Clinical Applications
Coronary Artery Disease
and Sulfonylureas
Pr PJ GUILLAUSSEAU
Department of Internal Medicine, Hospital
Lariboisière PARIS, and University Paris VII,
Denis-Diderot (France)
MGSD 12th Meeting, ISTANBUL, April 28th 2007
Type 2 diabetes mellitus (T2DM) is
a major cardiovascular risk factor
(MRFIT Study)
o Epidemiological study of 347 978 men
including 5163 diabetic patients
o Follow-up duration 12 years
o Mortality x 3 in DM
12/1000 vs 4/1000 patient-years in
nondiabetics
(matched for BP, smoking, and total cholesterol)
(Stamler et al. Diabetes Care. 1993;16:343.)
T2DM and coronary heart disease risk
(Framingham study)
CV events
men
women
Stroke
Claudication
Congestive heart failure
Coronary events
Myocardial infarction
Angina pectoris
Sudden death
Coronary death
1
2
3
4
5
6
Relative risk adjusted for age
(nondiabetic risk 1)
(Kannel WB, et al. Am Heart J. 1990;120:672–676.)
Prevalence of coronary heart
disease in T2DM compared with
nondiabetic population
o Risk of coronary death x 2-3
(1st cause of death)
o 1/3 of acute myocardial infarctions
are observed in diabetic patients
o 1/3 of patients attending coronary
intensive care units are diabetic
Prehistory
of sulfonylureas
The UGDP study…
1970
University Group Diabetes
Program (UGDP)
o North-American multicenter study
o Duration: 8 years (1961-1969)
o 1027 patients randomized into 5 groups
• Placebo
• Tolbutamide
• Phenformin
• Insulin
• Insulin
-
diet
fixed dosage 1.5 g/d
fixed dosage 100 mg/d
fixed dosage
adjusted dosage
(Klimt C et al. Diabetes. 1970;19(suppl 2):747-783)
University Group Diabetes
Program (UGDP)
Cardiovascular mortality (%)
Placebo
Tolbutamide
Insulin fixed dosage
Insulin adjusted dosage
4.9
12.7
6.2
5.9
After 8 years follow-up
(Meinert et al. Diabetes. 1970;19(suppl 2):789-830)
University Group Diabetes Program
Meinert et al.
1970
« Historical » period:
Effect of intensive treatment
with
sulfonylureas/insulin
in prevention of CHD in T2DM
the UKPDS…
1998
SHN-insulin and myocardial infarction
(UKPDS 33 Lancet. 1998;352:837-853.)
% of patients with MI
30
Conventional
Intensive
P=0.06
20
Myocardial infarction fatal or
nonfatal, sudden death
573/3867 patients (15%)
10
0
Risk reduction 16%
(CI 95% 0-29%)
0
3
6
9
12
Years after randomization
15
SHN-insulin and myocardial infarction
% of patients with MI
(UKPDS 33 Lancet. 1998;352:837-853.)
40
Conventional (896)
30
Chlorpropamide (619)
Glibenclamide (615)
Insulin (911)
20
10
C v G v I
P =0.66
0
0
3
6
9
12
Years after randomization
15
Present:
Can we obtain a better CHD
preventive effect with 3rd
generation sulfonylureas than
with glibenclamide or other older
sulfonylureas?
2000-2007
Impact of antidiabetic treatment on
the risk of MI and mortality:
The French USIC Study
o Prospective study performed in Nov 2000
in 369/443 coronary intensive care units
o 2320 patients
including 487 with T2DM
- 44% treated with sulfonylureas
- 56% with insulin and/or other
antidiabetic oral agents)
(Danchin N, et al. Diabet Metab Res Rev. 2005;21:143-149.)
Impact of antidiabetic treatment on
the risk of MI and mortality:
The French USIC Study
Results in T2DM treated with SUs
compared with T2DM not treated with SUs
- global intra-hospital mortality
10.2% vs 16.9% P0.035
- relative risk of intra-hospital mortality
in multivariate analysis involving 2 models
RR 0.44 and 0.37 P0.020
(Danchin N, et al. Diabet Metab Res Rev. 2005;21:143-149.)
Impact of antidiabetic treatment on
the risk of MI and mortality:
The French USIC Study
Comparison of patients treated on
preadmission with SUs vs other treatments
-
Older; 71 vs 68 years
More often dysliproteinemia (52% vs 42%)
Similar HbA1c on admission
Similar type and localization of MI
Similar Killip index on admission
(Danchin N, et al. Diabet Metab Res Rev. 2005;21:143-149.)
In-hospital mortality in 1268 diabetic patients
hospitalized for MI in France at end of 2005,
according to use of SUs as preadmission
antidiabetic treatment
10
8.7%
* P=0.025
7.8%
8
6
4.1%
4
SUs -
2
0
No drug
SUs +
No
SUs
drug
+
(Danchin N, et al. Abstract, IDF 2006)
In-hospital mortality in 1268 diabetic patients
hospitalized for MI in France at end of 2005,
according to use of SUs as preadmission
antidiabetic treatment
8
7.8%
6
3.0 %
4
GLIC +
Glim
2
0
Glib
Glib
GLIC
+ Glim
(Danchin N, et al. Abstract, IDF 2006)
Impact of antidiabetic treatment on
the risk of MI and mortality:
Danish Register Study
o Cases included:
- 6738 patients (867 with T2DM) admitted to
hospital in North Jutland County for a
first-time MI
- age and sex-matched with 67 374 controls
(3148 T2DM)
from the Civil Registration System
o Identification of antidiabetic drugs in cases and
controls from the Pharmaco-Epidemiological
Database
(Johnsen SP, et al. Am J Therap. 2006;13:134-140.)
Impact of antidiabetic treatment on
the risk of MI and mortality:
Danish Register Study
Study criteria:
- Risk of first-time MI
- Mortality during 30 days post-MI
In T2DM compared with controls,
after adjustment for comorbidities and
associated treatments
(Johnsen SP, et al. Am J Therap. 2006;13:134-140.)
Impact of antidiabetic treatment on
the risk of MI and mortality:
Danish Register Study
Results (1): Risk of first-time MI in T2DM
compared with controls
 Treatment with « old » sulfonylureas
glibenclamide
OR: 2.08 (1.77-2.45)
tolbutamide (UGDP) OR: 2.32 (1.48-3.64)
= Treatment with « new» sulfonylureas
gliclazide
OR: 1.37 (0.84-2.22)
glimepiride
OR: 1.36 (0.93-1.99)
(Johnsen SP, et al. Am J Therap. 2006;13:134-140.)
Relative risk of 1st-time MI according
to antidiabetic treatment
OR 2.32
[1.48-2.64]
OR 2.08
[1.77-2.45]
2,5
2
OR 1.36
[0.93-1.99]
OR 1.37
[0.84-2.22]
1,5
C
Glib
Tolb
1
Glicl
0,5
Glimp
0
C
Glib
Tolb
Glicl
Glimp
(Johnsen SP, et al. Am J Ther. 2006;13:134-140.)
Impact of antidiabetic treatment on
the risk of MI and mortality:
Danish Register Study
Results (2): 30-day mortality after MI in T2DM
compared with controls
= Insulin
OR 1.27 (0.92-1.74)
= Treatment with « new » sulfonylureas
OR 1.00 (0.53-1.90)
gliclazide
OR 0.30 (0.07-1.32)
glimepiride
OR 1.65 (0.78-3.47)
 Treatment with « old » sulfonylureas
OR 1.29 (1.00-1.67)
(Johnsen SP, et al. Am J Therap. 2006;13:134-140.)
30-day post MI mortality according to
antidiabetic treatment
OR 1.29
[1.00-1.67]
1.4
1.2
OR 1.0
[0.53-1.90]
1
0.8
Controls
0.6
Glib/Tolb
0.4
Glic/Glim
0.2
0
Controls
Glib/Tolb
Glic/Glim
(Johnsen SP, et al. Am J Ther. 2006;13:134-140.)
Use of sulfonylureas and mortality
after MI in T2DM: Danish nationwide
population-based study
o All diabetic patients (n=6644) admitted for a
1st-time MI
from Jan 1st 1996 to Nov 30th 2004
o Analysis according to preadmission treatment
- « old » SHN (glibenclamide, glipizide,
tolbutamide)
- « new » SHN (gliclazide, glimepiride)
Thisted H, et al. Circulation. 2007, submitted)
Use of sulfonylureas and mortality
after MI in T2DM: Danish nationwide
population-based study
Results - 30-day mortality after admission:
o New SUs: 19.0%
gliclazide: 17.4%, glimepiride: 19.4%
o Old SUs: 25.9%
 New SHN vs old SHN
 25% RR of death (P=0.009)
(Thisted H, et al. Circulation. 2007 submitted)
Use of Sulfonylureas and mortality
after MI in diabetic patients:
Danish nationwide population-based study
1,2
1,08
-25%
0,81
0,8
old SHN
new SHN
0,4
0
old Sus
new Sus
Thisted H, et al. EASD 2006
Coronary death rate according to the
insulin-secreting agents associated with
metformin in T2DM (Florence Register)
Gliclazide/
Glimepiride
OR 2.09
[1.07;4.11]
Glibenclamide
Monami M, et al. Diabetes Metab Res Rev 2006;2:477-82
Impact of type of sulfonylurea on the
risk of MI and mortality:
Florence Register Study
o Cohort study; 568 consecutive T2DM
patients included Jan 1st 1998 and Dec
31st 2001
Follow-up until Dec 31st 2004 at the
Diabetes and Metabolic Diseases Clinic of
University of Florence
o Treated with sulfonylureas
- glibenclamide
378
- gliclazide
190
(Monami M, et al. Diabet Metab Res Rev. 2007)
Impact of type of sulfonylurea on the
risk of MI and mortality:
Florence Register Study
o Study criteria:
- all-cause mortality
- causes of death
o Mean follow-up duration:
- 5.0  1.6 years death
- 4.4  2.0 years coronary events
(Monami M, et al. Diabet Metab Res Rev. 2007)
All-cause mortality in T2DM
according to SUs treatment
Gliclazide
P  0.006
Glibenclamide
(Monami M, et al. Diabet Metab Res Rev. 2007)
Incidence of coronary events in T2DM
according to SUs treatment
Gliclazide
P 0.016
Glibenclamide
(Monami M, et al. Diabet Metab Res Rev. 2007)
CONCLUSIONS
• We now have strong evidence that
sulfonylureas are not the same with regard
to coronary heart disease
• « Old » sulfonylureas, such as
glibenclamide, tolbutamide, and glipizide,
have been found to be associated with a
higher risk of coronary events and death
after MI than the « new » sulfonylureas,
such as gliclazide and glimepiride
CONCLUSIONS
o It has been proposed that the different
properties of the new sulfonylureas, mainly
gliclazide, explain this favorable effect
o Specific antioxidant effects, as
demonstated by in vitro and in vivo studies
o Specificity of binding of gliclazide to cell SUR receptors, thus preserving the
myocardial preconditioning phenomenom
CONCLUSIONS
Whatever the protective mechanism
involved, possibly both, these
properties are of particular
importance when choosing an
insulinotropic agent for the treatment
of T2DM
See you soon
with the results of
ADVANCE study