Cardiovascular Research 34 Ž1997.

73–80

Review
Sulfonylurea derivatives in cardiovascular research and in cardiovascular
patients
Carl E. Schotborgh a , Arthur A.M. Wilde a,b,)

a
Department of Clinical and Experimental Cardiology, Academic Medical Center, UniÕersity of Amsterdam, PO BOX 22700, 1100 DE Amsterdam,
Netherlands
b
The Heart-Lung Institute, UniÕersity of Utrecht, Utrecht, Netherlands
Received 28 October 1996; accepted 14 January 1997

Abstract

Sulfonylurea derivatives are hypoglycemic drugs frequently used in the treatment of non-insulin-dependent diabetes mellitus
ŽNIDDM.. In the b-cell sulfonylureas act by blocking ATP-sensitive potassium channels ŽK.ATP channels.. In several organ systems,

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including the cardiovascular system, sulfonylurea receptors and functional K.ATP channels have been identified. In the heart their role is
not clear; an endogenous cardioprotective effect has been suggested. There is no doubt that K.ATP channels are effectively blocked by
sulfonylureas. In the last decade sulfonylureas have been widely used as a pharmacological tool in experimental Žcardiac. research.
Blockade of K.ATP channels is the proposed cellular mechanism of action for all sulfonylurea-related effects. However, other membrane
currents are affected as well. In addition, myocardial metabolism is modified by sulfonylurea pretreatment. Hence, it should seriously be
questioned whether these drugs are suitable in assessing involvement of cardiac K.ATP channels in, for example, ischemia-related events.
The detrimental effects of sulfonylureas in experimental studies on myocardial ischemia have led to speculation whether the widespread
use of these drugs in patients with NIDDM, most often suffering from accompanying ischemic heart disease, should be reconsidered.
However, a review of the clinical literature reveals that the most consistent finding is a lower incidence of ventricular arrhythmias
associated with the use of glibenclamide, while no excess mortality has been shown for this agent in NIDDM with ischemic heart disease.
Despite some direct effects on systemic and coronary vasculature, there are, at present, no firm clinical data on the basis of which
sulfonylurea derivatives should be withheld from the cardiac patient.

Keywords: Sulfonylureas; Diabetes; Potassium channel, ATP-sensitive; Arrhythmias; Myocardial infarction; Myocardial ischemia

1. Introduction fonylurea receptors and functional K.ATP channels have

Sulfonylurea derivatives are hypoglycemic drugs fre-
quently used in the treatment of non-insulin-dependent
diabetes mellitus ŽNIDDM.. The mode of action of sul-
fonylureas on the b-cell has been elucidated and involves
blockade of the ATP-sensitive potassium channels ŽK.ATP
channels.. The b-cell sulfonylurea receptor has been puri-
fied and cloned w1x. In itself the sulfonylurea receptor
Žnamed SUR1. does not possess ion-conducting properties,
but together with an inwardly rectifying Kq channel Žcalled
Kir 6.2. it forms Kq channels with characteristics closely
resembling functional pancreatic K.ATP channels w2x. Sul-
been identified in several organ systems and their role and
function in physiological and pathophysiological states has
been described in many of them. In mitochondrial mem-
branes of various tissues, including myocardium, K.ATP
channels are also expressed w3–5x. On the molecular level
a second type of Žsarcolemmal. sulfonylurea receptor,
designated SUR2, has been identified, with the highest
expression levels in cardiac and skeletal muscle w6,7x. A
further subdivision has been described with the demonstra-
tion of a SUR2 subtype, designated SUR2A, exclusively
expressed in heart and skeletal muscle and SUR2B, ubiqui-
tously expressed in these and other extrapancreatic tissues

)
Corresponding author. Tel.: q31 20 5663265; fax: q31 20 6975458. Time for primary review 29 days.

0008-6363r97r$17.00 Copyright q 1997 Elsevier Science B.V. All rights reserved.

PII S 0 0 0 8 - 6 3 6 3 Ž 9 7 . 0 0 0 3 6 - 9
74 C.E. Schotborgh, A.A.M. Wilde r CardioÕascular Research 34 (1997) 73–80
w7,8x. In situ hybridization of the latter subtype shows
specific staining in the vascular structures of these tissues
and for example in the muscularis layer of intestine w7x. In
analogy with SUR1, co-expression of SUR2A and SUR2B
with Kir 6.2 reconstitutes functional K.ATP channels of
respectively the cardiac and skeletal type w6x and the
smooth muscle type w8x.
In general, K.ATP channels couple the metabolic state
of the cell to its electrical activity. Thus, in the b-cell a
regulatory role in determining insulin secretion has been
established. In systemic and coronary vasculature, K.ATP
channels are involved in the regulation of vascular tone w9x.
In neurons, K.ATP channels can modify neurotransmitter
release. However, in myocardial tissue the role is not clear;
an endogenous protective role has been suggested.
K.ATP channels are effectively blocked by sulfony-
lureas. This property has prompted many basic scientists to
use representatives of this group, most often gliben-
clamide, as a pharmacological tool in experimental re-
search. Blockade of K.ATP channels is the proposed cellu-
lar mechanism of action for all sulfonylurea-related effects.
Other effects of sulfonylurea derivatives have been de-
scribed as well but are seldom considered to play a role.
This review aims, in the first place, to address whether all
sulfonylurea effects are indeed to be explained by block-
ade of K.ATP channels.
Opening of myocardial K.ATP channels is cardioprotec-
tive, as is expressed in different functional and metabolic
variables w10x. Sulfonylureas consistently counteract the
beneficial effects of K.ATP channel openers Žsee Ref. w10x
for review.. In the absence of openers of K.ATP channels
sulfonylureas may even exert deleterious effects on is-
chemic hearts: for example, in terms of reduced time
before ischemic contracture develops w11,12x, increased
infarct size w13x, more stunning w11,14x, or prevention of
preconditioning w15x. However, ischemia-related arrhyth-
mias might be prevented by sulfonylurea pretreatment w16x.
The deleterious effects of sulfonylureas have led to specu-
lation whether the widespread use of these drugs in pa-
tients with NIDDM, most often suffering from accompany-
ing ischemic heart disease as well, should be reconsidered
w15–17x. In addition to the critical assessment of their
mechanism of action, relevant clinical data with respect to
these postulated deleterious effects will be discussed.
2. Effects on membrane currents
There can be no doubt that sulfonylurea derivatives
effectively block myocardial K.ATP channels. The most
widely used representative glibenclamide Žglyburide. is
one of the most potent sulfonylureas w18x. Clinically, in
patients on glibenclamide a wide concentration range is
encountered Ž0–1.5 mMrl; mean 0.5 mMrl. w19x. In vitro
experiments on isolated guinea-pig and rat ventricular
myocytes revealed that the efficacy of glibenclamide-in-
duced inhibition of myocardial K.ATP channels is, com-
pared to pancreatic b-cells, relatively low with a half-max-
imal inhibition concentration ŽIC 50 . in the order of 5–10
mM w20,21x. Although lower values for cardiac K.ATP
channels have been reported as well w22x, the affinity for
pancreatic K.ATP channels is presumably 3 orders of
magnitude higher w15,18,23,24x. In line with these findings
are the functional characteristics, including a higher affin-
ity for glibenclamide in the same order of magnitude of
SUR1 as of SUR2 w6x. Of particular relevance to the
question whether myocardial K.ATP channel block is in-
volved in the sulfonylurea-related deleterious effects is the
observation that its efficacy to block the channel is in-
creased by a reduction in pH w25x and is reduced after
prolonged metabolic stress w20,26x.
K.ATP channels are not the only cardiac ionic channels
inhibited by sulfonylureas. Recently, glibenclamide has
been demonstrated to block the cAMP-activated chloride
conductance Ž ICl, cAMP . w27x. The Hill coefficient for the
effect on ICl, cAMP and on K.ATP channels is roughly
similar, but the effective concentration range is consider-
ably higher Žhalf-maximal inhibition of ICl, cAMP "30 mM
w27x compared to 5–10 mM for half-maximal inhibition of
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K.ATP channels. Žsee above.. Glibenclamide also blocks
the cystic fibrosis transmembrane conductance regulator,
another chloride channel, expressed in the heart with un-
known function. The blocking action was irreversible with
half-maximal inhibition in a concentration range compara-
ble to affect ICl, cAMP w28x. It is not known whether factors
pertinent to ischemia modify the glibenclamide sensitivity
of these currents.
In non-cardiac tissue effects on other ion channelsrcur-
rents have been described. Whereas in pancreatic b-cells
sulfonylureas seem to be rather specific, with no effects at
relevant dosages on other Kq channels w29x, glibenclamide
has been shown to inhibit a voltage-gated, Ca2q- and
ATP-independent Kq current in the human neuroblastoma
cell line SH-SY5Y Žcells expressing several properties of
noradrenergic neurons. w30x. In vascular smooth muscle
cells glibenclamide Ž10 mM. has been shown to modulate
the L-type Ca2q channel current Žboth an increase and a
decrease have been described, depending on the presence
of the agonist BAY k-8644. w31x and to abolish, at the
single channel level, the potassium channel opener-induced
increase in the Ca2q-activated Kq channel w32x. In con-
trast, in isolated smooth muscle cells from rabbit portal
vein glibenclamide did not affect the Ca2q-activated Kq
channel w33x. In the same preparation glibenclamide inhib-
ited the potassium channel opener-induced block of the
oscillatory outward current w33x. This current is believed to
be elicited by Ca2q release from an intracellular store. The
modulating effects of both the potassium channel opener
pinacidil and glibenclamide suggest an effect on the kinet-
ics of calcium release from these stores, which putatively
represent the sarcoplasmic reticulum ŽSR.. A similar con-
 C.E. Schotborgh, A.A.M. Wilde r CardioÕascular Research 34 (1997) 73–80
clusion has been reached by Chopra et al. who described a
direct action of K.ATP channel modulators Žincluding
glibenclamide in concentrations ) 1 mM. on intracellular
calcium stores in cultured airway smooth muscle of the
rabbit w34x. Indeed, in skeletal muscle Ca2q transport
across the SR membrane is influenced by the state of Kq
channels in the SR membrane w35x. K.ATP channels may
be involved in this process.
3. Effects on myocardial energy metabolism
Sulfonylureas affect myocardial energy metabolism. In
aerobic rat hearts tolbutamide Žin clinically relevant
dosages. markedly stimulated glycogenolysis, glucose up-
take and utilization and at the same time decreased fatty
acid metabolism w36,37x. The latter effect is due to direct
inhibition of mitochondrial carnitine palmitoyltransferase,
which is the key regulatory enzyme in fatty acid oxidation
w38x. Alternatively, it may be speculated that blockade of
mitochondrial K.ATP channels, with, compared to the
sarcolemmal K.ATP channel, roughly similar affinity for
sulfonylureas w4x, is involved. As a result of stimulation of
anaerobic glycolysis lactate production is increased, prior
to any metabolic challenge w39,40x, and within 30 min
glycogen levels may decrease by 30% w36,37x. Due to
these effects the contribution of glucose metabolism to
ATP synthesis is greatly enhanced by tolbutamide w36,37x.
These effects, which are independent of insulin, are even
more pronounced in diabetic hearts w37x.
Observations that lactate production is inhibited during
myocardial hypoxia w20x and myocardial ischemia w41x
may reflect the reduced glycogen content prior to the
experimental event.
4. Impact on sulfonylurea action during metabolic inhi-
bition
Glibenclamide-sensitive effects during metabolic inhibi-
tion include hypoxia- and ischemia-related action potential
shortening, a rise in the extracellular potassium concentra-
tion ŽwKqx o ., a decrease in incidence of arrhythmias and
the occurrence of preconditioning. The question now to
address is whether it is possible that the sulfonylurea-in-
duced effects on membrane currents other than the K.ATP
channel or on myocardial glucose and free fatty acid
metabolism are of any relevance to these effects. It may be
argued that the relatively high concentrations needed to
affect other currents preclude any non-K.ATP channel
mediated effect. However, as mentioned before, with re-
gard to the blocking efficacy of glibenclamide, it has been
shown that intracellular pH sensitizes the channel to
75
glibenclamide w25x. Similar effects might be present for
any other sulfonylurea-mediated effect.
Particularly the shortening of the action potential and
the increased Kq efflux are widely believed to result from
hypoxiarischemia-induced activation of K.ATP channels.
This belief is almost exclusively based on the sulfonylurea
sensitivity of these phenomena Žsee Refs. w16x and w42x..
However, for example, with regard to the hypoxia-induced
action potential shortening a variety of other currents
might be involved, including ICl, cAMP as has been sug-
gested previously w43x. Indeed, modulation of the extracel-
lular chloride concentration and addition of chloride chan-
nel blockers Žwhich are devoid of any effect on the K.ATP
channel current. attenuate the early hypoxia-induced short-
ening of the action potential w44x. Hence, potentially the
glibenclamide-induced blockade of ICl, cAMP may be in-
volved in the attenuation of the hypoxia-related action
potential shortening. The observation that the forskolin-in-
duced shortening of the action potential is reversed by
glibenclamide w27x corroborates this suggestion. The 3–6-
fold difference in effective blocking concentration would
preclude glibenclamide-induced block of ICl, cAMP being
involved, but these values have been obtained in normoxic
conditions. Although in later stages of metabolic depriva-
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tion the glibenclamide K.ATP channel block becomes less
efficient w20,26x, no information is available on the block-
ing efficacy of other currents in similar conditions. We
have previously noted that the observed time-delay for the
channel to open in response to hypoxia w45x, ischemia w46x
or metabolic inhibition w47x is indeed difficult to reconcile
with involvement of K.ATP channels in early action poten-
tial shortening w42x.
In addition to theoretical considerations precluding a
causative role for any Kq channel in determining in-
creased Kq efflux, the latter arguments also hold for a
potential role of K.ATP channels in explaining increased
Kq efflux w42x. Further, the observation that glibenclamide
might prevent hypoxia-induced Kq efflux by "50%, which
occurred in the absence of any change in action potential
duration, also suggests that the sulfonylurea effect on Kq
efflux is not related to K.ATP channels w48x. Pivotal to an
alternative explanation for the sulfonylurea-induced effects
on Kq accumulation might be the reduced levels of glyco-
gen after pretreatment with sulfonylurea derivatives Žsee
above.. Such an effect will reduce glycolytic activity dur-
ing the subsequent ischemic episode. This may result in
less lactate production and in less intracellular acidifica-
tion. Attenuation of intracellular acidification has been
shown to be associated with less Kq accumulation w49x.
Indeed, ischemia-induced w41x and hypoxia-induced lactate
efflux w20x has been reported to be attenuated after gliben-
clamide pretreatment and we have observed an inverse
linear relationship between the pre-ischemic lactate pro-
duction by glibenclamide and the effect on extracellular
potassium wWilde et al., unpublished observationsx. In addi-
tion, 3 P-nuclear magnetic resonance spectroscopy during
76 C.E. Schotborgh, A.A.M. Wilde r CardioÕascular Research 34 (1997) 73–80
global ischemia in glycogen-depleted hearts Žby other
means, including which preconditioning. revealed less in-
tracellular acidification than in control hearts w50,51x. Ex-
tracellular acidification is not affected by glibenclamide in
a variety of species where it does attenuate the ischemia-
induced early rise in extracellular potassium w40x, but this
might well be a too crude measure for Žanaerobic. gly-
colytic activity. Lactate has been shown to reduce action
potential duration w52x, which in itself may involve K.ATP
channel activation w53x. Hence, the sulfonylurea-induced
decrease in lactate efflux may serve as an alternative
explanation for the related attenuation of action potential
shortening.
The favorable effects of sulfonylureas on the arrhyth-
mias during acute ischemia may relate to attenuation of the
action potential shortening and the attenuation of the rise
in wKqx o . Particularly slowing of conduction, which is
closely related to wKqx o , is considered to play a key role in
arrhythmogenesis in early ischemia.
With regard to preconditioning, two sulfonylurea-in-
duced effects can be regarded as seriously confounding
factors in explaining the modulatory effects of precondi-
tioning: Ž1. the effects on metabolism discussed above and
Ž2. the possible modulation of adenosine release, which
seems to be a critical mediator of preconditioning. In
general, preconditioning, which also leads to reduced
glycogen content prior to the index ischemic period, is
abolished by sulfonylureas Žsee Ref. w10x.. Pre-ischemic
reduction in glycogen content protects the heart from
subsequent prolonged ischemia, in terms of myocardial
injury Ži.e., preconditioning. w54x. However, the concomi-
tant sulfonylurea-induced prolonged action potential dur-
ing ischemia may outweigh this effect and therefore not
lead to attenuation of ischemic damage. Finally, gliben-
clamide has been shown to influence adenosine release.
Experimental results are controversial; ischemia-related
adenosine release in rabbits was not influenced by gliben-
clamide w55x, but in rats the 5X-nucleotidase-mediated
adenosine release was reduced by glibenclamide Žin a
concentration-dependent manner; EC 50 10 mM. w56x. Be-
cause the adenosine release during ischemia invoked in the
occurrence of preconditioning is mediated by the enzyme
5X-nucleotidase w57x, any sulfonylurea effect on this path-
way will have an impact on preconditioning.
In summary, in addition to blocking K.ATP channels
there are many other effects of sulphonylureas. Since these
effects might have impact on, probably all, ischemia-re-
lated events, the suitability of these drugs for assessment
of involvement of cardiac K.ATP channels has been seri-
ously questioned. Careful selection of the concentration
might provide useful information. However, in the absence
of relevant data on, for example, the blocking efficacy of
glibenclamide on other currents in pathophysiological con-
ditions, the statement that sulfonylureas cannot be used at
all to serve this purpose might even be correct. Likewise,
the use of glibenclamide to prove involvement of K.ATP
channels in vascular smooth muscle has been questioned
w58x.
5. NIDDM, sulfonylurea derivatives and cardiac disease
NIDDM patients are at increased risk of cardiovascular
morbidity and mortality w59,60x. In these patients sulfony-
lureas have always been the cornerstone of oral therapy
w61x, despite the early report of the University Group
Diabetes Program which suggested an association between
tolbutamide therapy and an increased risk of cardio-
vascular mortality w62x. However, shortly after its appear-
ance this report became extensively criticized for method-
ological and statistical reasons w63–65x. The results of 7
other epidemiological studies performed in the 1970s were
contradictory and not conclusive either w66x. Later Rytter et
al. retrospectively compared patients with IDDM to those
with NIDDM with respect to the prevalence and mortality
of acute myocardial infarction w60x. They found a signifi-
cantly higher mortality rate from acute myocardial infarc-
tion in NIDDM patients treated with oral hypoglycemic
agents than in NIDDM patients treated with insulin Ž50 vs
9.1%; distribution of hypoglycemic agents not specified..
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This difference could not be explained by better in-hospital
metabolic control in the insulin-treated patients. However,
the pre-hospital metabolic state, a determinant of outcome
in this study, was not reported for the two groups w60x. In
another analysis of diabetic patients presenting with my-
ocardial infarction, sulfonylurea treatment did not influ-
ence hospital outcome in terms of morbidity Žpump fail-
ure. and mortality w67x. In this study prior metabolic
control, assessed by glycosylated glucose, did not predict
outcome either. Finally, Ulvenstam et al. reported on the
long-term follow-up of diabetic men who survived a first
myocardial infarction w68x. Only a trend towards a higher
mortality among patients treated with sulfonylureas com-
pared to those on insulin ŽIDDM an NIDDM. was found
w68x. The interpretation of the results concerning the sub-
groups mentioned above is hampered by the small number
of patients and the lack of sufficient data on clinical
variables, such as metabolic control, infarction size and
concomitant treatment.
The discovery of the mode of action of sulfonylureas
Žblockade of pancreatic B-cell K.ATP channel. and of the
presence of K.ATP channels in the heart and vascular
tissue eventually gave rise to new discussions on the
clinical implications of the use of these agents in cardio-
vascular patients w15–17x. These discussions were largely
based on experimental data showing significant interaction
of sulfonylureas with the cardiovascular system. Most of
these, predominantly negative, data have been reviewed by
Smits and Thien w17x and by Leibowitz and Cerasi w15x and
will not be repeated here. We will focus on studies evaluat-
ing the Ždirect. cardiovascular effects of sulfonylureas in
man. In reviewing these data the principle interest is not
 C.E. Schotborgh, A.A.M. Wilde r CardioÕascular Research 34 (1997) 73–80
whether the sulfonylurea-related effects are mediated by
K.ATP channel block or not. As argued by Smits and
Thien w17x, plasma sulfonylurea concentrations in man on
chronic treatment may well be sufficient to block vascular
and cardiac K.ATP channels.
6. Direct cardiovascular effects of sulphonylureas in
man
6.1. Vascular tone
Whereas in different experimental models sulfonylureas
have been shown to interfere with coronary vascular smooth
muscle relaxation, there are no such data in man. In a
study by Nahser el al. w69x, evaluating maximal coronary
flow reserve and metabolic coronary vasodilation in dia-
betic and non-diabetic patients, no difference was found
between diabetic patients on insulin treatment and those on
sulfonylurea derivatives. This study, however, was not
designed to investigate the effects of these agents on
coronary flow characteristics. Furthermore, on the day of
the experiment oral hypoglycemic agents were withheld,
probably resulting in serum levels too low to elicit any
effect.
More data are available on the peripheral vascular
effects of sulfonylureas in man. The acute effects of
glibenclamide on baseline flow and hyperemic response to
arterial occlusion in the human calf were studied recently
w70x. After oral ingestion of 7.5 mg glibenclamide there
was a significant decline in baseline flow Ž30 and 42% of
control value after 1 and 2 h. and in peak reactive flow
Ž22, 30 and 28% of control value after 1, 2 and 3 h., and
an increase in the duration of the hyperemic response after
2 and 3 h. Total reactive hyperemic volume was not
significantly influenced by glibenclamide. Placebo did not
cause significant changes in any of these parameters w70x.
In another study it was demonstrated that the vasodilator
effect of diazoxide was significantly reduced by concomi-
tant infusion of glibenclamide w71x. An important finding
in these two studies is the fact that glibenclamide is able to
elicit measurable vascular effects at therapeutic serum
levels Ž250 ngrmls 0.5 mM. w19,72x. Taking into account
the high degree of binding to serum albumin Ž) 99%. w73x,
the serum levels of free glibenclamide in these studies
were lower than the threshold value for inhibition of the
effect of potassium channel openers on vascular activity
Ž25 ngrmls 0.05 mM. in the experimental model w74x.
These findings w70,71x might have clinical implications for
NIDDM patients with coronary disease treated with sul-
fonylureas. However, it should be emphasized that these
studies dealt with healthy volunteers and that there might
be different sensitivities for glibenclamide in coronary and
peripheral smooth muscle K-ATP channel receptors. In
addition, by design only the acute effects of the drugs were
investigated, but it has been demonstrated that gliben-
77
clamide induced an increase of the relative changes in
systemic vascular resistance index also after 4 weeks of
treatment whereas metformin, a biguanide, unrelated to
sulfonylureas, had no effect w75x.
6.2. Myocardial ischemia and preconditioning
Although the effect of sulfonylureas at therapeutic lev-
els on the human coronary vasculature remains to be
determined, some evidence that human myocardium is
sensitive to such levels of glibenclamide already exists.
The oral administration of 10 mg glibenclamide, prior to
the procedure, abolished the attenuation of ST-segment
shift at a second balloon inflation during coronary angio-
plasty w76x. Inhibition of collateral circulation recruitment
by glibenclamide as a possible explanation for this finding
was very unlikely Žbased on angiographic assessment.,
suggesting a direct myocardial effect of glibenclamide on
ischemic preconditioning. Also in an in vitro model using
right atrial trabeculae glibenclamide prevented ‘ischemic’
preconditioning w77x. Since preconditioning is thought to
protect the myocardium against subsequent ischemic
events, resulting in less extensive myocardial infarction
and better clinical outcome w78,79x, the use of gliben-
clamide might have deleterious effects in patients with
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repetitive myocardial ischemia treated with this agent.
6.3. Arrhythmias
In various experimental models of acute ischemia pre-
treatment with sulfonylureas proved antiarrhythmic during
myocardial ischemia w16x. Clinical data seem to corrobo-
rate these results. In a randomized crossover study in
NIDDM Žglibenclamide versus metformin., glibenclamide
significantly reduced the incidence of ventricular prema-
ture complexes and ventricular tachycardia during Žsponta-
neous. transient myocardial ischemia w80x. Glibenclamide
did not alter the ischemic burden nor did it interfere with
non-ischemia-related arrhythmias w80x. In a study on
NIDDM patients suffering from acute myocardial infarc-
tion, ventricular fibrillation ŽVF. occurred significantly
less frequently in the glibenclamide-treated group than in
NIDDM patients treated otherwise and than in non-diabet-
ics Ž1.7 vs 7.9 and 9.9%, respectively. w81x. Although
demographic, clinical and treatment parameters were com-
parable in the three groups, there was a much higher
mortality rate in the non-glibenclamide treated diabetic
patients, which was related to the higher incidence of heart
failure in this group w81x. This finding suggests the pres-
ence of an unknown confounder, prompting cautious inter-
pretation of the data from this study. On the other hand,
recently presented data from a large retrospective study on
patients with acute myocardial infarction, similarly showed
that the rate of VF in patients on glibenclamide was lower
than that for diabetics on gliclazide or insulin w82x. In this
study, in contrast to the former study w81x, VF rate was the
same as that of non-diabetics w82x.
78 C.E. Schotborgh, A.A.M. Wilde r CardioÕascular Research 34 (1997) 73–80
Studies involving first-generation sulfonylureas in dia-
betics with an acute myocardial infarction provided vari-
able results. A trend towards a higher incidence of early
VF was shown in diabetics on oral treatment Žmainly
sulfonylureas., as compared to those treated with insulin or
diet alone Ž12 vs 3 and 7%, respectively. w83x. In a similar
study comparing these three groups no difference in pri-
mary VF incidence was observed at all w84x. In both
studies time from onset of symptoms to hospital admis-
sion, a critical factor when it comes to the incidence of
primary VF, was however not reported.
6.4. Other effects
Some investigators reported a positive inotropic effect
of sulfonylureas w85,86x, whereas others failed to confirm
this finding w87,88x. In vitro studies showed evidence for
beneficial effects of certain sulfonylurea derivatives on
cardiovascular risk factors such as platelet aggregation and
fibrinolysis w15,66x. However, the clinical relevance of
these effects is unclear.
7. Summary
In summary, the most consistent finding concerning the
cardiac effects of sulfonylurea derivatives in NIDDM with
ischemic heart disease is the lower incidence of ventricular
arrhythmia associated with the use of glibenclamide, while
no excess mortality has been shown for this agent. The
effect of blockade of myocardial preconditioning by this
agent has still to be evaluated with respect to clinical
end-points. It should be noted that in the older studies an
excess of cardiovascular mortality in diabetics using sul-
fonylureas was an inconsistent finding and that in those
studies virtually only first-generation agents were used.
Furthermore, the findings of those studies might not be
applicable to current clinical practice. Based on the direct
effects described above there are, at present, no firm
clinical data on the basis of which sulfonylurea derivatives
should be withheld from the cardiac patient.
Acknowledgements
Dr. A.A.M. Wilde is a clinical investigator for the
Dutch Heart Foundation ŽNHS grant D95r014..
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