(Circulation. 1998;97:1427-1428.)
© 1998 American Heart Association, Inc.
Sulfonylureas and Cardiovascular Mortality in Diabetes: A Class Effect?
Thomas C. Wascher, MD
Department of Internal Medicine,
Diabetes and Metabolism Unit,
University of Graz,
Graz, Austria
To the Editor:
In a recent issue of Circulation, Cleveland and
coworkers1 provided excellent evidence that in
diabetic patients, chronic inhibition of the KATP
channel with oral sulfonylureas abolishes ischemic
preconditioning of explanted myocardium. The authors
conclude that this phenomenon might contribute to the increased
cardiovascular mortality in sulfonylurea-treated
diabetic patients, as found in the University Group Diabetes Programme
(UGDP).2 This extension of their findings in mainly
glibenclamide-treated patients (6 and 1 glipizide) to sulfonylureas as
a class, however, must be seen with some limitations because neither
experimental nor clinical data suggest a uniform effect of different
sulfonylureas on the cardiovascular system.
In experimental animals, inhibition of the cardiac
KATP channel with glibenclamide has been shown to
increase ischemia-reperfusion damage,3
whereas gliclazide, a sulfonylurea with pronounced in vivo
antioxidative properties,4 prevented such
damage.5
In studies in the human forearm, significant interaction with the
vascular KATP channel was found for
glibenclamide, whereas the effect was much less pronounced for
tolbutamide6 and even absent for the new drug
glimepiride.7
For tolbutamide (the sulfonylurea used in the UGDP), further evidence
of an increased cardiovascular morbidity in comparison
to glibenclamide or gliclazide was recently
reported,8 and a possible substance-specific
cardiotoxicity was suggested. Tolbutamide, as a first-generation
sulfonylurea, is used in the highest dose (up to 3000 mg) of all
currently available sulfonylureas (for review, see Reference 9). In a
recent survey from Australia, neither glibenclamide- nor
gliclazide-treated patients with myocardial infarction had higher
mortality rates than insulin-treated diabetic
patients.10 In the same survey,
glibenclamide-treated patients, on the other hand, had significantly
less ventricular fibrillation than those receiving
gliclazide or insulin.
Taken together, these data suggest that sulfonylureas, despite their
comparable actions on the pancreatic beta-cell
KATP channel, strongly differ in their ability to
interfere with vascular or cardiac KATP channels.
As a result, different effects on preconditioning, arrhythmias,
and reperfusion damage are reported. Therefore I suggest that based on
our current knowledge, a class effect of sulfonylureas with regard to
an increased cardiovascular risk must not be
hypothesized, and the effect described by Cleveland and coworkers must
be restricted to the substance(s) investigated.
References
1.
Cleveland JC, Meldrum DR, Cain BS, Banerjee A, Harken AH.
Oral sulfonylurea hypoglycemic agents prevent ischemic
preconditioning in human myocardium.
Circulation. 1997;96:29–32.[Abstract/Free Full Text]
2.
Klimt CR, Knatterud GL, Meinert CL, Prout TE. A study of the
effects of hypoglycemic agents on vascular complications in patients
with adult-onset diabetes. Diabetes. 1970;19:747–830.
3.
Cole W, McPherson C, Sontag D. ATP-regulated K+ channels
protect the myocardium against ischemic/reperfusion
damage. Circ Res. 1991;69:571–581.[Abstract/Free Full Text]
4.
Jennings PE, Scott NA, Saniabadi AR, Belch JJF. Effects of
gliclazide on platelet reactivity and free radicals in type II
diabetic patients: clinical assessment.
Metabolism. 1992;41(suppl 1):36–39.
5.
Shimabukuro M, Nagamine F, Murakami K, Oshiro K, Mimura G.
Chronic gliclazide treatment affects basal and post-ischemic
cardiac function in diabetic rats. Gen Pharmacol. 1993;25:697–704.
6.
Bijlstra PJ, Russel FGM, Thien T, Lutterman JA, Smits P.
Effects of tolbutamide on vascular ATP-sensitive potassium channels in
humans. Horm Metab Res. 1996;28:512–516.[Medline]
[Order article via Infotrieve]
7.
Bijlstra PJ, Lutterman JA, Russel FG, Thien T, Smits P.
Interaction of sulphonylurea derivatives with vascular
KATP channels in man. Diabetologia. 1996;39:1083–1090.[Medline]
[Order article via Infotrieve]
8.
vanStaa TP, Abenhaim L. Risk of adverse
cardiovascular effects in sulfonylurea users.
Pharmacoepidemiol Drug Safety. 1996;5:221. Abstract.[Medline]
[Order article via Infotrieve]
9.
Leibowitz G, Cerasi E. Sulphonylurea treatment of NIDDM
patients with cardiovascular disease: a mixed blessing?
Diabetologia. 1996;39:503–514.[Medline]
[Order article via Infotrieve]
10.
Davis TME, Parsons RW, Broadhurst R, Hobbs M, Jamrozik K.
Arrhythmias and mortality after myocardial infarction in
diabetic patients: relationship to diabetes treatment.
Diabetologia. 1996;39(suppl 1):A51. Abstract.
Response
Joseph C. Cleveland, Jr, MD;
Daniel R. Meldrum, MD;
Brian S. Cain, MD;
Anirban Banerjee, PhD;
; Alden H. Harken, MD
University of Colorado Health Sciences Center,
Department of Surgery,
Denver, Colo
We appreciate the interest of Dr Wascher in our recently
published work concerning chronic oral sulfonylurea ingestion and the
inhibition of myocardial preconditioning in human
tissue.1 Dr Wascher offers a very insightful
hypothesis to explain our findings. He astutely notes that the patients
reported in our series were taking either glibenclamide or glipizide,
and he questions whether our results can be uniformly extrapolated to
suggest that all sulfonylureas inhibit ischemic preconditioning
in human myocardium.
We agree with Dr Wascher that a uniform consistency of
cardiovascular KATP channel
inhibition with differing oral sulfonylureas is not
evident.2 3 Nevertheless, his hypothesis that our
results may only apply to glibenclamide- or glipizide-treated patients
can neither be supported nor refuted on the basis of our data. We argue
that it remains unknown whether other sulfonylurea agents could inhibit
ischemic preconditioning in human myocardium
because we did not encounter any patients who were taking agents other
than glibenclamide or glipizide. We certainly believe, however, that Dr
Wascher's observations are valid, and he raises a critically
important question of whether we can conclude that all sulfonylureas
could produce the same inhibitory effect on
ischemic preconditioning.
We believe that one other comment is important. In our opinion, it is
increasingly evident that the KATP channel plays
a central role in ischemic preconditioning in human
myocardium.1 4 5 Although our study
associates chronic KATP channel blockade with
inhibition of human preconditioning, it also questions whether chronic
inhibition of the KATP channel could explain the
increased cardiovascular mortality observed in the UDGP
study.6 While the particular sulfonylureas that
were studied may provide further insights into agent specific
cardiovascular mortality, we think the potential
significance of our data lies in the linking of the
KATP channel to cardioprotection of
ischemic preconditioning in human
myocardium.
Insightful questions by investigators such as Dr Wascher are
enlightening and extraordinarily valuable to properly interpret our
data. We think his hypothesis is plausible, and we await further
experience with other sulfonylurea agents in human myocardial
preconditioning to answer these relevant and valid questions.
References
1.
Cleveland JC, Meldrum DR, Cain BS, Banerjee A,
Harken AH. Oral sulfonylurea hypoglycemic agents prevent
ischemic preconditioning in human myocardium.
Circulation. 1997;96:29–32.
2.
Cole W, McPherson C, Sontag D. ATP-regulated K+ channels
protect the myocardium against ischemic/reperfusion
damage. Circ Res. 1991;69:571–581.
3.
Shimabukuro M, Nagamine F, Murakami K, Oshiro K, Mimura G.
Chronic gliclazide treatment affects basal and post-ischemic
cardiac function in diabetic rats. Gen Pharmacol. 1993;25:697–704.
4.
Speechly-Dick ME, Grover GJ, Yellon DM. Does ischemic
preconditioning in the human involve protein kinase C and the
ATP-dependent K+ channel? Circ Res. 1995;77:1030–1035.[Abstract/Free Full Text]
5.
Tomai F, Crea F, Gaspardone A, Versaci F, Depaulis R, Penta de
Peppo A, Chiarello L, Gioffre PA. Ischemic preconditioning
during coronary angioplasty is prevented by glibenclamide, a
selective ATP-sensitive K+ channel blocker. Circulation. 1994;90:700–705.[Abstract/Free Full Text]
6.
Klimt CR, Knatterud GL, Meinert CL, Prout TE. A study of the
effects of hypoglycemic agents on vascular complications in patients
with adult-onset diabetes. Diabetes. 1970;19:747–830.
