Drug Evaluation

Drugs 27: 301 -327 (1984)

0012-6667/84/0400-0301/$ 13.50/0
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Gliclazide
A Preliminary Review of its Pharmacodynamic Properties and
Therapeutic Efficacy in Diabetes Mellitus

B. Holmes, R.C. Heel, R.N. Brogden, T.M. Speight and

G.s. Avery
ADIS Drug Information Services, Auckland

Various sections of the manuscript reviewed by: A.L. Bloom, Department of Haernatol-
ogy, Uni versity Hospital of Wales, Cardiff, Wales; R.B. Jones, Andover, England; K.
Kobayashi, Department of Clinical Pathology and Clinical Laboratory, Hyogo College of
Medicine, Nish inomiya, Japan; F.X. Lesbre, Lyon , France; A. Marble, Joslin Diabetes
Center, Boston, Massachusetts, USA ; R.C. Paton, Department of Medicine, Un iversity
of Leeds , Leeds , England; L./. Rose, Division of Endocrinology and Metabolism, Hah-
nemann University, Ph iladelphia, USA; C.Th. Smit Sibinga, Red Cross Blood Bank
Groningen-Drenthe, Groningen , The Netherlands; D.F. Vloli, Institute of Clinical Med-
icine, U niv ersity of Rome, Rome, Ital y; I .R.B. Williams, Liste r Hospital , Ste verage, Eng-
land.

Contents

Summa ry 302
I . Pharma codynamic Studies 303
1.1 Hypoglycaemic Activity 304
1.2 Effect on Plasma Cholesterol , Triglycerides and Fatty Acids 305
1.3 Effects on the Blood 307
1.3.1 Effect on Platelet Adhesiveness 307
1.3.2 Effect on Platelet Aggregation 308
1.3.3 Effect on Platelet Metabol ism 308
1.3.4 Effect on Platelet Coagulant Factors 309
1.3.5 Effect on Fibrinolytic Activit y 310
1.3.6 Effect on Prostaglandin 12 Formation 310
1.4 Mechanism of Action 310
2. Toxicology 3 11
2.1 Acute Toxicity Studies 311
2.2 Chron ic Toxicity Studies 311
2.3 Effects on Reproduction 311
3. Pharmacok inetic Studies 312
3.1 Absorption 312
3.2 Distribut ion 312
3.3- Eliminat ion 313
3.3.1 Metabol ism 3 13
3.3.2 Excretion 314
3.3.3 Half-Life 314
Gliclazide: A Preliminary Review 302

3.4 Plasma Concentration and Clinical Effects 314

4. Therapeutic Trials 315
4.1 Open Studies 315
4.2 Controlled Trials 315
4.2.1 Gliclazide Compared with Tolbutamide 315
4.2.2 Glidazide Compared with Glibendamide 316
4.2.3 Glidazide Compared with Chlorpropam ide 316
4.2.4 Glidazide Compared with Various Other Oral Hypoglycaemic Agents 316
4.3 Studies in Patients with Diabetic Retinopathy 318
4.4 Studies in Patients with Diabetic Nephropath y 320
5. Side Effects 321
5.1 Hypoglycaemia 321
5.2 Weight Change 321
5.3 Laboratory Test Abnormalities 321
6. Drug Interactions 322
7. Dosage and Administrat ion 322
8. Place of Glidazide in Therap y 323

Summary Synopsis: Gliclazide' is a 'second generation ' oral hypoglycaemic agent. The particular
interest with this drug is that it has shown certain effects on the blood fo r which it is hoped
there may be some clinical benefit in diabetic angiopath ies. Both in animal and human
studies it has dem onstrated a reduction in platelet adhesiveness and aggregation, whilst
possible enhancement of platelet metabolism , reduction of coagulant fa ctors. as well as
increased fibrin olytic activity, are still being investigated. Initial trials ha ve suggested that
gliclazide therapy ma y reverse or at least slow down the progression of diabetic retino-
pathy. However, a fe w additi onal well-designed long term controlled studies are needed
to confirm these findings, and to clarify whether any beneficial effect on diabetic retinop-
athy is unique to gliclaz ide or also occurs with other oral hvpoglycaemic drugs.
Both newly diagnosed maturity onset diabetics as well as those previously treated with
sulphonylureas respond well to gliclazide therapy. In the small com parative studies which
have been reported, gliclazide was of comparable efficacy to other oral hypoglycaemic
agents.
Gliclazide has been well tolerated by most patients. the most frequently reported side
effects being gastrointestinal in nature which occurred in less than 2% of patients.

Pharmacodynamic Studies: The abil ity of glic\azide to lower blood glucose concen-
trati ons has been demonstrated in various animals, as well as in a small number of
health y subjects and in pat ients with maturity onset diabetes. On a weight basis , glic\azide
was man y times more potent than tolbutamide, the relative potency varying between
species (e.g. potency rat io of about I : 8 in rabbits and I : 27 in rats). As with other
sulphonylurea oral hypoglycaemic drugs , glic\azide was not act ive in panc reatectomised
animals. suggesting it has a direct action on the pancreas (postulated to be mediated by
increased calcium uptake in pancreatic islet cells) to increase insulin secretion. Single
do ses of glic\azide 80mg in diabetic patients have brought about significant decreases in
both fasting and postprandial blood glucose levels, the effect being slightly less prolonged
than that of glibenc\amide 5mg which produces more abrupt changes in blood glucose
concentrations, whilst tolbutamide 500mg produces a milder and relatively less prolonged
effect. Therapy with gliclazide has produced decreases in plasma cholesterol , tr iglyceride
and fatt y acid levels, with at least I of the decreased levels reaching a statisticall y sig-
nificant value at some stage during the administration of the drug. Gliclazide has dem-
onst rated some effects on the blood in both animal and human studies which it is pos-

I ' Diarnicron' (Servicr): 'G lim icro n' (Da i Nippon).

Gliclazide: A Preliminary Review 303

tulated may limit the progression of diabetic or other angiopathies. They include a
reduction of platelet adhesiveness and aggregation, whilst possible enhancement of plate-
let metabolism and anticoagulant factors as well as increased fibrinolytic activity are
being investigated.

Pharmacokinetics: Gliclazide has been consistently well absorbed after oral admin-
istration in animals, but peak plasma concentrations (2.8 and 3.9 rng/L) after a dose of
80mg, as well as time to reach peak concentrations (0.4 and 4.8 hours), have shown
greater variability in studies in man . Its relatively low volume of distribution (15.9 to
17.4L) suggesting only limited tissue distribution may in part be explained by its exten-
sive binding to plasma album in (85 to 97%). In common with other sulphonylureas,
gliclazide is apparently metabolised to either hydroxylated metabolites or N-oxygenated
compounds and the corresponding alcohol and carboxylic acid. 60 to 70% of a dose is
eliminated in the urine, with less than 20% of this as unchanged drug, while a further
10 to 20% of a dose is eliminated in the faeces. In contrast, 90% of all drug-related
material in the plasma is unchanged gliclazide. The elimination half-life of gliclazide may
vary between sexes, with values for males of around 8 hours and for females of II hours.

Therapeutic Trials: In open trials, 60 to 100% of maturity onset non-ketosis-prone

diabetes mellitus patients achieved satisfactory control of their blood glucose levels on
gliclazide therapy . These patients included those who were newly diagnosed as well as
those previously treated with other sulphonylurea drugs. However, as would be expected ,
gliclazide was not effective in insulin dependent diabetics, in whom substitution of in-
sulin with gliclazide resulted in loss of blood glucose control while addition of gJiclazide
therapy conferred no additional benefit compared with insulin alone . Combined therapy
involving gliclazide and a biguanide was sometimes effective in patients resistant to a
sulphonylurea alone. In mostly small comparative studies, gJiclazide was generally com-
parable to other oral hypoglycaemic drugs in terms of overall quality of control of blood
glucose levels. In patients with diabetic retinopathy, gliclazide therapy for periods up to
several years resulted in a significantly lower rate of deterioration of disease compared
with control groups treated with another hypoglycaemic agent, whilst overall stability in
the progress of the disease during gliclazide therapy was noted in shorter term open
studies. Gliclazide did not significantly alter renal funct ion in patients with diabetic
nephropathy.

Side Effects: Gliclazide is well tolerated by most patients. The most frequently re-
ported side effects have been gastrointestinal upset such as abdominal pain, nausea , vom-
iting, dizziness, skin reactions and symptoms of hypoglycaemia , the latter in most cases
resulting from overdosage or inadequate diet rather than an adverse effect of the drug .

Dosage and Administration: The recommended adult dose in maturity onset non-
ketotic diabetes mellitus is from 80 to 240mg daily . Maximum doses of 320mg have been
administered in an attempt to achieve control of blood sugar concentrations and should
this fail, addition of a biguanide may be successful in some cases, provided ketosis has
not developed .
Gliclazide, like other sulphonylurea drugs, is indicated only where diet fails to control
hyperglycaemia and glycosuria. It has no place in the treatment of juvenile diabetes or
where there is severe metabolic decompensation with acidosis .

1. Pharmacodynamic Studies same class ofhypoglycaemic agents as tolbutamide

and glibenclamide (fig. I). Its hypoglycaemic activ-
Gliclazide is a 'second generation' sulphonyl- ity has been demonstrated in animals, healthy sub-
urea oral hypoglycaemic agent. It belongs to the jects and diabetic patients.
Gliclazidc: A Preliminary Review
CI
Q-CO-NH_CH,-H'cD-so, - NH-CO-NH-{H,
OCH 3
H3C - { ) - S02 -
Fig. 1. Structural formulae of gliclazide. gfibenclamide and tolbutamide .
1.1 Hypoglycaemic Activity
Gliclazide proved to be about 7 to 10 times as
active as tolbutamide in decreasing blood glucose
in rabbits (Duhault et aI., 1972; Maekawa et aI.,
1978b; Schimizu et aI., 1976a) [25 mg/kg gliclazide
= 200 rug/kg tolbutamide), whilst the potency ratio
increased in rats (3 mg/kg gliclazide ==
80 mg/kg
tolbutamide) to around 27 (Duhault et aI., 1972;
Schimizu et aI., 1976). Gliclazide 10 and 25 mg/
kg orally also reduced blood glucose concentrations
in guinea-pigs and dogs . Increasing the dosage of
gliclazide from 2.5 rug/kg to 25 mg/kg resulted in
an increased duration of activity of up to 24 hours.
Tolbutamide did not show a similar effect, the dur-
ation of action remaining at around 10 to 12 hours
despite increased dosage . Gliclazide showed no ac-
tivity in pancreatectomised dogs and alloxan dia-
betic rats (Duhault et aI., 1972). This would appear
to indicate that, as with other drugs of this type,
gliclazide has a direct action on the pancreas to
increase insulin secretion.
Gliclazide 200mg was found to lower blood glu-
cose levels to a significantly greater extent than tol-
butamide 2g at 2 and 3 hours after administration
to 12 healthy subjects (Duhault et aI., 1972).
Administration of a single dose of gliclazide 80mg
produced a maximum reduction of 20% in blood
glucose levels after 2 hours, the levels returning to
control values 4 to 6 hours after administration of
304
Glibenclamic1e
NH - CO - NH - (CH 2b - CH 3
Tolbutamide
the drug in 23 healthy subjects (see also section
3.4) [Campbell et aI., 1980).
In patients with maturity onset diabetes melli-
tus, single doses of gliclazide (dose range 40 to
320mg) have been shown to decrease hyperglycae-
mia in response to oral (Campbell et aI., 1980) and
intravenous glucose (Stephan et aI., 1980), a stand-
ard meal (Charbonnel, 1980; Lagrue and Riveline,
1980; Lesbre, 1977; Shaw et aI., 1980; Violi et al.,
1982), after food given at 4 and II hours after drug
administration (Campbell et aI., 1980) and during
an arginine tolerance test (Brogard et aI., 1982). In-
vestigating the effects of single doses of various oral
sulphonylureas in 32 diabetic patients, Strata et aI.
(1980) found the action of gliclazide 80mg on fast-
ing blood sugar to be slightly less prolonged than
that of glibenclamide 5mg, which also produced a
more abrupt response, whilst tolbutamide 500mg
produced a less pronounced and less prolonged ef-
fect (fig. 2). Eight healthy subjects demonstrated a
significant decrease in blood glucose for 240 min-
utes after gliclazide 40,80 or 120mg, compared with
a control group, whilst the higher doses of 80 and
120mg produced significant rises in plasma insulin
levels (Ohneda et aI., 1977).
Treatment with gliclazide 80 to 240mg daily for
up to 7 months resulted in a significant rise in the
' insulinogenic index' [the ratio of the area under
the plasma insulin curve (~U/ml' hour) to the area
under the blood glucose curve (g/L> houri] in 18
Gliclazide: A Preliminary Review 305

non-ketotic diabetics . Low values of the insulino-

genic index were seen in 6 secondary treatment 150
failures during long term treatment, and surpris-
:g, 140
ingly also in some of the adequately controlled dia- Ol
E
betics. Two months of gliclazide therapy (160mg :- 130
1O
daily) in 8 subjects produced a significant decrease Ol
~ 120
in fasting blood glucose but no change in insulin '0

concentration (Marchand et aI., 1983). While these g

:0
110

results could suggest that the antidiabetic action of g' 100

:;:;
gliclazide may be related to an extrapancreatic ef- en
~ 90
fect, since the insulotropic action is apparently
Base 2 4 5 6 7 6
lacking in certain patients (Stephan et aI., 1980),
Time (hours)
this postulate is not supported by the findings in
animals described above . Any extrapancreatic ef- Fig. 2. Fasting blood sugar levels in 32 diabetics after a single
fect of gliclazide is thought not to involve the re- dose of placebo ( 6 -6). tolbutamide 500mg (0-0). gli-
ceptors (De Meyts et aI., 1983; Dolais-Kitabgi et benelamide 5mg (A-A) or gliclaz ide 60mg (e-e) [after
al., 1983; Marchand et al., 1983; Vigneri et aI., 1982) Strata et al., 1960).

but may take place at the 'post-receptor' level (un-

published data on file, Servier; Ward et aI., 1983).
1.2 Effect on Plasma Cholesterol ,
Triglycerides and Fatty Acids
Studies in rats and rabbits have revealed that
gliclazide reduces plasma concentrations of chol-
esterol, triglycerides and fatty acids (Marquie, 1977;
Puglisi and Colli, 1980; Smit Sibinga and Wier-
inga, 1980). Gliclazide demonstrated a protective
effect on x-ray induced experimental atheromato-
sis in rabbits treated with 5, IO or 25 rug/kg,
whereas glibenclamide 0.07 mg/kg had no effect
(Smit Sibinga and Wieringa, 1980).
However, results of similar studies in patients
with diabetes were less consistent. Thus, significant

Table I. Effects of gliclazide on plasma cholesterol . triglycerides and fatty acid concentrations in patients with diabetes

Reference No. of Dosage Duration Results·

patients (mg/day) (months)
cholesterol triglycerides fatty acids

Asmal et al. (1960) 11 220 (mean) 6 ++ ±

Berber and Tomkin (1962) 6 160 3 ± ±

King et al. (1977) 12 Not stated 3 + ±

Lagrue and Riveline (1980) 56 60-240 24.7 + +

Radic et al. (1980) 45 80-240 12 ++ + +
Sadayoshi et al. (1962) 41 20-240 12-60 ++
Stephan et al. (1960) 18 60-240 6-84 + +
Strata et al. (1980) 10 80 Not +
5 160 stated +
Villiger (1962) 65 160 3 ++ ++

a ++ = significant decrease ; + = apparent decrease (not statistically significant); ± = no signif icant effect.
Gliclazidc: A Preliminary Review 306

1.58 8

.....
....__-------L.... . . . . . . . ........
----
..... .......
1.36 7
.......
~ ~
o o
E E
.s .s
.Q 1.13 6 .9
ec .... - - - -II Gliclazide (n = 13) ec
o
Ql Ql
o o
5o 0.90
0 Chlorpropamide (n = 13) 5 g
o
o
-- ...---11----....- ----- ----
Ql
:g
o
Q; !en
>-
0> 068 4 ~
s:
'S o
"'
E
en
"'
E
en
"'
0:: 0.45 ' - - - - - - -.......- - - - - - - ' - - - - - - " ' - - - - - - -... "'
0::
-4 o 4 8
Time (months)

Fig. 3. Plasma cholesterol and triglyceride changes in 26 patients treated for a 3-month period with either gliclazide (mean dose 273
mg/day) or chlorpropamide (352 mg/day) [after Asmal et aI., 1980].

decreases in both plasma cholesterol (240 to 225 Two other studies reported no significant change
mg/dl) and triglyceride (236 to 175 mgjdl) levels in either cholesterol or triglyceride concentrations
were found in diabetics on gliclazide therapy by (Lagrue and Riveline, 1980; Stephan et aI., 1980)
Villiger(1982), whilst studies by Radic et al. (1980), [table I]. Berber and Tomkin (1982) noted an in-
Fukui et al. (1982) and Asmal et al. (1980; table I) crease in high density lipoprotein cholesterol in
reported significant decreases in cholesterol levels patients receiving gliclazide 160mg daily, and tol-
alone (2.59 to 2.3 g/dl and 5.2 to 4.33 mmol/L), butamide 1.5g daily (increased from 1.24 to 1.72
mmol/L and 1.42 to 1.68 mrnol/L, respectively) but
only the increase caused by gliclazide was statis-
Gl tically significant. However, total cholesterol and
Ol
c triglyceride levels showed no significant alteration
'"
s:
0
20
with either drug. No consistent alterations oc-
~
~
(/)
10 curred in plasma cholesterol or triglyceride levels
u in a 3-month study of patients receiving either
·0
'">..
t:
0 chlorpropamide 352 mg/day or gliclazide 273 mgj
~ day (fig. 3; Asmal et aI., 1980). Similarly , neither
-10
Q)
glipizide nor gliclazide significantly altered blood
~
lipids including cholesterol and triglycerides during
'"
E
(/)
-20
a 3-month treatment period (Strata et aI., 1980).
'"
0:: -30 Since only the mean values for the levels of chol-
Base 1 2 3 4 5 6 7 8 g esterol and triglycerides are quoted in these studies
Time (hours)
it is not possible to determine whether those
Fig. 4. Mean percentage changes in free fatty acids after pla-
patients with elevated pretreatment levels experi-
cebo (t . - t.) , tolbutamide 500mg (0----0) and gliclaz ide 80 enced a greater or lesser response to gliclazide than
(0 -0) and 160mg (.-11) [after Strata et aI., 1980] . those without elevated pretreatment levels.
Gliclazidc: A Preliminary Review 307

King et al. (1977) investigated the effect of single
doses of placebo, tolbutamide 500mg, and glicla-
zide 80 and 160mg, on levels of free fatty acids in
patients with diabetes (fig. 4). All drugs produced
about a 20 to 25% maximum decrease in free fatty
acids, with the peak effect occurring 4 to 5 hours
after administration.
1.3 Effects on the Blood
The relevance of platelet function, as measured
in the laboratory, to the clinical situation in dia-
betes is not yet known (Butterfield, 1980). How-
ever. it is known that both microangiopathy and
atherosclerosis involve interaction of blood vessel,
platelet and plasma factors which may be altered
in diabetes . Elevation of lipids and of coagulation
factors, particularly procoagulant factor VIII and
fibrinogen, have been reported in patients with
diabetes, and may playa part in influencing blood
rheology. Platelets may influence the development
of angiopathy by 2 distinct but interrelated prop-
erties - adhesion and aggregation (Bloom, 1980).
Aggregation and adhesion (in in vitro systems), and
certain of their mediating mechanisms, are re-
ported as being increased in diabetes (Colwell et
al., 1978). Agents which inhibit or reduce these re-
actions or lower the concentrations of the relevant
reactants may thus reasonably be postulated to limit
the progression of diabetic or other angiopathies.
However, this expectation is subject to the con-
straint that some of the platelet changes seen in
such patients may be secondary to the angiopathy
(Mustard and Packham, 1977), with consequent
increased platelet turnover and the presence of
young reactive platelets .
1.3.1 Effect on Platelet Adhesiveness
Platelet adhesiveness has been shown to be in-
creased in diabetes when measured by a number

Table II. Effect of gliclazide on platelet adhesiveness in patients with diabetes

Reference No. of Dosage Duration Decrease in adhesiveness'

patients (mg/day) (months)

Bobillo et at. (1975) 25 Not stated 3 ++ P < 0.001

Dettori (1980) 14 80-240 3 +
6 ++ P < 0.02
12 ++ P < 0.001
Jones et al. (1980) 12 80 3 ++ P < 0.025
6 ++ P < 0.001
Nakayama et al. (1979) 30 20-240 22 Maintained at medium to low level

Paton et at, (1981) 11 Adjusted for control 10 ++ P < 0.05b

Radic et al. (1980) 50 80-240 12 ++ Not stated

Shaw et al. (1980) 9 80-320 1 +

3 +
Thouverez (1972) 40 20 3 ++ P < 0.001
40 ++ (all doses)
80 ++
160 ++
Verry et al. (1974) 150 Not stated 3-24 +
Yamada et al. (1977) 9 Not stated 12-24 Maintained at normal to low level

a Retention index measured by method of Salzmann ; ++ =significant decrease ; + =apparent decrease (not statistically significant).
b Significant at 2 months only .
Gliclazidc: A Preliminary Review
of techniques, including the Salzman glass bead re-
tention index method (Colwell et aI., 1978). Intra-
venous and oral administration of gliclazide 10 to
50 mg/kg in rabbits (Desnoyers et aI., 1972) and
100 mg/kg orally in alloxan diabetic rabbits
(Kuwashima et al., 1979), as well as oral admin-
istration of 5 to 25 rug/kg/day in dogs, resulted in
a marked decrease in the retention index (Desnoy-
ers et aI., 1972). Schimizu et al. (1976b) carried out
a similar study in animals which confirmed these
findings with gliclazide, but which also demon-
strated that tolbutamide had no effect on platelet
adhesiveness. As a result of these early studies, fur-
ther investigations of the effects of gliclazide on
platelet adhesiveness in diabetic patients were car-
ried out. As can be seen from table II, gliclazide
20 to 320 mg/day administered for periods ranging
from I month to 2 years has in most trials brought
about a significant decrease in platelet adhesive-
ness. However the design of these studies has not
distinguished between an effect due to improve-
ment of hyperglycaemia and an effect of the drug
per se. In the only comparative study of this type,
gliclazide (80 to 240 rug/day) was similar to aspirin
(I to 3 g/day) and dipyridamole (150 to 500 mg/
day) in inhibiting the adhesiveness of human plate-
lets (Deguchi et al., 1978).
1.3.2 Effect on Platelet Aggregation
In diabetics there may be increased platelet ag-
gregation induced by adenosine diphosphate (ADP),
as indicated by both the primary aggregation re-
sponse and the release reaction (Colwell et aI.,
1978). Studies in rabbits have demonstrated sig-
nificant inhibition of ADP-induced aggregation by
gliclazide given as an infusion (3 or 10 rug/kg/min
for 4 to 8 min before administration of ADP), as
a single oral dose (30 to 100 mg/kg) or as contin-
uous therapy (20 rug/kg) for 7 days . Using the same
routes of administration, tolbutamide (10 to 30 mg/
kg/min, as an infusion; 50 to 150 mg/kg as a single
dose; and 100 rug/kg as continuous oral therapy)
had no effect on aggregation (Desnoyers and Saint-
Dizier, 1980; Schimizu et aI., 1976b). Kuwashima
et al. (1979) reported a significant reduction in
platelet aggregation induced by collagen (2 Ilg/ml)
308
in alloxan diabetic rabbits given gliclazide 100 mg/
kg orally for 4 weeks compared to a diabetic con-
trol group. Similarly, Arfors and Tangen (1977) re-
ported marked and highly significant inhibition of
ADP-induced platelet aggregation of human plate-
lets in vitro, using gliclazide concentrations of I and
2 mg/rnl.
However, studies in diabetics have been less
conclusive (table III), and the variability of find-
ings in such studies prevent meaningful conclu-
sions. Only 3 trials have reported a significant de-
crease in ADP-induced platelet aggregation for
gliclazide at some stage in the trial (Chan et aI.,
1982; Dettori, 1980; Violi et al., 1982), whilst others
have reported only a tendency toward inhibition
(Kato et al., 1976; Yamada et aI., 1977) or no effect
at all. In a comparative study, both glibenclamide
5 to 10mg and gliclazide 80 to 240mg resulted in
a return to normal in the aggregation values pro-
duced by ADP I umol/L, In this study, gliclazide
had no effect on aggregation induced by higher
concentrations (10 and 100 umol/L) of ADP, col-
lagen or adrenaline, while glibenclamide signifi-
cantly decreased the aggregation induced by col-
lagen (750 Ilg/ml) and adrenaline (10 urnol/L) [Klaff
et al., 1979]. In contrast, Chan et al. (1982) re-
ported a significant decrease in ADP-induced
platelet aggregation in patients receiving gliclazide
but not in those receiving glibenclamide.
1.3.3 Effect on Platelet Metabolism
Studies on platelet metabolism have examined
the thromboxane metabolic pathway and levels of
.B-thromboglobulin, which are believed to reflect the
level of platelet activity (Tsuboi et aI., 1981; Violi
et aI., 1982). Only one significant finding of a de-
creased level of .B-thromboglobulin (33%) in dia-
betic patients receiving gliclazide 80 to 160mg over
a 30-day period has been reported (Violi et al .,
1982). Tsuboi's investigation of the effect of glicla-
zide on prostaglandin and thromboxane synthesis
in guinea-pig platelets revealed an in vitro and ex
vivo inhibition of arachidonate release from plate-
let phospholipids. Gliclazide has induced a de-
crease in the heavy (large and very metabolically
active) populations of platelets C and D frequently
Gliclazide: A Preliminary Review 309

Table III. Effect of gliclazide (GI) and some other sulphonylureas on platelet aggregation in blood of diabetic patients

Reference No. of Dosage Duration Method of stimulating Inhibition of aggregation· ·b

patients (mg/ day) (months) aggregation
ADP adrenaline collagen

Non-comperetiv« trials
Dettori (1980) 14 80-240 3 ADP 1 " g/ ml ++ ++
6 Adrenaline 5 " g/ ml ++ ++
12 ++ ++

Shaw et al. (1980) 4 80-320 ADP 1, 2.5, 5 "g/ml +

Verry et al. (1974) 150 Not stated 3-24 Collagen

Violi et al. (1982) 18 80-160 15 days ADP 1.2 "mol/L +

30 days ++

Comparative stud ies

Chan et at, (1982) 35 GI20 ADP 1, 4 "mol/L GI + +
Gb15 Gb ±

King et al. (1977) 12 GI 3 ADP 10 "mol/L GI + +

Gp 3 Collagen 750 " g Gp + +

GI Gb

Klaff et al. (1979) 10 G180-240 ADP 1 " mol/L + +

Gb 5-10 10 Ilmol/L ± ±
100 "mol/L ± ±
Collagen 750 Ilg/ ml GI ± Gb ++
Adrenaline 1 "mol/L GI ± Gb ±
10 " mol/ L ± ++

a Method of evaluation of inhibition of aggregation used in most studies was that of Born (1962).
b + + = significant inhibition: + = apparent inhibition (not statistically significant): ± = no effec t.
Abbre viations : Gb = glibenclamide: Gp = glipizide (doses not stated): ADP = adenosine diphosphate.

present in diabetic patients, together with an in-
crease in light populations B and A (Desnoyers and
Saint-Dizier, 1980; Vainer and Verry, 1974). In-
terference with platelet synthetic activity which
mainta ins platelet glycogen storage has also been
claimed (Desnoyers and Saint-Dizier, 1980; Vainer
and Verry, 1974), but further studi es are required
to substantiate these initial observations.
1.3.4 Effect on Platelet Coagulan t
Factors
Studies using blood samples from rabbits showed
that gliclazide 10 to 20 rug/kg intravenously could
produce from 25 to 55% inhibition of the activa-
tion of coagulant factor XI by collagen. Oral
admin istration of 10 to 20 mg/kg resulted in 30 to
35% inhibition. Under the same experimental con-
ditions, tolbutamide 125 and 250 mg/kg orally and
glibenclamide 5 mg/kg orally had no inhibitory ac-
tivity. Gliclazide 20 and 40 ~g/ml was associated
with a significant decrease (63% and 50%, respec-
tively) in the activation of 'contact product-form-
ing activity' when incubated with human platelets
in the presence of adenosine diphosphate (Des-
noyers and Saint-Dizier, 1980).
Ani ma l studies showed decreased levels of fac-
tor V and VIII as well as platelet factor 4 after
adm inistration of gliclazide to rabbits (Hoshiyama
1980). Gliclazide (0.1 to 1.0 mmol/L) markedly in-
hibited the release of factor VIII from washed hu-
Gliclazide: A Preliminary Review
man platelets (Kajikawa et aI., 1978). Similarly a
significant decrease in factor VIII coagulant activ-
ity and factor VIII antigen was found in 10 diabetic
patients given 10 months' treatment with gliclazide
(Paton et aI., 1981), though again some of these
effects may have been due to an effect on blood
glucose levels. Antithrombin III activity remained
normal in 20 diabetics given gliclazide, but showed
a significant decrease in 15 diabetics on gliben-
clam ide (Chan et aI., 1982).
/.3.5 Effect on Fibrinolytic Activity
Vascular plasminogen activator levels are
thought to be decreased in 20% of diabetics. Des-
noyers and Saint-Dizier (1980) found that glicla-
zide 10 mg/kg given orally to rats significantly in-
creased plasminogen activator levels . In diabetic
patients, however, while 6 months' therapy with
gliclazide resulted in a trend towards increased lev-
els, these changes failed to reach statistical signifi-
cance (Chan et aI., 1982). When other oral hypo-
glycaemic agents were tested in the rat preparation,
tolbutamide 250mg, chlorpropamide 100mg and
dimethylbiguanide 500mg all produced apparent
increases in plasminogen activator levels , but again
these changes were not statistically significant
(Desnoyers and Saint Dizier 1980). However, Chan
et al. (1982) found that 6 months of glibenclamide
therapy in 15 diabetic patients significantly de-
creased plasminogen activator levels .
Further animal studies (Arfors and Tangen,
1977) reported a significant increase in primary and
haemostatic plug formation time after single doses
of gliclazide 100 rug/kg, as well as after continuous
dosing of 25 mg/kg for 7 days in rabbits. Almer
(1980) noted a return to normal in the vascular
fibrinolytic activity in 6 diabetics over a 6-month
treatment period with gliclazide, which was still
present at follow-up 4 years later (Almer et aI.,
1983), whilst Paton et al. (1981) monitoring 10 dia-
betics over a 6-month period found no significant
alteration of euglobulinysis nor of any of the other
factors used to assess fibrinolytic activity.
While such studies invite interesting specula-
tion. findings have not been conclusive. Thus, these
observations can only be considered a foundation
310
for further studies involving monitoring of
fibrinolytic activ ity during gliclazide therapy III
diabetics.
1.3.6 Effect on Prostaglandin 12 Formation
As prostaglandin 12 is a potent inhibitor of
platelet functions produced by vessel walls (Higgs
et aI., 1978; Moncada et aI., 1976), it has been pos-
tulated that the restoration of reduced prostaglan-
din 12 formation may prevent the tendency to
thrombus formation and microangiopathy in dia-
betic patients. Gliclazide (100 to 300 /lg/ml) en-
hanced the spontaneous prostaglandin 12 forma-
tion in the aorta of guinea-pigs and rats in vitro. A
similar effect was observed with tolazamide and
acetohexamide, but not with chlorpropamide, tol-
butamide and glibenclamide. In vivo. oral admin-
istration of gliclazide 100 to 300 mg/kg to strep-
tozin-diabetic rats restored the reduced formation
of prostaglandin 12 (Fujitani et aI., 1983).
1.4 Mechanism of Action
Like other hypoglycaemic sulphonylureas, gli-
c1azide appears to act directly on the pancreas to
increase insulin secretion (see section 1.1). There
is some evidence that changes in calcium transport
may be involved in this action. Thus gliclazide, like
other drugs in its class, has been shown to affect
the movement of calcium in isolated pancreatic
islet cells. The stimulant action of gliclazide upon
45Ca net uptake, and subsequent insulin release by
the endocrine pancreas, is inhibited by organic cal-
cium antagonists, e.g. verapamil. Hypoglycaemic
sulphonylureas and organic calcium antagonists also
exert opposite effects upon A23187-ionophore me-
diated calcium translocation in an artificial system.
It is postulated that ionophores located in the {3-
cell plasma membrane represent the target for the
primary action of gliclazide upon calcium trans-
port into islet cells (Malaisse et aI., 1980), and that
the mechanism of action could be related to a fa-
cilitated transport of cations across the cell plasma
membrane (Deleers et al., 1983).
Wh ile there is some evidence suggesting that gli-
clazide ma y also act at extrapancreatic sites (see
Gliclazide: A Preliminary Review 311

section 1.1), further studies are needed to confirm
these prelim inary find ings.
2. Toxicology
2.1 Acute Toxicity Studies
Single-dose toxicity studies revealed a low order
of acute oral toxicity with few adverse effects ap-
parent at dose levels up to 4 g/kg in mice, rats and
dogs. Gliclazide at doses of 30 and 100 rug/kg
intravenously caused a sustained hypertension and
a slight increase in heart rate in cats, whilst urinary
volume and electrolyte excretion (K+ and CI-) were
reduced in rats treated with large doses of glicla-
zide (1000 mg/kg orally) . The median lethal oral
dose in guinea-pigs was 1599 to 2068 mg/kg . Sub-
acute stud ies in dogs revealed a max imum toler-
ated dose of 150 mg/kg orall y and good tolerance
to dose levels up to 100 mg/kg orall y for 3 weeks
(unpublished data on file, Servier) .
2.3 Effects on Reproduction
Pregnant mice and rats given gliclazide at da ily
dose levels up to 500 and 480 mg/kg orall y, re-
specti vely, showed no adverse effects on the course
or outcome of pregnancy. Howe ver , pregnant rab-
bits given doses of 10 to 50 mg/kg orally showed
evidence of maternal and embryo toxic ity but no
teratogen icity. Fetal tissue drug concentratio ns in
the mouse were similar to those in the parental
body mass. Distribution of gliclazide was similar
in pregnant and non-pregnant mice. Postnatal de-
velopment in rats and mice was unaffected by
administration of gliclazide to the dams through-
out the entire gestation period. Gliclazide had no
ad verse effects on fertility, gestation or postnatal
5

2.2 Chronic Toxicity Studies 4

Six months' administration of gliclazide 25, 100

3
or 200 mg/kg orall y to rats revealed no significant
changes in haematological and biological para- E
Oi 2
meters, or in results of urinal ysis. No tissue changes .3
were observed. Female rats appeared more suscep- c
Q
tible to toxicity and showed slight increases in liver ~
C
enzymes together with slight decreases in eryth- Q)
o
c
rocyte counts, haematocrit values and haemoglob- 0
o
8 16 24 32 48
ulin concentrations at dosages of 200 mg/kg and '"
E
VI
higher. Doses up to 100 mg/kg orally for up to 2 '"
C.
3 'Slow'
months failed to produce any signs of toxicity in Q)
"0
'N
guinea-pigs. Similarly, administration of gliclazide '"
:§ 2
at dose levels up to 24 mg/kg orally for 12 months a
or up to 29 mg/kg for 6 months in dogs produced
no evidence of toxicity. 12 months of repeated doses
of 20, 60 and 180 mg/kg orall y in the rhesus mon-
key failed to reveal an y significant toxic effect of
8 16 24 32 48
gliclazide on the clinical condition, bodyweight , and
Time (hours)
food and fluid intake, or du ring detailed laboratory
investigations, ophthalmological examination and
comprehensive histopathological evaluations (un- Fig. 5. Plasma concentration of gliclazide in a 'fast' and 'slow'
publish ed data on file, Servier ; Matsuoka et aI., absorber after administration of 80mg on separate occas ions
1980), [after Campbell et al. 19801.
Gliclazidc: A Preliminary Review 312

mortality in the first generat ion of rats after doses of weight gain was noted with higher doses (Ka-
up to 200 mg/kg orally (unpublished data on file, wanishi et al., 1981 ).
Servier ). Similarly , in a published report even
higher doses (up to 800 mg/kg/day) did not alter 3. Pharmacokinetic Studies
fertility of either male or female rats and rabbits, 3.1 Absorption
or produce fetal abnormalities, although inhibition
Gliclazide has been well absorbed in animal
3.5 studies in several species, consistentl y reaching peak
plasma levels within 2 to 3 hours (Campbell et aI.,
1980; Miyazaki et al., 1983). In a stud y in healthy
3.0
volunteers, 7 subjects attained mean maximum gli-
E clazide plasma concentrations of 3.9 gil within 4
0;
..=, 2.5
hours of an 80mg dose, whilst 6 subjects attained
c
0
a lower peak concentration of 2.8 gil, which was
~ delayed for up to a further 4 hours (Campbell et
C 2.0
Q)
o
c al., 1980) [fig. 5]. However, it is not clear whether
0
o
1.5
this represents different rates of absorption , or
Ql
"0
'N whether it is due to differences in the rates of me-
to
~ tabolism of the drug. In another study in 6 healthy
e;, 1.0
to
subjects, peak plasma concentrations occurred
E within 2 to 4 hours after administration of glicla-
U>
to
1l: 0.5 zide 40mg, although a secondary increase in plasma
concentration occurred in I subject 10 hours after
adm inistration (Kobayashi et aI., 1981; fig. 6).
a 1234 6 10 24
Plasma concentration-time curves for a single dose
E of gliclazide were found to have a sim ilar profile
0;
..=, in health y subjects and diabetic patients , bearing
c
.Q in mind the different doses adm inistered (fig. 6a).
'§ Oral administrat ion of gliclazide 80 rug/da y for 7
C 8
Ql
U
days resulted in a slightly longer time to maximum
C 7
o
o concentration with the last dose administered, to-
6
Q)
"0 gether with an increased maximum plasma con-
'N 5
to centration and area under the curve from 0 to 24
:§ 4
e;, hours (table IV; fig. 6b) [Kobayashi et aI., 1981].
to 3
E Peak plasma levels were significantly lower and
U> 2
to
1l:
occurred significantly later, with overall absorption
1
being decreased by 20% in a group of 5 elderl y fe-
12 4 6 8 12 24 males (mean age 77 years) compared with a group
b Time after admin istration (hours)
of 5 younger females (mean age 26 years) [Forette
et al., 1982].
Fig. 6. (a) Plasma concentration-time curves for gliclazide in 6
heal thy sub jects given a single 40mg dose (after Kobayashi et 3.2 Distribut ion
al., 1981).
(b) Plasma concentration-time curves for 7 diabetic patients who
The volume of distribution of gliclazide in
took a single dose of gliclazide 80mg (e-e). and for the last
dose in 4 patients who were administered gliclazide 80 mg/day healthy and diabetic subjects was 15.9 to 17.4L
for 7 days (0 - 0). (Kobayashi et al., 1981 ), or 20 to 40% of bod y-
Gliclazide: A Preliminary Review 313

Table IV. Some pharmacok inetic parameters for gliclazide after oral administration

Reference Number and type Duration Dose Cp malit Tmax AUCO_24 Vd t Ya,1
of subject of study (I'g/ml) (h) (I'g/ml · h) (h)

Campbell et al. 7 healthy 1 dose 80mg 3.9 4

(1980) ' 6 healthy 1 dose 80mg 2.8 4-8
4 healthy Not 3 mg/kg 36.3% of 10.4
stated bodyweight
23 healthy 3 days 80mg 0.7-4.9
144 diabetic 80mg 0.3-8.2

Kobayashi et al. 12 healthy 1 dose 40mg 2.8 2.8 37.2 17.4L 12.3
(1981) 7 diabetic 7 days. 80mg 6.8 2.3 72 16L 12.6
4/7 diabetic 80mg 7.6 3.0 91.4 15.9L 12.3

Abbreviations: Cp max= maximum plasma concentration; Tma x = time to maximum plasma concentration; AUCO_24 = area under
plasma concentration-time curve from 0 to 24 hours ; Vd = volume of distribution; tv." = elimination half-life .

weight (Campbel1 et al., 1980) [table IV], there being
large intersubject variations. The volume of dis-
tribution was found to increase with age, values of
around 24L being found in elderly patients (Forette
et aI., 1982). These relati vely low values suggest
only limited tissue distribution, which could in part
be explained by the extent of protein binding. In
15 health y volunteers, gliclazide, in common with
other sulphonylureas, was extensively bound (85 to
97%) to plasma protein, but again there was a con-
siderable variability in the extent of binding be-
tween individuals (Campbel1 et aI., 1980). Koba y-
ashi et al. (1981) exam ined the distribution of
gliclazide-bound blood proteins in 2 healthy sub-
jects, and reported that fractionated serum proteins
of macroglobul in (M), "Y-globulin (lgG) , albumin
and smal1 molecular substances contained glicla-
zide at an average of 3.7,0.7,82.3 and 13.2%, re-
spectively, during the 24 hours after administra-
tion.
Benakis and Glasson (1980), using carbonyl 14C_
gliclazide 15 rng/kg and whole bod y autoradio-
graphy in the rat, showed a rapid and high degree
oflocalisation of rad ioacti vity in the liver and kid-
neys. The drug and its metabolites were identified
in 15 organs and tissues such as pancreas, adrenal
glands, lung, intestin e, muscle and skin tissue. Smal1
quantities were found in the brain and eye. Sim ilar
results were found by Miyazaki et al. (1983) after
administrat ion of 3H-gliclazide 10 rug/kg to rats .
3.3 Eliminat ion
3.3.1 Metabolism
Examination of radioactive metabolic products
of gliclazide in urine and plasma after administra-
tion of label1ed drug has led to proposals for the
major metabol ic pathways in man. As with other
sulphonylureas, gliclazide is oxidised to produce
either hydroxylated metabolites or N-oxygenated
compounds, and the corresponding alcohol and
carboxylic acid. Gliclazide is extens ively metab-
olised, less than 20% of the dose being excreted
unchanged in the urine. However, in plasma, gli-
clazide represents over 90% of all drug-related ma-
terial, the most important metabolite (an N-oxy-
genated derivative) being present only to the extent
of I %. Th is metabol ite has not demonstrated an y
hypoglycaemic action but claims have been mad e
that it possesses effects on platelet aggregation and
microthrombi format ion. The othe r metabol ites
seen in urine are only present in trace quantities
(less than 20 ng/m l) in plasma . The extensive pro-
tein bind ing of gliclazide and its lipid solubil ity,
which would inhibit glomerular filtration as well
as enhancing reabsorption offiltered mat erial from
Gliclazide: A Preliminary Review 314

the tubules, might help explain the extreme differ- carbutamide, chlorpropamide and metahexamide
ences between the amounts of gliclazide found in (25 to 50 hours). Mean elimination half-life in-
plasma and urine (Campbell et aI., 1980). creases with age (20.5 hours) in the elderly subject
(Forette et aI., 1982).
3.3.2 Excretion
Studies with 14C-gliclazide in animals and man 3.4 Plasma Concentration and Clinical Effects
have reported 60 to 70% of the dose to be excreted
in the urine and 10 to 20% in the faeces (Campbell A study in healthy volunteers fasted overnight
et aI., 1980; Miyazaki et aI., 1983). Elimination in before being given gliclazide 80mg demonstrated a
human faeces was slower than with other species, maximum reduction in plasma glucose levels (20%)
activity still being present in the 96-hour collection at 2 hours (Campbell et aI., 1980). Glucose con-
period (Campbell et aI., 1980). The extent of pro- centrations returned to control values 4 to 6 hours
tein binding in man would hinder the glomerular after administration, but ingestion of a meal at 4
filtration process, whilst gliclazide lipid solubility hours made analysis of the data more difficult. No
would enhance reabsorption from the tubules. The correlation between percentage drop in glucose and
same value for plasma clearance (13.5 ml/min) was gliclazide plasma concentrations was shown to ex-
found in a group of elderly subjects (mean age 77 ist over the whole 24-hour period , but if only the
years) as in a group of younger subjects (mean age concentrations from 0 to 4 hours were considered
26 years) [Forette et aI., 1982]. then the correlation was significant. There ap-
Rats given 14C-gliclazide 10 mg/kg intraven- peared to be a 'threshold' gliclazide concentration
ously demonstrated a maximum concentration in of 0.25 gIL required for hypoglycaemic action . Sa-
the bile after 2 to 5 hours, and during the 8-hour
monitoring period 20% of the dose was circulating
in the bile (Benakis and Glasson , 1980). Similarly ,
c:
biliary excretion of radioactivity amounted to 40% o
of the dose of 3H-gliclazide 10 mg/kg given to rats ~ 4
C
(Miyazaki et aI., 1983). Since the radioactivity in Q)
o
c: 3
human faeces after administration of labelled drug 8
OJ
is not thought to be due to unchanged drug, it is 'N
't:l
2
postulated that biliary excretion also takes place in :§ '" I
",. - - -
'
man (Campbell et aI., 1980). 0> ~,

",_1 I
EE
en _
"'0> I
I
I
"
' -- --- 80mg
- - - - 40mg
3.3.3 Half-Life 0:: 3 0
4 8 12 16 20 24
Plasma concentrations of gliclazide in healthy Q)

subjects and diabetic patients have been shown to en 110

8::l 100 U p'
0-----0- - - -
----------0 40mg
decline exponentially as a single phase [Campbell 0> 90 ''0 ' 80mg
et aI., 1980; Kobayashi et aI., 1981; Sadayoshi et ~ '680
~ c; 70
al., 1982]. Campbell et al. (1980) reported consid- 0:: .s
60 t Meals
'-'----,r-'----r----'--,--,---,---r-
erable variation in the elimination half-lives (6.1 4 8 12 16 20 24
to 14.3 hours), with healthy male subjects having Time (hours)
a significantly shorter mean half-life (8 hours) com-
pared with females (11 hours). Gliclazide is there-
Fig.7. Relationship between the estimated curve for plasma gli-
fore eliminated in man at an intermediate rate
clazide concentrat ion and plasma glucose concentration in
compared with other sulphonylureas, not as rap- healthy subjects (each plot represents the mean value after
idly as tolbutamide, glibenclamide or tolazamide single-dose oral administration for 3 volunteers) [after Sada-
(half-lives 4 to 9 hours) , but faster than occurs with yoshi et aI., 1982).
Gliclazide: A Preliminary Review
dayoshi et al. (1982) reported a significant 'mirror
image' relationship between glucose blood concen-
trations and plasma concentrations of the drug in
3 healthy volunteers (fig. 7). Similarly, in a pla-
cebo-controlled study, diabetics given gliclazide 40
to 240mg as a single dose and a glucose load of 50g
at time-zero followed by a meal at 4 hours, dem-
onstrated a maximum fall in glucose levels at 2
hours, a positive correlation between gliclazide
plasma and plasma glucose reduction during the
period 0 to 4 hours, and a 'threshold' concentration
of glicJazide for hypoglycaemic activity . But in dia-
betics this minimum effective concentration was
higher (1.5 g/L), possibly reflecting the decreased
sensitivity of the pancreatic tl-cell to respond to
glicJazide stimulation (Campbell et al., 1980).
4. Therapeutic Trials
As with other sulphonylureas, the frequency with
which blood glucose concentrations are well con-
trolled by glicJazide may be influenced by several
factors; for example, the quality of response to pre-
vious oral hypoglycaemic drugs, the duration of the
diabetes, and whether or not patients have been
treated previously. Many trials have documented
patients' previous therapy and the duration of the
diabetes, but few have related these factors to blood
glucose control on gliclazide (Baba et al., 1983; Fu-
kui et al., 1976; Plauchu and Pousset, 1972).
4.1 Open Studies
Many workers have recorded an overall signifi-
cant decrease in blood sugar concentrations during
open trials with glicJazide (Bodansky et al., 1982;
Brogard et al., 1982; Gibson et al., 1982; Iunes et
al., 1983; Lagrue and Riveline, 1980; Lesbre and
Canicave, 1977; Medbak et al., 1980; Mukaino et
al., 1977; Paton et al., 1980; Ponari et al., 1979;
Rubinjoni et al., 1978; Sakamoto et al., 1976; Wai-
ters and McCarthy, 1980). Others, on the basis of
varying criteria, have evaluated gliclazide therapy
as producing 'satisfactory' control of hyperglycae-
mia in 60 to 100% of patients with maturity onset
diabetes mellitus (Cabezas-Cerrato and Fernandez-
315
Cruz, 1975; Canivet, 1972; Fukui et al., 1976; Na-
kayama et al., 1979; Oli, 1980; Sadayoshi et al.,
1982; Strata et al., 1980; Villegas Cinco and Fer-
nando, 1978) [table V]. The dosage of gliclazide in
such studies has ranged from 40 to 320mg daily,
but 80 to 240mg has been sufficient in most
patients. In addition to those studies tabulated,
several others reported a decrease in glycosylated
haemoglobin during treatment with gliclazide
(Gibson et al., 1983; Guillausseau et al., 1983; Jad-
zinski et al., 1983).
In a 6-month study (Charbonnel , 1980) involv-
ing 156 patients who had not been previously
treated with hypoglycaemic agents, both the mean
fasting and postprandial blood sugar levels fell sig-
nificantly 2.05 to 1.17 and 2,48 to 1.43 g/L, re-
spectively). Patients previously treated with sul-
phonylureas (114) and biguanides (29) alone also
experienced significant decreases in fasting and
postprandial blood sugar levels on gliclazide com-
pared with previous therapy, but those previously
taking a combination of sulphonylurea and big-
uanide did not develop a significant improvement
in blood sugar control during gliclazide therapy .
Thus, in this as in other studies (Fukui et al., 1976;
Plauchu and Pousset, 1972), the percentage de-
creases in blood sugar levels were much greater in
the previously untreated patients (43%) when com-
pared with those previously treated with suiphon-
ylureas (9.6%), biguanides (18.4%) or combination
therapy (3.6%). In a large multicentre study (Strata
et aI., 1980) involving patients previously treated
with oral hypoglycaemic agents and in a few cases
with insulin, together with previously untreated
patients, gliclazide was able to establish control of
blood glucose below a level of J.3 g/L (fasting blood
sugar) in 45 to 77% of diabetics.
4.2 Controlled Trials (Table VI)
4.2.1 Gliclazide Compared with Tolbutamide
A 3-month study was conducted by Berber and
Tomk in (1982) on 12 insulin-dependent diabetics ,
6 of whom received glicJazide 160mg daily in ad-
dition to their insulin therapy . Mean fasting blood
sugar levels in the glicJazide group increased slightly
Gliclazidc: A Preliminary Review
from 10 to 11 .2 mmol/L whilst in the insulin-only
group fasting blood sugar decreased from 12 to 7.1
mmol/L, Clearly, gliclazide therapy had no bene-
ficial effect in these insulin-dependent diabetics. In
the same study, 6 maturity onset insulin-inde-
pendent diabetics received gliclazide 160mg daily
and another 6 were given tolbutamide 1.5g daily
for the duration of the trial. Mean fasting blood
sugar levels fell significantly (7.4 to 4.95 mmol/L)
in the tolbutamide group, but the fall in the glicla-
zide group did not reach statistical significance (7.6
to 6.0 mmol/L) ,
4.2.2 G/ic/azide Compared with G/ibenc/amide
Several studies involving comparisons of glicla-
zide therapy with that of glibenclamide found no
significant difference in the quality of blood sugar
control produced by the 2 drugs (table VI). Only
one study (Balabolkin et aI., 1983), reported a sig-
nificantly greater decrease in blood glucose levels
with gliclazide compared with treatment with gli-
benclamide after 2 months' therapy. Fagerberg and
Gamstedt (1980) found no differences in fasting
blood glucose levels or 2-hour postprandial levels
after I, 6 and 12 months of therapy. They con-
cluded that their 16 maturity onset non-insulin-de-
pendent diabetics previously controlled on gliben-
clamide could be equally well controlled with
glicazide in equipotent dosages. Klaff et al. (1979),
studying 10 newly diagnosed maturity onset dia-
betics, reported a significant lowering of postpran-
dial blood glucose levels after both glibenclamide
(12.2 to 9.3 mmol/L) and gliclazide (12.2 to 7.8
mmol/L) were added to their diet, and the differ-
ence between the groups was not significant. The
larger double-blind multicentre trial by Baba et al.
(1983) involving 277 patients also found no sig-
nificant difference in control of fasting blood sugar
levels by both drugs. Gliclazide produced good
control (fasting blood sugar l.l to 1.39 gIL) in 49%
of patients whilst glibenclamide did the same in
51%.
4.2.3 Glic/azide Compared with
Chlorpropamide
In 26.maturity onset diabetics, 3 months' therapy
316
with either gliclazide or chlorpropamide resulted in
significant decreases in mean fasting blood glucose
levels when compared with pretreatment levels.
However, once again the difference in degree of
control effected by the 2 drugs was not significant.
The dosage of chlorpropamide (352 rug/day) was
greater than that of gliclazide (273 mg/day) at all
intervals during the study period. Considering the
percentage reduction of pre-therapy blood glucose
levels, I of the 13 patients on chlorpropamide
achieved a greater than 50% reduction, with 3 in
the range 30 to 50%, while none of the 13 gliclazide
patients achieved greater than 50% reduction, I
showed a response in the range 30 to 50%, and the
majority (9 patients) fell in the 10 to 30% range
(Asmal et aI., 1980) [fig. 8].
When substituted for acetohexamide or chlor-
propamide in 17 patients , gliclazide in daily doses
ranging from 160 to 240mg was shown to produce
a significantly better degree of diabetic control. 64%
of patients achieved a superior degree (reduction
in blood glucose exceeding 2.0 gIL) of control of
fasting blood glucose, with 79% also showing a su-
perior reduction in postprandial blood glucose lev-
els. The efficacy of gliclazide was maintained over
the 9-month study period (unpublished report on
file, Servier).
4.2.4 G/ic/azide Compared with Various Other
Oral Hypoglycaemic Agents
Gliclazide has been found to be both at least as
effective (Cabral et aI., 1982; Regnault, 1980) and
more effective (Kosaka et aI., 1983b) than other
oral hypoglycaemic agents in maintaining blood
sugar control. No significant difference in the
changes in fasting blood sugar was seen between
the patients receiving gliclazide (alone or in com-
bination with a biguanide or insulin) and a 'control
group' (taking another sulphonylurea, alone or in
combination with a biguanide or insulin alone) in
a study of 140 maturity onset diabetics over an 18-
month period (Regnault, 1980) [table VI]. Patients
receiving gliclazide (80 rug/day) over a 2-year pe-
riod had better control offasting blood sugar levels
than a similar group of patients who received other
sulphonylurea therapy over the same period. Con-
Table V. Some open stud ies of gliclaz ide in patients with maturity onset diabetes mellitus o
;:S'
e;-
Reference Number and Dosage Duration Response (% of pat ients) Criteria for response N
0:
type of (mg/day) (months) (fasting blood suga r) !1
excellent good fair poor );>
patients
"tl
Cabezas-Cerrato and 80 3-6 39 40 15 Excelle nt < 1.2 gIL 2
Fernandez Cruz Good < 1.4 gIL 3'
(1975) Poor < 1.5 gIL .,..,::s
Failure > 1.5 gI L (6% of pts) '<
~
Canivet 42 (PT) 80-320 1-8 63 17 20 Good < 1.5 gIL '"-<
iii'
(1972) 9 (NPT) Fair 1.5-2.0 gI L l;:
Poor > 200mg

Fukui et at. 32 40-240 6-12 68 16 16 Good < 1.4 gIL

(1976) Fair 1.4-1.7 gIL
Poor > 1.7 gIL

Nakayama et al. 30 20-240 12-30 63 20 Not stated

(1979)

ali (1980) 21 80-320 9 38 33 9.5 Excellent < 7.2 mmol/L (RBS)

Good 7.2-8.3 mmol/L
Fair 8.3-10 mmol/L

Plauchu and Pousset 23 (PT) 160 Not stated 47 26 21 Not stated

(1972) 9 (NPT) 44 44

Sadayoshi et al. (1982) 41 20-240 12-60 53 24 Not stated

Shaw et al. (1980) 50 (NPT) 80-320 2-22 46 16 18 20 Excellent < 7.5 rnrnolrt, (PPS)
Good < 8.5 mmol/L
Fair < 10 rnmol/t,
Poo r > 10 rnmoljt,

Strata et al. (1980)d 20 (PT): 22 (NPT) 160-240 1-6 45 47 8 Excellent < 1.3 gIL
30 (PT): 1 (NPT) 80-240 Not stated 77 17 6 Good 1.3-1.7 gIL
11 (PT); 21 (NPT) 40-240 6-12 75 9 16 Poor > 1.7 gIL
37 (PT); 16 (NPT) 40-240 32-44 53 42 5
14 (PT): 23 (NPT) 80-240 1-38 67 22 11

Villegas-Cinco and 17 (PT) 80-240 2-3 74 26 Good < 1.1 gIL

Fernando (1978) 34 (NPT) Fair < 1.3 gIL

a Multicentre study. Results shown are from the individual centres .

Abbreviations: PT = prev iously treated ; NPT = not previously treated : RBS = random blood sugar ; PPS = postprandial blood sugar .
I ::
......
Gliclazide: A Preliminary Review 318

trol in both these groups was not as good as that
produced in the group treated by diet alone, but
the severity of diabetes in these patients would have
been much less than in the dru g-treated groups
(Kosaka et aI., 1983b).
4.3 Studies in Patients with Diabetic
Retinopathy
Diabetic retinopathy has a variable natu ral his-
tory. In order to study the evolution oflesion s and
the effects of any therapeutic interventio n, qua n-
titative eva luatio n is important. There are a nu m-
ber of methods available. Photographic grading will
on ly indicate major changes, while poi nt counting
methods are valid and repeatable but time con-
suming . Fluorescein angiograms are most accurate
in early and mild retinopathy, and vitreous fluo-
rescence gives an accurate numerical value .
Treatment of diabetic retinopathy has consisted
of correcting only I of the many factors involved
in its development - that of dist urbed glucose me-
tabolism . Correction of haemobiological abnor-
malities (such as increased blood viscosit y, agglu-
tination of the red cells or formation of platelet
aggregates which constitute intracapillary micro-
thrombi) has yet to be addressed .
Examinati on of serial photographs taken during
the passage of fluorescein thr ough the retina in
normal or pancreatomised dogs revealed a protec-
tive effect of gliclazide (10 rug/kg intravenously)
against capillary obstruction induced by a constant
adenine diphosphate infusion (Duhau lt et aI., 1980).
This finding, together with its already demon-
strated effects on platelets, has led to studies of gli-
clazide in patients with diabetic retinopathy.
Several auth ors (Canivet, 1972; Fuk ui et aI.,
1976; Plauchu and Pousset, 1972) reported no sig-
nificant change in fundoscopic or other examina-
tions of the eye during 'open' treat ment with gli-
clazide, but the period of treatment (maximum of
12 months) was too short to conclude that the drug
had prevented the development or progression of
diabetic retinopathy. A longer open stud y reported
stabilit y in the progress of the disease in 47 of the
60 eyes examined, whilst II of the 13 with reti-

14

12 !:......-:~------ * p < 0.023

~ 10
'0 '""'-..(>-_----u *
E
.sc
Q
8
~
C
Q)
0 4 400
C>
c
0
0
Q)
300 .s
Q)
III III
0 0
0 2 200 -c
:::l
en
0> :::l
t'Cl
E
100 0
n:'"
t'Cl
0 0
-4 -2 0 2 4 6 8 10 12
Time (weeks)

Fig. 8. Mean blood gluco se concentrations during administration 01gliclazi de (e and . ) or chlorprop amide (0 and 0 ) in 26 diabetics
(alter Asmal et al.. 1979).
Gliclazide: A Preliminary Review 319

Table VI. some controlled trials of gliclazide in patients with maturity onset diabetes

Reference Design Number of Drug and dosage" Duration Resultsb

patients (mg/day) (months) (quality of control of
fasting blood sugar)

Glic/azide compared with various other oral hypoglycaemic drugs

Cabral et al. (1982) non-blind G 19 40-160 37 Gliclazide group =
14 Control group 'control" group

Kosaka et al. db G 81 G 80 24 Diet ~G ~5

(1983a.b) 5116 5
78 diet Diet alone

Regnault (1980) db 140 Gliclazide group 18.5 Gliclazide group =

(G. G + B. G + I) 'control' group
'Control' group
(5.5+ B.I)

G/ic/azide compared with tolbutam ide

Berber and Tomkin 6c G 160 + I 3 G <I
(1982) 6c I
6 G 160 + diet
6 T 1.5g + diet T >G

Glic/azide compared with glibenc lamide

Baba et al. (1983) db Gb 131 Gb 2.5-10 6 Gb = G
multicentre G 146 G 40-160

Balabolkin et al. Gb 20 Not stated 6·8 weeks G > Gb

(1983) G 27

Fagerberg and co 16 Gb 2.5-15 6 up to 12 Gb = G

Gamstedt (1980) G 120·400

Klatt et at, (1979) co 10 Gb 5-10 4-6 weeks on Gb = Gd

G 80-240 each drug

Minami et al. (1981) Not stated G 12 G 40-120 36 Gb = G

Gb 13 Gb 2.5-7.5

Gliclazide compared with chlorpropamide

Asmal et al. (1980) 1 month washout 26 G 273 mean 3 G=C
then ra C 352 mean

Unpublished report co 17 G 80·240 5-9 G >C

on file. 5ervier 14 C 250 G >A
3 A 500

a Dosage was adjusted to obtain optimum contro l of blood sugar unless otherwise stated.
b > significantly better control of blood sugar; ~ better control of blood glucose; = equivalent control; < significantly poorer control
of blood sugar.
c Insulin-dependent diabetic patients.
d Postprandial blood sugar.
e Control group were taking other oral hypoglycaemic agents.
Abbreviations: db = double-blind; co = crossover; ra = random allocation; G = gliclazide; B = biguanide; I = insulin; 5 = sulphonylurea;
P = placebo; T = tolbutamide; Gb = glibenclamide; C = chlorpropamide; A = acetohexamide.
Gli clazidc: A Preliminary Review
3
c:
.Q 2
a;
13
x
Q)
c
'iii
o illustrating the difficulties inherent in evaluating
a.
~ the effects of treatment on this condition. Thus,
'"
c the rate of worsening of retinopathy was lower in
§
Before During
gliclazide gliclazide
Fig. 9. Change in urinary protein excretion before and during
therapy with gliclazide 80mg daily in 10 diabetics with pre-ex-
isting constant proteinuria over a 9-month treatment period. The
data points indicate means of all values before treatment and
all values during treatment for each patient (after Jones et aI.,
1980).
nopathy present at entry into the trial did not ex-
perience a deterioration of the disease over the 2.5-
year monitoring period (Lesbre et aI., 1977). Sev-
eral recent controlled studies, some against other
sulphonylureas, using multiple methods of assess-
ment (e.g. retinopathy and fluorescein angio-
graphy) suggest a lesser progression of retinopathy
with gliclazide in the short term (6 months) [Baba
et aI., 1983; Chan et aI., 1982], and medium term
(Cabral et aI., 1982; Charbonnel et aI., 1977; Ko-
saka et al., 1983; Lesbre and Canicave, 1977; Min-
ami et aI., 1981 ; Regnault et aI., 1980). Charbonnel
(1977) reported a significantly lower rate of de-
terioration in the gliclazide group (24%) compared
with a control group receiving other hypoglycaem-
ics (55%), as well as a significantly greater number
of gliclazide patients (43%) showing an impro ve-
ment in the status of their retinopathy compared
320
with the control group (19%), after 18 to 32 months
of therapy . In another small controlled study , ret-
inopathy improved or remained stable in 11/12
patients receiving g1iclazide 80mg daily for a 3-year
period and in 9/13 patients receiving glibenclam-
ide 5mg daily (Minami et aI., 1981).
Kosaka et al. (1983c,d), using 3 methods of
evaluation of diabetic retinopathy in a 2-year
double-blind trial, found that the results of eval-
uation varied with the method employed, further
the gliclazide group (109 assessments) than in a
group receiving other sulphonylureas (177 assess-
ments), or in a group treated with diet alone (120
assessments) when estimated according to the se-
verity of the disease, whereas no difference existed
among the groups when evaluation was by a paired
comparison method. However, the rate of wors-
ening of retinopathy as estimated by ranking of
photofluorographic findings was higher in the gli-
clazide group.
4.4 Stud ies in Patients with Diabetic
Nephropathy
Diabetic nephropathy is a serious disorder car-
rying a high mortality. The earliest clinical indi-
cation is interm ittent proteinuria, which later be-
comes continuous and graduall y increases in
amount. Decline of renal function may not occur
for several years, but once it begins, end-stage renal
failure may occur rapidly. Gliclazide has not yet
been studied widely in renal patients, initial studies
have been in patients with type I diabetes mellitus,
but, since it is extensivel y metabolised and the me-
tabolites have not shown any hypoglycaemic activ -
ity, it may be an appropriate choice if an oral hypo-
glycaemic drug is to be used in diabetic patients
with proteinuria or other early indications of renal
dysfunction.
Mean urinary prote in excretion in 12 diabetics
with pre-existing constant proteinuria was not sig-
nificantly altered during 9 months of treatm ent with
gliclazide 80mg daily (Jones et aI., 1980) [fig. 9].
Gliclazide: A Preliminary Review
Similarly, in 15 patients with pre-existing mild pro-
teinuria « 3g every 24 hours), who received gli-
c1azide 80 to 240mg daily for 24 months, a sig-
nificant reduction in proteinuria occurred (p <
0.0I), whilst in those with higher levels of protein-
uria no significant worsening was observed during
the treatment period (Lagrue and Riveline , 1980).
5. Side Effects
At dosages used in the treatment of maturity
onset diabetes mel1itus, gliclazide is well tolerated
by the majority of patients. The most frequently
reported side effects have been gastrointestinal up-
set, such as abdominal pain, nausea or vomiting,
dizziness, skin reactions , and symptoms of hypo-
glycaemia which in most cases have been the result
of overdosage or inadequate diet rather than an ad-
verse effect of the drug.
Of 727 patients included in studies of metabolic
and haemod ynamic effects (unpublished data on
file, Servier), ad verse effects occurred in 7.6% of
patients. Gastrointestinal disturbances accounted
for 1.7% of adverse effects and necessitated with-
drawal in 5 cases, while skin reactions occurred in
0.7% of patients and required withdrawal in 3 cases.
9 below average were shown to gain weight after 10
8
7
6 in figure 10.
</l 5
E
Ql
4 5.3 Laboratory Test Abnormalities
iii
a.
'0 3
;;;
2
D
E centrations of AST and/or ALT (Asmal et aI., 1980;
:J
Z 1
+20 + 15 + 10 +5 0 -5 - 10 - 15 - 20
Fig. 10. Distribution of percentage change in weight after 1 year
of gliclazide therapy in 50 diabetics (0 = females; • = males)
[after Radic et aI., 1980).
321
5. 1 Hypoglycaemia
Symptoms of hypoglycaemia have been re-
ported by several investigators (Charbonnel, 1980;
Forette, 1977; Lagrue and Riveline, 1980; Masber-
nard and Portal, 1972; Shaw et aI., 1980; Villegas-
Cinco and Fernando , 1978; unpublished data on
file, Servier). Of the 727 patients included in stud-
ies of metabolic and haemodynamic effects (un-
published data on file, Servier), hypoglycaemia or
'apparent hypoglycaemia' occurred in 5.2% (38) of
patients, but in most cases was corrected by dosage
reduction. Only 3 patients required termination of
the drug due to hypoglycaemia.
5.2 Weight Change
Most studies reported no significant overall
change in weight of patients whilst taking g1iclazide
(Asmal et aI., 1980; Baba et aI., 1983; Bodansky et
aI., 1982; King et aI., 1977; Lagrue and Riveline ,
1980; Lesbre and Canicave, 1977; Stephan et aI.,
1980). However, some authors (Almer et aI., 1983;
Charbonnel , 1980; Donnet et aI., 1982; Forette ,
1977; Oli, 1980) have reported a significant weight
loss in obese patients after treatment with g1icla-
zide for periods from 6 months to 4 years. Normal
weight patients did not experience a significant
change in weight (Charbonnel , 1980), whilst those
months of gliclazide therapy (Forette, 1977). The
distribution of percentage change in weight after I
year of gliclazide treatment in 50 diabetics is shown
Apart from I or 2 isolated cases of raised con-
Masbernard and Portal, 1972) no significant alter-
ation of hepatic function has been reported. Blood
urea nitrogen levels have been reported to be both
increased (Villegas-Cinco and Fernando, 1978) and
decreased (unpublished data on file, Servier). Sim-
ilarly, both significant increases and significant de-
creases in eosinophils have been documented as
Gliclazide: A Preliminary Review
well as decreased red and white blood cell counts
in different trials (Baba et al., 1983; unpublished
data on file, Servier). However, the clinical im-
portance of these changes is questionable as they
have not yet been supported by other studies . It is
believed that in some of the studies the haemato-
logical values were distorted on entry into the trial
by subjects with unusually high or low counts, so
the significant changes brought the values to within
the normal range of these subjects. Gliclazide was
shown to have no effect on thyroid function in 15
diabet ic patients given 160mg for 6 months (Tour-
niaire and Orgiazzi, 1980).
6. Drug Interactions
Although drug interactions with gliclazide have
not been systematically studied, many drugs have
been co-administered without the need to alter
therapy (Campbell et al., 1980; Charbonnel, 1980).
As gliclazide is highly protein bound and has a
relatively small volume of distribution, drugs that
displace gliclazide from its binding sites on plasma
protein may temporarily increase the concentra-
tion of unbound drug and theoretically could cause
hypoglycaemia. Therapeutic concentrations of as-
pirin, phenylbutazone, and sulphafurazole (sulfi-
soxazole) displace gliclazide from human plasma
and increase the free drug concentration from 3%
to 5-8%, but other highly bound drugs including
warfarin, chlorthiazide, clofibrate and chlorpro-
pamide do not significantly alter the extent of
binding of gliclazide (Campbell et al., 1980).
Drugs which may inhibit the metabolism of gli-
clazide in the liver could result in hypoglycaemic
episodes as has occurred with other sulphonylureas
administered with drugs such as chloramphenicol,
dicoumarol ,sulphaphenazole, phenylbutazone, oxy-
phenbutazone or clofibrate. As monoamine ox-
idase inhibitors have been shown to stimulate in-
sulin secretion in animals, hypoglycaemia could re-
sult from their concomitant administration with
gliclazide. Aspirin (200 rug/kg orally), phenelzine
(15 mg/kg intramuscularly) and phenylbutazone
(100 rng/kg orally) all prolonged the hypogly-
caemic effect of gliclazide (25 rug/kg), but did not
322
significantly alter the magnitude of the response
when studied in rabbits for 24 hours (unpublished
data on file, Servier). On the other hand , a drug
interaction with imidazole type antifungal drugs
(miconazole, econazole, clotrimazole and ketocon-
azole) was reported with sulphonylureas and gli-
clazide (Niemegeers et al., 1981; Loupi et al., 1982;
Meurice et al., 1983). Intolerance to alcohol may
occur in some sulphonylurea-treated patients. This
effect has been reported in 1 patient taking glicla-
zide (Canivet, 1972).
{j-Adrenoceptor blocking drugs may mask the
signs of hypoglycaemia and possibly inhibit glu-
coneogenesis and may be a problem particularly in
poorly controlled cases. Propranolol (1.0 rug/kg)
promoted the recovery from the lowered blood glu-
cose induced by gliclazide (1.0 mg/kg) in rabbits
(Maekawa et al., 1978a).
Diminution of the hypoglycaemic action of the
drug may occur with the concomitant administra-
tion of thiazide diuretics, corticosteroids and oes-
trogens.
7. Dosage and Administration
Gliclazide, as with other sulphonylurea drugs,
is indicated only in maturity onset stable diabetes,
where dietary modifications fail to control hyper-
glycaemia and glycosuria. Gliclazide is not effec-
tive in insulin-dependent diabetics, and so is not
indicated in juvenile diabetes mellitus.
The recommended dose in newly diagnosed dia-
betics is to begin with 80mg daily with breakfast,
and increase by 40 to 80mg as required in single
or divided dosage to a maximum of 240 rug/day.
However, in therapeutic trials, therapy was often
started at a lower level of 40mg daily, and in some
cases a total daily dose of 320mg (as a single or
twice daily dose) was needed before patients
achieved satisfactory control (see section 3.1). No
significant differences in blood sugar levels, and
quality of blood sugar balance, were seen in 21 dia-
betics given gliclazide either once or twice a day
(Schrub et al., 1972), suggesting that a convenient
once daily dose schedule may be appropriate in at
least some patients .
Gliclazide: A Preliminary Review
Dose titration starting from 80 to l60mg daily,
depending on the severity of the diabetes, is rec-
ommended when substituting gliclazide for other
oral hypoglycaemic agents.
If adequate control of hyperglycaemia is not
achieved with dietary measures and maximum
dosage of gliclazide, the response has been im-
proved in a number of patients by the concomitant
administration of a biguanide. The dosage of the
biguanide should be adjusted gradually until con-
trol is achieved .
8. Place of Gliclazide in Therapy
In open trials, glicazide reduced blood sugar
levels to normal in newly diagnosed patients with
maturity onset diabetes failing to respond to diet-
ary measures alone, and maintained or improved
control in patients previously managed on other
sulphonylureas or biguanides. Gliclazide has been
generally well tolerated, the most frequently re-
ported side effects being gastrointestinal in nature.
Although there were differing reports, and reported
experience in formal studies is limited, most ob-
servers noted that gliclazide did not seem to give
rise to an increase in weight, did not alter renal
function when administered to a small number of
patients with diabetic nephropathy and generally
did not change or in a few cases significantly de-
creased plasma levels of cholesterol, triglycerides
or free fatty acids, thus seemingly avoiding what
can sometimes be undes irable effects with other
hypoglycaemic agents.
Comparative trials, not surprisingly, suggest that
gliclazide likely controls blood glucose levels in ap-
propriately selected patients as effectively as other
oral hypoglycaemic drugs. Thus, particular interest
with gliclazide is related primarily to its effects on
the blood. Some data from animal studies , and
studies in patients with diabetic retinopathy, sug-
gest that the effects of this drug on platelet aggre-
gation and haemostasis may possibly be beneficial,
reversing or at least slowing progression of reti-
nopathy . In the cases where other hypoglycaemic
agents were also tested for these properties they
were generally found to be less active , or in some
323
cases inactive. Quite clearly, any oral hypogly-
caemic drug which could be shown with certainty
to halt or reverse diabetic retinopathy would be a
major advance. However, further evidence is re-
quired to confirm any clinical benefits of the ef-
fects of gliclazide on the blood in the long term,
and to show more clearly whether any such clinical
benefits are unique to gliclazide or also occur with
other oral hypoglycaemic drugs.
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