Diabetes Research and Clinical Practice, 14 (199 1) S2 l-S36

0 1991 Elsevier Science Publishers B.V. 016%8227/91/%03.50 s21

DIABET 00563

The mode of action and clinical pharmacology of gliclazide:

a review
D.B. Campbellt, R. Laviellez and C. Nathan2
Servier Research and Development. Fulmer. Slough, U.K. and ZIRIS. Courbevoie Cedex, France

Summary

Gliclazide is a sulphonylurea drug with an intermediate half-life of around 11 hours. It is extensively

metabolised, and renal clearance accounts for only 4% of total drug clearance. The molecule contains
an azabicyclo-octyl group which confers special properties on the basic sulphonylurea moiety. Gliclazide
stimulates insulin secretion through the /3 cell sulphonylurea receptor, and possibly through a direct effect
on intracellular calcium transport. It specifically improves the abnormal first phase insulin release in type
2 diabetes, and also has an effect on the second phase. This pattern of insulin release is thought to explain
the lower incidence of hypoglycaemic episodes and weight gain compared with some other sulphonylureas.
There is also a reduction in hepatic glucose production and improvement in glucose clearance, without
changes in insulin receptors. This suggests a possible post-receptor effect on insulin action, perhaps by
stimulation of hepatic fructose-2,6_bisphosphatase and muscle glycogen synthase. Gliclazide reduces platelet
adhesion, aggregation and hyperactivity and increases librinolysis. These actions, thought to be independent
of its hypoglycaemic activity, may make gliclazide useful in halting the progression of diabetic micro-
angiopathy.

Key words: Kinetics; Metabolism; First phase insulin response; Sulphonylurea; Diabetic complication; Insulin
receptors; Haemobiology

Introduction agents which will all reduce blood glucose in type

2 diabetes, providing acceptable control with re-
The sulphonamide group of drugs has been remark- latively few side effects. They do not, however,
able in providing a large number of important prevent micro- or macrovascular disease, and con-
therapies, including antibiotics, acetazolamide, thi- sequent blindness, renal failure and atherosclerosis.
azide diuretics, vasodilators and the sulphonylu- With this in mind, researchers in France some 20
reas. Today we have an increasing number of oral years ago decided that there was a need for an
agent which would not only control blood glucose
Correspondence 10: D.B. Campbell, Servier Research and De- effectively, but also reverse or at least retard the
velopment, Fulmer Hall, Windmill Road, Fulmer, Slough SL3 complications of diabetes.
6HH. U.K.
s22

Chemical development sensitive radioimmunoassay exists, but there is

some degree of cross reactivity with metabolites
It has long been known that, in addition to or and other sulphonylureas which precludes its use
because of hyperglycaemia, both type 1 and 2 for detailed pharmacokinetics [9].
diabetic patients develop microangiopathy and ma-
croangiopathy. These are related to hyperaggrega- Healthy volunteers
tion and adhesion of platelets [l], increased fibrin
deposition and reduced plasminogen activator [2]. Absorption
There is also increased blood viscosity [3], lipid More than 80% of an oral dose of gliclazide is
deposition and atherosclerosis. A search was there- absorbed [5] with peak levels occurring after ap-
fore made for hypoglycaemic compounds which proximately 3 to 4 hours (Table l), although a few
also had haemobiological activity, and gliclazide, individuals have a more delayed peak [9] occurring
which contains a novel azabicyclo-octyl ring, was at 8 hours. Maximum plasma levels depend on the
selected as the most promising [4,5]. dose prescribed [lo]; for an 80 mg dose, the levels
are approximately 5 pg ml-r with a range of 1 to
10 r_lg ml-r which can be partly explained by
Physiochemical properties differences in body weight (r = -0.684, P< 0.001).
Bioavailability is approximately 100% from tablets
Gliclazide, 1-(1-azabicyclo[3,3,O]oct-3-yl)-3-@-to- and does not appear to be affected by food or fibre
lysulphonyl)urea, molecular weight 323.4, is a weak or guar gum [ 111. The timing of the food may be
acid with a pKa of 5.8, which has a greater lipid important since administration up to 30 minutes
solubility than, for instance, tolbutamide with a after food reduced peak drug levels [12] though
partition coefficient between buffer (pH 7.4) and not necessarily the therapeutic response [13]. Gli-
chloroform of greater than 1000 and with its clazide is therefore best administered up to 30
heterocycle ring, resembles second generation sul- minutes before meals so that drug and glucose
phonylurea compounds. absorption are in phase [14].

Distribution
Biological assay Gliclazide, like most other sulphonylureas, is highly
bound to albumin in plasma (95% range 85-99%)
The most sensitive, specific assays for gliclazide use [5]; a few drugs can displace gliclazide in vitro [ 151,
high performance liquid chromatography [6-81. A but no such clinically significant interactions have

TABLE I
Pharmacokinetics of gliclazide after a single oral dose to healthy human volunteers

Reference Sex Age Dose T,,, CPrn,, t/z Vd/Fd CL/Fd

(Y) (mg) (h) @g/ml) (h) (1) (ml mint)

Mahajan et al., 1984 [I 171 3F-6M 22+ 1 80 4+1 3.9+ 1.9 10.2+ 3.8 26f7 32+13
Hopkins et al.. 3F-5M 34+13 80 6+2 5.0+ 1.4 8.0+ 1.8 13+4 18+ 4
1975 [I 141
Kobayashi et al.. 1984 [24] 12Mb 36-t 5 40 3-+1 5.61 1.8~ 12.3 + 3.9 17t7 16+ 6
Forette et al.. 1982 [22] 4F 26+ 4 80 4fl 6.3 + 2.6 11.8+0.7 13t5 13+ 6
Oida et al.. 1985 [19] 5Mb 37i 1 40 4d 5.2 * 0.4c 8.1+ 1.1 12d 17d

dApparent oral values assuming complete absorption (F=l); bJapanese subjects - all others are European; ccorrected for an 80
mg dose assuming linearity; dindividual value to calculate standard deviation not given
 S23

been reported. The volume of distribution is ap- Metabolism

proximately 19 1, which is comparable to other
sulphonylureas [16].
Elimination
Plasma concentrations of gliclazide decline with a
terminal half-life of approximately 11 hours (Table
l), which is intermediate compared with other
sulphonylureas [16], allowing once or twice daily
dosing to maintain 24 h blood glucose control [ 171.
Oral plasma clearance is low (around 20 ml min-1)
and is comparable to other sulphonylureas, suggest-
ing little first pass metabolism in man. Coadmi-
nistration of cimetidine with gliclazide [ 171 and
other sulphonylureas [ 181 may lead to hypoglycae-
mia since cimetidine is known to inhibit hepatic
microsomal oxidation.
Excretion
Studies with [iC]gliclazide administered to volun-
teers have shown that the radioactivity is rapidly
and extensively excreted into urine (81% of the
dose) with the remainder being eliminated in faeces
over a 48 h period [5]. The renal clearance of
unchanged total gliclazide is low (0.5 ml min-1) due
to the high protein binding with less than 1% found
in the urine, thus making it possible to use the
drug in renal failure.
Gliclazide is extensively metabolised to at least 8
identified metabolites by three major metabolic
routes: (a) oxidation of the tolyl group to carboxylic
acid; (b) hydroxylation of the azabicyclo-octyl
moiety; and (c) glucuronidation. Metabolism in
Caucasian and Japanese subjects is similar [19].
In contrast to the low urinary levels of unchanged
drug, gliclazide represents more than 90% of the
total radioactivity found in plasma [5,19]. The
difference is due to the higher water solubility of
the metabolites [19]. Trace levels of plasma me-
tabolites have been observed by autoradiography
but none was individually greater than l-2% and
none was found to have hypoglycaemic activity
[20]. In contrast to tolbutamide gliclazide meta-
bolism does not exhibit genetic polymorphism in
debrisoquine phenotyped subjects [21].
Disease and the elderly
Gliclazide is more slowly absorbed in the elderly
(T maxof 6 h) (see Table 2) and plasma levels tend
to be approximately 25% lower whilst the distri-
bution volume is increased to 24 1 and the half-
life to 20 h [22]. The apparent clearance, which
dictates steady state blood concentration, remains

TABLE 2

Pharmacokinetics of gliclazide in the elderly, diabetic and renal patients

Reference Patient Dose Age No. T,,, CP,,, t/: Vd/F* CL/Fd
(Freqjmg) (Y) (h) (h) (L) (ml mini)

Kobayashi et al.. Diabetic S/80 48+10 12 3.0 -t 2.0 4.5k2.2 11.6f5.2 18+8 18+2
1984 [24] (193 mg 100 ml-)a
Campbell, Diabetic/renal s/40 46+16 6 4.0-t 1.0 3.1 kO.8 14.8 * 8.4 29f 18 26f 17
1985 [I 151 (44 +4l ml min-r)c
Campbell, Renal s/40 40+20 II 5.05 1.0 3.1 * 1.0 22.4 t 5.0 30*14 21+ 9
1985 [115] (13*9 ml min-r)C
Forette et al., Elderly S/80 77*4 5 6.0f 1.0 4.0 + 6.0 20.5f4.0 24+ 7 l4+ 3
1982 [22] (7 l-82)b
Kobayashi et al., Diabetic R/80 - 4 3.0t 1.2 7.6 f 2.4 12.3 + 2.6 16& 6~ 14+ 4~
1981 [29] (193 mg 100 ml-r)r

S = single dose; R = repeat dose for 7 days: - = not given; + = standard deviation,
Fasting blood glucose; bage range; Ccreatinine clearance; dapparent oral values assuming complete absorption (F = 1): cafter repeated
dosing - taken from AUC over one dosing interval (O-24 h).
 S24

unchanged at around 15 ml min-1, leading to com- a dose dependent effect of gliclazide on platelets,
parable steady state levels in young (3.3 (*g ml-l) independent of hypoglycaemic activity.
and in elderly subjects (4.5 pug ml-i) [23]. Similarly,
there are no significant differences in the diabetic
subject [24]. In renal disease with or without
diabetes, the volume of distribution and half-life
(approximately 20 h) are increased [25], but the
small change in plasma gliclazide clearance is
unrelated to creatinine clearance [5] and no dosage
changes are necessary. No studies have been un-
dertaken in patients with hepatic disease, but it
can be anticipated that the dosage should be
reduced, as gliclazide is extensively metabolised. I
3 6 9
Blood glucose CCxICentmtlOns (mmol/l )

Kinetic-dynamic relationships

Single dosing 40
(b)
t
Gliclazide causes a dose-dependent fall in blood
zd I
glucose concentration in both volunteers and type
5 30
2 diabetic patients, but peak insulin responses
precede peak drug levels [26], and the two are not i_ \

clearly related. This may be because of feedback

s I
regulation of insulin secretion [27]. a r=- 0.691
10 p<o.o5
t
Repeated dosing
Following repeated administration, gliclazide plas-
Ghclazide plosmo concentrations (pg/ml)
ma concentrations reach steady state after about
3 days dosing with an accumulation ratio of ap- Fig, 1.Relationship between platelet and plasma concentrations
proximately two-fold, but with some intersubject of (a) glucose: (b) gliclazide. Values are mean values from 11
variation ranging from 0.3 to 8 pg ml-i after an type 2 patients taken over a IO-month treatment period at 2
monthly intervals at a dosage of 80-320 mg day-l.
80 mg dose [5]; this appears to be dose [23] and
weight [28] related. None of the kinetic parameters
change significantly after repeated dosing, suggest-
ing no inhibition or induction of kinetics [29]. With Hypoglycaemic activity
repeated dosing, plasma drug levels correlate with
dose, but not with insulin levels [28], glucose Insulin secretion is impaired in type 2 diabetes, and
concentrations [28], HbAi, [30] and body weight there is insulin resistance, particularly in obese
[30]. Gliclazide also reduced platelet retention con- patients. As a result, hepatic glucose production
comitantly with the reduction in blood glucose is increased and peripheral glucose uptake and
making it difficult to dissociate these activities [31]. utilisation are reduced. Ideally, antidiabetic drugs
In a further analysis [32], platelet retention was should improve both P-cell function and insulin
found to be inversely related to plasma gliclazide action. Gliclazide is an effective hypoglycaemic
levels, but was not significantly related to blood agent in experimental models and in patients with
glucose concentrations (see Fig. 1). This suggests type 2 diabetes (see review by Holmes et al [33]).
 S25

Efficacy persists for some years [34,35] and the omised dogs and alloxan diabetic rats [48]. The
incidence of side effects, especially hypoglycaemia insulinotropic action has been confirmed in vivo
[30,36] is low. There is relatively little weight gain, with animal models of type 2 diabetes [49] and
and patients who are dieting can continue to lose in vitro with pancreatic tissue, isolated islets [50]
weight [23,34,37-401. and isolated perfused rat pancreas [51]. There is
Gliclazide ameliorates the defect in first phase a dose-related stimulation of insulin from pancre-
insulin response to intravenous glucose in type 2 atic tissue over therapeutic concentrations of gli-
patients [41,42]. There is a smaller effect on tardive clazide (0.2-20 pg ml-t) in the presence of glucose,
phase secretion, and this may explain a relatively which is characterised by a rapid early peak of
lower incidence of hypoglycaemia and lack of insulin, followed by a slower and sustained secon-
weight gain with gliclazide. dary phase [52]. Sulphonylureas stimulate insulin
release through a specific sulphonylurea receptor
P-cell pancreatic activity on the plasma membrane of the /?-cell which is
closely linked to an adenosine triphosphate sen-
Like all sulphonylureas, gliclazide causes a rapid sitive potassium channel (K+,r,). Although com-
rise in immunoreactive insulin and prolonged de- pounds vary widely in the binding affinities to this
crease in glycaemia following intravenous injection receptor, there is a reasonable correlation between
in dogs [47]. The effect is abolished in pancreatect- binding and clinical dosage [53], Rb+ efflux from

TABLE 3

Effects of gliclazide on insulin receptors and glucose turnover

Reference Patienta No. Dose ,Period Result Condition&

(mg) (months) (%)

Hepatic glucose production D

Ward et al., 1985 [44] OD 6 80-160 3 -81 40 mU kg-t h-1
Bak et al.. 1989 [45] D 9 160-320 2 -43 75 PU ml-t
Wajchenberg et al., 1987 [43]
FBSd > 200 mg dl-t D 5 80-160 3 -86/-47 basal/6 PU ml-r
FBGd < 200 mg dl-t D 4 80-160 3 NC/-28 basal/6 PU ml-1
Lisato et al., 1988 [46] D 8 240 SDc -71 IO PLJ ml-t

Glucose clearance
Ward et al., 1985 [44] D 6 SO-160 3 +33 300 mU kg-1 h-1
Bak et al., 1989 [45] D 9 160-320 2 +50 75 @U ml-1
Johnston et al., 1988 [63] D 20 160 2 +46 100 @U kg- h-t
Ma et al., 1989 [65] D 9 160 4 +31 120 mU rn? min 4.5 mU h-1
Wajchenberg et al., 1987 [43]
FBGd> 200 mg dl-t D 80-160 3 +90 6 PU ml-1
FBGd< 200 mg ml-1 D 80-160 3 +51 6 /IU ml-r
Marchand et al., 1983 [I 161 D 160 2 NC
Lisato et al., 1988 [46] D 240 SDc NC 10 @LJml-1

Insulin binding
Ward et al., 1985 [44] OD 80-160 3 NC RBC, monocytes
Bak et al., 1989 [45] D 160-320 2 NC Solskeletal muscle
Wa.jchenberg et al., 1987 1431 D 80-160 3 NC/-30~ RBC
Marchand et al., 1983 [I 161 D 160 2 NC RBC
-
aD =diabetic; OD =obese diabetic; binsulin levels or infusion rate and human cells (insulin binding): SD = single oral dose;
dFBG = fasting blood glucose; eB,,, affinity only; NC = nonsignificant change, all other values are significant.
S26

(b) Gliclazide

Fig. 2. The action of (a) glucose and (b) gliclazide on insulin secretion from the fl-cell. (a) Glucose is (1) transported into the
cell (2) increasing the ATP/ADP ratio which (3) inhibits the K+ ATP channel by binding to the cytoplastnic side of the membrane.
This depolarises (4) the cell which (5) opens the voltage-dependent channel allowing (6) an increase in cytosolic calcium to (7)
activate insulin release. In addition, (8) glucose may have a direct effect on Ca *+ channels by increasing c-AMP. Finally (g) the
intracellular Cal+ activates the CaJ+ dependent KT channel to repolarise the cell. (b) Gliclazide (1) binds the sulphonylurea receptor
through a lipid matrix and (2) inhibits the K+ ATP channel which (3) depolarises the cell and (4) stimulates intracellular Calf
transport which is (5) translocated within the cell before (6) stimulating insulin microtubules (7). Gliclazide may also have a direct
effect on Ca?+ transport distal to locus of action of channel blockers.

insulinomas [54], and other measures of effect the glucose stimulated cyclic AMP mediated insulin
suggesting that the receptor is at least indirectly release [50].
functional. K+Arr channels have now been found in many
The binding of gliclazide and other sulphonyl- cells of the body, including cardiac muscle [58],
ureas to the receptor on the extracellular surface and they may play a physiological role in protecting
of the P-cell inhibits the efflux of Kf from the cell the cell against ischaemia and cell death by indi-
(Fig. 2). Subsequent depolarization of the cell and rectly stabilising intracellular K+ and calcium levels
change in the membrane potential activates the [59]. This may explain the protective activity of
opening of membrane voltage-dependent calcium gliclazide on cardiac arrhythmias experimentally
channels, allowing extracellular calcium to enter induced in dogs by coronary artery occlusion, since
the P-cell. This increase in free intracellular calcium they would inhibit the loss of K+ from ischaemic
ion acts as a second messenger to induce phos- cardiac muscle [60]. Recently it has been shown
phorylation of proteins which in turn stimulate that gliclazide may also exert an effect on potassium
extracellular insulin release. There is also evidence transport by indirectly inhibiting the Na+, K+-
to suggest that gliclazide may have a primary direct ATPase pump transport mechanism [61]. The im-
action on increasing Caz+ inflow into islet cells, portance of this finding has yet to be determined
in addition to its indirect action through sulpho- [6]. The initial elevation of insulin levels disappears
nylurea K+*rr binding site [55,56]. In addition, it during long term sulphonylurea treatment, but
alters the distribution of calcium within the cells, blood glucose concentrations remain lower. In an
increasing the levels in the cytoplasmic matrix and attempt to explain this apparent paradox, it has
secretory granules [57]. Indeed, temporal differen- been suggested that sulphonylureas also improve
ces in the action of sulphonylureas on intracellular insulin action. This might result from an increase
calcium distribution may explain their different in receptor affinity or number, or improved post-
effects on 1st and 2nd phase insulin secretion. It receptor function, with enhanced glucose uptake,
has also been suggested that gliclazide may enhance storage and metabolism.

Hepatic glucose production
Portal vein insulin concentrations greater than 200
~1 ml-i will suppress hepatic gluconeogenesis and
glucose output [41], and this action is thought to
be important in controlling basal glucose concen-
trations. Sulphonylureas also reduce hepatic glu-
cose production (HGP) to some extent, though
there are apparent differences between them [42].
Gliclazide significantly reduced HGP by an average
of 50% (Table 3) and although this may be greater
than other sulphonylureas, no direct comparisons
have been made. Using [3H]glucose infusions to
measure glucose turnover at both basal and con-
stant steady state insulin levels (6 PU ml-i) Waj-
chenberg et al. [43] found that patients treated with
gliclazide for 3 months showed significant reduc-
tions in HGP particularly in insulin resistant
patients with high initial blood glucose concentra-
tions (fasting glucose > 200 mg dl-I).
Similarly, other workers found large reductions
in HGP [44,45] under euglycaemic clamp condi-
tions when there were no significant increases in
basal or stimulated insulin levels, suggesting a direct
improvement in insulin sensitivity. Lisato et al. [46]
found that, after a single dose of gliclazide, HGP
was reduced by 70% but that this effect was
abolished by inhibiting insulin and C-peptide se-
cretion with somatostatin, implying that the
gliclazide activity was primarily on insulin secre-
tion.
Glucose clearance
In most studies (Table 3), gliclazide significantly
increases peripheral glucose uptake and clearance
by approximately 50% and the effect seems to be
greater in patients with high (> 200 mg dl-1) initial
blood glucose concentrations [43]. In several studies
[43,45,62,63], neither basal nor stimulated insulin
levels increased significantly, although there was
a trend towards higher glucose uptake, leading these
authors to conclude that gliclazide has a direct effect
on insulin resistance. Similarly, Chiasson et al. [64]
were able to compute an increase in insulin sen-
sitivity of more than 100% in healthy volunteers
and by 50% in diabetic patients after a single dose
of 80 mg gliclazide and an IVGTT using a minimal
S27
mathematical model to assess in vivo insulin
resistance. In contrast, Ma et al. [65] found a
significant increase in glucose clearance but in this
case it was accompanied by an increase (+28%)
in insulin levels after 4 months of treatment.
Similarly Cerasi et al. [66] showed that after 6
months treatment, there was no improvement in
insulin efficiency since the ratio of glucose clearance
to endogenous insulin levels remained unaltered.
Interestingly, following a single dose of gliclazide
(240 mg) when insulin levels were initially high,
Lisato et al. [46] found no change in glucose
clearance, in contrast to the results from chronic
studies.
Insulin binding
Gliclazide has not been shown to have a consistent
effect on receptor number or affinity in any of
several different cells including human erythrocy-
tes, monocytes, lymphocytes and skeletal muscle
(see Table 3).
Post-receptor activity
The findings that oxidative insulin sensitive glucose
clearance is significantly increased following gli-
clazide treatment without, in some cases, significant
increases in insulin levels and with no change in
insulin receptors could suggest that there is an
improvement in insulin action [44,67]. If gliclazide
has a direct effect on HGP, it could be due to
its inhibition of gluconeogenesis and enhancement
of glycolysis through stimulation of fructose-2,6-
bisphosphatase 1681, a key enzyme in the control
of glucose synthesis from lactate or pyruvate which
is reduced in the liver of diabetic animals. A post-
receptor action on glucose clearance is supported
by the finding that gliclazide increases the fractional
velocities of muscle glycogen synthase activity stim-
ulated by glucose-6-phosphate in biopsy samples
taken from treated patients, but only when stimu-
lated by insulin [45,63]. This is an important finding
since the activity of glycogen synthase in skeletal
muscle is significantly reduced in obese insulin
resistant [69] and non-obese [70] type 2 diabetic
patients. These changes were achieved with no
increases in post-insulin receptor kinase phospho-
S28

Fig. 3. The haemobiological actions of gliclazide. Gliclazide reduces (1) platelet adhesiveness and the (2) release of platelet factors
(5HT. ADP, PG peroxides). reducing (3) platelet aggregation which would occur due to continual diabetic vascular damage and
interaction with underlying collagen. The reduction in release of platelet factors also reduces (4) vasoconstriction and vascular
permeability allowing (5) more 0, to be transported and reducing the anoxia and (6) reperfusion damage produced by oxygen
free radicals (02-) which are also reduced by gliclazide. The stimulation (7) of tissue plasminogen activator (t-PA) to increase
fibrinolysis also reduces vascular damage, (8) basement membrane thickening with a reduction in the necessity for repair enzyme
NABG and the potential for (9) long term atherosclerosis. (-) Reduces; (f) increases.

rylation activity or alterations in pyruvate dehy- Haemobiological activity

drogenase, hexokinase or glutamate dehydrogenase
[63]. These results may help to explain the sub- Although blood glucose can now be controlled with
stantial increase in glucose clearance observed in some confidence with insulin or oral agents, dia-
these and other studies (Table 3) and the marked betic patients still develop long term micro- and
increase (55%) in glucose storage and stimulated macroangiopathies leading to atherosclerosis, car-
oxidative glycolysis (30%) observed in patients diac disease [73], retinopathy and renal failure.
where indirect calorimetry was undertaken before The regulation of coagulation, thrombus forma-
and 2 months after gliclazide administration [71]. tion and degradation involving platelets, vessel
walls and circulating factors is known to be ab-
Other actions normal in diabetes [74,75]. The platelets are denser,
more active, contain more P-thromboglobulin
Sulphonylureas may reduce the absorption of in- (PTG), and aggregate more extensively in the
gested glucose through the small intestine. Using presence of adenosine diphosphate (ADP), adre-
an isolated in vitro preparation of a complete naline and collagen and there is an increase in
functional intestinal-pancreatic unit from fed rats platelet turnover. Prostacyclin [76] and plasmino-
with intact arterial and venous blood supply, it was gen activator in the vessel walls are reduced in
shown that gliclazide at levels likely to be found diabetes, increasing platelet aggregation and retar-
in the gastrointestinal tract (200 pg ml-r) reduced ding fibrinolysis. The hyperaggregability of plate-
the transport of glucose across the intestinal lumen lets and production of thrombi, particularly in
in either direction. This appeared to be due to an microvessels, block the circulation leading to local
increase in metabolic utilization of glucose by the vasoconstriction, anoxia, oxygen free radical pro-
intestine, without an increased lactate production duction, tissue damage, leakage, regrowth, base-
~721. ment membrane thickening and an eventual focus
for lipid infiltration and deposition, to form athero-
 s29

sclerotic plaques, retinopathy, nephropathy and platelets which are less active [83] and an overall
cardiovascular disease. reduction in platelet density [89]. Gliclazide halves
platelet hyperactivity, apparently by inhibiting the
synthesis and action of thromboxane A2 (TXAz)
Platelet adhesion and aggregation [82,91,92] and increasing the concentration of in-
traplatelet cyclic AMP (Fig. 4).
In both diabetic animals and man, gliclazide has Low cyclic AMP levels are found in hyperactive
been shown to reduce significantly the abnormal platelets and gliclazide has been shown to increase
platelet adhesiveness and subsequent aggregation the formation of intraplatelet cyclic AMP ex vivo
[33,77] (Fig. 3). Thus, intravenous or oral admin- in treated diabetic patients using [jH]adenosine or
istration at doses ranging from 5-100 mg kg-i adenine as precursors [93]. This activity is thought
gliclazide reduced Salzman glass bead retention and to occur by inhibiting glycolysis and maintaining
adhesiveness of platelets in rabbits [78,79] and dogs glycogen levels thereby stimulating adenylate cy-
[78] whilst tolbutamide did not [80]. Similarly, clase activity [93,94], since gliclazide has no inhib-
Duhault et al. [60] found that gliclazide pretreat- itory action on phosphodiesterase. The resulting
ment in dogs reduced the retinal capillary occlusion effect is a demonstrable reduction in the release
caused by carotid injection of ADP to aggregate of platelet factors, such as 5HT, P-glucuronidase,
platelets, whilst tolbutamide was inactive. In many ATP, ADP [95] and factors IV, V and VIII in
clinical studies reviewed by Holmes et al. [33] in animals and factor VIII in man [96], and an
more than 350 patients treated for up to 2 years, inhibiting effect on collagen-stimulated activation
there were significant reductions in platelet adhe- of platelet coagulation factor XI [83]. Despite these
sion with effects comparable to those achieved with effects on platelet function, no consistent changes
high dose aspirin or dipyridamole [8 11. Other more in coagulation or bleeding time have been reported
recent studies [34,82] have confirmed these earlier in the clinical studies where this has been examined.
findings with a reduction in adhesiveness of up to
25% maintained over a 3 year period. Gliclazide
has been shown to reduce platelet aggregation in Free radical activity
animals [79,83] whilst tolbutamide does not; similar
observations were made in diabetic [79] patients Free radicals, particularly the superoxide oxygen
in response to ADP [84-861, adrenaline [87] and free radical, are involved in the disruption of
collagen [85,88]. Similarly, treatment with glicla- cardiovascular homeostasis and are implicated in
zide for periods up to 9 months have reduced the oxygen reperfusion injury, atherosclerosis, EDRF
plasma PTG, an index of platelet hyperaggregation, turnover, and neutrophil phagocytosis. They could
by up to 60% [84,89] and intraplatelet /3TG by therefore contribute to diabetic macrovascular
45% [89]. There is some debate as to whether these disease, particularly since diabetic patients are
platelet effects are merely a consequence of lowering under greater oxidative stress [97], show greater
of blood glucose [31,89] or, as seems more likely, free radical activity [89] and have an impaired
an independent effect of gliclazide [32,87], since antioxidant defence mechanism [8]. Florkowski et
normalisation of blood glucose does reduce flTG al. [82] have shown that, following gliclazide treat-
[90] but apparently not to the same extent as ment, there is a reduction in the platelet aggregation
gliclazide. Other oral hypoglycaemic drugs have a markers of TXB2 and /3TG which coincided with
variable effect on platelet function [85,86,89]. Gli- a reduction in free radical activity as shown by
clazide is specifically taken up by the platelets a lowering of lipid peroxidases by 55% and oxi-
concentrating in the lysosome-like sub-cellular gra- dative proteins by 78%. Subsequently, Scott et al.
nules [88], with a reduction in heavy and meta- [99] found that gliclazide at therapeutic levels of
bolically active platelets and an increase in light 5 1.18 ml-i had a marked free radical scavenging
s30

(a) lb)

PHOSPHOLlPlDS THROMSOXANE A2
I

4
I
ARACHIDONIC ACID
PHOSPHOLIPASE A2 I-, GLICLAZIDE

BOUNDCa- __+
1 FREE&+ __, [m]

CYCLOOXYGENASE I-) ASPIRIN

PROTEIN KINASE

ENDOPEROXIDES

T SYNTHETASE/ \ P SYNTHETASE

THROMBOXANE A2 1
GLICLAZIDE ,+, ,-I D,PR,DAMlJLE

ADENYL CYCLASE FHOSPHODIESTERASE

[GLYCOLYSIS] _, ATP 5 AMP

INCREASES DECREASES
AGGREGATION AGGREGATION

Fig. 4. The action of gliclazide on prostaglandin metabolism in the reduction of platelet adhesion and aggregation. Gliclazide is
thought to act at two sites within the platelet in the arachidonic activation of aggregation by: (a) inhibiting phospholipase Al
thereby reducing platelet thromboxane Al without affecting cell wall prostacyclin; (b) reducing thromboxane A: function by increasing
adenylcyclase activity thereby increasing platelet CAMP, whtch activates the protein kinase induced reduction in free Ca?+ to bound
Caz+ which opposes the thromboxane A2 stimulation of aggregation.

activity in vivo which was not observed with

glibenclamide, and since glibenclamide had no anti-
platelet effect either (Fig. 5) these results imply
a specific effect and a possible link with the an-
tiplatelet activity of gliclazide, perhaps through its
effect on prostaglandin synthesis and activity.
In addition to these effects on platelets gliclazide
was shown to reduce blood and plasma viscosity
significantly at low shear rates (erythrocyte filtra-
tion time), without altering other viscosity para-
meters and before any change in HbA,,, suggesting
a direct effect of the drug, independent of its
hypoglycaemio effect [ 1001. In addition, gliclazide,
at therapeutic concentrations, has been shown to Drug concentration (pg .ml-)
improve red blood cell filterability and deforma-
Fig. 5. The effect of gliclazide and glibenclamide on the
bility which can be abnormal in diabetic patients scavenging of free radicals induced by the photo oxidation of
[loll. This improvement may occur in those pa- o-dianisidine. 8, gliclazide; Cl, glibenclamide. (After Scott et
tients with less severe diabetic complications [ 1021. al. 1990 1991).
 s31

Vascular activity significantly, suggesting that it may be delaying the

onset and activation of basement membrane de-
Gliclazide stimulates endothelial prostacyclin syn- gradation [61]. In animals, gliclazide also has been
thesis in rat aorta in vitro [103] and in treated shown to have a protective effect on atherosclerotic
diabetic animals [104] and increases tissue plasmi- lesions induced by cholesterol diet in the rabbit
nogen activator (t-PA) levels by 20% in animals [ 1091 and type 2 diabetic sand rats [ 1 lo].
[83], unlike other sulphonylureas. Similarly, in type
2 diabetic patients treated with gliclazide, t-PA is
increased towards levels found in normal subjects,
whilst chlorpropamide [105] and tolbutamide [106] Conclusions
were inactive. There was also an increase in pre-
kallikrein, an intrinsic activator of plasminogen and This review has considered the mode of action of
levels of free plasminogen which returned to pre- gliclazide in the light of the present knowledge of
treatment levels after discontinuation of therapy diabetes and its complications. Gliclazide has an
[107]. At least part of this activity is independent intermediate half-life of around 11 h, which allows
of blood glucose control since Gram et al. [106] 24-h control with twice daily dosing, and the
have shown a small but significant improvement reduced peaks and troughs in drug concentration
in the extrinsic t-PA and intrinsic prekallikrein may also avoid the hyperinsulinaemia which occurs
activity of fibrinolysis in type 1 patients with no with the high peaks of the more rapidly eliminated
@-cell function treated with gliclazide for 6 months. sulphonylureas. Gliclazide is of intermediate po-
Others have shown, using a i2sI-label, that the tency in stimulating insulin secretion, and this might
alterations in the network of fibrin fibres in clotted avoid overstimulation of the failing P-cell whilst
plasma induced by diabetes and hyperglycaemia maintaining good control. This could explain the
are counteracted by gliclazide but not by gliben- lower incidence of secondary failure on gliclazide
clamide and that the fibrin networks which were (7%) compared with the more potent glipizide
developed in the presence of gliclazide lysed more (26%) and glyburide (18%) reported by Harrower
quickly than controls [ 1081. [ 1111. Other mechanisms, such as a greater reduc-
Microangiopathy results in vascular damage and tion in HGP, might also explain this observation
increased vascular permeability, as shown by small [ 1121.
vessel leakage in diabetic retinopathy. In experi- Gliclazide stimulates insulin secretion via the
mental alloxan treated rats, where permeability is sulphonylurea receptor, but might have additional
increased by 30% due to their diabetic state, gli- actions on calcium movement within the cell which
clazide restored the capillary permeability after 2 may help to explain why gliclazide avoids hyper-
weeks treatment, whereas tolbutamide was inactive insulinaemia by rendering the diabetic pattern of
[60]. Similarly only gliclazide normalised the adren- insulin release, particularly the first phase of insulin
aline threshold in diabetic rats, thereby reducing secretion more nearly normal, and by allowing
the raised index of vasoconstriction observed in insulin to return to pretreatment levels with chronic
these diabetic animals [60]. The lysosomal enzyme treatment. Certainly, the avoidance of hyperinsu-
N-acetyl-P-glucosamidase (NABG), which controls linaemia due to this more physiological action must
arterial smooth muscle proliferation and regrowth be advantageous, particularly with regard to the
of membrane glycoprotein and mucopolysaccha- occurence of severe hypoglycaemia, obesity, lipid
rides after vascular damage, is higher in diabetic abnormalities, atherosclerosis and hypertension, all
subjects compared to normals, particularly those of which are features of Syndrome X [ 1131.
who are uncontrolled and have microvascular com- It is still not clear how sulphonylureas reduce
plications. Gliclazide in 82 diabetic patients treated HGP or increase glucose clearance, since peripheral
for 6 months has been shown to reduce NABG insulin concentration returns towards normal du-
S32

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