Review Article

Drugs37: 58-72 (1989)

0012-6667/89/0001-0058/$07.50/0
© ADIS Press Limited
All rights reserved.

Sulphonylurea Antidiabetic Drugs

An Update of Their Clinical Pharmacology and Rational
Therapeutic Use

Arne Melander, Per-Olof Bitzen, Ole Faber and Leif Groop

Division of Clinical Pharmacology, Department of Research in Primary Health Care ,
Lund University Health Sciences Centre, Dalby , Sweden ; Department of Community
Health, Lund University Health Sciences Centre, Dalby, Sweden; Department of
Medicine, Hersholm Hospital, Hersholm, Denmark; and Fourth Department of
Medicine, Helsinki University Hospital, Helsinki, Finland

Contents Summary 59
I. Clinical Pharmacology ; 60
1.1 Chemistry and Mechanism of Action of Sulphonylureas 60
1.2 Additional Effects of Sulphonylureas 61
1.2.1 Increased Insulin Action 61
1.2.2 Reduced Hepatic Extraction of Insulin 61
1.2.3 Effects on Plasma Lipids 61
1.2.4 Effects on Platelets and Fibrinolysis 61
1.2.5 Effect on Basement Membranes 62
1.3 Pharmacological and Pharrriacokinetic Differences amongSulphonylureas 62
1.3.1 Potencies 62
1.3.2 Onset and Duration of Action 62
2. Indication for Sulphonylurea Use 63
3. Treatment of NIDDM 63
3.1 Therapeutic Aims in the Treatment of NIDDM 63
3.1.1 Normalisation of Blood Glucose 63
3.1.2 Improved Acute Insulin Release 63
3.1.3 Improved Insulin Action 64
3.1.4 Breaking the Vicious Circle of Hyperglycaemia 64
3.2 The Role of Sulphonylureas in Reducing Cardiovascular Morbidity and Mortality .64
3.3 Screening and Early Intervention 65
3.4 Efficacy of Diet Regulation and Sulphonylurea Use in Early NIDDM 65
3.5 Clinical Comparisons Between Sulphonylureas 65
3.6 B Cell Desensitisation by Continuous Exposure to Sulphonylureas 66
3.7 Primary and Secondary Treatment Failures of Sulphonylureas 66
4. Adverse Effects of Sulphonylureas 66
4.1 Long Lasting Hypoglycaemia 67
4.1.1 Chlorpropamide 67
4.1.2 Glibenclamide 67
5. Selection of a Sulphonylurea 68
6. Sulphonylurea Dosage 68
6.1 Optimal Dosage and Time of Administration 68
Clinical Pharmacology of Sulphonylureas 59

6.2 Number of Daily Doses 68

7. Drug Interactions 68
8. Conclusions 69

Summary Apartfrom the amelioration ofsymptoms, a majoraim ofthe treatment ofnon-insulin-

dependent diabetes mellitus (NIDDM, type 2 diabetes) should be the prevention of car-
diovascular complications. These are associated with the chronic hyperglycaemia that is
characteristic of NIDDM, and the risk of complications is already increased in subjects
with impaired glucose tolerance (IGT). For these reasons, and because hyperglycaemia
appears to be a self-perpetuating condition, treatment should be introduced as early as
possible and should be aimed at normalisation ofbloodglucose. To enable earlydetection
and intervention, screening is necessary. As diet regulation alone rarely suffices to nor-
malise bloodglucose, addition of sulphonylurea drugs is indicated in many cases. If in-
troduced in the IGT phase, sulphonylureas drugs combinedwith diet regulation may post-
pone the development of IGT to manifest NIDDM, and may reduce the increased risk of
cardiovascular morbidity and mortality.
Sulphonylureas stimulate insulin release, possibly via interaction with receptors in the
pancreatic B cells. In addition, such treatment enhances the reduced insulin action. This
might be a primary effect but is also a consequence ofthe increased access to insulin and
the subsequent reduction of hyperglycaemia. Sulphonylureas may enhance insulin avail-
ability by reducing insulin clearance. Effects on bloodlipids are probably secondary phe-
nomena.
Fast and short acting sulphonylureas may improve the impaired meal-induced acute
insulin release. If combined with weight-reducing diet regulation and introduced early,
such treatment can maintain (near) normal bloodglucose levels and an improved insulin
actionfor several years without increasing basal insulin secretion, without chronic hyper-
insulinaemia, and without weight increase. If not combined with diet regulation, sul-
phonylurea therapy is likely to fail. If introduced when NIDDM is advanced, the efficacy
ofthesedrugs is limited, withsecondary failures developing at a rateof 5 to /0% peryear.
Continuous (24-hour-a-day) exposure to drug treatment could possibly desensitise the B
cell to sulphonylurea stimulation.
'Second-generation 'sulphonylurea drugs have a higherpotency than 'first-generation '
drugs, but this need not signify a greater clinical efficacy. The effect of several of these
drugs may be increased if they are ingested half an hour before meal(s). Short acting
sulphonylureas may be saferthan long acting ones, which seem more likely to causelong
lastingandfatal hypoglycaemia, at least in elderly patients. Hypoglycaemia may be aug-
mented by the concomitant use ofalcohol, aspirin, sulphonamides and trimethoprim, and
by intercurrent illness with decreased caloric intake. Thiazides and s-blockers may coun-
teract the efficacy of sulphonylurea drugs.

Non-insulin-dependent diabetes mellitus cose. In addition, the action of insulin is reduced

(NIDDM, type 2 diabetes) is a condition charac-
terised by chronic hyperglycaemia and a relative
insulin deficiency. The kinetics of insulin secretion
are changed, with reduced or absent acute insulin
release in response to stimulation by meals or glu-
(DeFronzo et al. 1983).
In more than 75% of NIDDM patients the dis-
ease is diagnosed after the age of 40. The majority
of patients are overweight, and diet regulation with
weight reduction is necessary in most. As this rarely
Clinical Pharmacology of Sulphonylureas 60

leads to euglycaemia, the addition of sulphonyl-
urea drugs is indicated in many patients.
1. Clinical Pharmacology
l.l Chemistry and Mechan ism of Action of
Sulphonylureas
By definition, sulphonylureas share the same
structure (fig. I), and have a common mechanism
of action, leading to blood glucose reduction by re-
lease of insulin from the pancreatic B cells (Jack-
son & Bressler 1981). It is possible that this in-
volves binding to, and activation of, receptors on
the B cell surface; sulphonylureas might mimic the
action of some gastrointestinal peptide with insu-
lin-releasing properties (Brown & Foubister 1984;
Geisen et al. 1985;Siconolfi-Baez& Lebovitz 1985).
Therapy with sulphonylureas may also improve in-
sulin secretion secondarily, as reduction of hyper-
glycaemia improves B cell function (Ferner et al.
1988; section 3.1.4).
In the 'first-generation' sulphonylureas, such as
tolbutamide and chlorpropamide (fig. 1), R, is a
phenyl ring with simple substituent groups and R 2

R,-S02NHCNH-R2
II
0
A, R2

°llJ
Compound R, R2 Compound

Carbutamide -CH2CH2CH2CH3 Glibornuride CH3 0

NH2 0

Tolbutamide CH3 0
-CH2CHzCHzCH3 Gliclazide CH3 0 -(])
Chlorpropamide
ClO
-CHzCHzCH3 Glibenclamide 9H ZCHZ O
NH
I
C=O
- -0
Acetohexamide
g -
CH3 - C O
-0 (rG"'
CI ~

Tolazarnide CH3 0
-0 Glipizlde fH zCHZ O
NH
-0
-{)
I
C= O

~N
Glisoxepide yH ZCHZ O
NH
I
C=O
I
N~
CH3
\(\
CH(' <, O/

Fig. 1. Chemical structur es of sulphonylureas,

Clinical Pharmacology of Sulphon ylureas
is .an aliphatic side chain. In the 'second genera-
tion' drugs, for example glibenclamide(glyburide)
and glipizide (fig. 1), R 1 is a more complex radical
and R z is a cyclohexyl group instead of the ali-
phatic side chain. These substitutions have given
the newer sulphonylureas drugs a much higher se-
lective binding capacity to the B cells (Siconolfi-
Baez & Lebovitz 1985), and this might explain why
the newer agents have a 1000-fold higher potency
than the older ones (Melander 1987).
1.2 Additional Effects of Sulphonylureas
1.2.1 Increased InsulinAction
Sulphonylurea therapy is associated with an in-
creased tissue sensitivity to insulin (improved in-
sulin action) [Beck-Nielsen et al. 1979; Feldman &
Lebovitz 1969; Greenfield et al. 1982a; Kolterman
& .Olefsky 1984; Lebovitz et al. 1977; Simonson et
al. 1984; Ward et al. 1985]. This may be a primary
effect, but it is also a consequence of the increased
access to insulin and the ensuing reduction of
hyperglycaemia following the increased exposure
to insulin (see section 3.1.3).
1.2.2 Reduced Hepatic Extraction of Insulin
Recent studies suggest that sulphonylureas may
promote an increased systemic availability of in-
sulin due to reduced hepatic extraction of the in-
sulin secreted from the pancreas. So far, evidence
suggestive of reduced hepatic extraction of insulin
has been demonstrated only for glipizide (Almer et
al, 1982; Groop et al. 1987a, 1988; Scheen et al.
1984) and glibenclamide (Beck-Nielsen et al. 1986).
This could be either a primary or a secondary ef-
fect, dependent on the increased rate of insulin se-
cretion (Shapiro et al. 1987). Even effective diet
regulation seems to reduce hepatic insulin extrac-
tion; hence the effect may also be a consequence
of glucose reduction and improved insulin action
in the liver (Bitzen et aI., unpublished data).
1.2.3 Effects on Plasma Lipids
Untreated NIDDM is characterised by low con-
centrations of high density lipoprotein (HDL)-
cholesterol, hypertriglyceridaemia and elevated
61
concentrations of very low density lipoprotein
(VLDL), while the concentration of low density
lipoprotein (LDL)-cholesterol is usually normal
(Greenfield et al. 1982b; Howard et al. 1978; Tas-
kinen et al, 1982; Taylor et al. 1981).
There are controversial data on the effect of sul-
phonylureas on plasma lipids. In several cross-sec-
tional studies , treatment with sulphonylureas has
been associated with low HDL-cholesterol concen-
trations (Berry & Bar-On 1981; Calvert et al. 1978;
Eder 1980; Kennedy et al. 1978; Lisch & Sailer
1981), but this may be related to inadequate blood
glucose control rather than to a direct drug effect.
Results from prospective studies are inconsistent:
sulphonylurea drugs have been reported to in-
crease (Paisey et al. 1978), to decrease (Tarnai et
al. 1981), and to have no effect on (Greenfield et
al. 1982b; Taylor et al, 1982) plasma HDL-chol-
esterol. Lowering of the plasma glucose concentra-
tion is usually associated with a lowering of the
triglyceride concentration. It should also be noted
that there is an inverse relationship between plasma
triglyceride and plasma HDL-cholesterol concen-
trations. In addition, the plasma insulin concen-
tration shows an inverse correlation with the plasma
HDL-cholesterol concentration (Groop et al.
1987a). Thus, if the plasma insulin concentration
is raised by treatment, the HDL-cholesterol con-
centration tends to fall.
In a Hl-year study conducted in subjects with
impaired glucose tolerance (IGT), tolbutamide-
treated subjects had a reduction of total serum tri-
glycerides and cholesterol (Sartor et al. 1980b).
Direct effects of sulphonylureas on plasma lip-
ids are unlikely; in NIDDM subjects whose insulin
secretion had been attenuated and who had been
maintained on exogenous insulin , glipizide had no
influence on plasma lipids in a double-blind pla-
cebo-controlled study (Sartor et al, 1987).
1.2.4 Effects on Platelets and Fibrinolysis
Several reports suggest that sulphonylureas, and
particularly gliclazide, may reduce platelet adhe-
siveness and platelet aggregation (Holmes et al,
1984). However, it is likely that the antiplatelet ef-
fects are secondary to the blood glucose reduction
Clinical Pharmacology of Sulphonylureas
evoked by such drugs, and there is no convincing
evidence that gliclazide is superior to any other sul-
phonylurea with regard to . antiplatelet effects
(Holmes et at. 1984; King et at. 1977).
Glipizide and gliclazide may be able to increase
the fibrinolytic activity , whereas chlorpropamide is
associated with low fibrinolytic activity (Almer
1980).
1.2.5 Effect on Basement Membranes
In subjects with .chemical diabetes (impaired
glucose tolerance), glipizide reportedly reversed the
increase in basement membrane thickness that may
be a sign of diabet ic microangiopathy (Camerini-
Davalos et at. 1983). The relevance of this finding
has been discussed and debated previously (Johan-
sen 1983; Mizroch 1983; Siperstein 1983).
1.3 Pharmacological and Pharmacokinetic
Differences among Sulphonylureas
1.3.1 Potencies
While sulphonylureas appear to have 'Similar
principal pharmacodynamic properties, their
clinical effects may differ due to variations in
chemical structure, causing dissimilarities in selec-
tive B cell binding and thus in potency. Tolbut-
amide and chlorpropamide appear to be active only
when their plasma concentrations exceed 50 to 100
Ilmol/L (Melander 1987), and acetohexamide and
tolazamide seem to have a potency in the same
range (Ferner & Chaplin 1987; Jackson & Bressler
1981). Glibenclamide, glipizide and presumably
glisoxepide are much more potent , being active at
concentrations of 50 to 100 nmol/L (Melander
1987). Gliquidone, glibornuride and gliclazide are
intermediate in potency (Ferner & Chaplin 1987;
Jackson & Bressler 1981). The 1000:1 potency ratio
between the least and the most potent sulpho-
nylureas parallels the difference in selec~ive bind-
ing to B cells (Melander 1987; Siconolfi-Baez & Le-
bovitz 1985). However, it must be emphasised that
the .diversity in potency does not signify a corre-
sponding difference in clinical efficacy (section 3.5).
62
1.3.2 Onset and Duration ofAction
The structural alterations among the various
sulphonylurea drugs also cause differences in phar-
macokinetics , i.e. in the rate and degree of absorp-
tion, and in the rate and extent of distribution, me-
tabolism and excretion. These differences in turn
lead to clinically relevant variations in the rate of
onset and in the duration of action. The rate of
onset is significant since it relates to the capacity
to improve acute insulin release (see sections 3.1.2,
3.4 and 3.6). The duration of action is particularly
important as it may influence the probability of
certain adverse effects (see sections 4 and 4.1) and
also relates to the issue of discontinuous sul-
phonylurea exposure (see sections 3.4 and 3.6). It
may be noted in this context that certain individ-
uals have a much slower absorption of sulphonyl-
urea drugs than do other patients, as shown for
gliclazide, glipizide and glibenclamide (Campbell
et al. 1980; Hartling et at. 1987b; Ikegawi et at.
1986).
The most fast and short acting sulphonylurea
presently available is glipizide, which also has
complete absorption (Wahlin-Boll et at. I982a).
Chlorpropamide is the most slow and long acting
one (Jackson & Bressler 1981; Melander 1987).
Glibenclamide is slower in onset than glipizide,
partly because it is more slowly and incompletely
absorbed , at least. from the non-micronised form-
ulation that is the only available one in North and
South America, Asia and some other areas (Arn-
qvist et at. 1983). However, glibenc1amide is slower
in onset even when these 2 drugs are infused at
equal rates and at similar plasma concentrations
(Groop et at. 1987b), and it also has a slower onset
and a longer duration than glipizide in the perfused
isolated rat pancreas (Artini et at. 1973).
The longer duration of glibenclamide may also
be due partly to a longer elimination half-life, al-
though there are highly divergent reports on this
parameter, from less than 2 hours (Jackson & Bres-
sler 1981) to 25 hours (Behrle 1980). Another pos-
sible hypothesis, which has not been examined,
suggests a slower distribution, and a third option
is accumulation of a polar, active metabolite (Behrle
1980).
Clinical Pharmacology of Sulphonylureas
Finally , there is evidence that glibenclamide, in
contrast to other sulphonylureas, may accumulate
within B cells (Hellman et al. 1984). Irrespective
of the mechanism(s) involved, glibenclamide ap-
pears long acting. A comprehensive review of the
kinetic-dynamic relationships of the various drugs
has recently been published (Ferner & Chaplin
1987).
2. Indication for Sulphonylurea Use
The exclusive indication for sulphonylurea
treatment is NIDDM, and these agents are effec-
tive only in NIDDM subjects with a.certain degree
of insulin secretion. By measuring the B cell secre-
tory capacity, it is possible to identify those patients
whose B cell impairment is so advanced that sul-
phonylurea treatment will not succeed (Hartling et
al. 1987a). The most widely applied test is based
on measurement of the C-peptide increase in re-
sponse to intravenous glucagon (Hartling et al.
1987a; Madsbad et al. 1981).
In recent years, combination therapy with sul-
phonylureas and insulin has been extensively tested,
mainly in NIDDM patients with residual B cell
function. In general, glycaemic control has been the
same irrespective of whether a sulphonylurea drug
has been added; the only difference has been that
those receiving sulphonylurea required a lower in-
sulin dose (Gerich 1985; Groop et al. 1984; Ha-
melbeck et al. 1982). No effect of sulphonylureas
has been recorded in insulin-dependent diabetes
mellitus (IDDM) subjects (Grunberger et al. 1982)
or in NIDDM subjects with attenuated insulin se-
cretion (Sartor et al. 1987). However, this need not
signify that combination therapy is useless in sub-
jects with residual insulin secretion; the comb ina -
tion of insulin at night and a sulphonylurea in the
daytime may be of value.
3. Treatment of NIDDM
3.1 Therapeutic Aims in the Treatment of
NIDDM
3.1.1 Normalisation of Blood Glucose
Apart from alleviating subjective symptoms, a
major aim of treatment should be the prevention
or minimisation of complications. These are at least
63
partially related to the chronic hyperglycaemia, and
the risk of cardiovascular complications is already
increased in early NIDDM and even in the pre-
NIDDM or borderline phase (Donahue et al. 1987;
Fuller et al. 1980; Jarrett et al. 1982; Persson 1977).
Therefore, and because hyperglycaemia seems to
be a self-perpetuating condition (Unger & Grundy
1985), treatment should be introduced as early as
possible, and should be aimed at normalisation of
blood glucose (Holman & Turner 1977; Kilo 1985).
To enable early intervention, screening or case
finding programmes must be employed (Bitzen &
Schersten 1986). Although hypocaloric diet regu-
lation can be very effective in reducing fasting blood
glucose (Bitzen et al. 1988a; Liu et al. 1985)it rarely
suffices to maintain euglycaemia (Bitzen et al.
1988a; Gerich 1985; Hadden et al. 1986; UK
Prospective Study 1983). Therefore, sulphonylu-
reas must be added to therapy in many patients
(see section 3.4). Indeed, if introduced in the IGT
phase, a sulphonylurea drug in combination with ,
diet restriction may postpone the development of
IGT to manifest NIDDM (Sartor et al. 1980b), may
reduce cardiovascular morbidity (Persson 1977)and
may even lessen the increased risk of cardiovas-
cular mortality (Knowler et al. 1987) [see section
3.2].
3.1.2 Improved Acute Insulin Release
An early defect in IGTINIDDM is the delayed
and reduced acute insulin release in response to
meals or glucose, which helps to explain the pro-
longed elevation of postprandial glucose and the
subsequent hyperinsulinaemia (Cerasi et al . 1973;
DeFronzo et al. 1983; Luft et al. 1981; O'Rahilly
et al. 1986; Turtle 1970). Although diet regulation
is able to improve the acute insulin release under
strict, short term conditions (Savage et al. 1979),
little or no such improvement may be achieved
even by intense diet regulation efforts in outpatient
care (Bitzen et al. 1988a). In the latter situation,
however, fast acting sulphonylureas can improve
the acute insulin release and postprandial glucose
control (Bitzen et al. 1988b). This also supports the
view that diet regulation and sulphonylurea use are
complementary rather than alternative treatments.
Clinical Pharmacology of Sulphonylureas
3.1.3 Improved Insulin Action
Reduced insulin action is another early defect
in IGT/NIDDM. Strict diet regulation, leading to
significant weight reduction , improves insulin ac-
tion considerably (Beck-Nielsen et al. 1980; Bitzen
et al. 1988a; Henry et al. 1986; Liu et al. 1985;
Savage et al. 1979), and sulphonylurea treatment
also improves insulin action (Beck-Nielsen et al.
1979; DeFronzo et al. 1983; Feldman & Lebovitz
1969; Greenfield et al. 1982a; Lebovitz et al. 1977;
Liu et al. 1985; Mandarino & Gerich 1984; Si-
monson et al. 1984; Ward et al. 1985). Insulin ac-
tion is improved both in the liver and in extra-
hepatic tissues, probably as a result ofa postreceptor
effect (Mandarino & Gerich 1984; Simonson et al.
1984).
Recent in vitro studies indicate that sulphonyl-
urea drugs can enhance insulin action by a direct
effect (Neufeld et al. 1987;Rogers et al. 1987; Wang
et al. 1987). However, improved insulin action
during therapy has only been observed in NIDDM
patients with residual B cell function; no such ef-
fect occurs in NIDDM patients whose insulin se-
cretion has been attenuated (Sartor et al. 1987), or
in IDDM patients (Grunberger et al. 1982). There-
fore it is most likely that the improvement in in-
sulin action seen in NIDDM patients with residual
B cell function is a consequence of the enhanced
access to insulin, and the subsequent reduction of
hyperglycaemia.
3.1.4 Breaking the Vicious Circle of
Hyperglycaemia
There is reason to assume that hyperglycaemia,
albeit with varying intensity and rate, is a self-per-
petuating condition leading to a vicious circle un-
less firm therapeutic measures are taken (Unger &
Grundy 1985). Elevation of blood glucose impairs
both the rate and extent of insulin secretion (Luft
et al. 1981; Reaven 1980), and also impairs insulin
action (Luft et al. 1981;Olefsky et al. 1985; Reaven
1980). This further signifies that impaired B cell
function leads to impaired insulin action and vice
versa. Thus, it may be a purely academic issue
whether the primary defect in NIDDM is impaired
insulin secretion or impaired insulin action; they
64
reciprocally promote and aggravate each other and
hence establish a vicious circle. Conversely, reduc-
tion of hyperglycaemia improves both B cell func-
tion (Ferner et al. 1988) and insulin action, irre-
spective of the type of treatment (see section 3.1.3).
This is a strong argument in favour of early inter-
vention, with complete normalisation of blood glu-
cose as a major therapeutic aim.
3.2 The Role of Sulphonylureas in Reducing
Cardiovascular Morbidity and Mortality
The University Group Diabetes Program
(UGDP) study caused an intense debate concern-
ing the efficacyand toxicity of sulphonylureas. The
UGDP report maintained that the long term effi-
cacy of sulphonylureas (tolbutamide) was negligi-
ble whereas the risk of cardiovascular mortality was
increased (University Group Diabetes Program
1970). However, this report has been criticised
(Fuller 1983; Karam et al. 1975; Kilo et al. 1980;
Williamson & Kilo 1979), and re-evaluations sug-
gest that the increased incidence of cardiovascular
mortality need not have been due to the drug; it
may have been caused by over-representation of
high risk patients in the tolbutamide group (Wil-
liamson & Kilo 1979). Alternatively, tolbutamide
may exert a hazardous effect in patients with ad-
vanced NIDDM, whereas this drug seems to have
a beneficial potential in early and pre-NIDDM, as
outlined below.
Treatment of IGT subjects for 10 to 12 years
with a combination of diet advice and tolbutamide
appeared to postpone the development ofNIDDM
(Sartor et al. 1980b). In addition, the increased risk
of cardiovascular morbidity was considerably re-
duced by the combination of diet advice and tol-
butamide (Persson 1977), and this was associated
with reduced blood pressure and reduced blood
lipids (Sartor et al. 1980b). Furthermore, the rate
of both total and cardiovascular mortality was re-
duced in the tolbutamide group according to a pre-
liminary study (Knowler et al. 1987). Although
these observations need confirmation, they em-
phasise the importance of early detection and treat-
ment of NIDDM.
Clinical Pharmacology of Sulphonylureas
3.3 Screening and Early Intervention
The findings described above support the view
that sulphonylurea therapy is beneficial rather than
harmful. However, they also suggest that such
treatment may be most beneficial when initiated
in the very early phase of NIDDM, or even in the
pre-NIDDM phase.
To enable early treatment to be implemented,
screening or case finding programmes must be em-
ployed..A simple case finding procedure has been
devised and applied in primary health care, based
on a single random blood glucose sample taken any
time during the day (Bitzen & Schersten 1986). This
study shows that a random value ~ 7 mmol/L sug-
gests the presence ofNIDDM with high specificity,
predictability and sensitivity. In subjects thus de-
tected, an oral glucose tolerance test (OGTT) can
then be used to confirm (or refute) the diagnosis.
The study also demonstrates that urine glucose tests
are unreliable for early NIDDM screening.
3.4 Efficacy of Diet Regulation and
Sulphonylurea Use in Early NIDDM
In 32 screening-detected NIDDM patients re-
cruited as described above (Bitzen & Schersten
1986), the efficacy of diet regulation alone and in
combination with glipizide, a fast and short acting
drug, has been studied over a 4-year period (Bitzen
1988; Bitzen et al. 1988a,b). The results indicate
that weight-reducing diet regulation alone has little
or no influence on the acute insulin release and
hence on the net postprandial glucose elevation,
but can be highly effective in reducing fasting blood
glucose. About 25% of the subjects maintained
(near) normal fasting blood glucose levels (~ 6
mmol/L) for more than 4 years by hypocaloric diet
regulation alone, and these subjects also had a pro-
nounced improvement in insulin action (Bitzen
1988; Bitzen et al. 1988a).
About 50% ofthe subjects (who had a mean pre-
treatment blood glucose of 9.0 mmol/L) attained
(near) normal fasting blood glucose levels after the
addition of 20mg glipizide or less to maintained
hypocaloric diet regulation, and they also had an
65
improved insulin action (Bitzen 1988). Moreover,
this combination was effectivein maintaining (near)
normal blood glucose control for almost 4 years
(mean fasting blood glucose 6.7 mmol/L), without
increasing basal insulin secretion, without chronic
hyperinsulinaemia, and without weight increase
(Bitzen 1988).
The final 25% (with initial values of 8.2 mmol/
L) had no reduction of fasting blood glucose de-
spite the addition of 20mg glipizide and 1.0g met-
formin daily. Before treatment these patients did
not differ from the glipizide responders in weight,
glucose control, basal insulin secretion or glucose
and insulin responses to a test dose of glipizide.
However, they did differ in compliance with diet
regulation as judged from the absence of weight
reduction, and the drug failure was probably due
to non-compliance with diet rather than to a pri-
mary inability to respond to sulphonylurea therapy
(Bitzen 1988).
3.5 Clinical Comparisons Between
Sulphonylureas
There are few well-controlled long term clinical
comparisons, particularly between short and long
lasting sulphonylureas (Ferner & Chaplin 1987). A
recent investigation compared glibenclamide and
glipizide in a placebo-controlled crossover study
during two 6-month periods (Groop et al. 1987a).
Dosage was governed by the basal glucose level so
that the daily dose was increased until fasting blood
glucose was < 8 mmol/L, or until a maximum daily
dose of 25mg had been reached. There were great
interindividual differences in the final daily dose,
but the mean final doses were similar, about 15mg
of both drugs, and most patients took the drugs 3
times daily. While minor differences could be seen
in the influence of the 2 agents on insulin secretion
and insulin action, the overall glucose control was
similar, with a 24-hour mean blood glucose reduc-
tion from about 10.5 to about 8.5 mmol/L (Groop
et al. 1987a). This supports the view that, when
dosage is individualised and governed by the effect
on fasting blood glucose, there is little or no dif-
ference in clinical efficacy between su1phonylureas.
Clinical Pharmacolog y of Sulphonylureas
This is also the overall impression from most other
comparisons of different sulphonylurea agents
(Ferner & Chaplin 1987). However, this does not
signify that the choice of drug is irrelevant in the
long term perspecti ve.
3.6 B Cell Desensitisation by Continuous
Exposure to Sulphonylureas
A recent study (Karam et aI. 1986) showed that
the insulin-releasing effect of a single injection of
tolbutamide disappeared during treatment with an-
other such drug (tolazamide) and reappeared after
withdrawal of the second sulphonylurea. This sug-
gests that chronic, continuous exposure may de-
sensitise the B cell to sulphonylurea, in analogy with
the desensitisation of any cell to continuous stimu-
lation by an endogenous or exogenous agonist
(Karam et aI. 1986). It is of interest in this context
that sulphonylureas in high concentrations inhibit
insulin biosynthesis in vitro- (Andersson & Borg
1980).
This also suggests that the insulintropic effect
of sulphonylureas might be best maintained during
long term therapy if the dosage promotes a dis-
continuous exposure, i.e. if the plasma drug con-
centration falls below the threshold level during
(part ot) the night. In a long term study, the im-
provement of acute insulin release caused by a
single dose of glipizide was maintained for a pro-
longed period in subjects whose sulphonylureas ex-
posure was discontinuous (~ 10mg once daily), but
it was attenuated in subjects with continuous ex-
posure (~ 20mg in divided doses) [Bitzen et aI.,
unpublished data] . It must be emphasised, how-
ever, that this difference could also relate to dif-
ferences in the severity of NIDDM.
On the other hand, an increase in the dosage of
g1ipizide from 15 to 25mg may impair rather than
improve glucose control (WAhlin-BolI et aI. 1982b),
suggesting the possibility of desensitisation at high
and continuous exposure to sulphonylureas. These
findings indicate that such treatment may be most
efficacious in the long term if performed with fast
and short acting drugs in low and/or once-daily
dosage. Moreover, it seems probable that, if high
66
dosage has been necessary to obtain normalisation
of blood glucose initially , subsequent dose reduc-
tion might be appropriate. Indeed, maintenance of
high dosage could promote a secondary failure.
3.7 Primary and Secondary Failures of
Sulphonylureas
It is well known that some NIDDM patients gain
little or no blood glucose reduction during treat-
ment with sulphonylureas. One reason for such
primary failures is an inappropriate indication, i.e.
the patient has too little B cell capacity to secrete
insulin. Another, and probably more common,
cause is that the patient has not complied with diet
regulation (Bitzen et aI., unpublished data; Liu et
aI. 1985).
Some secondary failures may also relate to non-
compliance with diet regulation, e.g. in situations
where the patient has maintained a hypocaloric diet
regulation for some time during sulphonylurea
therapy but does not continue this dietary regimen.
Another cause of secondary failures could be
chronic, continuous exposure at high dosage, as
suggested above.
Perhaps the most common cause of both pri-
mary and secondary failures is that the drugs are
not introduced until the disease is advanced. On
average, the rate of secondary failures is about 5
to 10% per year (Gerich 1985; Shen & Bressler
1977).
4. Adverse Effects of Sulphonylureas
The frequency of adverse effects is low, and they
are mostly mild and reversible upon withdrawal of
the drug. Adverse effects include nausea , dizziness ,
headache, alcohol intolerance (mainly with chlor-
propamide), water retention and hyponatraemia
(mainly with chlorpropamide), allergic reactions
(mostly urticaria and erythema), agranulocytosis
and thrombocytopenia, icterus , and hypoglycae-
mia (Jackson & Bressler 1981). The inference that
sulphonylureas may enhance cardiovascular mor-
tality (University Group Diabetes Program 1970)
is apparently unfounded (see section 3.2).
Clinical Pharmacology of Sulphonylureas
4.1 Long Lasting Hypoglycaemia
The most serious adverse effect of sulphonylu-
reas is long lasting hypoglycaemia, which may lead
to permanent neurological damage and may even
have a fatal outcome, at least in the elderly. It
should also be emph asised that long lasting hypo-
glycaemia may be misdiagnosed as a cerebrovas-
cular insult. In a review of almost 800 cases of
hypoglycaemia, more than 200 were prolonged and
hence severe. Most subjects had been taking chlor-
propamide, a long acting sulphonylurea (Seltzer
1979). Of all hypoglycaemic patients referred to
hospitals, 10% died and 3% had permanent neu-
rological damage (Seltzer 1979). In another study,
12 of 14 reported chlorpropamide-induced hypo-
glycaemic reactions were prolonged, but none of
these subjects died (Asplund et al. 1983).
4.1.1 Chlorpropamide
A probable reason for the ability of chlorpro-
pamide to provoke long lasting hypoglycaemia is
that this drug disappears very slowly and hence ac-
cumulates easily; its elimination half-life is ~ 36
hours, as compared with about 8 hours for tolbut-
amide (Jackson & Bressler 1981). The very long
half-life is a consequence of a slow and incomplete
metabolic degradatio n in conjunction with slow
renal excretion of the unchanged compound. AI-
kalinisation of the urine accelerates the elimination
of chlorpropamide because this increases the ion-
ised fraction (Neuvo nen & Karkkainen 1983).
4.1.2 Glibenclamide
In most European and many other countries,
glibenclamide has replaced chlorpropamide as the
sulphonylurea drug most frequently employed in
clinical practice. It has also become the sulphonyl-
urea most commonly associated with long lasting
and sometimes fatal hypoglycaemia. It is reason-
able to suggest that this is at least in part due to
the widespread use of this potent drug. However,
glibenclamide may also be more likely than most
other sulphonylureas to provoke long lasting hypo-
glycaemia (Ferner & Neil 1988). Indeed, the hy-
poglycaemic reactions following glibenclamide may
67
be more severe than those evoked by chlorpropam-
ide. A retrospective study reviewed all serious cases
of sulphonylurea-associated hypoglycaemia re-
ported to the Swedish Board of Health and Welfare
from 1975 to 1982 (Asplund et al. 1983). Of the 60
glibenclamide-associated cases, 24 were long last-
ing and severe, and 10 of these patients died. Of
the 14 chlorpropamide-associated cases, 12 were
long lasting but none was fatal. None of the few
cases associated with glipizide or tolbutamide was
long lasting, and none of the patients died.
Normally , hypoglycaemia will promote release
of counter-regulatory ho~ones such as adrenaline
and glucagon, whereby hepatic glucose output is
increased and the hypoglycaemia counteracted. It
follows that a long lasting hypoglycaemic reaction
can occur only if there is sustained suppression of
hepatic glucose output. In a recent study (Groop
et al. 1987b), glibenclamide was shown to cause a
50% greater suppression of hepatic glucose output
than glipizide, at similar plasma concentrations of
the 2 compounds. This provides experimental sup-
port for the suggestion that treatment with gliben-
clamide may be more liable to provoke long lasting
hypoglycaemia than is treatment with glipizide.
A recent Swiss study (Berger et al. 1986) also
suggests that long lasting, severe hypoglycaemia is
more common after glibenclamide and chlorpro-
pamide than after more short acting agents such as
glipizide, glibornuride and tolbutamide. In the
treatment of hypoglycaemia it may be noted that,
in contrast to effects on chlorpropamide (Neuvo-
nen & Karkkainen 1983), urine alkalinisation can-
not promote the elimination of glibenclamide and
most other sulphonylureas, as they are metabolised
to a much greater extent (Ferner & Chaplin 1987).
All the patients with severe hypoglycaemia in
the Swedish study were over the age of 75 years
(Asplund et al. 1983). In addition, most had a com-
plicating factor such as a drug interaction or acute
energy deprivation due to gastroenteritis (Asplund
et al. 1983). This argues for particular caution in
using sulphonylureas in the very old, especially in
combination with other drugs. In fact one may en-
tirely refrain from using sulphonylurea therapy in
Clinical Pharmacolog y of Sulphonylureas
this age segment, unless subjective symptomatic
hyperglycaemia necessitates drug use.
5. Selection 0/ a Sulphonylurea
As stated previously, there is little or no evi-
dence that one sulphonylurea has a higher clinical
efficacy than another, at least not when dosage is
individualised according to the fasting glucose lev-
els. Tradition and the abundance of previous
clinical experience should favour the older sul-
phonylureas, and tolbutamide, the oldest one still
in use, also has an excellent safety record. The use
of chlorpropamide might be discouraged, as it
seems to carry the largest risk of adverse reactions.
If, on the other hand, it is assumed that the drug
with the highest potency will be most likely to at-
tain maximum clinical efficacy, glibenclamide or
glipizide should be selected. As there is little or no
difference in efficacy between these agents (Groop
et al. 1987a), either one could be used. However,
if the safety aspect is included, glipizide may be
favoured as it seems less likely than glibenclamide
to cause long lasting, and hence severe and even
fatal, hypoglycaemia. Moreover, if the concept of
discontinuous sulphonylurea exposure in long term
treatment is adopted, glipizide would offer another
advantage as it is the most fast and short acting of
these drugs.
6. Sulphonylurea Dosage
6.1 Optimal Dosage and Time of
Administration
The optimum daily dosage of the drug selected
for treatment is difficult to define, as it is depend-
ent on the degree of impairment of B cell function
before treatment, as well as the degree of compli-
ance with diet regulation. Furthermore, the dose-
response curve may be bell-shaped (Wahlin-Boll et
al. 1982b), and the steady-state concentrations of
several, if not all, sulphonylureas show a large
interindividual variation following standard doses
(Ferner & Chaplin 1987; Melander et al. 1978; Sar-
tor et al. I980a).
Moreover, the rate of absorption and the time
68
of appearance of drug in blood relative to the time
of meal intake may be more important than the
dose size; a dose of glibenclamide 2.5mg half an
hour before breakfast is more effective than 7.5mg
together with breakfast (Sartor et al. 1982). Glipi-
zide (Wahlin-Boll et al. 1980)and tolbutamide (Sil-
ins et .al. 1984) are also more effective when given
half an hour before, rather than with, a meal. The
efficacy of glipizide is highly dependent on its ab-
sorption rate (Bitzen et al. 1988b; Wahlin-Boll et
al. 1982a), and the time to reach the threshold con-
centration correlates with the time to the nadir of
blood glucose (Hartling et al. 1987b). These find-
ings also emphasise the significance of developing
optimum biopharmaceutic formulations of sul-
phonylureas (Arnqvist et al. 1983; Ferner & Chap-
lin 1987; Wahlin-Boll et al. I982a).
6.2 Number of Daily Doses
By tradition, tolbutamide is usually admini-
stered in doses of 0.5 to lg 3 times daily; whether
tolbutamide could be equally effective when given
once or twice daily has not been studied. Two in-
dependent studies suggest that once-daily and 3
times daily adm inistration of glipizide are thera-
peutically equivalent, provided the total daily dose
is 7.5mg or more (Ostman et al. 1981; Wahlin-Boll
et al. 1986). With such dosage regimens, an effec-
tive concentration is present for at least 16 hours
per day even with once-daily administration
(Wahlin-Boll et al. 1986).
Glibenclamide has frequently been admini-
stered once daily. However, use of a divided dos-
age regimen of this drug has been associated with
slightly improved blood glucose control (Matsuda
et al. 1983). The reason for this is obscure in view
of the long duration of action of this drug.
7. Drug Interactions
Several drugs can interfere with the efficacy of
sulphonylureas, by influencing either pharmaco-
kinetics or pharmacodynamics, or both. Alcohol,
aspirin, sulphonamides, trimethoprim and anti-
cholinergic agents have all been involved in serious
Clinical Pharmacology of Sulphonylureas
instances of sulphonylurea-related hypoglycaemia
(Asplund et al. 1983).
Alcohol (ethanol) can cause hypoglycaemia in
itself, and can also prolong the hypoglycaemic ef-
fect of sulphonylurea, as recently shown with glip-
izide (Hartling et al. 1987b). The significance of
ethanol related sulphonylurea-hypoglycaemia is
emphasised by the fact that 80% of all severe cases
with signs of irreversible brain damage were caused
by sulphonylurea drugs and/or by excessive ethanol
intake (Seltzer 1979).
On the ,other hand, thiazides (Murphy et al.
1982) and ,a-blockers (Zaman et al. 1982) may re-
duce the long term blood glucose lowering effects
of sulphonylureas. This is important, as these agents
are first-line drugs in the treatment of hypertension
and as such are likely to be prescribed to many
patients with NIDDM.
8. Conclusions
Recent studies of the effects and efficacy of sul-
phon ylureas indicate that these drugs should be
reappraised. It is possible that they release insulin
by activation of specific receptors in the B cell. If
introduced in subjects with IGT, sulphonylurea
treatment in combination with diet regulation may
postpone the development ofNIDDM, reduce car-
diovascular morbidity and reduce the increased risk
of cardiovascular mortality. If introduced in
screening-detected NIDDM patients and com-
bined with hypocaloric diet regulation, these drugs
are able to attain and maintain (near) normal blood
glucose levels for several years. However, it is cru-
cial that weight-reducing diet regulation is main-
tained, otherwise sulphonylurea therapy may fail.
Many primary and secondary failures associated
with sulphon ylurea therap y may in fact be blamed
on inadequate compliance with diet regulation.
Fast and short acting sulphonylurea drugs are
able to improve the characteristic impairment of
acute insulin release, and this improvement can be
maintained for several years. Continuous (24-hour-
a-day) exposure could possibly desensitise the B cell
to sulphonylurea stimulation. When combined with
weight-reducing diet regulation, fast and short act-
69
ing sulphonylurea therapy can enhance meal-stim-
ulated insulin secretion and improve insulin action
without an increase in basal insulin secretion, with-
out chronic hyperinsulinaemia, and without weight
increase. These drugs may also be safer than long
acting ones, since the latter may be more apt to
provoke long lasting, severe hypoglycaemia. This
is most likely to occur in the elderly and may be
augmented by intercurrent illness, alcohol, aspirin
and some other drugs. Thiazides and ,a-blockers
should be avoided in patients receiving sulphonyl-
urea therapy, since such combinations may result
in diminished blood glucose lowering effects.
References
Almer L-O. Vascular fibrinolytic activity in long term treatment
with second generation sulfonylurea compounds. Acta Endo-
crinologica (Suppl , 239): 53-55, 1980
Almer L-O, Johansson E, Melander A, Wilhiin-Boll E. Influence
of sulphonylureas on the secretion , disposal and effect of in-
sulin. European Journal of Clinical Pharmacology 22: 27-32,
1982
Andersson A, Borg LAH. Effects of glipizide on the insulin pro-
duct ion by isolated mouse pancrea tic islets. Acta Endocrinol-
ogica (Suppl. 239): 37-4 1, 1980 .
Amq vist HJ, Karlberg BE, Melander A. Pharmacokinetics and
effects of glibenclarnide in two formulations, HB419 and
HB420, in type 2 diabetics . Annals of Clinical Research 15
(Suppl, 37): 2 1-25, 1983
Artini D, Abbiati R, Orsin i G, Parenti MA, Bloch K, et al. Phar-
macodynamic aspects of two sulfonylurea derivatives , glipi-
zide and glibenclarnide, Diabeto logia 9 (Suppl.): 311-316, 1973
Asplund K, w iholm B-E, Lithner F. Glibenc1amide-associated
hypoglycaemia: a report on 57 cases. Diabetologia 24: 412-417,
1983
Beck-Nielsen H, Hother Nielsen 0 , Andersen PH, Pederson 0,
Schmitz 0 . In vivo action of glibenc1amide. Abstract no. 26.
Diabetologia 29: 515A, 1986
Beck-Nielsen H, Pedersen 0 , Lindskov HO. Increased insulin
sensitivity and cellular insulin binding in obese diabetics fol-
lowing treatment with g1ibenc1amide. Acta Endocrinologica 90:
451-462, 1979
Beck-Nielsen H, Pedersen 0 , Sorensen NS. Effects of dietary
changes on cellular insulin binding and in vivo insulin sen-
sitivity. Metabolism 29: 482-487, 1980
Behrle M. Untersuchung zur Pharmakokinetik von G1ibenc1amid
bei nierengesunden und niereninsuffizienten Diabetikem. The-
sis. Ruprecht-Karl-Universitat , Heidelberg, West Germany,
1980
Berger W, Cardiff F, Pasquel M, Rump A. Die relative Haufigkeit
der schweren Sulfonylharnstoff-H ypoglykarnie in den letzten
25 Jahren in der Schweiz. Schweizerische Medizinische Woch-
enschrift 116: 145-151, 1986
Berry EM, Bar-On H. Comparison of sulphonylurea and insulin
treatm ent on lipid levels in maturity-onset diabetic men and
women . Israeli Journal of Medical Sciences 17: 384-387, 1981
Bitzen P-O. On the early detection and treatment of non-insulin-
dependent d iabetes mellitus in primary health care. PhD The-
sis, Universit y of Lund, 1988
Bitzen P-O, Melander A, Schersten B, Svensson M. Efficacy of
Clinical Pharmacology of Sulphonylureas
dietary regulation in screening-detected NIDDM primary health
care patients with different degrees of hyperglycaemia. Dia-
betic Medicine, in press, 1988a
Bitzen P-O, Melander A, Schersten B, Wilhiin-Boll E. The influ-
ence of glipizide on early insulin release and glucose disposal
before and after diet regulation in diabetic patients with dif-
ferent degrees of hyperglycaemia. European Journal of Clinical
Pharmacology 35 (I): 31-37, 1988b
Bitzen P-O, Schersten B. Assessment of laboratory methods for
detection of unsuspected diabetes in primary health care. Scan-
dinavian Journal of Primary Health Care 4: 85-95, 1986
Brown RG, Foubister AJ. Receptor binding sites of hypoglycemic
sulfonylureas and related [(acylamino)alkyl] benzoic acid.
Journal of Medicinal Chemistry 27: 79-81,1984
Calvert GD , Mannik T, Graham JJ, Wise PH, Yeates RA. Effects
of therap y on plasma-high-density-lipoprotein-cholesterol con-
centration in diabetes mellitus. Lancet 2: 66-68, 1978
Camerini-Davalos RA, Velasco C, Glasser M, Bloodworth JBM.
Drug-induced reversal of early diabetic microangiopathy. New
England Journal of Medicine 309: 1551-1556, 1983
Campbell DB, Adriaenssens P, Hopkins YW, Gordon B, Wil-
liams JRB. Pharmacokinetics and metabolism of gliclazide: a
review. In Keen et al. (Eds) Gliclazide and the treatment of
diabetes , International Congress and Symposium Series No.
20, pp, 71-82, Academic Press, London , 1980
Cerasi E, Efendic S, Luft R. Dose response relation between in-
sulin and blood glucose levels during oral glucose loads in pre-
diabetic and diabetic subjects. Lancet 1: 794-797, 1973
DeFronzo RA, Ferrannini E, Koivisto V. New concepts in the
pathogenesis and treatm ent of non-insulin-dependent diabetes
mellitus . American Journal of Medicine 74 (Suppl. IA): 52-
81, 1983
Donahue RP, Abbott RD, Reed DM, Katsuh iko Y. Postchallenge
glucose concentration and coronary heart disease in men of
Japanese ancestry: Honolulu Heart Program. Diabetes 36: 689-
692, 1987
Eder HA. Lipid metabolism in diabetes: the role of sulfonylureas
in the treatment of insulin-independent diabetes. Colloqium
Proceedings, pp. 13-17, Science and Medicine, New York, 1980
Feldman JM , Lebovitz HL. Appraisal of the extrapancreatic ac-
tions of sulfonylureas. Archives of Internal Medicine 123: 314-
322,1969
Ferner RE, Chaplin S. The relationship between the pharmaco-
kinetics and pharm acodynamic effects of oral hypoglycaemic
drugs. Clinical Pharma cokinetics 12: 379-401, 1987
Ferner R, Neil HAW. Sulphonylureas and hypoglycaemia. British
Medical Journal 296: 949-950, 1988
Ferner R, Rawlins MD, Alberti KGMM . Impaired B-cell re-
sponses improve when fasting blood glucose concentration is
reduced in non-insulin-dependent diabetes. Quarterly Journal
of Medicine, New Series 66: 137-146, 1988
Fuller JH . Clinical tria ls in diabetes mellitus. In Mann et al. (Eds)
Diabetes in epidemiological perspective, pp, 265-285, Church-
ill Livingstone, Edinburgh, 1983
Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H. Coronary -
heart-disease risk and impaired glucose tolerance . Lancet I:
1373-1376, 1980
Geisen K, Hitzel V, Okomonopoulos R, Punter J, Weyer R, et
al. Inhibit ion of 3H-glibenclamide binding to sulfonylurea re-
ceptors by ora l ant idiabetics . Arzneimittel-ForschungJDrug
Research 35: 707-712, 1985
Gerich JE. Sulfonylureas in the treatment of diabetes mellitus.
Mayo Clinic Proceedings 60: 439-443, 1985
Greenfield MS, Doberne L, Rosenthal M, Schultz B, Widstrom
A, et al. Effect of sulfonylurea treatment on in vivo insulin
secretion and action in patients with non-insulin-dependent
diabetes mellitus. Diabetes 31: 307-312, 1982a
Greenfield MS, Doberne L, Rosenthal M, Vreman HJ, Reaven
70
GM . Lipid metabolism in non-insulin-dependent diabetes
mellitus. Archives ofinternal Medicine 142: 1498-1500, 1982b
Groop L, Groop P-H, Stenman S, Saloranta C, Totterman K-J,
et al. Comparison of pharmacokinetics, metabolic effects and
mechanisms of action of glyburide and glipizide during long-
term treatment. Diabetes Care 10: 671-678, 1987a
Groop L, Groop P-H, Stenman S, Saloranta C, Totterrnan K-J,
et al. Do sulfonylureas influence hepatic insulin clearance?
Diabetes Care II : 689-690, 1988
Groop L, Harno K, Tolppanen EM. The combination of insulin
and sulphonylurea in the treatment of secondary drug failure
in patients with type II diabetes. Acta Endocrinologica 106:
97-101, 1984
Groop L, Luzi L, Melander A, Groop P-H, Ratheiser K, et al.
Different effects of g1yburideand glipizide on insulin secretion
and hepatic glucose production in normal and NIDDM sub-
jects . Diabetes 36: 1320-1328, 1987b
Grunberger G, Ryan J, Gorden P. Sulfonylurea do not .affect in-
sulin binding or glycemic control in insulin-dependent dia-
betics. Diabetes 31: 890-896, 1982
Hadden DR, Blair ALT, Wilson EA, Boyle DMcC, Atkinson AB,
et al. Natural history of diabetes presenting age 40-69 years: a
prospective study of the influence of intensive dietary therapy .
Quarterly Journal of Medicine 59: 579-598, 1986
Hamelbeck H, Klein W, Zoltobrocki M, Schoffling K. Gliben-
clarnide-insulin combination in the management of secondary
failure of sulfonylurea medication . Deutsche Medizinische
Wochenschrift 107: 1581-1583, 1982
Hartling SG, Binder C, Faber OK: C-peptide and proinsulin . In
Alberti & Krall (Eds) The diabetes annual 3, pp. 382-397, EI-
siever, New York, 1987a
Hartling SG, Faber OK, Wegmann M-L, Wilhiin-Boll E, Melan-
der A. Interac tion of ethanol and glipizide in humans. Dia-
betes Care 10: 683-686, 1987b
Hellman B, Sehlin J, Taljedal I-B. Glibenclamide is exceptional
among hypoglycaemic agents in accumulating progressively in
B-cell rich pancreatic islets. Acta Endocrinologica 105: 385-
390, 1984
Henry RR, Wallace P, Olefsky JM. Effects of weight loss on
mechanisms of hyperglycemia in obese non-insulin-dependent
diabetes mellitus. Diabetes 35: 990-998, 1986
Holman RR, Turner RG. The quest for basal normoglycemia .
Lancet I: 469-474, 1977
Holmes B, Hell RC, Brogden RN, Speight TM, Avery GS. Gli-
c1azide: a preliminary review of its pharmacodynamic prop-
erties and therapeutic efficacy in diabetes mellitus. Drugs 27:
301-327, 1984
Howard BV, Savage PJ, Benniion U , Bennett Ph. Lipoprote in
composition in diabetes mellitus. Atherosclerosis 30: 153-162,
1978
Ikegawi H, Shima K, Tanaka A, Tahara Y, Hirota M, et al. Inter-
individual variation in the absorption of g1ibenclamide in man.
Acta Endocrinologica III : 528-532, 1986
Jackson EJ, Bressler R. Clinical pharmacology of sulphonylurea
hypoglycaemic agents. Drugs 22: 211-245; 295-320, 1981
Jarrett RJ, McCartney P, Keen H. The Bedford Survey: ten year
mortality rates in newly diagnosed diabetics , borderline dia-
betics and normoglycaemic controls and risk indices for cor-
onary heart disease in borderlin e diabetics. Diabetologia 22:
79-84, 1982
Johansen K. Glipizide for reversal of early diabetic microangio-
pathy. Correspondence. New England Journal of Medicine 310:
1389, 1983
Karam JH , Matin SB, Forsham PH. Antidiabetic drugs after the
University Group Diabetes Program. Annual Review of
Pharmacology 15: 351-366, 1975
Karam JH , Sanz N, Salamon E, Nolte MS. Selective unrespon-
siveness of pancreatic B-cells to acute sulfonylurea stimulation
Clinical Pharmacology of Sulphonylureas
during sulfonylurea therap y in NIDDM . Diabetes 35: 1314-
1320, 1986
Kennedy AL, Lappin TRJ, Lavery TD , Hadden DR, Weaver JA,
et al. Relation of high-density lipoprotein cholesterol concen-
tration of type of diabetes and its control. British Medical
Journal 2: 1191-1194, 1978
Kilo C. Value of glucose control in preventing complications of
diabetes. American Journal of Medicine 79 (Suppl. 2B): 33-37,
1985
Kilo C, Miller P, Williamson JR. The crux of the UGDP: spu-
rious results and biologically inappropriate data analysis. Dia-
betologia 18: 179-185, 1980
King JB, Kalk WJ, Vinik AI, Jackson WPU, Bracher M, et al.
An elevation of the effects of some sulphonylureas on platelet
function . South Africa Medical Journal 5I: 124-126, 1977
Knowler WC, Sartor G, Schersten B. Effects of glucose tolerance
and treatment of abnormal tolerance on mortality in Mal-
mohus County , Sweden. Abstract no. 280. Diabetologia 30:
541A, 1987
Kolterman OG, Olefsky JM. The impact of suiphonylurea treat-
ment upon the mechanisms responsible for the insulin resist-
ance in Type II diabetes. Diabetes Care 7 (Suppl. I): 81-88,
1984
Lebovitz HE, Feinglos MN, Bucholtz HK, Lebovitz FL. Poten-
tiati on of insulin action : a probable mechanism for the anti-
diabet ic action of sulfonylurea drugs. Journal of Clinical Endo-
crinologyand Metabolism 45: 601-604, 1977
Lisch H-J, Sailer S. Lipoprotein patterns in diet, sulphonylurea,
and insulin treated diabetics . Diabetologia 20: 118-122, 1981
Liu GC, Coulston AM, Lardinois CK, Hollenbeck CB, Moore JG,
et al. Moderate weight loss and sulfonylurea treatment of non-
insulin-dependent diabetes mellitus. Archives ofinternal Med-
icine 145: 665-669, 1985
Luft R, Wajngot A, Efendic S. On the pathogenesis of maturity-
onset diabetes. Diabetes Care 4: 58-63, 1981
Madsbad S, Krarup T, McNair P, Christiansen C, Faber 0 , et al.
Practical clinical values of the C-peptide response to glucagon
stimulation in the choice of treatment in diabetes mellitus. Acta
Medica Scandinavica 210: 153-156, 1981
Mandarino U , Gerich JE. Prolonged sulfonylurea administration
decreases insulin resistance and increases insulin secretion on
non-insulin-dependent diabetes mellitus: evidence for im-
proved insulin action at a postreceptor site in hepatic as well
as extrahepati c tissues. Diabetes Care 7 (Suppl. I): 89-99, 1984
Matsuda A, Kuzuyat T, Sugita Y, Kawashima K. Plasma levels
of glibenclamide in diabetic patients during routine clinical
administration determined by a specific radioimmunoassay.
Hormone and Metabolic Research 15: 425-428, 1983
Melander A. Clinical pharm acology ofsulfonylureas. Metabolism
36: 12-16, 1987
Melander A, Sartor G, Wahlin E, Schersten B, Blitzen P-O. Serum
tolbutamide and chlorpropamide concentrations in patients with
diabetes mellitus. British Medical Journal I: 142-144, 1978
Mizroch S. Glipizide for reversal of early diabetic microangio-
pathy. Correspondence. New England Journal of Medicine 310:
1389, 1983
Murphy MB, Lewis PJ, Kohner E, Schumer B, Dollery CT. Glu-
cose intoleranc e in hypertensiv e patients treated with diuretics:
a fourteen- year follow up. Lancet 2: 1293-1295, 1982
Neufeld ND, Harris M, Corbo LM, Koduri A. Effect of glyburide
in type II diabetes mellitus: studies of monocyte membrane
fluidity, lipid composition, and insulin binding. Diabetes 36:
1351-1355, 1987
Neuvonen PJ, Karkkainen S. Effects of charcoal, sodium bicarb-
onat e and ammonium chloride on chlorpropamide kinetics.
Clinical Pharm acology and Therapeutics 33: 386-393, 1983
Olefsky JM , Ciraldi TP, Kolterman OG. Mechanisms of insulin
resistance in non-insulin-dependent (type II) diabetes. Amer-
ican Journal of Medicine 79: 12-22, 1985
71
O'Rahilly SP, Rudenski AS, Burnett MA, Nugent Z, Hosker JP,
et al. Beta-cell dysfunction, rather than insulin insensitivity , is
the primary defect in familial type 2 diabetes. Lancet 2: 36()'
363, 1986
Ostman J, Christenson I, Jansson B, Weiner L. The antidiabetic
effect and pharmacokinetic properties of glipizide, Acta Med-
ica Scandinavica 210: 173-180, 1981
Paisey R, Elkelels RS, Hambley J, Magill P. The effects of chlor-
propamide and insulin on serum lipids, lipoproteins and frac-
tional triglyceride removal. Diabetologia 15: 81-85, 1978
Persson G. Cardiovascular comp lications in diabetics and sub-
jects with reduced glucose tolerance. Acta Medica Scandinav-
ica (Suppl. 605), 1977
Reaven GM. Insulin-independent diabetic mellitus: metabolic
characteristics. Metabolism 29: 445-454, 1980
Rogers BJ, Standaert ML, Pollet RJ. Direct effects of sulfonylurea
agents on glucose transport in the BC3H-1 myocyte. Diabetes
36: 1292-1296, 1987
Sartor G, Lundquist I, Melander A, Schersten B, Wahiin-Boll E.
Improved effect of glibenclamide on administration before
breakfast. European Journal of Clinical Pharmacology 21: 403-
408, 1982
Sartor G, Melander A, Schersten B, Wahlin-Boll E. Serum gli-
benclamide in diabetic patients, and influence of food on the
kinetics and effects of glibenclamide. Diabetologia 18: 17-22,
I980a
Sartor G, Schersten B, Carlstrom S, Melander A, Norden A, et
al. Ten-year follow-up of subjects with impaired glucose tol-
erance: prevention of diabetes by tolbutamide and diet regu-
lation . Diabetes 29: 41, 1980b
Sartor G, Ursing D, Nilsson-Ehle P, Wahlin-Boll E, Melander A.
Lack of primary effect of sulphonylurea (glipizide) on plasma
lipoprote ins and insulin action in former type 2 diabetics with
attenuated insulin secretion. European Journal of Clinical
Pharmacology 33: 279-282, 1987
Savage PJ, Bennion U , Hock EV, Nagulesparan M, Mott D, et
al. Diet-induced improvement of abnormalities in insulin and
glucagon secretion and in insulin receptor bind ing in diabetes
mellitus . Journal of Clinical Endocrinology and Metabolism
48: 999-1007, 1979
Scheen AJ, Lefebvre PJ, Luyckx AS. Glipizide increases plasma
insulin but not C-peptide level after a standardized breakfast
in type 2 diabetic patients . European Journal of Clinical
Pharmacology 26: 471-474, 1984
Seltzer HS. Severe drug-induced hypoglycemia: a review. Com-
prehensive Therapy 5: 21-29, 1979
Shapiro ET, TiIlil H, Miller MA, Frank BH, Galloway JA, et al.
Insulin secretion and clearance: comparison after oral and
intravenous glucose. Diabetes 36: 1365-1371, 1987
Shen SW, Bressler R. Clinical pharmacology of oral antidiabetic
agents. New England Journal of Medicine 296: 787-793, 1977
Siconolfi-BaezL, Lebovitz HE. Characteristics of a specific plasma
membrane sulfonylurea receptor. Diabetes 34 (Suppl, I): 228-
232, 1985
Silins RA, Butcher MA, Marlin GE. Improved effect of tolbut-
amide when given before food in patients on long-term therapy.
Correspondence . British Journal of Clinical Pharmacology 18:
647-648, 1984
Simonson DC, Ferrannini E, Bevilacqua S, Smith D, Barrett E,
et al. Mechanism of improvement in glucose metabolism after
chronic glyburide therap y. Diabetes 33: 838-845, 1984
Siperstein MD. Diabetic microangiography and the control of
blood glucose. New England Journal of Medicine 309: 1577-
1579, 1983
Tarnai T, Nakai T, Yamada S, Kobayashi T, Hayashi T, et al.
The effects of glibenclamide and insulin on plasma high den-
sity lipoprotein in diabetics. Artery 9: 477-493, 1981
Taskinen M-R, Nikkila EA, Kuusi T, Harno K. Lipoprotein li-
pase activity and serum lipoprotein in untreated Type 2 (in-
Clinical Pharmacology of Sulphonylureas
suiin-independent) diabetes associated with obesity. Diabeto-
logia 22: 46-50, 1982
Taylor KG, John WG, Matt hews KA, Wright AD. A prospective
. study of the effect of 12 months treatment on serum lipids and
apolipoproteins A-I and B in Type 2 (non-insulin-dependent)
diabetes . Diabetologia 23: 507-510, 1982
Taylor KG, Wright AD, Carter TJN , Valente AJ, Betts SA, et al.
High-density lipoprotein cholesterol and apolipoprotein A-I
levels at diagnosis in patients with non-insulin dependent dia-
betes. Diabetolog ia 20: 535-539, 1981
Turtle JR . Glucose and insulin secretory response patterns fol-
lowing diet and tolazamide therapy in diabetics. British Medi-
cal Journal 3: 606-610, 1970
UK Prospective Study of Therapies of Maturity-Onset Diabetes.
l, Effect of diet, sulfonylurea, insulin or biguanide therapy on
fasting plasma glucose and body weight over one year. Dia-
betologia 24: 404-411, 1983
Unger RH , Grundy S. Hyperglycemia as an inducer as well as a
consequence of impaired islet cell function and insulin resist-
ance: implications for the management of diabetes. Diabeto-
logia 28: 119-121, 1985
University Group Diabetes Program. A study of the effects of
hypoglycemic agents on vascular complications in patient with
adult -onset diabetes . Diabetes 19 (Suppl. 2), 1970
Wahiin-Boll E, Almer L-O, Melander A. Bioavailability, phar-
macokinetics and effects of glipizide in type 2 diabetics. Clinical
Pharmacokinetics 7: 363-372, 1982a
Wahlin-Boll E, Groop L, Karhumaa S, Groop P-H, Totterrnan
K-J, et al. Therapeutic equivalence of once- and thrice-daily
glipizide. European Journal of Clinical Pharmacology 31: 95-
99, 1986
72
Wahiin-Boll E, Melander A, Sartor G, Schersten B. Influence of
food intake on the absorption and effect of glipizide in dia-
betics and in healthy subjects. European Journal of Clinical
Pharmacology 18: 279-283, 1980
Wahlin-Boll E, Sartor G, Melander A, Schersten B. Impaired ef-
fect of sulfonylurea following increased dosage. European
Journal of Clinical Pharmacology 22: 21-25, 1982b
Wang PH, Beguinot F, Smith RJ. Augmentation of the effects of
insulin and insulin-like growth factors I and II on glucose up-
take in cultured rat skeletal muscle cells by sulfonylureas. Dia-
betologia 30: 797-803, 1987
Ward G, Harrison LC, Proietto J, Aitken P, Nankervis A. ou-
c1azide therapy is associated with potentiation of postbinding
insulin action in obese, non-insulin-dependent diabetic sub-
jects. Diabetes 34: 241-245, 1985
Williamson JR, Kilo C. Effect of tolbutamide (TOLB) treatment
on cardiovascular (CV) mortality in the University Group
Diabetes Program (UGDP). Abstracts of the 10th IDF, no. 663F,
p. 255, Excerpta Medica International Congress Services no.
481, 1979
Zaman R, Kendall MJ, Biggs PI. The effect of acebutolol and
propranolol on the hypoglycaemic action of glibenclamide.
British Journal of Clinical Pharmacology 13: 507-512, 1982
Authors' address: Dr Arne Me/ander, Professor of Clinical
Pharmacology, Division of Clinical Pharmacology, Department
of Research in Primary Health Care, Lund University Health Sci-
ences Centre , S-240 10 Dalby (Sweden).