DRUG EVALUATION

Drugs 46 (I): 92-125, 1993

0012-6667/93/0007-0092/$17.00/0
© Adis International Limited. All rights reserved.
DREll99

Gliclazide
An Update of its Pharmacological Properties and Therapeutic Efficacy in
Non-Insulin-Dependent Diabetes Mellitus
Katharine J. Palmer and Rex N. Brogden
Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by: A.H. Barnett, The University of Birmingham, Department of
Medicine, East Birmingham Hospital, Birmingham, England; J. Gram, Department of Clinical Chemistry, Section
for Thrombosis Research, Ribe County Hospital in Esbjerb, Esbjerb, Denmark; P.-J. Guillausseau, Medecine
Interne Nutrition Endocrinologie, H6pital Lariboisiere, Paris, France; A.D.B. Harrower, Medical Unit, Monklands
District General Hospital, Airdrie, Scotland; P.E. Jennings, York District Hospital, York, England; C. Kilo, Kilo
Diabetes and Vascular Disease Research Foundation, St Louis, Missouri, USA; K. Kosaka, The Institute for
Diabetes Care and Research, Asahi Life Foundation, Tokyo, Japan; R.G. Larkins, University of Melbourne, De-
partment of Medicine, Royal Melbourne Hospital, Melbourne, Victoria, Australia; A. Mizuno, Department of
Laboratory Medicine, School of Medicine, University of Tokushima, Tokushima, Japan; D. Porte Jr, Division
of Endocrinology and Metabolism, Veterans Association Medical Center, Seattle, Washington, USA; C. Schnack,
Department of Medicine, Rudolfstiftung Hospital, Vienna, Austria; T. W. IIan Hae/ten, Department of Endocrin-
ology, University Hospital, Groningen, The Netherlands; B.L. Wajchenberg, Endocrine Section, Hospital das C1in-
icas, Sao Paulo, Brazil; G.c. Weir, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.

Contents
93 Summary
95 I. Pharmacodynamic Properties
95 1.1 Hypoglycaemic Activity
95 1.1.1 Pancreatic Effects
99 1.1.2 Extrapancreatic Effects
101 1.2 Haemobiological Effects
102 1.2.1 Platelets
103 1.2.2 Fibrinolysis
104 1.2.3 Coagulation
104 1.2.4 Specificity of Effects
104 1.3 Free Radical Levels
105 1.4 Plasma Lipids
106 2. Pharmacokinetic Properties
106 2.1 Absorption and Plasma Concentrations
108 2.2 Distribution, Metabolism and Elimination
108 2.3 Relationship between Plasma Concentrations and Pharmacodynamics
109 3. Therapeutic Efficacy
109 3.1 Glycaemic Control
109 3.1.1 Blood Glucose Levels
JJ3 3. I.2 Glycosylated Haemoglobin
113 3.2 Secondary Failure Rate
1/4 3.3 Effect on Insulin Requirements
114 3.4 Effect on Bodyweight
Gliclazide: An Update 93

115 3.5 Effect on Diabetic Retinopathy

1/7 3.6 Effect on Diabetic Nephropathy
117 4. Tolerability
lI8 4.1 Hypoglycaemia
1/8 4.2 Cardiovascular Effects
119 5. Drug Interactions
JJ9 6. Dosage and Administration
/20 7. Place of Gliclazide in Therapy

Summary
Synopsis
Gliclazide is a second generation sulphonylurea oral hypoglycaemic agent used in the treatment
of non-insulin-dependent diabetes mellitus (NIDDM). It improves defective insulin secretion and
may reverse insulin resistance observed in patients with NIDDM. These actions are reflected in a
reduction in blood glucose levels which is maintained during both short and long term adminis-
tration. and is comparable with that achieved by other sulphonylurea agents. Gradually accu-
mulating evidence suggests that gliclazide may be useful in patients with diabetic retinopathy. due
to its haemobiological actions. and that addition of gliclazide to insulin therapy enables insulin
dosage to be reduced.
Thus. gliclazide is an effective agent for the treatment of the metabolic defects associated with
NlDDM and may have the added advantage of potentially slowing the progression of diabetic
retinopathy. These actions. together with its good general tolerability and low incidence of hypo-
glycaemia have allowed gliclazide to be well placed within the array of oral hypoglycaemic agents
available for the control of NlDDM.

Pharmacodynamic Properties
Gliclazide reduces blood glucose levels in healthy volunteers and patients with non-insulin-
dependent diabetes mellitus (NIDDM) by correcting both defective insulin secretion and peri-
pheral insulin resistance. Unstimulated and stimulated insulin secretion from pancreatic Jj-cells
is increased following administration of gliclazide, with both the first and second phases of se-
cretion being affected. This occurs via the binding of gliclazide to specific receptors on pancreatic
Jj-cells which results in a decrease in potassium effiux and causes depolarisation of the cell. Sub-
sequently, calcium channels open, leading to an increase in intracellular calcium and induction
of insulin release. In addition, gliclazide increases the sensitivity of Jj-cells to glucose.
Gliclazide may have extrapancreatic effects which restore peripheral insulin sensitivity, such
as decreasing hepatic glucose production, and increasing glucose clearance and skeletal muscle
glycogen synthase activity. These effects do not appear to be mediated by an effect on insulin
receptor number, affinity or function.
There is some evidence that gliclazide improves defective haemobiological activity in patients
with NIDDM. A reduction in platelet adhesion has CO!1sistently been observed but the effect of
the drug on platelet aggregation is less well defined. Data available regarding the effect of gliclazide
on platelet function and production of arachidonic acid metabolites are encouraging but require
further substantiation. Limited data suggest that gliclazide may increase levels of tissue plasmin-
ogen activator, and reduce levels of free radicals hence preventing vascular damage mediated by
these chemical species. These properties appear to be specific actions of the drug on platelets and
blood vessel walls, rather than an indirect effect of improved glycaemic control.
Data regarding the effect of gliclazide on plasma lipids are inconsistent, with reports of de-
creases or no change in plasma cholesterol and triglyceride levels after repeated administration.

Pharmacokinetic Properties
Oral absorption of gliclazide is similar in patients and healthy volunteers, although intersubject
variation in time to reach peak plasma concentrations (tmax ) and age-related differences in peak
plasma concentrations (Cmax) and t max have been observed. Single-dose oral administration of
94 Drugs 46 (J) 1993

gliclazide 40 to 120mg results in a Cmax of 2.2 to 8 mg/L within 2 to 8 hours. Cmax and tmax
are increased after repeated gliclazide administration, although drug accumulation has not been
observed. Steady-state concentrations are achieved after 2 days' administration of gliclazide 40
to 120mg. Administration of gliclazide with food reduces Cmax and delays tmax.
The volume of distribution of gliclazide in healthy volunteers and patients is low (13 to 24L)
which may be partially explained by extensive protein binding (85 to 97%). The elimination half-
life (t'h) of gliclazide after single-dose and repeated oral administration of 40 to 120mg to healthy
volunteers and patients is 8.1 to 20.5 hours, although age- and gender-related differences in t'h
have been reported. Plasma clearance is approximately 0.78 Llh (13 ml/min). Gliclazide is ex-
tensively metabolised to 7 metabolites which are predominantly excreted in the urine, the most
abundant urinary metabolite being the carboxylic acid derivative. 60 to 70% of the dose is excreted
in the urine and 10 to 20% in the faeces. While. very little of the dose recovered in the urine is
unchanged parent compound, this represents over 90% of all drug-related material in the plasma.
Renal insufficiency has little effect on the pharmacokinetic profile of gliclazide.

Therapeutic Efficacy
Gliclazide effectively controls blood glucose levels in patients with NIDDM, with good or
excellent control achieved in 62 to 97% of patients. Recent studies have found that gliclazide
reduces fasting (by 12 to 62.1%) and postprandial (by 18 to 26.7%) glucose levels and the increase
in plasma glucose induced by the glucose tolerance test. These effects are observed in newly
diagnosed and previously treated patients, although effects may be reduced in the latter group of
patients, and do not appear to be affected by the severity (assessed by pretreatment fasting blood
glucose levels) or duration of disease. Good glycaemic control is also indicated by a reduction
in glycosylated haemoglobin levels in patients treated with gliclazide.
When combined with insulin therapy, gliclazide allows a reduction in insulin dosage which
may prove advantageous in reducing macroangiopathic complications ofhyperinsulinaemia. Lim-
ited data suggest that gliclazide is associated with a low rate of secondary failure.
Data from comparative trials have demonstrated that gliclazide is equivalent to other oral
hypoglycaemic agents in terms of glycaemic control; however, data accumulating from small scale
studies suggest that long term administration of gliclazide may delay the progression of diabetic
retinopathy to a greater extent than other sulphonylureas or diet. Nevertheless, these encouraging
initial findings require further clarifiaction. Preliminary findings suggest that gliclazide has little
or no effect on diabetic nephropathy. It has no consistent effect on bodyweight in obese or non-
obese patients.

Tolerability
Data derived before 1984 from large patient numbers, and from more recent small scale trials,
indicate that gliclazide is well tolerated by most patients. Mild gastrointestinal and central nervous
system disturbances, and dermatological effects are occasionally noted, while haematological dis-
orders are rarely observed. Gliclazide is associated with a low incidence of hypoglycaemia.

Dosage and Administration

Gliclazide is recommended for the treatment ofNIDDM in adults who have failed to respond
to dietary restrictions. The daily dose generally required for adequate glycaemic control is 160mg
but this may be increased to a maximum of 320 mg/day. Dosages of over 160 mg/day should
be administered in 2 doses with morning and evening meals.
Gliclazide is contraindicated in insulin-dependent diabetes mellitus, diabetes complicated by
ketosis and acidosis, diabetic pre-coma and coma, pregnancy and after severe trauma or infection.
Use should be avoided in patients with severe renal andlor hepatic failure. The risk ofhypogly-
caemia can be reduced by careful monitoring of blood glucose levels and appropriate adjustment
of the dosage. In the case of hypoglycaemia due to overdosage, gastric lavage and intravenous
administration of hypertonic glucose should be performed.
Several metabolic drug interactions may occur which can increase plasma gliclazide concen-
Gliclazide: An Update 95

trations and lead to hypoglycaemia, such as displacement from plasma proteins reduced clearance
and inhibition of metabolism of gliclazide. Induction of metabolism of glic~ide leading to re-
duced glycaemic control can also occur. Concomitant administration of gliclazide with agents
that suppress the manifestations of hypoglycaemia or increase insulin secretion should be avoided.
Administration of gliclazide with drugs that increase blood glucose levels should be accompanied
by monitoring of blood glucose levels to prevent hyperglycaemia.

Type II or non-insulin-dependent diabetes anism of action and therapeutic use of gliclazide.

mellitus (NIDDM) is the most common form of
diabetes mellitus, accounting for approximately 75%
of patients with diabetes seen in clinical practice
(Campbell 1991). The characteristic feature of the
disease is hyperglycaemia due to insulin resistance,
increased hepatic glucose production and reduced
insulin secretion. Dietary control is the first-line
treatment for NIDDM; however, often because of
poor compliance, up to 50% of patients eventually
require additional pharmacological therapy, usu-
ally with an oral hypoglycaemic agent (Campbell
1991). The ideal pharmacological agent would cor-
rect the metabolic dysfunction causing the disorder
and decrease the risk of associated macro- and
microvascular diseases.
Gliclazide [1-(3-azabicyclo-[3,3,0]-oct-3-yl)-3-(P-
tolylsulphonyl) urea] is a second generation sul-
phonylurea, of the same class as glibenclamide (fig.
1), which" is widely used in the treatment of
NIDDM. The pharmacology and clinical efficacy
of the drug were first reviewed in the Journal in
1984 (Holmes et al. 1984). Subsequently, there has
been an accumulation of data regarding the mech-
HOC-oSO,NHCONH-{J)
Gllclazlde
CI
This update reviews this information and re-eval-
uates gliclazide as an oral hypoglycaemic agent.
1. Pharmacodynamic Properties
1.1 Hypoglycaemic Activity
Two primary features of NIDDM have been
identified:
1. Defective insulin secretion. An initial loss of
first-phase secretion is followed by a reduction in
the response of second-phase secretion to physio-
logical stimulation (Pfeiferet al. 1981).
2. Resistance to insulin. This leads to a reduction
in peripheral glucose uptake and utilisation and an
increase in hepatic glucose production, culminat-
ing in hyperglycaemia (DeFronzo et al. 1982).
Thus, an effective hypoglycaemic agent should
improve pancreatic p-cell function, so increasing
insulin secretion, and correct the insulin response
in peripheral tissues and reduce hepatic glucose
production (Chiasson et al. 1991).
Gliclazide reduced blood glucose levels in ani-
mal models and in healthy volunteers (reviewed by
Holmes et al. 1984; Matthews et al. 1991). In
patients with NIDDM, a single dose of gliclazide
40 to 320mg reduced the extent and duration of
hyperglycaemia induced by oral and intravenous
glucose, and food (reviewed by Holmes et al. 1984;
Chiasson et al. 1991; Scott & Donnelly 1987). The
mechanism by which this effect is achieved has been
investigated.

~CONHcti'H'C-oso,NHCONH-0 1.1.1 Pancreatic Effects

Effect on Insulin Levels and Secretion

OCH, Glibenclamide
A number of methods of assessing p-cell secre-
tory activity have been used. Insulin levels can be
Fig. 1. Structural formulae of gliclazide and glibenclamide. measured directly using radioimmunoassay, or in-
96
580 * creatic ,B-cells. In patients with NIDDM, repeated
Gllclazlde
::J
~ 435
E et al. 1989; Scott & Donnelly 1987). The effect of
.s
.!:
3
UJ 290
.!:
as
E mgjday for 8 to 21 weeks (Bak et al. 1989; Chang
UJ
as
a::: 145
-100 30 60 90 120
Time (min)
Fig. 2. Mean plasma insulin levels during an oral glucose
tolerance test after 3 months' administration of gliclazide 40
to 320 mg,lday or placebo to 18 patients with non-insulin-
dependent diabetes mellitus; * p < 0.05 vs placebo (after Chang
et al. 1990).
directly by measuring C-peptide levels. This pep-
tide is secreted in a 1: 1 ratio with insulin and,
since it is not metabolised by the liver, has a longer
half-life than insulin, thus providing a better in-
dicator of insulin secretion than plasma insulin
levels. Insulin levels after stimulation of ,B-cells can
be measured using the glucose tolerance test; how-
ever, although this is the simplest method, results
obtained from this test may be confounded by
changes in glucose levels. Hyperglycaemic clamp
techniques can also be used and have the advan-
tage of maintaining patients' glucose levels at a
predetermined rate. Therefore, stimulation of in-
sulin secretion by infusions of glucose are not af-
fected by endogenous alterations of glucose levels.
The amino acid, arginine, has an insulinogenic ef-
fect and has been used as an alternative stimulus
of insulin secretion.
Oral or intravenous administration of gliclazide
causes an increase in unstimulated plasma insulin
levels (Matthews et al. 1991; Ohneda et al. 1977).
An intravenous infusion of gliclazide 80mg caused
a rapid increase in insulin levels from 6 to 44 mUI
L in a single healthy volunteer (Matthews et al.
1991), suggesting an immediate effect on pan-
Drugs 46 (1) 1993
treatment with gliclazide 160 to 320 mgjday for 4
or 8 weeks resulted in an increase in mean post-
prandial plasma insulin levels of 45 to 74% (Bak
gliclazide on fasting insulin levels is equivocal with
several trials reporting no change in this parameter
after repeated administration of gliclazide 40 to 320
et al. 1990; Noury & Nandeuil 1991; Wing et al.
1993), while other studies reported significant in-
creases (44 to 200%) in fasting insulin levels with
a similar dosage regimen (Johnson et al. 1991;
Wajchenberg et al. 1980, 1992).
An overall increase in insulin levels in response
to stimulation by a glucose load has also been dem-
onstrated following repeated administration of gli-
clazide 40 to 320 mgjday for 3 to 6 months to
patients with NIDDM (Chang et al. 1990; Coutu-
rier 1986; Sinay et al. 1988) [for example see figure
2]. C-peptide levels were also significantly in-
creased by 3 to 12 months of gliclazide therapy
(Brogard et aI. 1984; Quatraro et al. 1986; Sinay et
al. 1988).
Insulin is secreted in a biphasic manner; the first
phase occurring within 10 minutes of, and the sec-
ond phase up to 160 minutes after, stimulation. A
single dose (80mg) of or repeated administration
(80 to 268 mgjday) of gliclazide increased insulin
secretion during the first and second phases in
patients with NIDDM and healthy subjects (table
I). This effect was apparent using either glucose tol-
erance tests or glucose clamp techniques. In 1 study,
gliclazide was found to increase the 2 phases of in-
sulin secretion in patients with NIDDM to those
seen in healthy volunteers after a glucose load
(Chiasson et al. 1991). The stimulatory effect of
gliclazide on insulin secretion during glucose
clamping was most obvious at glucose concentra-
tions of 7.5 to 10 mmol/L, which is likely to be
clinically beneficial as many patients with NIDDM
have fasting blood glucose levels of about 8 mmol/
L (Veneman et al. 1991). At higher hyperglycaemic
glucose clamp concentrations of 15 and 32 mmol/
L, responses were largely unaffected (van Haeften
et al. 1991).
Gliclazide: An Update
Table I. The effect of gliclazide on first and second phases of insulin secretion in patients with non-insulin-dependent diabetes
mellitus (NIDDM) and healthy individuals
Reference No. of participants Gliclazide
(diagnosis) (mg/day)
[duration]
Chiasson et al. (1991) 4 (NIDDM) 80 [single dose]
Della Casa et al. 10 (NIDDM) 240-268 [6mo]
(1991)
Johnson et al. (1991) 10 (NIDDM) 160 [Sw]
van Haeften et al. 8 (healthy) 80 [single dose]
(1991)
a Compared with placebo.
b Compared with pretreatment.
c Compared with no treatment.
Abbreviations and symbol: mo = months; w = weeks; t indicates increase.
Data from animal studies have provided some
evidence that the effect of gliclazide on insulin se-
cretion differs from that of glibenclamide. In iso-
lated perfused rat pancreas, therapeutic concentra-
tions of gliclazide (2.5 mg/L) induced a biphasic
increase in insulin secretion with each phase last-
ing up to 8 minutes and returning to basal levels
after infusion of the drug was terminated. Similar
effects were observed with tolbutamide (50 mg/L)
and gliquidone (0.3 mg/L). In contrast, glibenclam-
ide (0.05 mg/L) produced a slower more prolonged
increase in insulin release and insulin levels did
not return to basal levels during a 20-minute pe-
riod after termination of drug infusion (Gregorio
et a1. 1992) [fig. 3]. Furthermore, the stimulatory
effect of gliclazide on insulin levels was reduced as
glucose levels in the perfusate fell (Gregorio et a1.
1992). This indicates that the effect of gliclazide is
modified according to the glycaemic state. The
profile of insulin secretion induced by gliclazide
may be clinically relevant as it closely resembles
the normal pattern of insulin secretion in healthy
volunteers. This may be responsible for the low
incidence of hypoglycaemia observed with the drug
(section 4.1).
Clinical data substantiate the findings from ani-
mal studies, as gliclazide had an immediate and
short lasting effect on insulin secretion when as-
sessed during glucose tolerance tests. Following
97
Test Change in insulin secretion ("!o)
1st phase 2nd phase
Glucose tolerance t 1328 t1608
Glucose tolerance t3091 b t 54b
Glucose tolerance t 750b t167 b
Glucose clamp t 22c t 25C
(8 or 32 mmolfL)
treatment with gliclazide 240 mg/day for 3 months,
12 patients with NIDDM showed a rapid increase
in C-peptide levels which occurred over the period
4 to 20 minutes after an intravenous glucose load
(Brogard et a1. 1984).
In several studies, the effect oflong term admin-
istration of gliclazide on insulin levels did not cor-
relate with the effect on blood glucose levels (Bro-
gard et a1. 1984; Hosker et a1. 1989; Ma et a1. 1989;
Scott & Donnelly 1987; Wajchenberg et a1. 1992).
For example, in 9 patients treated with gliclazide
80 to 160 mg/day, blood glucose levels were de-
creased after 3 and 12 months' treatment while in-
sulin levels were increased at 3 months but had
fallen to pretreatment levels after 12 months
(Wajchenberg et a1. 1992). However, in all studies
where changes in insulin levels were transient or
not observed, significant increases in C-peptide
levels were described, suggesting that stimulation
of pancreatic {3-cells had indeed occurred.
Gliclazide appears to increase the sensitivity\\of
pancreatic {3-cells to glucose: a single oral dose of
80mg to 8 healthy volunteers 90 minutes before the
test, significantly decreased the glucose concentra-
tion inducing 50% stimulation of insulin release
(ED 50) of the first phase of glucose clamp-induced
insulin secretion from 9.14 to 7.56 mmoljL (Vene-
man et a1. 1991). There was no effect on the ED50
of the second phase or the maximal ,a-cell respon-
98 Drugs 46 (1) 1993

siveness of the first or second phases of secretion.
In contrast, another study found that gliclazide
80mg administered 30 minutes before a glucose
clamp, induced a trend towards an increase in pan-
creatic {1-cell glucose sensitivity of the first phase
of insulin release and significantly increased that
of the second phase (van Haeften et al. 1991). The
ratio of plasma insulin levels to glycaemia meas-
ured during the glucose tolerance test, another
measure of {1-cell sensitivity, was found to be sig-
nificantly increased by 104 to 168% after 5 months'
treatment with gliclazide 80 to 160 mg/day in 7
patients (Couturier 1986).
Glucose requirements during constant blood
glucose concentrations induced by a glucose clamp
provide a measure of peripheral insulin action, and
were significantly (104%) increased by g1iclazide 160
mg/day for 8 weeks compared with pretreatment
values; however, this value was still significantly
lower than that observed in healthy volunteers.
Moreover, gliclazide appeared to reverse insulin
insensitivity in adipose tissue: in untreated patients
with NIDDM, insulin infusion failed to suppress
plasma nonesterified fatty acids, glycerol and 3-hy-
droxybutyrate levels, while drug treatment nor-
malised this response (Johnson et al. 1991).
Data from animal and clinical studies demon-
strated that glucagon levels are not affected by gli-
c1azide (Brogard et al. 1984; Couturier 1986; Gre-
gorio et al. 1992; Kilo et al. 1991; Scott & Donnelly
1987), indicating that the drug has no effect on
pancreatic a-cell function. Furthermore, following
administration of gliclazide 160 mg/day to patients
with NIDDM, levels of the gastrointestinal insu-
Iinotropic factors, gastrin, gastric inhibitory poly-
peptide and pancreatic polypeptide, were not
changed (Scott & Donnelly 1987).
Mechanism of Gliclazide-Induced
Insulin Secretion
Gliclazide, like other sulphonylureas, appears to
act directly on the pancreas to stimulate insulin
secretion, since it has no effect on blood glucose
levels in pancreatectomised dogs and alloxan dia-
betic rats (DuhauIt et al. 1972). The action of the
drug on the pancreas is mediated via specific re-
ceptors on the surface of pancreatic {1-cells. Glicla-
zide binds with high affinity to these receptors, as

Gllcazlde (2.5 mg/L) Gllbenclamlde (0.05 mg/L)

2175 2175
[==:J c::::::J
~
"'0
E
--E
:::J
0

E: 1450 E: 1450
Qi Qi
> >
~ ~
c c:
:J :J
'"c:
I/)
c
725 725
'E" Of
E
'"'"
Q.
'"'"
Q.

0 0
4 20 40 60 4 20 40 60
Time (min) Time (min)

Fig. 3. Effect of gliclazide (2.5 mg/L) and glibenclamide (0.05 mg/L) infused for 20 minutes on insulin release from isolated
perfused rat pancreas at glucose concentration 5 mmol/L. Shaded area represents drug infusion period (after Gregorio et al.
1992).
Gliclazide: An Update
4 cium ion (Ca 2+) uptake in pancreatic islet cells
Chlorpropamide
Tolbutamide
6 dicated that gliclazide had an effect on Ca 2+ con-
~ Gllclazlde
"0
.§.
'::J:.v
0>
....0 8 cells (Gobbe et al. 1989). In these experimental
Glipizide
!:::. Gliquidone
Glibenclamide
1•
10
I i i
10 8 6
-log Ko .• (mol/L)
Fig. 4. Correlation between in vitro inhibition of specific
[3HlglibencJamide binding to and inhibition of rubidium
(86Rb+) efflux from rat RINm5F insulinoma cells by various
hypoglycaemic agents (after Schmid-Antomarchi et al. 1987).
K<i = 50% inhibition of specific [3HlglibencJamide binding,
Ko.5 = 50% inhibition of A TP-sensitive rate of 86Rb+ efflux.
assessed by its ability t~ displace [3H]-glibenclam-
ide from rat islet tumour cells, with a I«I (disso-
ciation constant) of 600 nmol/L (Schmid-Anto-
marchi et al. 1987).
Binding of gliclazide to the receptor affects the
transport of ions across the {1-cell membrane. Ru-
bidium (Rb+) effiux, a measure of potassium ion
(K+) movement, in insulinomas was decreased by
gliclazide (Schmid-Antomarchi et al. 1987). A
strong correlation exists between efficacy of bind-
ing to the sulphonylurea receptor and inhibition of
Rb+ effiux (Schmid-Antomarchi et al. 1987) [fig.
4]. This inhibitory effect on K+ appears to be due
to a decrease in the function of adenosine triphos-
phate (ATP)-sensitive K+ channels. Another ex-
planation for the effect of gliclazide on {1-cell K+
levels may be that it acts upon the sodium (Na+),
K+ pump. Indeed, gliclazide 76 J.Lmol/L decreased
Na+, K+-ATPase activity in a rat pancreatic islet
preparation in the presence of glucose 3.3 mmol/
L by 46% (Gronda et al. 1989).
Initial studies in which gliclazide increased cal-
99
(Couturier & Malaisse 1980) and, in a more indi-
rect model of Ca 2+ influx, increased 45Ca effiux
into isolated rat islet cells (Lebrun et al. 1982), in-
ductance. These findings were confirmed in a sub-
sequent study, in which gliclazide 25 mg/L caused
an increase in Ca 2+ inflow into rat pancreatic islet
models the effects of gliclazide could be attenuated
by the calcium antagonist verapamil, an agent
which acts selectively at voltage-sensitive Ca2+
channels (Godfraind et al. 1986), thus, indicating
that the increase in Ca 2+ inflow induced by glicla-
zide occurs mainly through these channels (Gobbe
et al. 1989). Gliclazide was found to stimulate Ca 2+
inflow in the presence of glucose. Under these con-
ditions the Ca 2+ channels in the {1-cell will already
be maximally operational and the cell depolarised.
Therefore, further stimulation of Ca 2+ inflow in-
duced by gliclazide may be occurring via stimu-
lation of another pathway, such as a native Ca 2+
ionophore (Lebrun et al. 1982). Gliclazide also al-
ters the distribution of Ca2+ within cells, inducing
an increase in levels of the ion in the cytoplasmic
matrix and secretory granules (Semi no et al. 1987).
Thus, the proposed mechanism by which glicla-
zide induces insulin secretion is as follows. Binding
of gliclazide to sulphonylurea receptors on pan-
creatic {1-cells inhibits ATP-sensitive K+ channels,
resulting in a decrease in K+ effiux and a subse-
quent depolarisation of the cell. This causes open-
ing of voltage-dependent Ca 2+ channels and, to-
gether with an effect on native ionophores, increases
intracellular Ca 2+ levels. Ca 2+ acts as second mes-
senger and is thought to induce the phosphoryla-
tion of proteins which stimulate insulin release.
1.1.2 Extrapancreatic Effects
Although there have been many reports of gli-
clazide increasing insulin levels, several studies
failed to observe such an effect in spite of reporting
a reduction in blood glucose levels (Donatelli et al.
1985; Marchand et al. 1983; Noury & Nandeuil
1991). These findings led to suggestions that the
positive effect of gliclazide on glycaemia may be
100 Drugs 46 (1) 1993

mediated, in part, by extrapancreatic effects such
as increased peripheral responsiveness or sensitiv-
ity to insulin.
Effect on Hepatic Glucose Production
and Clearance
Insulin-stimulated hepatic glucose production
was significantly decreased by 31 to 85% and glu-
cose clearance was significantly increased by 21 to
93% after administration of gliclazide 80 to 320 mgt
day for 8 to 16 weeks in patients with NIDDM
(table II). Basal levels of these processes were not
affected by gliclazide treatment. Effects on glucose
production and clearance appeared to be greater in
patients with initial fasting blood glucose levels of
> ILl mmol/L (Wajchenberg et al. 1988; table II).
Changes were generally not accompanied by in-
creases in basal or stimulated insulin levels (Bak
et al. 1989; Johnson et al. 1991; Wajchenberg et al.
1988), suggesting a direct improvement in insulin
sensitivity. Indeed, insulin sensitivity was signifi-
cantly increased to that observed in healthy volun-
teers, after a single dose of gliclazide 80mg, as-
sessed by glucose utilisation after a glucose tolerance
test (Chiasson et al. 1991). Hosker et al. (1989) re-
ported that 6 weeks' treatment with gliclazide 80
mg!day had no effect on insulin sensitivity; how-
ever, the insulin sensitivity of the patients in this
study did not differ from that of healthy individ-
uals at baseline. Another study reported that 6
months' treatment with gliclazide 240 to 268 mgt
day (mean) in 10 patients had no effect on insulin
sensitivity, assessed by unchanged insulin and ur-
inary C-peptide to glucose ratios (Della Casa et al.
1991).
Effect on Muscle Glycogen Synthase
In healthy individuals, skeletal muscle is re-
sponsible for the majority of insulin-stimulated
glucose uptake (Shulman et al. 1990). Within the
muscle, glucose is converted to glycogen, a reaction
regulated by glycogen synthase. Since this enzyme
is activated by insulin, the activity of glycogen syn-
thase may be a major determinant of insulin-me-

Table II. The effect of gliclazide on glucose metabolism and insulin binding in patients with non-insulin-dependent diabetes mellitus
(NIDDM). All changes are expressed as percentages

Reference No. of patients Gliclazlde Glucose Hepatic Muscle Insulin binding

(mg/day) clearance a glucose glycogen (cell type)
[duration] production a synthase
activity"

Bak et al. (1989) 9 160-320 [8w] t32-50* ~31-42* t 37* ... (skeletal
muscle)
Johnson et al. 10 160 [8w] t137*
(1991)
Ma et al. (1989) 9 160 [16w] t45*
Marchand et al. 8 160 [8w] t21 ... (erythrocytes)
(1983)
Wajchenberg et al. 14 80-160 [12w]
(1988) FBG >11.1 mmol/L t93* ~85* ... (erythrocytes)
FBG <11.1 mmol/L t50* ... (erythrocytes)
Ward et al. (1985) 6 80-160 [12w] t34* ... (erythrocytesl
monocytes)
Wing et al. (1993) 10 80-320 [12w] t45* t receptor conc
(monocytes)

a Insulin-stimulated activity.
Abbreviations and symbols: conc = concentration; FBG = fasting blood glucose; w = weeks; t indicates increase; ~ indicates decrease;
... indicates no change; * p < 0.05 vs pretreatment.
Gliclazide: An Update
diated glucose disposal and can be used to deter-
mine insulin action. Glycogen synthase is activated
by dephosphorylation and the activated form is
more sensitive to allosteric regulation by glucose
6-phosphate. Thus, assessment of glucose 6-phos-
phate activation of glycogen synthase also provides
an estimate of insulin effects in skeletal muscle. In
NIDDM, skeletal muscle becomes insensitive to
insulin, probably due to a post-receptor defect
(Kolterman et al. 1981).
An in vitro investigation provided evidence that
gliclazide may have a direct effect on skeletal
muscle. Glucose uptake into isolate perfused rat
skeletal muscle was increased 162% from basal lev-
els by addition of gliclazide 300 mg/L and a half-
maximal response was achieved with a concentra-
tion of gliclazide of 100 mg/L (Pulido et al. 1992).
However, these concentrations are in excess of those
observed after therapeutic doses (section 2.1).
Nevertheless, gliclazide does have some effects on
skeletal muscle during clinical use. Insulin-stimu-
lated glycogen synthase activity in skeletal muscle
was found to be significantly lower in patients with
NIDDM compared with healthy volunteers (John-
son et al. 1991), a defect which was improved (37
and 137%), but not normalised, by treatment with
gliclazide 160 to 320 mg/day for 8 weeks (table II).
An increase in insulin-stimulated glycogen syn-
thase activity was also demonstrated by a reduc-
tion in the concentration of glucose 6-phosphate
required to achieve half-maximal activation of the
enzyme (Ao.s): Ao.s was reduced from 0.3 mmolj
L to 0.2 mmoljL after 8 weeks' therapy with gli-
clazide 160 to 320 mg/day (Bak et al. 1989). Since
an increase in glycogen synthase activity was not
observed in patients whose hyperglycaemia was
controlled by diet alone in these studies, the effect
of gliclazide on the enzyme may be a direct effect
of the drug on skeletal muscle rather than a phen-
omenon secondary to improved blood glucose
control.
Effect on Insulin Binding
Gliclazide has no direct effect on insulin recep-
tors either in vitro or in vivo. The number and af-
finity of insulin receptors in rat hepatocytes was
101
not affected by in vitro incubation with gliclazide
0.7, 7 or 70 mg/L for 20 hours (Dolais-Kitabgi et
al. 1983). Similarly; gliclazide 80 to 320 mg/day
did not generally influence the number or affinity
of insulin receptors in human erythrocytes or mon-
ocytes (table II); however, studies using blood cells
may be of limited relevance to the interpretation
of insulin action in peripheral tissues. A single study
provided more meaningful data, reporting that 8
weeks' administration of gliclaz"ide 160 to 320 mg/
day had no effect on the number or affinity of in-
sulin receptors in skeletal muscle biopsy samples
either at basal insulinaemia or during hyperinsu-
linaemia (Bak et al. 1989; table II). In this study
the activity of insulin receptors was also unaffected
by gliclazide treatment, with no change observed
in insulin receptor-mediated phosphorylation of the
synthetic peptide poly(Glu 80Tyr20). The lack of
substantial effects of gliclazide on insulin receptors
suggests that any effects of the drug on insulin ac-
tion may be mediated at a postreceptor level.
1.2 Haemobiological Effects
Although blood glucose levels can now be con-
trolled with some confidence using diet and/or oral
hypoglycaemic agents, many patients with diabetes
mellitus still develop long term micro- and
macroangiopathies resulting in atherosclerosis,
cardiac disease, retinopathy and renal failure. This
suggests that abnormalities of processes apart from
glucose metabolism are associated with diabetes
mellitus. Indeed, studies have demonstrated dys-
function of coagulation and fibrinolysis in patients
with diabetes mellitus, evidenced by increased
platelet adhesiveness and aggregation, raised levels
of thromboxane A2 (TXA2), platelet factor 4 and
/1-thromboglobulin and reduced production of
prostaglandin (PG)I2 and tissue plasminogen ac-
tivator (t-PA) in vascular walls (reviewed by Zie-
gler & Drouin 1991). This may lead to hyperag-
gregability of platelets and the formation of thrombi
in the microvessels, resulting in blockage of blood
flow, anoxia and oxygen free radical production.
These effects culminate in the formation of ath-
102
erosclerotic plaques and may influence the devel-
opment of micro- and macrovascular disease.
1.2.1 Platelets
Numerous studies have demonstrated that gli-
clazide reduces platelet adhesion: platelets from
healthy volunteers incubated with gliclazide 1000
~mol/L (323 mg/L) in vitro showed reduced ad-
herence to rabbit vessel wall (Mizuno et al. 1989)
and in vivo administration of gliclazide 20 to 320
mg/day for 3 to 36 months significantly decreased
platelet adhesion in patients with NIDDM (Bobillo
et al. 1975; Dettori 1980; Jones et al. 1980; Paton
et al. 1981; Radic et al. 1980; Zurro Hernandez &
Lavielle 1986).
~gliclazide-induced reduction of platelet aggre-
gationhas consistently been demonstrated in ani-
mal models (reviewed by Holmes et al. 1984). In
vitro models using human platelets from both
healthy volunteers and patients with NIDDM have
demonstrated that gliclazide 1 to 10 000 ~mol/L
(0.323 to 3234 mg/L) produces a dose-dependent
reduction in adenosine diphosphate (ADP)- and
platelet activating factor-induced platelet aggrega-
tion which ranged from approximately 3 to 96%
(Mizuno et al. 1989; Phenekos et al. 1992). Glicla-
zide also inhibited in vitro platelet aggregation in-
duced by phospholipase A2, arachidonic acid,
PGG2 or PGH2, and collagen, with concentrations
which inhibited aggregation by 20% of 1000, 100,
200 and 1000 ~mol/L (323, 32.3, 64.6 and 323 mgf
L), respectively (Mizuno et al. 1989).
Despite the consistency of in vitro data, the con-
centrations of gliclazide required to reduce platelet
aggregation were generally greater than plasma gli-
clazide concentrations observed after administra-
tion ofa therapeutic dose of the drug (section 2.1).
Furthermore, an effect of gliclazide on platelet ag-
gregation has proved difficult to consistently dem-
onstrate in vivo, with only 5 of 8 studies reporting
a significant reduction in platelet aggregation fol-
lowing administration of gliclazide 80 to 320 mgt
day for 1 to 24 months to patients with NIDDM
(table III).
An early trial comparing gliclazide (80 to 240
mgfday for 1 month) and glibenclamide (5 to 10
Drugs 46 (1) 1993
mg/day for 1 month) found that both agents re-
duced ADP-induced aggregation, while only gli-
benclamide reduced aggregation induced by colla-
gen and adrenaline (epinephrine) [Klaffet al. 1979;
table III]. However, a more recent comparative
study has provided some evidence that any inhib-
itory effect of gliclazide on platelet aggregation dur-
ing clinical use is not shared by glibenclamide (table
III). Gliclazide, substituted for glibenclamide in 15
patients, reduced collagen-induced platelet aggre-
gation from 65.1 % at baseline to 50.8% after 3
months and 49.3% after 6 months of treatment, ef-
fects which were significantly different from the lack
of effect observed in 14 patients maintained on
equivalent doses of glibenclamide (Jennings et al.
1992) [fig. 5]. While such findings may indicate that
gliclazide induces positive haemobiological effects
while some alternative agents do not, the effects of
usual clinical doses of gliclazide on platelet aggre-
gation still require further clarification in appro-
priately designed, well controlled trials.
The effect of gliclazide on other platelet func-
tions is also equivocal, with reports of significant
decreases (33 to 60%) [Collier et al. 1989; Flor-
kowski et al. 1988; Violi et al. 1982] or no effect
(Paton et al. 1981) on i3-thromboglobulin levels in
patients receiving gliclazide 80 to 32D mgfday for
1 to 12 months. The effect of the drug on throm-
boxane B2 (TXB2) levels is also inconsistent, with
decreases (Florkowski et al. 1988; Fu et al. 1992)
or no effect (Collier et al. 1989; Larkins et al. 1988)
observed in patients receiving gliclazide 80 to 240
mgfday for 3 to 24 months. Limited data from a
single clinical study support initial in vitro and in
vivo animal data that gliclazide stimulates the for-
mation of P0I2 (reviewed by Holmes et al. 1984).
In this study, gliclazide 80 to 240 mg/day for 3
months induced a 59% increase in PGI2 (assessed
by 6-keto-PGIJ) and decreased the ratio of TXA2
to PGIz, in 25 patients who had been receiving gli-
benclamide alone or in combination with phen-
formin (Fu et al. 1992).
Although no significant effect on PGI2-stimu-
lated platelet cyclic adenosine monophosphate
(cAMP) formation in vitro at concentrations of up
to 100 000 ~mol/L (32 gfL) were noted (Mizuno et
Gliclazide: An Update 103

Table III. The effect of gliclazlde and other sulphonylureas on platelet aggregation in patients with non-insulin-dependent diabetes
mellitus

Reference Drug (no. of patients) Dosage Platelet aggregator

(mg/day)
ADP collagen adrenaline
[durationl
(epinephrine)

Noncomparatlve studies
Dettori (1980) Gliclazlde (14) 80-240 [3-12mol
Shaw et al. (1980) Gliclazide (4) 80-320 [1 mol 0
Vloll et al. (1982) Gliclazlde (18) 80-160 [1 mol l

Comparative studies
Chan et al. (1982) Gliclazide (20) [6mol
Glibenclamide (15) 0
Jennings at al. (1992) Gllclazlde (15) [6mol
Glibenclamide (14) 0
King et al. (1977) Gliclazide (12)B [3mol 0 0
Gllpizlde (12)B [3mol 0 0
Klaff et al. (1979) Gllclazide (10)a 80-240 [lmol l 0 0
Glibenclamide (10)B 5-10 [1 mol l l l
Larkins et al. (1988) Gliclazide (26) [24mol 0 0 0
Placebo (15) 0 0 0

a Crossover study.
Abbreviations and symbols: ADP = adenosine diphosphate; mo = months; 0 indicates no effect on platelet aggregation; llndlcates
significant decrease in platelet aggregation.

al. 1989), gliclazide 80 to 240 mg/day significantly
increased (17%) PGEl-induced release of cAMP
from platelets in 12 newly-diagnosed patients with
NIDDM (Collier et a1. 1989). Initial studies found
that gliclazide decreased platelet density, and heavy
populations of platelets C and D, while increasing
the light populations of platelets A and B (reviewed
by Holmes et al. 1984). Recent studies have found
that gliclazide 80 to 320 mg/day has no effect on
platelet count, or platelet release of serotonin (5-
hydroxytryptamine; 5-HT) or ADP (Collier et al.
1989; Paton et al. 1981).
1.2.2 Fibrinolysis
Preliminary data from animal studies and
clinical trials in patients with NIDDM indicated
that gliclazide increased t-PA levels (Chan et al.
1982; Desnoyers & Saint-Dizier 1980) and that this
effect was prolonged, being observed after 24 and
48 months of gliclazide therapy (Almer 1984). Gli-
clazide 160 or 240 mg/day was administered to 10
patients with NIDDM previously treated with tol-
butamide, who had no detectable plasma t-PA ac-
tivity at baseline. The change from tolbutamide to
gliclazide treatment was associated with a signifi-
cant increase in t-PA activity and levels after 3
months of gliclazide treatment. Although, 8 of the
10 patients showed decreased t-PA activity after 12
months of treatment compared with values ob-
tained at 3 months, and a similar pattern of de-
crease in t-PA levels was also observed, mean ac-
tivity and levels were still elevated compared with
pre-gliclazide treatment (Gram et al. 1989). t-PA
levels after venous occlusion, a procedure which
increases fibrinolytic activity, were also increased
(by 23%) after 12 months of treatment with glicla-
zide. Although this study reported that gliclazide
had no effect on plasma levels of plasminogen ac-
tivator inhibitor (PAl), another reported that PAl
levels decreased following administration of glicla-
zide for 24 and 48 months (Almer 1984).
104
Gliclazide
80
o Glibenclamide
.--- .---
.---
.---
*
.--- *
r---
a;
Q)
tiS
a...
20
o ADP-induced platelet aggregation was observed
Baseline 3 6
Duration of treatment (months)
Fig. 5. Effect of 3 and 6 months' treatment with gliclazide
(n = 16) or glibenclamide (n = 14) on platelet aggregation
induced by collagen in patients with non-insulin-dependent
diabetes mellitus; * p < 0.05 vs glibenclamide (after Jennings
et al. 1992). Before the study all patients had received gli-
benclamide with or without adjunctive metformin therapy
for at least 2 years.
1.2.3 Coagulation
Several studies have demonstrated that glicla-
zide 80 to 320 mg/day for 6 to 12 months has no
effect on fibrinogen levels in patients with NIDDM
(Collier et al. 1989; Gram et al. 1988; Paton et al.
1981). A single study found that gliclazide (mean
daily dose 185.5mg for 9 months) was associated
with a significant increase (55%) in fibrinogen lev-
els but at all time points the levels were within the
reference range for healthy volunteers, indicating
that this was not likely to be a clinically significant
effect (Aorkowski et al. 1988). Initial studies found
that gliclazide decreased levels of factors V and
VIII, and antithrombin III (Holmes et al. I 984).
1.2.4 Specificity of Effects
Recently there has been an accumulation of data
suggesting that any haemobiological effects of gli-
clazide are specific actions of the drug on platelets
and vessel walls rather than an indirect effect of
an improvement in glycaemic control. In studies
Drugs 46 (1) 1993
in which gliclazide therapy was substituted for other
oral hypoglycaemic agents, there was no change in
glycaemic control but an inhibition of platelet ag-
gregation, increases in PGI2 and fibrinogen levels
and t-PA function, and decreases in the levels of
TXA2, ,6-thromboglobulin and free radical prod-
ucts were observed (Aorkowski et al. 1988; Fu et
al. 1992; Jennings et al. I 992). In addition, the
stimulatory effect of gliclazide 160 mg/day for 6
months on t-PA levels was observed in 23 patients
with insulin-dependent diabetes mellitus (type I)
who had no significant pancreatic ,6-cell function,
thus, indicating that the drug effect was independ-
ent of an insulin-induced action on metabolic state
(Gram et al. 1988). Furthermore, a reduction in
following administration of gliclazide 80 to 160 mg/
day for 30 days in 5 patients with NIDDM in whom
drug treatment had no effect on blood glucose lev-
els (Violi et al. 1982).
1.3 Free Radical Levels
The effect of gliclazide on free radical levels is
of interest as these chemical species have a possible
role in the development of vascular disease by
causing vascular damage and stimulating produc-
tion of TXA2 while inhibiting that of PGI2
(McCord 1985; Stringer et al. 1989). Under normal
circumstances there is a balance between the pro-
duction and scavenging of free radicals; however,
in patients with NIDDM there is a reduction in
scavenger levels (superoxide dismutase and lysate
thiol) resulting in an increase in free radical levels
which places the patients under oxidativ~ stress
(Collier et al. 1990). Furthermore, the levels of the
products offree radical activity, such as diene con-
jugates, are higher in diabetic patients with mi-
croangiopathy than in patients without complica-
tions (Jennings et al. 1987).
In vitro, gliclazide acts as a free radical scav-
enger at concentrations of 0.5 to 5 mg/L, approx-
imately the plasma concentrations achieved after a
dose of 80mg (section 2.1). In contrast, glibenclam-
ide had no effect at concentrations of up to 25 mg/
L, over 200 times the therapeutic concentration
Gliclazide: An Update 105

Ql
• Gliclazide Florkowski et al. (1988) observed that in 15 patients
:« o Glibenclamide undergoing treatment with gliclazide (mean daily
'S 180
E
=5 ::; 160 * * dose 185.5mg for 9 months) a significant reduction
QlC; in oxidative products of lipids and proteins oc-
~ §.. 140 curred: total diene conjugate and fluorescent IgG
o >-
:D ~ 12
- - - - -0 - - - - - - - -a levels were reduced by 55 and 78%, respectively,
~~ 10~--------------'-------------, and thiobarbituric acid reactivity reduced by 86%.
o 3
1.4 Plasma Lipids

Insulin resistance has profound effects on lipid

jl ::--------:-------~,
UJ SOOt * * metabolism, causing an impairment of suppression
of lipolysis and leading to elevated circulating lev-
els of nonesterified fatty acids. This condition, to-
gether with the obesity and abnormalities of co-
0 3 6 agulation and fibrinolysis often observed in patients
with NIOOM, represent a cluster of cardiovascular

l°L____ _
risk factors that can cause angina, myocardial in-
UJ
Ql
farction, stroke and peripheral vascular disease, and
"C
"x also a number of microvascular complications such

- 0i--------~
e
Ql~
c...J
"CO
"0. E portant aspect of its therapeutic potential in
::::i3
0 3 6
Duration of treatment (months)
Fig. 6. Effect of 3 and 6 months' treatment with gliclazide
(n = 16) or glibenclamide (n = 14) on measures of oxidative
stress in patients with non-insulin-<iependent diabetes mel-
litus; * p < 0.05 between treatments (after Jennings et al.
1992). Before the study all patients had received glibenclam-
ide with or without adjunctive metformin therapy for at least
2 years.
(Scott et al. 1991). A similar effect was observed
in vivo; 15 patients with NIOOM who were under
oxidative stress (as assessed by raised lipid per-
oxides and reduced plasma thio1s and erythrocyte
superoxide dismutase activity) were switched from
glibenclamide therapy to gliclazide while 14 other
patients remained on glibenclamide. After 3 and 6
months' treatment, lipid peroxides were reduced
and superoxide dismutase activity was increased
more effectively in gliclazide- compared with gli-
benclamide-treated patients (fig. 6) [Jennings et al.
1992]. However, oxidative status remained abnor-
mal compared with healthy volunteers. Similarly,
as neuropathy, nephropathy and retinopathy. Thus,
the effect of gliclazide on plasma lipids is an im-
NIDOM.
Although animal studies have shown that gli-
clazide reduces plasma levels of cholesterol, tri-
glycerides and fatty acids (Marquie 1978; Puglisi &
Colli 1980; Smit Sibinga & Wieringa 1980), data
obtained from studies in patients are less conclu-
sive. The effect of gliclazide on total cholesterol is
contentious with several studies reporting a sig-
nificant decrease in total cholesterol of 2 to 16% in
patients with NIOOM treated with gliclazide 20 to
320 mg/day for 3 to 36 months (reviewed by
Holmes et al. 1984; Collier et al. 1989; Fu et al.
1992; Gram et al. 1989; Kilo et al. 1991; Zurro
Hernandez & Lavielle 1986), although numerous
other studies have reported no significant changes
in this parameter (reviewed by Holmes et al. 1984;
Page et al. 1993). An increase in high density lipo-
protein (HOL) cholesterol of to to 39% has been
observed in patients treated with gliclazide 80 to
240 mg/day for 3 months (Berber & Tomkin 1982;
Fu et al. 1992), in particular the HOL3 fraction (Fu
et al. 1992), although other studies found that 2 to
6 months' treatment with gliclazide 80 to 320 mg/
106 Drugs 46 (1) 1993

Table IV. Pharmacoklnetic properties of gliclazlde after oral administration to healthy volunteers and patients with non-insulin-
dependent diabetes mellitus (NIDDM)

Reference No. of patients Duration of Gliclazide Cmu tmu AUCo-24h Vd t\<ll

(diagnosis) study (mg) (mg/L) (h) (gIL, h) (L) (h)

Campbell et al. (1980) 7 (healthy) Single dose 80 3.9 4

6 (healthy) Single dose 80 2.8 4-8
4 (healthy) 3 mg/kg 36.3%a 10.4
23 (healthy) 3 days 80 mg/day 0.7-4.9
144 (NIDDM) 3 days 80 mg/day 0.3-8.2
Forette et al. (1982) 5 (NIDDM, 26y) Single dose 80 6.3 4 13 11.8
5 (NIDDM, 77y) Single dose 40 4.0b • 6· 24· 20.5
Kobayashi et al. (1981) 12 (healthy) Single dose 40 2.8 2.8 37.2 17.4 12.3
7 (NIDDM) Single dose 80 6.8 2.3 72.0 16.0 12.6
4 (NIDDM» 7 days 80 mg/day 7.6 3.0 91.4 15.9 12.3
Oida et al. (1985) 4 (healthy) Single dose 40 2.5 3.9 37.3 8.1
Shiba et al. (1986) 7 (healthy) Single dose 40 2.4 2.0 16.5
8 (NIDDM) Single dose 40 2.2 2.2 12.3
10 (NIDDM) Single dose 120 8.0 2.0 10.5

a Percentage of bodyweight.
b Corrected to 80mg.
Abbreviations and symbols: AUCo-24 = area under the plasma concentration-time curve from time 0 to time 24h; Cmu = maximum
plasma concentration; t max = time to reach Cmu; t\<ll = elimination half-life; Vd = volume of distribution; y = years of age (mean);
• p < 0.05 VB younger patients.

day had no effect on HDL (Delargy et al. 1985;
Marchand et al. 1983; Page et al. 1993). A reduc-
tion in low density lipoprotein cholesterol (19%)
was reported in 1 trial following administration of
gliclazide 80 or 240 mgfday for. 3 months (Fu et
al. 1992), while 2 other studies failed to observe
such an effect after 4 to 6 months at a similar dos-
age (Delargy et al. 1985; Page et al. 1993). A single
dose of gliclazide 80 or 160mg reduced levels of
free fatty acids by 20 to 25% (King et al. 1977).
The effect of gliclazide on plasma triglycerides
has aIso varied, with most studies indicating that
administration of 80 to 240 mgfday for 3 to 25
months to patients has no effect on this parameter
(reviewed by Holmes et al. 1984; Fu et al. 1992;
Gram et al. 1989; Page et aI. 1993), although sig-
nificant decreases of 18 to 30% in plasma triglyc-
eride levels have been reported (Collier et al. 1989;
Villiger 1982; Zurro Hernandez & Lavielle 1986).
Since a low-fat diet is likely to lower plasma
lipid levels, diet must be taken into consideration
when evaluating the effect of a drug on plasma lipid
levels. In 1 study involving newly diagnosed
patients, gliclazide was administered in combina-
tion with a low-fat diet and, therefore, the reduc-
tion in cholesterol observed may have been a diet-
rather than drug-induced phenomenon (Collier et
aI. 1989). However, 3 other studies involved
patients in whom dietary restrictions had been used
unsuccessfully to control blood glucose levels, and
subsequent gliclazide treatment induced a reduc-
tion in cholesterol levels (Kilo et al. 1991; Rub-
injoni et al. 1978; Zurro Hernandez & Lavielle
1986).
2. Pharmacokinetic Properties
The following sections are an overview of data
presented in the previous review (Holmes et al.
1984) with additional pharmacokinetic data added
where appropriate.
2.1 Absorption and Plasma Concentrations
Administration of a single oral dose of gliclazide
Gliclazide: An Update 107

40 to 120mg to healthy volunteers and patients with to 4.9 mgjL in healthy volunteers (Campbell et al.
NIDDM resulted in peak plasma concentrations 1980; Kobayashi et al. 1981). Cmax values appear
(Cmax) of2.2 to 8 mgjL within 2 to 8 hours (Camp- to increase after repeated oral administration of
bell et al. 1980; Kobayashi et al. 1981; Oida et al. gliclazide. In lO patients with NIDDM, plasma gli-
1985; Shiba et al. 1986) [table IV; fig. 7]. Some clazide concentrations were measured before and
intersubject variation in gliclazide absorption has 2 hours after administration of gliclazide 120mg
been reported, with 'fast' [time to reach Cmax (tmax) for 5 consecutive days. On day 1 mean Cmax 2
= 0 to 4 hours] and 'slow' (tmax = 4 to 8 hours) hours after drug administration was approximately
absorbers identified in a group of healthy volun- 8 mgjL increasing to approximately lO.8 mgjL on
teers (Campbell et al. 1980; Kobayashi et al. 1981). day 5 (Shiba et al. 1986). In another study, Cmax
Mean plasma gliclazide concentrations 24 hours values were higher and t max values prolonged after
after administration of a single dose of 40, 80 or repeated oral administration of 80 mgjday (Cmax
120mg were 7 to 50% of the Cmax values (Kobay- = 7.6; t max = 3.0h) than after a single 80mg dose
ashi et al. 1981; Shiba et al. 1986). There does not (Cmax = 6.8 mgjL; t max = 2.3h) to patients with
appear to be any significant difference in the daily NIDDM (Kobayashi et al. 1981). There does not
absorption profile of gliclazide in healthy volun- appear to be any drug accumulation after repeated
teers and patients with NIDDM (Kobayashi et al. administration as area under the plasma concen-
1981). tration-time curve (AUC0-24h) values were not sig-
Steady-state concentrations are reached after 2 nificantly increased after repeated administration
days' administration of gliclazide 40 to 120mg to compared with single-dose administration (Koba-
patients with NIDDM (Shiba et al. 1986). Follow- yashi et al. 1981).
ing repeated oral administration of gliclazide 80mg Age-related differences in certain absorption
for 3 to 7 days, Cmax values ranged from 0.3 to parameters of gliclazide h~ve been reported: Cmax
8.2 mgjL in patients with NIDDM and from 0.7 values were significantly lower and occurred sig-
nificantly later in a group of 5 elderly women (mean
age 77 years) compared with a group of 5 younger
women (mean age 26 years); however, there was
10
:::r no significant difference in mean steady-state
.... 9 plasma gliclazide concentrations (4.5 mgjL), sug-
~
c:
.2
8 gesting that the differences in these absorption
1ii 7 parameters are unlikely to be clinically significant
~
c: (Forette et al. 1982; table IV).
GI
u 6
c:
0
There is some debate as to the most appropriate
u 5 time to administer gliclazide in relation to meals.
01
"t:I
·N 4 Two studies in a total of 18 patients with NIDDM
as
:§ 3 who had been stabilised on gliclazide, found that
OJ oral administration of the drug after food signifi-
..E
as

as
2 cantly delayed t max (by up to 187 minutes) com-
pared with administration 30 minutes before, im-
a:::
0 I mediately before or with a meal, and in 1 study
2 4 6 8 10 24 significantly reduced Cmax (Batch et al. 1990; Ish-
Time after administration (hours)
ibashi & Takashina 1990). Batch et al. (1990) re-
Fig. 7. Plasma gliclazide concentrations following single \dose
ported that the timing of gliclazide administration
oral administration of 40mg to healthy volunteers (n = 7)
and 40 or 120mg to patients with non-insulin-dependent had no differential effect on plasma glucose, in-
diabetes mellitus (n = 8 and 10, respectively) [after Shiba et sulin or C-peptide patterns; however, Ishibashi and
al. 1986]. Takashina (1990) reported that administration of
108
gliclazide 30 minutes before a meal was associated
with significantly lower postprandial hyperglycae-
mia than administration immediately before or
after a meal.
2.2 Distribution, Metabolism and Elimination
The mean apparent volume of distribution of
gliclazide in healthy volunteers and patients with
NIDDM ranged from 13 to 24L in different studies
(Forette et al. 1982; Kobayashi et al. 1981) or 36.3%
of bodyweight (Campbell et al. 1980), and an age-
related increase in this parameter was observed
(Forette et al. 1982) [table IV]. Like other sul-
phonylureas, gliclazide is extensively protein bound
(85 to 97%) [Campbell et al. 1980; Kobayashi et
al. 1981]. The mean gliclazide content of macrog-
lobulin, ,),-globulin, albumin and small molecular
substances in the 24-hour period after administra-
tion of 40mg to a healthy volunteer was 3.7, 0.7,
82.3 and 13.2%, respectively (Kobayashi et al.
1981 ).
The major route of elimination of gliclazide and
its metabolites is via the urine. Following admin-
istration of [14C]-gliclazide, 60 to 70% of the ra-
dioactivity was recovered in the urine and 10 to
20% in the faeces (Campbell et al. 1980). Urinary
excretion accounted for 45% of a 40mg dose after
24 hours and 61 % after 96 hours (Oida et al. 1985).
Gliclazide is extensively metabolised in humans
to 7 metabolites which can be classified according
to the type of biotransformation: the 2 major me-
tabolites (carboxylic acid and hydroxymethyl de-
rivatives) are oxidised while the remaining 5 are
hydroxylated. The metabolites do not have hypog-
Iycaemic activity. Metabolism of the parent com-
pound is extensive, with 1 study failing to detect
any unchanged drug in the urine (Oida et al. 1985).
The carboxylic acid metabolite is the most abun-
dant urinary metabolite (20%) followed by the hy-
droxymethyl metabolite (16%) with the other me-
tabolites representing 3 to 9% of dose (Oida et al.
1985). However, in the plasma, unchanged glic1a-
zide represents over 90% of all drug-related ma-
terial (Campbell et al. 1980; Oida et al. 1985).
Animal studies demonstrated that gliclazide
Drugs 46 (J) 1993
undergoes enterohepatic recirculation (Benakis &
Glasson 1980; Miyazaki et al. 1983) and there is
some evidence to suggest that this also occurs in
humans (Campbell et al. 1980).
The mean elimination half-life (tl/2) of gliclazide
after a single dose or repeated oral administration
of 40 to 120mg to healthy volunteers and patients
with NIDDM ranged from 8.1 to 20.5 hours (table
IV). Thus, gliclazide is eliminated at an inter-
mediate rate compared with other sulphonylureas
-less rapidly than tolbutamide (t'l2 = 7 hours), glip-
izide (tl/2 = 4 to 7 hours) and glibenclamide (t'l2 =
5.7 to 10 hours), but more rapidly than chlorpro-
pamide (tl/2 = 33 to 43 hours) [Balant 1981). Gen-
der- and age-related differences in t'l2 of gliclazide
have been reported: 11.8 hours in young women
and 20.5 hours in elderly women (Forette et al.
1982), and 8 hours in healthy men and 11 hours
in healthy women (Campbell et al. 1980). Plasma
clearance of gliclazide was approximately 0.78 LI
h (13 ml/min) in young and elderly women (For-
ette et al. 1982).
The effect of renal insufficiency on the phar-
macokinetics of gliclazide is an important consid-
eration since diabetes is often associated with
nephropathy (section 3.6). t'l2 was slightly, but not
significantly, prolo.nged in patients with renal in-
sufficiency compared with healthy volunteers: oral
administration of a single dose of glic1azide 40 or
80mg had a t'l2 of 14.7 hours in 6 patients with
diabetes and renal insufficiency (creatinine clear-
ance = 2.64 L/h), 22.4 hours in 11 patients without
diabetes but with more severe renal insufficiency
(creatinine clearance = 0.78 L/h) and 12.7 hours
in 9 healthy volunteers. Apparent clearance was not
significantly affected by renal insufficiency, de-
creasing from 1.92 Llh in healthy volunteers to 1.26
Llh in patients with more severe renal insuffi-
ciency (Campbell et al. 1985). These results suggest
that gliclazide dosage alterations are not required
in patients with renal insufficiency.
2.3 Relationship between Plasma
Concentrations and Pharmacodynamics
Although there is a dose-dependent relationship
between gliclazide dosage and plasma concentra-
tion (section 2.1; Shaw et al. 1985), no simple cor-
Gliclazide: An Update
relation with hypoglycaemic activity exists. For ex-
ample, administration of a single oral dose of
gliclazide 80mg to healthy volunteers who had been
fasted overnight, resulted in maximum reduction
in blood glucose levels (20%) at 2 hours. However,
maximum plasma gliclazide concentrations were
not attained until 4 hours after drug administra-
tion (Campbell et al. 1980). Another study failed
to find any correlation between plasma gliclazide
concentrations and fasting blood glucose levels after
1 month's administration of gliclazide 120 to 400
mgjday (Fagerberg & Gamstedt 1980).
Data suggest that gliclazide induces an 'all or
nothing' effect, such that a threshold dose is re-
quired for a hypoglycaemic effect to be observed
but increasing the dose above this level will not
result in greater hypoglycaemic activity. Studies in
healthy volunteers have. demonstrated that the
threshold plasma gliclazide concentration is 0.25
mgjL, while in patients with NIDDM a higher
threshold concentration of 1.5 mg/L was identified
(Campbell et al. 1980). The difference in threshold
concentration may be due to decreased sensitivity
of pancreatic (j-cells in NIDDM. A clinical study
found that increasing the dosage of gliclazide to
above 160 mgjday during long term administra-
tion may not lead to greater hypoglycaemic activ-
ity (Shaw et al. 1985).
3. Therapeutic Efficacy
Assessment of the efficacy of an agent in treat-
ing the symptoms of diabetes is complicated by nu-
merous factors which must be taken into consid-
eration when evaluating clinical trials' data. The
initial profile of the patients involved in terms of
age, duration of diabetes, previous treatment,
bodyweight and fasting blood glucose levels can
have significant effects on treatment outcome, and
drug effects may be diluted by inclusion of patients
who are unlikely to respond to treatment. The dur-
ation of follow-up is also important and must be
sufficient to allow accurate assessment oflong term
efficacy and secondary failure rate. The criteria of
efficacy employed are also crucial and may in-
clude:
109
• alleviation of acute symptoms of hyperglycae-
mia, in which the percentage of patients achieving
good or poor control of blood glucose levels (as
defined by pre-determined criteria) is calculated, or
the ability of the drug to reduce blood glucose or
glycosylated haemoglobin levels to an arbitrary
level;
• evaluation' of primary and secondary failure rates
observed with treatment;
• effect of treatment on hyperlipidaemia and obes-
ity;
• efficacy in reducing premature morbidity and
mortality associated with diabetes by reducing the
occurrence of cardio-, and micro- and macrovas-
cular disease.
Many of the trials investigating the efficacy of
gliclazide in treating patients with NIDDM have
been nonblinded, noncomparative studies, while
large scale double-blind, placebo-controlled trials
are scarce. Furthermore, few studies have at-
tempted to determine the relationship between gli-
clazide efficacy and patient profile, which would
allow the most optimal patient group in which to
use the drug to be defined. Since diet may be suc-
cessful in controlling some patients, the use of a
dietary run-in period or diet-treated control group
is necessary for determining the number of patients
in whom drug treatment is essential, and several
trials were conducted in this manner (Bak et al.
1989; Brogard et al. 1984; Chang et al. 1990; Col-
lier et al. 1989; Donatelli et al. 1985; Guillausseau
1991; Johnson et al. 1991; Noury & Nandeuill991;
Sinay et al. 1988; Zurro Hernandez & Lavielle
1986).
3.1 Glycaemic Control
3.1.1 Blood Glucose Levels
At the time of the previous review in the Jour-
nal (Holmes et al. 1984) much of the data regard-
ing the therapeutic effect of gliclazide on blood glu-
cose levels had been presented as the percentage of
patients who fulfilled predefined criteria of excel-
lent, good, fair or poor control of blood glucose
levels. For example, in the study by Shaw et al.
(1980) excellent control was defined as a postpran-
110 Drugs 46 (1) 1993

Table V. Trials assessing the effect of gliclazide (G) and other oral hypoglycaemic agents (OHA) on glycaemic parameters In patients
with non-insulin-dependent diabetes mellitus

Reference Duration Pretreatment Previous Design Treatment Duration Response (% decrease from baseline)
of fasting blood treatment (mg/day) of
fasting postprandial glycosylated
diabetes glucose level [no. treatment
blood blood haemoglobin
(years) (mmol/L) patients]
glucose glucose
level level

Noncomparative trials
Brogard et al. 8.3 Diet G 24Q8 [12] 3mo 21.7·
(1984)
Guillausseau 6.2 9.3 Insulin G 80-32Q8 60mo 26.7· 25.4· 22.3·
(1991) and OHA [16]
Kilo et al. 8 >8.24 Diet and/ G 40-320 12mo 35.3· 18· 30.5*'
(1991) orOHA [29]
Scott & 8-11 Diet G 160- [7] 1mo 35· 26.7·
Donnelly
(1987)
Sinayet al. 5.2 6.6 G 160- [7] 6mo 23.8· 19.2 0
(1988)
Wajchenberg >11.1 G 80-160 [9] 12mo 62.1· 46.4·
et al. (1992)
Ward et al. 13.4 Diet G 80-160 [6] 3mo 36.7·
(1985)
Wing et al. <8mo 12.2 None G 80-23Q8 3mo 28.6· 25.3·
(1993) [10]
Zurro 12.7 Diet G 80-320 36mo 45.7·
Hernandez & [44]
Lavielle (1986)

Comparative trials
Placebo/diet/exercise
Bak et al. NO >7 Diet db, co G 160-32Q8 2mo 17.9t
(1989) [9] 3wk
Placebo- [9]
Chang et al. NO 12.1 None db, co, r G 40-320mg 3mo 37.2t 23·ot
(1990) [18]
Placebo [18] 15 11.2
Donatelli et al. 3mo 7.5-15.3 None sq G 120-240- SOd 23.4·
(1985) [10] 15d
Diet [10] 1.9
Johnson et al. NO 12.1 None r, pi G 16Q8 [10] 2mo 50.4·t 37.9·t
(1991) Diet [10] 21.8· 19.8·
Page et al. 5.5-5.8 None db G 80 [8] 6mo 12·
(1993) Placebo [8] 0
Diet/ 3.6
exercise [14]

OHA
Collier et al. NO 14-15 None G 80-24OS 6mo 54.9· 47.4·
(1989) [12]
M 1500- 50.D* 48.3·
300QII [12]
Gliclazide: An Update III

Table V. Contd

Reference Duration Pretreatment Previous Design Treatment Duration Response (% decrease from baseline)
of fasting blood treatment (mg/day) of
fasting postprandial glycosylated
diabetes glucose level [no. treatment
blood blood haemoglobin
(years) (mmol/L) patients]
glucose glucose
level level

Harrower 2.6-5 Diet G 20-320 12mo 30.8*

(198S) [20]
GP 2.5-20 +10
[20]
GQ 30-120 28.6*
[19]
GB 2.5-30 18.2*
[19]
C 100-500 0
[18]
Noury & 3 7.8 Diet mc G 80-240 3mo 17.6* 18.1* 7.9*
Nandeuil and/or [27]
(1991) OHA M 1700 [30] 13.8* 17.5* 13.2*

V8 in8ulln
Quatraro et al. 12.1 16.1 Insulin G 40-240b 12mo 43.1*f 26.2*f
(1986) and OHA [15]
Insulin [15] 5.8 2.5

a Treatments administered in conjunction with dietary restrictions.

b Gliclazide administered in conjunction with insulin.
Abbreviations and symbols: C = chlorpropamide; co = crossover; d = days; db = double-blind; GB = glibenclamide; GP = glipizide;
GQ = gliquidone; M = metformin; mc = multicentre; mo = months; NO = newly diagnosed; pi = parallel; r = randomised;
sq = sequential; wk = weeks; * p < 0.05 vs baseline; t p < 0.05 VB other treatment.

dial blood glucose level of <7.5 mmoljL, good as
<8.5 mmoljL, fair as < 10 mmoljL and poor as
> 10 mmoljL. In individual studies, gliclazide 20
to 320 mg/day for 1 to 44 months produced good
or excellent control in 62 to 97%, fair control in
9.5 to 26% and poor control in 5 to 20% of patients
(reviewed by Holmes et al. 1984), and 2 recent trials
have confirmed these initial findings (Akanuma et
al. 1988; Robb & Lowe 1984).
The effect of gliclazide on blood glucose levels
was also presented in early trials. Gliclazide sig-
nificantly decreased blood glucose levels (Bodan-
sky et a1. 1982; Brogard et a1. 1982; Paton et a1.
1981), and studies performing more detailed anal-
yses of the effect of gliclazide on fasting and post-
prandial blood glucose levels found significant re-
ductions in these parameters (Charbonnel 1980;
Gibson et a1. 1982; Iunes & Franco 1983; Klaff et
a1. 1979; Lesbre et al. 1977; Mukaino et a1. 1977;
Ponari et a1. 1979; Rubinjoni et a1. 1978; Sakamoto
et a1. 1976; Violi et a1. 1982; Wajchenberg et a1.
1980). Subsequent trials have demonstrated that
gliclazide 40 to 320 mg/day reduces fasting blood
glucose levels by 12 to 62.1 % and postprandial
blood glucose levels by 18 to 26.7% (table V). Re-
sponse to the glucose tolerance test was also im-
proved, with a reduction in blood glucose levels
and mean plasma glucose AVC induced by this
challenge (Brogard et a1. 1984; Chiasson et a1. 1991;
Chang et al. 1990; Couturier 1986; Donatelli et a1.
1985; Page et a1. 1993; Sinay et a1. 1988; Wajch-
enberg et a1. 1992; Ward et a1. 1985) [for example
112
see fig. 8]. Although several trials reported blood
glucose levels in patients stayed elevated after
treatment with gliclazide compared with those ob-
served in healthy individuals (4.4 to 5.8 mmol/L)
[Donatelli et al. 1985; Johnson et al. 1991; Wing
et al. 1993], gliclazide reduced fasting blood glu-
cose levels from a mean of 1l.5 (range 6.6 to 16.1)
mmol/L to a mean of7.3 (range 5 to 9.2) mmol/L.
The effects of gliclazide on blood glucose levels
were observed following both short term admin-
istration (l to 3 months) and longer term admin-
istration of up to 5 years. Furthermore, the drug
appears to be effective both in patients with mod-
erately raised blood glucose levels « 11 mmol/L)
and those with more s.evere diabetes as assessed by
pretreatment blood glucose levels of 11 to 16 mmol/
L. Inter-study comparisons suggest that the drug is
equally effective in newly diagnosed patients and
those who have had NIDDM for 3 to 12 years (table
V). However, other studies found that the decrease
in blood glucose levels achieved with gliclazide
therapy was greater in previously untreated patients
than in those who had been unsuccessfully treated
with other oral hypoglycaemic agents such as sul-
phonylureas and biguanides or combination therapy
(Charbonnel 1980; Plauchu & Pousset 1972). These
results have been confirmed by Shaw et al. (1985).
In this 3-month trial, gliclazide 40 to 320 mg/day
significantly reduced blood glucose levels by 32.5%
in 106 patients in whom diet had failed, but had
no effect on blood glucose levels (4% reduction) in
118 patients previously treated with other oral hy-
poglycaemic agents. Further analysis of these data
revealed that the patients in whom the poorest re-
sponse to gliclazide was observed were those pre-
viously treated with the second generation sul-
Phonylurea glihenclamide (2% decrease in blood
glucose levels), while patients who had previously
failed to respond to chlorpropamide, tolbutamide
or biguanides showed a reduction in blood glucose
levels of 31 to 39% during treatment with glicla-
zide.
Few large scale trials have been performed com-
paring gliclazide with other oral hypoglycaemic
agents. Initial trials involving 78 to 146 patients
per treatment group found that gliclazide 40 to 160
Drugs 46 (1) 1993
mg/day (alone or combined with biguanide or in-
sulin) for 6 to 24 months showed control of blood
glucose levels equivalent to glibenclamide 2.5 to 10
mg/day (Baba et al. 1983) and other oral hypo-
glycaemic agents such as sulphonylureas alone or
combined with a biguanide or insulin (Regnault
1980). In another study, gliclazide 80 mg/day pro-
vided better control than other sulphonylureas but
less control than dietary restrictions (Kosaka et al.
1983). Smaller trials involving up to 30 patients
per group indicated that glic1azide 40 to 320 mg/
day provided equivalent glycaemic control to gli-
benclamide 2.5 to 15 mg/day (Fagerberg & Gam-
stedt 1980; Klaff et al. 1979; Minami et aI. 1981)
and chlorpropamide 352 mg/day (mean) [Asmal et
al. 1980], while in I study, better control was pro-
vided by tolbutamide 1.5 g/day combined with diet
than gliclazide 160 mg/day plus diet (Berber &
Tomkin 1982).
Recent comparative data have demonstrated
that gliclazide 40 to 320 mg/day for 3 to 12 months
induced a greater reduction in fasting blood glu-
cose levels than placebo (Chang et al. 1990; Page
et al. 1993) or diet alone (Johnson et al. 1991; Page
et al. 1993), while administration of gliclazide 80
to 240 mg/day for 3 to 6 months provided equiv-
alent reductions in blood glucose levels to metfor-
min 1500 to 3000 mg/day (Collier et al. 1989;
Noury & Nandeuil 1991) [table V]. Furthermore,
the protocol of several studies has involved switch-
ing patients from one oral hypoglycaemic agent,
such as glibenclamide or tolbutamide, to gliclazide,
and in all instances control of blood glucose levels
was not affected by the change of treatment (Fu et
al. 1992; Gram et al. 1989; Jennings et al. 1992).
In a single trial, 30 patients receiving insulin therapy
due to secondary failure of oral hypoglycaemic
agents, with poor metabolic control despite this
change in therapy, received insulin therapy alone
or in combination with gliclazide 40 to 240 mg/
day for 12 months (Quatraro et al. 1986). The lat-
ter combination providing significantly better gly-
caemic control. In conclusion, gliclazide appears to
be generally comparable to other oral hypogly-
caemic agents in terms of control of blood glucose
levels.
Glic1azide: An Update 113

25 also achieved with gliquidone 30 to 120 mg/day

~ (28.6%) and glibenclamide 2.5 to 30 mg/day (18.2%)
o but not with chlorpropamide 100 to 500 mg/day
E 20
§. (no change) or glipizide 2.5 to 20 mg/day (10% in-
Before
* crease) [Harrower 1985]. Furthermore, at the end
G)
~ 15 .. *
CD
I
I --~-
... * *
.... - .... _* *
of the treatment period, more gliclazide-treated
U)
8::J 10 After .... - • patients had normal glycosylated haemoglobin lev-
Cl els (80%) than recipients of glibenclamide (74%),
«I
~ 5
* glipizide (40%), gliquidone (40%; p < 0.01) or
.!!! chlorpropamide (17%; p < 0.01). Gliclazide ap-
D...
pears to induce a similar reduction in glycosylated
O+-'-~--'---'---'---'---T
o4 10 20 30 40 50 60 haemoglobin levels as metformin and a greater re-
Time (min) duction than diet, and in the only study comparing
gliclazide and insulin, the sulphonylurea induced a
Fig. 8. Plasma glucose levels during an intravenous glucose greater reduction than insulin alone (table V).
tolerance test before and after 3 months' treatment with gli-
c1azide 240 mgJday in 12 patients with non-insulin-depend-
ent diabetes mellitus; * p < 0.05 vs pretreatment (after Bro- 3.2 Secondary Failure Rate
gard et al. 1984).
Secondary failure to an oral hypoglycaemic agent
remains an ill-defined condition but in clinical trials
3.1.2 Glycosylated Haemoglobin drug treatment has been considered to have failed
In healthy individuals, 6 to 10% of haemoglobin if a patients' postprandial blood glucose level is
exists in a glycosylated form while in patients with consistently:;;. 10 mmol/L and glycosylated haemo-
diabetes this proportion is abnormally elevated to globin levels of > 10% are observed while using a
over 10%. The level of glycosylated haemoglobin maximal dosage of sulphonylurea (Aschner & Kat-
is dependent on blood glucose levels and can, tah 1992; Harrower & Wong 1990). Determination
therefore, be used as a measure of glycaemic con- of secondary failure rate requires long term follow-
trol (Karam et al. 1991). up of patients; therefore, trials that assess the effect
Initial trials reported that gliclazide 40 to 320 of drug treatment over periods of <6 months are
mg/day was able to reduce levels of glycosylated inadequate to calculate this phenomenon. Indeed,
haemoglobin (reviewed by Holmes et al. 1984), long term studies have found a secondary failure
findings which have been confirmed by investi- rate with tolbutamide of 10 to 25% with each suc-
gations in which gliclazide 40 to 320 mg/day for 2 cessive year resulting in a failure rate of 90% over
to 60 months generally caused a significant reduc- a lO-year period (reviewed by Jackson & Bressler
tion in glycosylated haemoglobin levels from a 1981), indicating that extensive follow-up periods
mean of 11.0 (range 7.4 to 14) to 7.9% (range 7 to are required to accurately assess secondary failure
9), a reduction of 7.9 to 47.4% compared with pre- rate.
treatment levels (table V). A trial in 50 patients reported a secondary fail-
In a placebo-controlled trial gliclazide induced ure rate of 6% over a 36-month treatment period
a significantly greater reduction in glycosylated with gliclazide 80 to 320 mg/day (Zurro-Hernan-
haemoglobin levels than placebo (23.0% vs 11.2%) dez & Lavielle 1986), while another trial found that
[Chang et al. 1990]. In a total of 96 patients ad- 1 of 36 (2.8%) patients receiving gliclazide 80 to
ministered oral hypoglycaemic agents for 12 320 mg/day required additional treatment with
months, gliclazide 40 to 320 mg/day induced a sig- metformin after 18 months to maintain metabolic
nificant reduction in glycosylated haemoglobin control (Guillausseau 1991). A large scale trial has
levels of 30.8% while significant reductions were specifically investigated the secondary failure rate
114
occurring during treatment with gliclazide, com-
paring it with that occurring in glibenclamide- and
glipizide-treated patients. A total of 248 patients
with NIDDM who failed to maintain glycaemic
control with supervised dietary restrictions for at
least 6 months, were randomised to receive glicla-
zide (n = 86), glibenclamide (n = 84) or glipizide
(n = 78). After exclusion of primary failures, the
remaining patients were followed for 5 years dur-
ing which secondary failure rates were lower with
gliclazide (7% over 5 years) than with glibenclam-
ide (17.9% over 5 years) or glipizide (25.6% over 5
years) treatment, with the difference between gli-
clazide and glipizide being significant (Harrower &
Wong 1990). Body mass index appeared to be a
predictor of treatment failure since this parameter
was significantly lower in the failure group com-
pared with responders.
3.3 Effect on Insulin Requirements
It has been estimated that up to 20% of patients
with NIDDM have only a minimal initial response
to sulphonylureas (Pugh et al. 1992), while others
become secondary failures to this treatment. The
use of a combination of a sulphonylurea and in-
sulin is a possible therapeutic approach in these
patients. Since sulphonylureas, such as gliclazide,
increase endogenous insulin release and partially
reverse peripheral insulin ~sistance (section 1.1.1),
it is predicted that combining gliclazide with in-
sulin will enable lower doses of insulin to be ad-
ministered. This may avoid hyperinsulinaemia
which can occur in insulin-treated patients and has
been implicated in macroangiopathic complica-
tions (Stout 1990).
In several small trials, patients receiving insulin
therapy due to secondary failure of oral hypogly-
caemic agents and who had not obtained optimal
glycaemic control with insulin, were administered
a combination of gliclazide 40 to 320 mg/day and
insulin for up to 12 months. This regimen pro-
vided good glycaemic control, as evidenced by sig-
nificant reductions in fasting blood glucose levels,
and allowed reductions in insulin requirements of
37 to 47% (Almeida Ruas et al. 1991; Aschner &
Drugs 46 (1) 1993
Kattah 1992; Quatraro et al. 1986). The percentage
of patients who were able to reduce insulin re-
quirements ranged from 72 to 85% while 15 to 22%
of patients were able to suspend insulin treatment.
In I trial, a direct correlation was found between
reduction in insulin dose and previous duration of
insulin monotherapy, suggesting that those patients
who had been using insulin monotherapy for the
shortest period of time were those who could re-
duce their insulin requirement to the greatest ex-
tent (Aschner & Kattah 1992).
3.4 Effect on Bodyweight
Up to 85% of patients with NIDDM are obese
(Karam et al. 1991) and, therefore, a treatment
which reduces bodyweight while controlling blood
glucose levels would be advantageous in these in-
dividuals. Unfortunately, a common and undesir-
able adverse effect of some sulphonylurea agents
is weight gain.
The effect of gliclazide on bodyweight has been
reported in a number of trials, although this as-
sessment was not the primary purpose of the trial.
Most trials involving non-obese patients reported
that administration of gliclazide 40 to 320 mg/day
for 1 to 12 months had no significant effect on
bodyweight (Aschner & Kattah 1992; Bak et al.
1989; Brogard et al. 1984; Chang et al. 1990; Har-
rower 1985; Johnson et al. 1991; Klaff et al. 1979;
Ma et al. 1989; Page et al. 1993; Sinay et al. 1988;
Wajchenberg et al. 1988, 1992; reviewed by Holmes
et al. 1984); however, a single trial reported that
body mass index increased significantly in 12
patients receiving gliclazide 80 to 240 mg/day for
6 months (Collier et al. 1989). Ten months of treat-
ment with gliclazide increased bodyweight in
patients who were below normal weight (Forette
1977).
The effect of gliclazide on bodyweight in over-
weight or obese patients is equivocal. In a number
of studies gliclazide treatment for 3 to 60 months
had no effect on bodyweight (Almer 1984; Cou-
turier 1986; Della Casa et al. 1991; Guillausseau
1991; Kilo et al. 1991; Noury & Nandeuil 1991;
Quatraro et al. 1986; Robb & Lowe 1984; Wajch-
Gliclazide: An Update
enberg et al. 1980; Wing et al. 1993), while a single
trial in 6 obese patients reported an average weight
gain of 4.5kg after 3 months' administration of gli-
clazide 80 to 160 mg/day (Ward et al. 1985). How-
ever, several early trials reported significant weight
reduction in obese patients after treatment with gli-
clazide for 6 to 48 months (reviewed by Holmes
et al. 198'4). In a later study, Zurro Hernandez and
Lavielle (1986) reported that after 36 months'
treatment with gliclazide 80 to 320 mg/day in com-
bination with a low-carbohydrate diet, bodyweight
had significantly decreased from 68.2 to 64.0kg in
a group of 44 patients. However, of the 44 patients,
25 were initially obese and bodyweight had nor-
malised in only 13 of these patients by the end of
the treatment period.
In only 1 trial has the primary purpose of the
investigation been to assess the effect of gliclazide
on bodyweight (Shaw et al. 1985). 224 patients who
had previously been treated with diet or other oral
hypoglycaemic agents and who were no more than
120% of ideal bodyweight, were treated with gli-
clazide 40 to 320 mg/day for 3 months, and a sta-
tistically significant, although clinically insignifi-
cant, mean reduction in bodyweight of 0.62kg was
observed. When the results were analysed further
it was apparent that the patients who had lost the
most weight were those who had previously been
treated with oral hypoglycaemic agents.
3.5 Effect on Diabetic Retinopathy
Retinopathy is a common complication of dia-
betes with up to 80% of patients eventually devel-
oping the disorder. Retinopathic lesions can be di-
vided into 2 types: background or non-proliferative
and the more severe proliferative type. Approxi-
mately 10 to 18% of patients with non-proliferative
retinopathy progress to the proliferative stage and
about 50% of those with proliferative disease will
become blind within 5 years (Foster 1991).
The findings that gliclazide has some haemo-
biological actions in addition to its ability to main-
tain glycaemic control, have led to investigation of
the effect of the drug in microvascular disorders
such as diabetic retinopathy. Patients involved in
115
clinical trials had no or mild retinopathy at the start
of the trial. Retinopathy was assessed using fun-
doscopic examinations and fluorescein angio-
graphy, and frequently a retinopathy severity score
was determined which ranged from 0 or 1 (absence
of or mild disease) to 5 or 8 (severe disease).
In several initial trials there was no significant
change in fundoscopic or other examinations of the
eye during administration of gliclazide (reviewed
by Holmes et al. 1984); however, the treatment pe-
riod was too short (up to 12 months) to conclude
that the drug had prevented progression of diabetic
retinopathy. Longer term trials have provided some
evidence that gliclazide is able to slow the rate of
progression from mild to more severe forms of ret-
inopathy. Administration of gliclazide for 18
months to 3 years was associated with no change
or an improvement in retinopathy in 43 to 91 % of
patients compared with 19 to 73.3% of patients re-
ceiving alternative treatments including other sul-
phonylureas or diet (table VI). The number of
patients in whom retinopathy score became worse
over the treatment period was lower during glicla-
zide therapy than other treatments (table VI). Fur-
thermore, in 4 trials gliclazide improved the retino-
pathy score of a number of patients to a greater
extent than those receiving other treatments, sig-
nificantly so in 2 trials (table VI). However, an-
other trial reported that 2 years of combined gli-
clazide and insulin treatment resulted in a
significantly (higher number of patients in whom
retinopathy score increased (41.2%), indicating a
worsening of the disease, compared with placebo-
insulin treatment (26.7%), and that there was no
significant difference in retinopathy score at the end
of 2 years between insulin-treated patients receiv-
ing placebo or gliclazide and non-insulin-treated
patients administered gliclazide. or glibenclamide
(Jerums et al. 1987). The 2-year treatment period
used in this trial may have contributed to the ne-
gative findings, being insufficient for the effects of
gliclazide in retinopathy to be observed; although,
another trial of 2.5 years' duration suggested that
a positive effect of gliclazide on retinopathy can be
observed over this treatment period (Lesbre et al.
1977).
116 Drugs 46 (1) 1993

Table VI. The effect of long term administration of gliclazide and other treatments on the progression of diabetic retinopathy in
patients with non-insulin-dependent diabetes

Reference No; of Treatment! Duration Effect on retinopathy (% of patients)

patients drug (years)
worsened no change improved
(mg!day)

Akanuma et al. (1988) 21 Gliclazide (40-240) >4 19 69 11.9

19 Other SU 29.7 64.9 5.04
20 Diet 27.0 67.9 5.4
Cabral et al. (1985) 19 Gliclazide 38 15.8 84.2· b
14 Other SU 50 50b
Charbonnel et al. (1980) Gliclazide 18-32mo 24· 43·
Other OHA 55 19
Jerums et al. (1987) 17 Gliclazidec 2 41.2t
15 Placeboc 26.7
Lesbre et al. (1977) 30 Gliclazide (40-120) 2.5 9 51 40
Minami et al. (1981) 12 Gliclazide (40-120) 3 8 33 58
13 Glibenclamide (2.5-4) 3 31 54 15
Regnault et al. (1979) 31 d e
Gliclazide 3 24.1· 33.3 42.6·
28d Other sue 54.6 26.4 19

a Mean duration of treatment.

b Includes patients who showed improvement or no change.
c Administered with insulin therapy.
d Includes patients with insulin-dependent and non-insulin-dependent diabetes mellitus.
e Administered alone. with insulin or with biguanides.
Abbreviations and symbols: mo = months; OHA = oral hypoglycaemic agents; SU = sulphonylureas; • p < 0.05 vs other treatment;
t p < 0.05 vs baseline.

A single trial found that the rate of progression
to preproliferative retinopathy was significantly
lower during at least 4 years of treatment with gli-
clazide 160 to 240 mg/day than with other sul-
phonylureas (fig. 9), and that the increase in inci-
dence of retinopathy over the treatment period was
significantly lower in gliclazide recipients (7.1%)
than in patients treated with othet sulphonylureas
(13.6%) or diet (21.7%) [Akanuma et al. 1988].
However, during the study period 45% of patients
withdrew from therapy, due to a variety of reasons
including poor metabolic control.
Thus, the data available at present concerning
the efficacy of gliclazide in delaying the progression
of diabetic retinopathy are conflicting. Further long
term, well controlled trials with larger patient
numbers are required before the effect of gliclazide
in diabetic retinopathy can be accurately assessed.
Furthermore, the effects of gliclazide when started
in patients who already have proliferative disease
needs to be explored, as well as the action of the
drug in treating retinopathy rather than delaying
its progression.
3.6 Effect on Diabetic Nephropathy
Diabetic nephropathy is a leading cause of death
and disability in diabetic patients (Foster 1991). In
the early stages the disease is characterised by mi-
croproteinuria, defined as excretion of albumin of
30 to 300 mg/day. This may progress in some
patients to macroproteinuria (albumin excretion
>300 mg/day). Following the onset of macropro-
teinuria there is a steady decline in renal function.
Analysis of drug effects on diabetic nephropathy
is problematic because proteinuria varies widely in
the initial stages of the disease and predicting the
onset of progressive stages in individual patients is
difficult. Furthermore, it is a slowly progressing
Gliclazide: An Update
disorder and, therefore, long term studies are re-
quired to determine drug efficacy. Gliclazide has
not been extensively studied in diabetic nephro-
pathy with only a small number of patients in-
volved in trials of up to 2 years' duration; there-
fore, available data must be interpreted with
caution.
In an initial trial, gliclazide 80 to 240mg daily
for 24 months significantly reduced albumin ex-
cretion in IS patients with mild pre-existing pro-
teinuria (Lagrue & Riveline 1980). However, it is
possible that this effect was due to an improve-
ment in glycaemic control. Other trials have not
provided evidence that gliclazide has a positive ef-
fect on diabetic nephropathy. Gliclazide 80 mgjday
for 9 months had no effect in 12 patients with pre-
existing constant proteinuria (Jones et al. 1980),
while a more recent investigation found that
administration of gliclazide for 24 months to 9
patients in the early stages of nephropathy had no
effect on total proteinuria, or albumin, transferrin
or IgG clearance (Jerums et al. 1987). Although
there was no progression to overt diabetic nephro-
pathy in patients treated with gliclazide, there was
also no progression of the disease in placebo-treated
patients.
.
~12
>-
'.r:::*
;::10
"iii
Q.
o headedness and dizziness which occurred in 4 to
!" 8
~ 27% of patients (Kilo et al. 1991; Shaw et al. 1985,
.,>
;; 6
~
(5
Q.
., 4
Q. * clazide therapy (Asmal et al. 1980; Masbernard &
g2
" nando 1978, data on file, Servier); however, more
'" 0
"0
E
Gticlaz,de Other sulphonytureas Diel
Fig. 9. Incidence of preproliferative retinopathy observed
among 60 patients after 5 years' treatment with gliclazide 160
to 240 mg/day, other sulphonylureas or diet; • p < 0.05 vs
other sulphonylureas (after Akanuma et al. 1988).
117
4. Tolerability
At dosages used in the treatment of NIDDM,
gliclazide is well tolerated by the majority of
patients. Manufacturers' tolerability data discussed
in the previous review (Holmes et al. 1984) re-
ported that adverse events were observed in 7.6%
of the 727 patients who had been treated with gli-
clazide. Gastrointestinal disturbances accounted for
1.7% and skin reactions for 0.7% of the adverse
events (Holmes et al. 1984).
Updated tolerability data including large patient
numbers have not been published. However, many
recent trials in small numbers of patients (n = 9
to 50) have reported no adverse events following
short (I to 3 months) and long term (3 to 36
months) administration of gliclazide 80 to 320 mgj
day (Akanuma et al. 1988; Aschner et al. 1992; Bak
et al. 1989; Chang et al. 1990; Noury & Nandeuil
1991; Zurro Hernandez & Lavielle 1986). In stud-
ies where administration of gliclazide has been as-
sociated with adverse events, those documented
were usually mild and did not require cessation of
treatment. However, in I trial 2 patients from 47
withdrew from treatment due to nausea and rash
(Shaw et al. 1985). In addition to hypoglycaemia
(section 4.1), adverse events which have been de-
scribed include gastrointestinal disturbances
(nausea, diarrhoea, gastric pain, constipation,
vomiting) with an incidence of 2 to 22%, derma-
tological effects (rash, pruritus, urticaria, erythema,
flushing) with an incidence of 8 to 14% and light-
data on file, Servier).
During initial trials there were isolated reports
of raised ALT and AST levels associated with gli-
Portal 1972) and both increases and decreases in
blood urea nitrogen levels (Villegas-Cinco & Fer-
recent trials have reported that gliclazide has no
effect on these and other biochemical parameters
(Akanuma et al. 1991 ; Aschner et al. 1992; Robb
& Lowe 1984). Significant increases or decreases
in eosinophils, and decreases in red and white blood
118
cell counts were occasionally reported in early trials
(Baba et al. 1983; data on file, Servier), which ap-
pear to be reflected in rare reports of haematolog-
ical disorders such as thrombocytopenia, agranu-
locytosis and anaemia (data on file, Servier).
4.1 Hypoglycaemia
Hypoglycaemia has often been associated with
sulphonylurea therapy. However, gliclazide ap-
pears to be associated with a low incidence of this
adverse effect, possibly due to the relatively phys-
iological effect that the drug has on insulin secre-
tion (section 1.1.1).
Symptoms of hypoglycaemia, such as sweating,
dizziness, tremor, visual disturbances, intense hun-
ger, slurred speech, weakness, poor concentration
and confusion, have been reported during treat-
ment with gliclazide, with an incidence ranging
from 3.8 to 16.7% (reviewed by Holmes et al. 1984;
Aschner & Kattah 1992; Collier et al. 1989; Martin
& Kesson 1985; Paton et al. 1981; Shaw et al. 1985).
In many cases a reduction in gliclazide dose pre-
vented further hypoglycaemic episodes. A number
of other trials have reported that hypoglycaemia
was not a problem during administration of glicla-
zide; for example, Akanuma et al. (1988) found that
during 4 years' treatment with gliclazide 160 to 240
mg/day to 21 patients with NIDDM, no hypogly-
caemic episodes occurred. In a retrospective com-
parative trial of 198 patients treated with gliclazide
(n = 80), glibenclamide (n = 74) or chlorpropam-
ide (n = 44), a hypoglycaemic episode had oc-
curred during the previous 6 months in 13.8% of
patients receiving gliclazide, 13.8% receiving chlor-
propamide and 31.5% of glibenclamide recipients
(Jennings et al. 1989). A total of 11 patients had
taken drugs that were known or thought to increase
the risk of hypoglycaemia, and the prevalence of
hypoglycaemic symptoms was higher in patients
taking concomitant medication than in those tak-
ing oral hypoglycaemic agents alone. However,
since the number of patients who had taken ad-
ditional medication was similar in each treatment
group, drug interactions were unlikely to be re-
Drugs 46 (1) 1993
sponsible for the intergroup difference in incidence
of hypoglycaemic episodes.
4.2 Cardiovascular Effects
In 1970 the University Group Diabetes Pro-
gram (UGDP) published a report which suggested
that the use of tolbutamide and diet was associated
with a higher rate of cardiovascular mortality than
diet or insuli~ therapy alone (UGDP 1970). De-
spite continued criticism and discussion of these
findjngs (Kilo et al. 1980), the effect of sulphonyl-
ureas on cardiovascular parameters has since been
a focus of attention.
Recent animal studies have suggested intraper-
itoneal administration of gliclazide may have ar-
rhythmogenic effects in ischaemic rat heart, and
bolus intravenous injection may increase blood
pressure, myocardial contractile force and cardiac
index in dogs (Ballagi-Pordfmy et al. 1990, 1991).
In a Hungarian retrospective clinical study, re-
ported as an abstract, survival time after acute
myocardial infarction of 220 patients with NIDDM
treated with gliclazide, tolbutamide, chlorpropam-
ide or carbutamide was significantly shorter (5.1
years) than that observed in 243 patients treated
with glibenclamide, 320 with insulin or 184 with
diet (9.1 to 9.2 years) [Pogatsa et al. 1992].
While these data suggest that gliclazide may have
the potential to produce adverse cardiovascular ef-
fects, the doses used in animal studies were in ex-
cess of the usual therapeutic doses and the clinical
relevance of intravenous bolus injections can be
questioned. The clinical data are derived from a
nonblinded retrospective study, that is available
only in abstract form which fails to give details of
patient populations, methodology or statistical an-
alysis. Furthermore, gliclazide has been an estab-
lished agent for the treatment of NIDDM for a
number of years without adverse cardiovascular ef-
fects being reported. Indeed, in recent clinical trials
blood pressure and electrocardiographical para-
meters were unaffected by the drug (Akanuma et
al. 1991; Aschner et al. 1992; Jerums et al. 1987;
Kilo et al. 1991), although palpitations were re-
ported by 1 patient after administration of glicla-
Gliclazide: An Update 119

zide 320 mg/day (Kilo et al. 1991). Thus, the lim-
ited data regarding the possibility that gliclazide
may induced adverse cardiovascular effects must
be viewed in context.
5. Drug Interactions
A number of well recognised drug interactions,
also common to other sulphonylureas, have been
described for gliclazide and are shown in table VII.
Although coadministration of miconazole and
gliclazide is not recommended, concomitant
administration of another azole antifungal agent,
fluconazole, with gliclazide did not adversely affect
glycaemic control (Rowe et al. 1992). Concomitant
administration of gliclazide and perhexiline ma-
leate may result in hypoglycaemia, although the
mechanism of this effect is unclear. Hypoglycae-
mia has also been observed following administra-
tion of gliclazide 160 mg/day plus cimetidine 800
mg/day, possibly due to cimetidine-induced im-
pairment of glucose absorption or handling, or a
reduction in hepatic metabolism of gliclazide (Ar-
chambeaud-Mouveroux et al. 1987).
An interaction between sulphonylureas and al-
cohol has been observed, and a case report has de-
scribed facial flushing and nausea within 20 min-
utes of drinking alcohol in a 58-year-old man
treated with gliclazide (Conget et al. 1989).
Concomitant administration of gliclazide with
agents that increase blood glucose levels should not
be considered without careful monitoring of blood
glucose levels to avoid hyperglycaemia.
6. Dosage and Administration
Gliclazide, as with other sulphonylurea drugs,
is indicated only in NIDDM when dietary restric-
tions have failed. It is not effective in insulin-de-
pendent (type I) diabetes. Gliclazide therapy should
be commenced at a total daily dose of 40 to 80mg.
The dosage may be increased to a maximum of 320
mg/day to obtain good glycaemic control, but in
most patients a dosage of 160 mg/day is adequate.
A single dose should not exceed 160mg and, there-

Table VII. Potential drug interactions with gliclazide

Type of interaction Drug Mechanism of interaction Clinical effect

Increase in plasma Sulphonamides, phenylbutazone, Displacement of gliclazide from Hypoglycaemia

gliclazide clofibric acid, salicylates, vitamin K plasma protein
concentrations antagonists
Allopurinol, phenylbutazone, Reduction of renal excretion of Hypoglycaemia
salicylates, coumarin gliclazide
Sulphonamides, phenylbutazone, Inhibition of hepatic metabolism of Hypoglycaemia
clofibric acid, miconazole, vitamin K gliclazide
antagonists

Reduction in plasma Barbiturates, phenytoin, rifampicin Induction of metabolism of gliclazide Reduction in glycaemic
gliclazide (rifampin) control
concentrations

Stimulation of insulin Theophylline, caffeine, monoamine Hypoglycaemia

secretion oxidase inhibitors

Increase blood Corticosteroids, diuretics, estrogens, Reduction in glycaemic

glucose levels estroprogestogens, pure control
progestogens, phenytoin

Suppression of ~-Adrenoceptorantagonists, Suppression of mimetic effect of Hypoglycaemia

manifestations of monoamine oxidase inhibitors adrenaline (epinephrine)
hypoglycaemia
120
fore, if a higher dose is required the dosage should
be divided and taken twice daily. Gliclazide should
be administered with morning and evening meals.
In obese patients and those not showing an ade-
quate response to gliclazide, additional therapy such
as a biguanide may be required.
Gliclazide is contraindicated in NIDDM com-
plicated by ketosis and acidosis, diabetic precoma
and coma, patients undergoing surgery, after sev-
ere trauma or during infections. It should also not
be used during pregnancy or in patients with severe
renal and/or hepatic failure. To reduce the risk of
hypoglycaemia a number of precautions should be
taken when gliclazide is first prescribed, including
adjusting the dose of gliclazide according to blood
and urinary glucose levels during the first few
months, and beginning treatment with low doses
in patients with renal and/or hepatic impairment.
Hypoglycaemic symptoms can also be reduced by
prescribing a diabetic meal plan, consisting of 3
meals and 3 snacks a day.
Hypoglycaemia may also occur if the patient's
dietary intake is reduced or after accidental or de-
liberate overdose. In the case of overdose, gastric
lavage should be performed and correction of
hypoglycaemia attempted by intravenous admin-
istration of hypertonic glucose (10 or 30%) with
continued monitoring of the patient's blood glu-
cose levels.
7. Place 0/ Gliclazide in Therapy
Studies conducted since gliclazide was previ-
ously reviewed in the Journal have investigated the
mechanism of action of the drug in more detail,
and have demonstrated that gliclazide reduces
blood glucose levels in patients with NIDDM by
pancreatic, and possibly extrapancreatic, effects.
Initial studies reported that gliclazide was generally
comparable with other oral hypoglycaemic agents
in terms of glycaemic control. Few new compara-
tive data of any significance have been presented
since to support or refute these claims and, there-
fore, the main differentiating feature of gliclazide
appears to be its possible effects on the vascular
system.
Drugs 46 (1) 1993
There is some evidence that gliclazide, unlike
other sulphonylureas, may slow the progression of
the vascular complications of diabetes mellitus.
Gliclazide increases t-PA levels and reduces plate-
let adhesion and possibly aggregation, and reduces
levels of free radicals. Preliminary animal and
clinical data suggested that gliclazide might be
beneficial in slowing the progression of diabetic
retinopathy. Subsequent small scale studies have
provided some data to confirm these initial find-
ings, with long term administration of gliclazide (2
to 5 years) being associated with a greater inci-
dence of unchanged or improved retinopathy para-
meters than other treatments such as alternative
sulphonylurea drugs or diet. However, further long
term data in large patient numbers are required to
substantiate these findings.
When combined with insulin therapy, gliclazide
may allow a reduction in insulin dosage which may
reduce the macroangiopathic complications of hy-
perinsulinaemia. Furthermore, gliclazide is well
tolerated by most patients, with gastrointestinal and
cutaneous reactions being the most commonly ob-
served adverse events. The drug appears to be as-
sociated with a lower incidence of hypoglycaemia
than other oral hypoglycaemic agents, possibly be-
cause of a more physiological action on pancreatic
{j-cells. Limited animal and clinical data have in-
dicated that gliclazide may induce adverse cardio-
vascular effects and, although the quality of these
data may be questioned, the finding warrants fur-
ther investigation.
In conclusion, through long term extensive
clinical experience gliclazide is now an established
agent in the treatment of NIDDM. The drug ef-
fectively maintains glycaemic control by pan-
creatic and possibly extra pancreatic actions, and is
well tolerated by most patients. The low incidence
of hypoglycaemia associated with the drug repre-
se~ts an advantage over other agents. In addition,
if actions on the haematological and vascular sys-
tems are substantiated, the drug may offer clinical
benefits in selected groups of patients, especially
those with or likely to develop diabetic retinopa-
thy.
Gliclazide: An Update
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