Khalifa abdallah.glycemic control
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Transcript of Khalifa abdallah.glycemic control
Does Tight Glycemic Control
Improve CV Diabetic Complications?
Khalifa Abdallah
Prof. of Internal Medicine
Diabetes, Metabolism & Lipidology Unit
Alexandria Faculty of Medicine
No
UKPDS: elevated blood glucose levels increase the risk of diabetic complications
Study population: White, Asian Indian and Afro-Caribbean UKPDS patients (n = 4,585)
Adjusted for age, sex and ethnic group
Error bars = 95% CI Adapted from Stratton IM, et al. BMJ 2000; 321:405–412.
20
40
60
80
Incidence per
1,000 patient-years
5 6 7 8 9 10 11
Myocardial
infarction
Microvascular
disease
Updated mean HbA1c (%)
0 0
HbA1c
6.5%
Intensive vs. conventional management
Time from randomization (years)
Media
n A
1C (
%)
Conventional Treatment (n=1138)
Intensive Treatment (n=2729)
9
8
7
6
0 0 3 6 9 12 15
} 0.9%
Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.
UKPDS
NS = not significant; PVD = peripheral vascular disease.
*Per 1000 patient-years.
**Combined microvascular and macrovascular events.
Adapted from United Kingdom Prospective Diabetes Study Group (UKPDS) Lancet 1998;352:837-853.
Intensive Glucose Control Significantly Reduced Microvascular Disease
Rate* Conventional Intensive
glucose glucose control control % Risk
(n=2729) (n=1138) reduction p
Macrovascular events
• MI 17.4 14.7 16 0.052
• Stroke 5.0 5.6 –11 NS
• PVD 1.6 1.1 35 NS
• Diabetes-related death 11.5 10.4 10 NS
• All-cause mortality 18.9 17.9 6 NS
Microvascular events 11.4 8.6 25 0.0099
All events** 46.0 40.9 12 0.029
57% risk reduction
in non-fatal MI, stroke or CVD death*
(P = 0.02; 95% CI: 12–79%)
Cu
mu
lati
ve in
cid
en
ce o
f
no
n-f
ata
l M
I, s
tro
ke
or
de
ath
fro
m C
VD
Conventional
treatment
Intensive
treatment
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Years
0.06
0.04
0.02
0.00
Adapted from DCCT. N Engl J Med 1993; 329:977–986. DCCT/EDIC. JAMA 2002; 287:2563–2569.
DCCT/EDIC. N Engl J Med 2005; 353:2643–2653.
DCCT/EDIC: glycaemic control reduces the risk of non-fatal MI, stroke or death from CVD in type 1 diabetes
0
7
1 6
Hb
A1C (
%)
9
8
2 3 4 5 7 8 9
Conventional treatment
Intensive treatment
11 12 13 14 15 16 17 10
*Intensive vs conventional treatment
DCCT (intervention period EDIC (observational follow-up)
DCCT (intervention period) EDIC (observational follow-up)
Years
A1c Reduction With Intensive & Conventional Management
0 2 4 6 8 10
Years from randomization
5 7 3 1 9
8
9
10
7 HbA
1c (%
)
6
0
Intensive
Conventional
DCCT Research Group. N.Eng.J.Med. 1993;329:977–986.
9.1%
7.2%
UKPDS: Post-Trial Changes in HbA1c
UKPDS results
presented
Mean (95%CI)
UKPDS 80. N Eng J Med 2008; 359
After median 8.5 years post-trial follow-up
Aggregate Endpoint 1997 2007
Any diabetes related endpoint RRR: 12% 9%
P: 0.029 0.040
Microvascular disease RRR: 25% 24%
P: 0.0099 0.001
Myocardial infarction RRR: 16% 15%
P: 0.052 0.014
All-cause mortality RRR: 6% 13%
P: 0.44 0.007
RRR = Relative Risk Reduction, P = Log Rank
UKPDS: Legacy Effect of Earlier Glucose Control
N Eng J Med 2008
UKPDS: Post-Trial Monitoring: Patients
880
Conventional
2,118
Sulfonylurea/Insulin
279
Metformin
1997
# in survivor cohort
2002
Clinic
Clinic
Clinic
Questionnaire
Questionnaire
Questionnaire
2007
# with final year data
379
Conventional
1,010
Sulfonylurea/Insulin
136
Metformin
P
P
Mortality 44% (1,852) Lost-to-follow-up 3.5% (146)
Mean age
62±8 years
N Eng J Med 2008
Intensive vs. conventional management
Time from randomization (years)
Media
n A
1C (
%)
Conventional Treatment (n=1138)
Intensive Treatment (n=2729)
9
8
7
6
0 0 3 6 9 12 15
} 0.9%
Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.
UKPDS
Median A1c
Conventional : 7.9 %
Intensive : 7%
Key insights from the latest
randomised trials
ACCORD ADVANCE and VADT- No Significant Effect
on Macro or Micro Vascular Outcomes
ACCORD ADVANCE VADT
No. of participants 10,251 11,140 1791
Participant age ,years 62 66 60
Duration of diabetes at study entry, years
10
8
11.5
HbA1C at Baseline, % 8.1 7.5 9.4
Participants with prior cardiovascular event, %
35
32
40
Duration of follow-up, years
3.4 5.0
6
Summary of ACCORD, ADVANCE and VADT
ACCORD ADVANCE VADT
No. of participants 10,251 11,140 1791
Participant age ,years 62 66 60
HbA1C at Baseline, % 8.1 7.5 9.4
Significant Effect on Macrovascular Outcomes?
No No No
Significant Effect on Microvascular Outcomes?
NA Significant for nephropathy, not
retinopathy
No
Rosiglitazone use, (intensive vs. standard)
90% vs. 58% 17% vs. 11% 85% vs. 78%
Duration of follow-up, years
3.4
5.0
6
Summary of ACCORD, ADVANCE and VADT
ACCORD ADVANCE VADT
No. of participants 10,251 11,140 1791
Participant age ,years 62 66 60
HbA1C at Baseline, % 8.1 7.5 9.4
Significant Effect on Microvascular Outcomes?
NA Significant for nephropathy, not
retinopathy
No
Rosiglitazone use, (intensive vs. standard)
90% vs. 58% 17% vs. 11% 85% vs. 78%
Duration of follow-up, years
3.4
5.0
6
No
No
No
Significant Effect on Macrovascular Outcomes?
Summary of ACCORD, ADVANCE and VADT
Incidence of Severe Hypoglycemia (%)
ACCORD ADVANCE VADT
Intensive arm 16.2 2.7 21.2
Standard arm 5.1 1.5 9.9
A1c & Hypoglycemia Increase incidence of Hypoglycemia
HbA1c (%)
5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0
Complications
Hypoglycaemia
10.5
DCCT Research Group. N.Eng.J.Med. 1993;329:977–986.
Asymptomatic Episodes of Hypoglycemia May Go Unreported
• In a cohort of patients
with diabetes, more than
50% had asymptomatic
(unrecognized)
hypoglycemia, as
identified by continuous
glucose monitoring1
• Other researchers have
reported similar
findings2,3
1. Copyright © 2003 American Diabetes Association. Chico A et al. Diabetes Care. 2003;26(4):1153–1157. Reprinted with permission from the American Diabetes Association.
2. Weber KK et al. Exp Clin Endocrinol Diabetes. 2007;115(8):491–494. 3. Zick R et al. Diab Technol Ther. 2007;9(6):483–492.
0
25
50
75
100
All patients
with diabetes
Type 1
diabetes
Pat
ient
s, %
Type 2
diabetes
55.7 62.5
46.6
Patients With ≥1 Unrecognized
Hypoglycemic Event, %
n=70 n=40 n=30
Severe Hypoglycemia Causes QTc Prolongation
P=NS
P=0.0003
Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.
Euglycemic clamp (n=8)
Hypoglycemic clamp
2 weeks after glibenclamide withdrawal (n=13)
0
360
370
380
390
400
410
420
430
440
450
Me
an
QT
in
terv
al, m
s
Baseline (t=0)
End of clamp (t=150 min) ACCORD?
Significant QTc prolongation
during
hypoglycemia
Conclusions
• Although observational trials demonstrated
that the relationship between glycemic control
and CV diabetic complications was log-linear
and extended down to the normal A1c with no
threshold, yet randomized clinical trials failed
to confirm this hypothesis
• There is no solid evidence that tight glycemic
control ( A1c <6.5 %) has clear benefit on
reducing CV outcome in type 2 diabetic
individuals but there is definite evidence that
tight glycemic control increases the risk of
severe hypoglycemia
•Older patients with long standing
diabetes and existing co-morbidities do
not benefit from intensive glycemic
control
•Controlling nonglycemic risk factors
(hypertension, dyslipidemia, obesity, …)
with standard glycemic control (A1c <
7%) is still the recommended strategy to
prevent CV diabetic complications)
Conclusions-Cont.
Thank you