/day or glibenclamide 20 mg/day). In the 1-year studies, the
sole between-group differences in major outcome
measures (table IV) were a greater increase in FPG
with glimepiride 1 to 8 mg/day (n = 465) than
glibenclamide 2.5 to 20 mg/day (n = 453) [+0.9 vs
+0.5 mmol/L, p < 0.005] in 1 study[57] and a greater
increase in HbA1C with glimepiride 1 to 8 mg/day (n
= 427) than glibenclamide 1.75 to 14 mg/day (n =
425) [+0.25 vs +0.09%, p < 0.05] in another.[58] The
increases in HbA1C were statistically signifiDrugs 1998 Apr; 55 (4)
Glimepiride: A Review
577
Table IV. Efficacy of glimepiride (GLI) in patients with type 2 (non-insulin-dependent) diabetes mellitus: double-blind dose-titration multicentre
parallel-group randomised comparisons with other sulphonylureas. Dosages were titrated until FPG was 5 to 8.3 mmol/L (90 to 150 mg/dl)[54,56]
or 3.9 to 8.3 mmol/L (70 to 150 mg/dl)[55,57,58]
Reference
WO, Titr, Maint
and total
treatment
durations
Dosage
Total no. of FPG (mmol/L)
evaluable baseline change
patients
baseline
change
baseline change
NR
NR
HbA1c (%)
PPG (mmol/L)
Comparisons with glibenclamide (glyburide, GLB)
Dills et al.[66]
GLI 1-16mg od
GLB 1.25-20mg od
289a
288a
13.1
12.9
-2.7
-2.4
8.5
8.5
-0.85
-0.83
Draeger et al.[57]
4wkWO
12wkTitr
9mo Maint
12mo
2wkWO
GLI 1-8mg od
465
8.8
+0.9
8.03
+0.38
GLB 2.5-20 mg/day
(od or bid)
453
8.8
+0.5"
7.80
+0.31
Protocol 311[58]l
2mo Titr
10mo Maint
12mo
2wkWO
GLI 1-8mg od
427
9.5
+0.1
8.41
+0.25*
425
9.5
-0.1
8.44
+0.09
96
6.4
107
6.3
NR Titr
GLB 1.75-14 mg/day
NR Maint
(od or bid)
12mo
Comparison with gliclazide (GLC)
Protocol 301 F[55) O WO
GLI 1-4mg od
8wkTitr
GLC 80-320 mg/day
6wk Maint
(Od or bid)
14wk
Comparison with glipizide (GLP)
Protocol 301 [51]
3wk WO
GL1 1-1 6 mg/day
12wkTitr
(od or bid)
9mo Maint
GLP 2.5-40 mg/day
12mo
NC
NC
5.02
4.99
+0.7
+0.04
-2.9
-2.8
9.2
8.5
NR
NR
444
128
-2.6
8,4
-0.5
16.2
-3.3
208
12.6
-2.4
8.3
-0.4
15.8
-3.3
(od or bid)
a Stratified according to high or low FPG levels.
Abbreviations and symbols: bid = twice daily; FPG = fasting plasma glucose; HbA1c = glycosylated haemoglobin; Maint = maintenance;
NC = no change; NR = not reported or not specified; od = once daily; PPG = 2h-postprandial plasma glucose; Titr = titration; WO = washout;
* p < 0.05, ** p < 0.005 vs comparator ________________________________
cant, but were considered by the investigators to be
not clinically significant (clinical significance was
not systematically examined).
Two of 3 glimepiride/glibenclamide comparative studies found lower fasting insulin levels in
glimepiride than glibenclamide groups,[57,58] and 2
trials found lower C-peptide levels with glimepiride. [56,58] No significant differences in lipid levels
were seen between treatments in the 2 studies reporting lipid testing.[57,58] Overall, usual recommended dosages of glimepiride and glibenclamide
were similarly effective. Patients in 2 of these trials
were allowed to continue study medication for up
to 2.4[57) or 2.8 years,[58,59] with no clinically relevant
differences in efficacy noted between groups.
© Adis International Limited. All rights reserved.
See section 5 for a commentary on differences in
adverse events between these treatments.
4.2.2 Comparison with Gliclazide
A 14-week study compared glimepiride 1 to 4
mg/day with gliclazide 80 to 320 mg/day in 203
evaluable patients and determined that glimepiride
1mg was equivalent in efficacy to gliclazide 80mg
(95% confidence interval 63.3 to 86.4mg).[55] Patients were randomised to continue with gliclazide
or were switched to glimepiride from previous
gliclazide therapy without a washout period.
Glycaemic control was good at baseline and was
maintained without major variations in both treatment groups. However, FPG, PPG and HbA1c were
Drugs 1998 Apr; 55 (4)
Langtry & Balfour
578
relatively low (for diabetic patients) at baseline and
although not significantly altered by either treatment, the lack of washout period, uncertain disease
severity at baseline and short duration of therapy
make it difficult to generalise these results. Further
longer term comparisons between glimepiride and
gliclazide are needed to determine whether differences in efficacy exist between these 2 agents.
Table V. Effects of glimepiride/insulin (GI) and insulin/placebo (PI)
combinations after 24 weeks' administration to 145 evaluable
obese patients with type 2 (noninsulin-dependent) diabetes mellitus
and secondary sulphonylurea failure (FPG 10 to 16.7 mmol/L after
glimepiride 8 mg/day for 8 weeks)[60,61]
Parameter
Treatment
groupa
Baselineb End-point
FPG (mmol/L)
HbA1c (%)
Gl
PI
Gl
13.9
14.4
9.7
7.6
7.6
7.6
-6.3
-6.9
-2.1
PI
Gl
PI
9.9
7.7
0/2
8/11
-2.2
WD due to adverse
events/total WD
4.2.3 Comparison with Glipizide
[51]
A 1-year study enrolling 802 patients found
that glimepiride 1 to 16 ing/day reduced FPG to a
greater extent than did glipizide 2.5 to 40 mg/day
over weeks 2 to 10 (p < 0.05). However, 51% of
glimepiride and 53% of glipizide recipients required the highest dosages allowed in the study (16
and 40 mg/day, respectively) and this highest
glimepiride dose is outside the usual recommended
dosage range.[51] There were no between-group differences in FPG, H,bA1C or PPG at end-point. This
suggests that glimepiride and glipizide have equivalent clinical efficacy, but that glimepiride may
achieve a more rapid response.
4.3 Combination with insulin
In patients in whom glimepiride or other sulphonylureas alone are no longer effective, a glimepiride plus insulin combination results in lower
requirements for exogenous insulin and more rapid
achievement of moderate control of blood glucose.
Glimepiride plus insulin was compared with insulin plus placebo in a randomised double-blind
trial aimed at achieving euglycaemia. Results of
this trial are not yet published in full. 208 obese
patients with type 2 diabetes insufficiently controlled by full dosages of sulphonylureas received
glimepiride titrated up to 8mg twice daily. Those
with laboratory-monitored FPG of 10 to 16
mmol/L (180 to 300 mg/dl) at the end of 8 weeks'
glimepiride monotherapy (n - 145) were randomised to continue glimepiride 16 mg/day with the
addition of insulin (GI group) or to receive insulin
plus placebo (PI group). Insulin (70% NPH, 30%
Regular; 70/30) was started at 10 U/day administered before the evening meal and adjusted weekly
until laboratory-monitored FPG was 7.8 mmol/L
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Change
a GI group n = 72; PI group n = 73.
b Baseline readings were taken at the end of 8wk of glimepiride
therapy, before the start of insulin therapy. Abbreviations: FPG
= fasting plasma glucose; HbA1c = glycosylated haemoglobin; WD =
withdrawals.
(140 mg/dl) [patients also self-monitored capillary blood glucose levels]. After 24 weeks, FPG
and HbA1c, which had been similar between groups
at baseline, had each decreased to a similar degree
in the GI and PI groups (table V).[60,61] The time
course of effects on FPG indicates that the GI group
experienced more rapid lowering of blood glucose
(fig. 3), with statistically significant differences between groups after 2 and 4 weeks of treatment.
These statistical differences occurred in part because of an initial increase in FPG in the PI
group.[60]
Bodyweight (baseline values not reported) increased by 4.3kg in the GI group (vs 4.0kg in the
PI group). However, a distinct reduction in insulin
requirements was seen in the GI group; the mean
daily insulin dose was 49U at end-point in the GI.
group, compared with 78U in the PI group (p <
0.001). Only 4 of 72 (6%) GI patients needed
>1OOU of insulin each day versus 9 of 73 (14%) PI
patients. Furthermore, 95% of GI patients versus
84% of PI patients achieved the target patientmonitored capillary blood glucose range of <6.7
mmol/L.[60] There were no between-group differences in blood pressure, fasting insulin or fasting
glucagon levels. Fasting C-peptide levels, however, were significantly lower at end-point in the
PI group (0.6 nmol/L) than the GI group (0.8
Drugs 1998 Apr; 55(4)
Glimepiride: A Review
nmol/L, p < 0.001).[60] For a discussion of the
incidence of hypoglycaemia in this study, see section 5.
5. Tolerability
As assessed in more than 4200 patients who received the drug in US or European comparative
clinical trials, glimepiride is well tolerated, with
adverse events that are generally characteristic of
the sulphonylurea class of antihyperglycaemic
drugs.[47,62] Of the patients studied, >1500 were
maintained on the drug for 1 year and >800 for >1
year.[47] >2300 additional patients received glipizide, glibenclamide or placebo in these comparative clinical trials (see section 4.2 for dosages
used).
Two analyses of glimepiride tolerability[47,62]
reported the incidence of treatment emergent signs
and symptoms (TESS; excluding signs or symptoms of hypoglycaemia) that were possibly or
probably related to treatment and of deaths, discontinuations due to adverse events or other serious
adverse events (DDOS). Patients included those
enrolled in glimepiride and comparator groups in
US and European clinical trials. The results of
Duration of treatment (wk)
Fig. 3. Initial reductions in fasting plasma glucose (FPG) from
baseline with glimepiride 8 mg/day plus insulin (Gl, n = 72) or
insulin plus placebo (PI, n = 73).[60] Patients had type 2 (noninsulin-dependent) diabetes mellitus that was resistant to sulphonylurea monotherapy. Values at 12 weeks are approximate;
exact FPG values were not reported. Symbol: * p < 0.05.
© Adis International Limited. All rights reserved.
579
these analyses are shown in figure 4. Although
clear relationships are seen between comparators
in the US trials, the differences have hot been
tested statistically. Nonetheless, the incidence of
common TESS was higher with glimepiride than
placebo, but was lower with glimepiride than
glibenclamide or glipizide. The incidence of
DDOS in US trials was highest in patients receiving placebo (due to the inclusion of hyperglycaemia, which occurred in 17% of patients), but was
lower in glimepiride recipients than in patients receiving other sulphonylureas. In the European trials, however, the incidence of common TESS was
similar across all groups and although DDOS occurred less often in glimepiride than glibenclamide
recipients, these events occurred least often in patients receiving glipizide. The most common TESS
occurring in patients receiving glimepiride in US
and European trials included dizziness, headache,
asthenia and nausea, while the most common
DDOS included hyperglycaemia, surgery and
myocardial infarction.[47]
Serious adverse events occurred in all study
groups assessed in safety reviews.[47,62] In US and
European trials, the incidence of serious adverse
events was 2% in placebo recipients, 8% in glimepiride recipients, 8.8% in glipizide recipients and
12.4% in patients receiving glibenclamide. The
most common events occurring in glimepiride recipients were similar in nature to those seen with
the other sulphonylureas, and included cardiovascular, digestive, respiratory, metabolic and nutritional events. Most of these events were not considered to be related to the use of study medication,
but the incidence and nature of those that were
drug-related was not reported.[47]
Hypoglycaemia is known to occur in conjunction with sulphonylurea therapy, but it has a higher
incidence with the use of glibenclamide than with
other drugs of this class.[63] In US trials comparing
glimepiride (n = 741) with placebo (n = 294), hypoglycaemia occurred at a cumulative incidence of
13.9 versus 2%.[47] In a 1-year US comparative
study,[47,56] hypoglycaemia occurred in 10% of 289
glimepiride recipients and 16.3% of 288 patients
receiving glibenclamide. In a 1-year US compariDrugs 1998 Apr; 55 (4)
58O
Langtry & Balfour
Fig. 4. Tolerability of glimepiride in comparative clinical trials. Incidence of common treatment emergent signs and symptoms (TESS;
excluding signs or symptoms of hypoglycaemia) and of deaths, discontinuation due to adverse events or other serious adverse
events (DDOS) in patients receiving glimepiride, placebo, glibenclamide (glyburide) or glipizide in US and European clinical trials.[47]
The numbers of patients in each treatment group in US trials were: placebo 294, glimepiride 2011, glibenclamide 322 and glipizide
258. In European trials they were: glimepiride 1489, glibenclamide 1132 and glipizide 115.
son with glipizide, symptomatic hypoglycaemia
occurred in 21.2% of 544 glimepiride recipients
and 20.6% of 258 glipizide recipients.[47] The incidence of hypoglycaemia during the first month of
a comparative trial was 1.7% with glimepiride and
5.6% with glibenclamide. Laboratory-confirmed
hypoglycaemia was less common than symptomatic hypoglycaemia in US comparative trials; it occurred in, respectively, 1.5 and 0% of glimepiride
and placebo recipients, 1.7 and 2.4% of glimepiride
and glibenclamide recipients and 0.9 and 1.2% of
glimepiride and glipizide recipients.[47] The suggestion that glimepiride may result in lower rates
of hypoglycaemia than these other 2 sulphonylureas now requires confirmation in clinical trials
specifically designed to examine this question.
When glimepiride plus concomitant insulin (GI)
was compared with insulin plus placebo (PI) for 6
months,[60] similar proportions of patients in the 2
groups experienced adverse events (92% GI and
90% PI). The most common adverse events in this
© Adis International Limited. All rights reserved.
study were reported to be of short duration and consistent with hypoglycaemia (but were not confirmed by blood tests). There was also a higher incidence of mild hypoglycaemia (51 vs 37%) and
lower incidence of moderate hypoglycaemia (11 vs
15%) with GI than PI. Two GI patients dropped out
of the study after randomisation (not because of
hyperglycaemia or adverse events). However, of
the 11 patients in the PI group who dropped out, 8
withdrew because of inadequate glycaemic control
or reasons potentially related to this.
6. Dosage and Administration
Glimepiride monotherapy may be added to a
regimen of diet and exercise in patients with type
2 diabetes mellitus. The usual starting dosage of
glimepiride in the US is 1 to 2mg administered
orally once daily with the first main meal of the
day.[41] Thereafter, dosages are individualised according to FPG and HbA1c levels. Dosage titration
should take place at 1- to 2-week intervals on the
Drugs 1998 Apr; 55 (4)
581
Glimepiride: A Review
basis of blood glucose response; increments in
daily dosage should not exceed 2mg at a time.
HbA1C levels should be monitored at 3- to 6-month
intervals during therapy; these and FPG levels help
to determine the minimum effective dose and to
detect the development of primary or secondary
failure. Usual maintenance dosages of glimepiride
are 1 lo 4mg once daily. The use of dosages of >8
mg/day is not recommended.
In the UK, the recommended starting dosage is
glimepiride 1 mg/day. This can be gradually increased to 6 mg/day, but dosages of >4 mg/day are
thought to be of benefit only in exceptional situations.[64]
In patients in whom the effectiveness of glimepiride appears to decrease after a period of effective
use (i.e. those with secondary failure), glimepiride
may be combined with insulin. The manufacturer
recommends that FPG at initiation of this combination be in the range of >8.32 mmol/L (>150
mg/dl). In the US, the recommended glimepiride
dosage in this combination regimen is 8mg once
daily with the first main meal of the day. Low-dose
insulin is added to this and adjusted upward at approximately weekly intervals as needed to control
fasting blood glucose. Capillary blood glucose levels should be monitored daily during maintenance
therapy and insulin dosages adjusted according to
these and to HbA1C levels.[41]
Patients previously maintained on other antihyperglycaemic drugs may be switched to glimepiride without a transition period. However, because
of the possibility of an overlap of effect of longeracting sulphonylurcas, such as chlorpropamide,
when patients are switched from these agents to
glimepiride they should be monitored closely for
signs of hypoglycaemic reactions during the first 1
to 2 weeks.[41]
In elderly, malnourished or debilitated patients
or those with renal or hepatic impairment glimepiride treatment should be initiated, titrated and mainlained cautiously to avoid hypoglycaemic reactions. Glimepiride is not recommended for use in
women who are pregnant or breastfeeding or in
children.[41]
© Adis International Limited. All rights reserved.
It is recommended that patients receiving
glimepiride are informed of potential risks of cardiovascular mortality that are thought to be associated with the use of sulphonylurea drugs and that
they are told about alternative treatments.[41]
7. Place of Glimepiride in the
Management of Type 2
Diabetes Mellitus
Type 2 diabetes mellitus is characterised by insulin secretory defects and insulin resistance.[65]
As a slowly progressive disorder, it usually re
sponds initially to diet and exercise alone. However; a gradual deterioration of giycaemic
control often results in the need for oral treatment
with antidiabetic agents. Further possible
deterioration may necessitate the use of
combinations of oral agents and possible
eventual use of exogenous insulin injections
either alone or combined with oral agents.[66,67]
Sulphonylurea agents are the mainstays of
oral antidiabetic therapy. They stimulate insulin
release from the pancreas[66] and are thought to be a
good first choice for most patients with type 2
diabetes.[68] However, metformin may be
recommended for patients who are overweight,
since it tends to reduce bodyweight.[69]
Glimepiride is conveniently administered in a
once-daily dose with breakfast. It has few known
drug interactions. Although adverse events associated with its use are characteristic of the sulphonylurea class, it may produce fewer total events or
serious adverse events and less hypoglycaemia
than glibenclamide. It has been suggested that this
difference in incidence of hypoglycaemia may be
caused by inappropriately high initial glibericlamide dosages rather than resulting from an intrinsically lower risk with glimepiride (W. Waldhausl,
personal communication), but in any case the difference requires confirmation in wider patient use.
In relation to other sulphonylureas,
glimepiride appears to be as efficacious as
glibenclamide or glipizide and possibly also
gliclazide when used to treat patients with type 2
diabetes not well control-led by diet. Furthermore,
it may reduce blood gluDrugs 1998 Apr; 55 (4)
Langtry & Balfour
582
cose more rapidly than glipizide and appears to
produce less hypoglycaemia than glibenclamide.
Pharmacological studies suggest that glimepiride has
fewer or less severe effects on cardiovascular variables
than glibenclamide and similar effects to gliclazide
(section 2.3); additional studies of these features in
clinical settings would help to clarify
the
importance of these findings. In addition, further
studies are needed to determine the efficacy of
glimepiride monotherapy in relation to gliclazide or
metformin and to evaluate combinations of
glimepiride with metformin or other oral anti-diabetic
agents.
Yearly secondary failure rates range from 1.4%
with gliclazide to 5.6% with glipizide.[70] When
sulphonylureas fail to maintain glycaemic control and
subsequent combination oral antidiabetic therapy is
unsuccessful, insulin monotherapy may provide a
return to near normal blood glucose levels. However,
this return is often at the expense of an increase in
bodyweight
(not
normally
seen
with
sulphonylurea/insulin combinations) and the use of
large doses of insulin each day (e.g. >1 U/kg).[71]
When combined, sulphonylureas and insulin are
thought to have complementary actions, with insulin
decreasing blood glucose levels and so preventing
hyperglycaemia-induced reductions in -cell function,
allowing the sulphonylurea to promote endogenous
insulin release.[72] It has been suggested that
combinations of oral agents may not be effective in
patients with secondary failure who have little
remaining -cell function;[72] some -cell function is.
also required if combination of a sulphonylurea with
insulin is to be effective.[73]
A combination of exogenous insulin plus
glimepiride was able to reduce glycaemia to normal
levels in most patients, and the glimepiride
component substantially reduced the requirements for
exogenous insulin. Glimepiride plus insulin appeared
to act more rapidly to reduce blood glucose, which
may be why mild hypoglycaemia was more common
with this combination. Although body-weight
changes occurred with glimepiride plus insulin, it
would be interesting to see if future studies show the
same increase in bodyweight when the combination
is used in nonobese patients or in the
© Adis International Limited. All rights reserved.
lower (8 mg/day) glimepiride dosages that are now
recommended.
In many therapeutic trials, upper dosage limits
exceeded (hose now recommended for use. In some of
the comparative trials that titrated study drug
dosages to achieve specific blood glucose endpoints, for example, a majority of patients had dosages titrated to 16 mg/day before they met the therapeutic targets. With 8 mg/day not then established as
the acceptable upper limit for dosage, a 16 mg/ clay
dosage was also used in the insulin combination
study. However, subsequent studies showed little
difference between dosages of glimepiride 8mg
once or twice daily. Until further studies are
conducted using only dosages within the recommended range, it cannot be determined whether
some effects seen with glimepiride may be exaggerated by the use of higher doses that will not be
used in practice. However, since dosages >8 mg/
day did not appear to provide additional benefits
over those seen with lower dosages (see section
4.1), it is possible that restricting the dose to 8
mg/day will result in a lowering of the risk of adverse
events. In any case, further examination of the
effects within the now recommended dosage range
is needed.
In conclusion, glimepiride is a new once-daily
sulphonylurea that may have a slightly different
profile of adverse events compared with other
agents in its class. Future studies should examine
the use of glimepiride in combination with other
oral antidiabetic agents in patients with type 2 diabetes mellitus. In the meantime, glimepiride may
be considered an alternative to other sulphonylureas for use as monotherapy in patients with type 2
diabetes mellitus insufficiently controlled by diet
and exercise alone. It may also be used in combination with insulin in patients in whom diet and
exercise plus oral antihyperglycaemic therapy have
failed to control blood glucose.
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Correspondence: Heather D. Langtry, 41 Centorian Drive,
Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand. E-mail: [email protected]
Drugs 1998 Apr; 55 (4)