1. Does Tight Glycemic Control
Improve CV Diabetic Complications?
No
Khalifa Abdallah
Prof. of Internal Medicine
Diabetes, Metabolism & Lipidology Unit
Alexandria Faculty of Medicine

2. UKPDS: elevated blood glucose levels
increase the risk of diabetic complications
80
HbA1c
6.5%
Microvascular
60 disease
Incidence per Myocardial
40
1,000 patient-years infarction
20
0
0 5 6 7 8 9 10 11
Updated mean HbA1c (%)
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.

3. UKPDS
Intensive vs. conventional management
9
Conventional Treatment (n=1138)
} 0.9%
8
Intensive Treatment (n=2729)
Median A1C (%)
7
6
0
0 3 6 9 12 15
Time from randomization (years)
Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.

4. 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
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.

5. DCCT/EDIC: glycaemic control reduces the risk of non-
fatal MI, stroke or death from CVD in type 1 diabetes
9
Conventional treatment
HbA1C (%)
8
Intensive treatment
7
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Years
DCCT (intervention period EDIC (observational follow-up)
0.06
Cumulative incidence of
non-fatal MI, stroke or
death from CVD
57% risk reduction
0.04 in non-fatal MI, stroke or CVD death* Conventional
(P = 0.02; 95% CI: 12–79%) treatment
0.02 Intensive
treatment
0.00
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
DCCT (intervention period) EDIC (observational follow-up) Years
*Intensive vs conventional treatment
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.

6. A1c Reduction With Intensive &
Conventional Management
10
Conventional
9.1%
9
HbA1c (%)
8
Intensive
7.2%
7
6
0
0 1 2 3 4 5 6 7 8 9 10
Years from randomization
DCCT Research Group. N.Eng.J.Med. 1993;329:977–986.

7. UKPDS: Post-Trial Changes in HbA1c
Mean (95%CI)
UKPDS results
presented
UKPDS 80. N Eng J Med 2008; 359

8. UKPDS: Legacy Effect of Earlier Glucose
Control
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
N Eng J Med 2008

9. UKPDS: Post-Trial Monitoring: Patients
1997 2002 2007
# in survivor cohort # with final year data
2,118 Clinic Questionnaire 1,010
Sulfonylurea/Insulin Sulfonylurea/Insulin
P
880 Clinic Questionnaire 379
Conventional Conventional
P
279 Clinic Questionnaire 136
Metformin Metformin
Mean age Mortality 44% (1,852)
62±8 years Lost-to-follow-up 3.5% (146)
N Eng J Med 2008

10. UKPDS
Intensive vs. conventional management
9
Conventional Treatment (n=1138)
} 0.9%
8
Intensive Treatment (n=2729)
Median A1C (%)
7
Median A1c
6
Conventional : 7.9 %
Intensive : 7%
0
0 3 6 9 12 15
Time from randomization (years)
Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.

11. Key insights from the latest
randomised trials

12. 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 10 8 11.5
study entry, years
HbA1C at Baseline, % 8.1 7.5 9.4
Participants with prior 35 32 40
cardiovascular event, %
Duration of follow-up, 3.4 5.0 6
years

13. 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 No No No
Macrovascular
Outcomes?
Significant Effect on NA Significant for No
Microvascular nephropathy, not
Outcomes? retinopathy
Rosiglitazone use, 90% vs. 58% 17% vs. 11% 85% vs.
(intensive vs. standard) 78%
Duration of follow-up, 3.4 5.0 6
years

14. 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 NA Significant for No
Microvascular nephropathy, not
Outcomes? retinopathy
Rosiglitazone use, 90% vs. 58% 17% vs. 11% 85% vs.
(intensive vs. standard) 78%
Duration of follow-up, 3.4 5.0 6
years
Significant Effect on
Macrovascular No No No
Outcomes?

15. 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

16. A1c & Hypoglycemia
Increase incidence of Hypoglycemia
Complications
Hypoglycaemia
5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5
HbA1c (%)
DCCT Research Group. N.Eng.J.Med. 1993;329:977–986.

17. Asymptomatic Episodes of Hypoglycemia May Go
Unreported
100 • In a cohort of patients
with diabetes, more than
75
62.5 50% had asymptomatic
Patients, %
55.7
46.6 (unrecognized)
50
hypoglycemia, as
25
identified by continuous
glucose monitoring1
n=70 n=40 n=30
0
All patients Type 1 Type 2 • Other researchers have
with diabetes diabetes diabetes reported similar
Patients With ≥1 Unrecognized findings2,3
Hypoglycemic Event, %
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.

18. Severe Hypoglycemia Causes QTc Prolongation
450 P=0.0003
440
Mean QT interval, ms
430
420 P=NS
410
400
390
380 Significant QTc prolongation
370 during
360 hypoglycemia
0
Euglycemic clamp Hypoglycemic clamp
(n=8) 2 weeks after
glibenclamide withdrawal
Baseline (t=0) (n=13)
End of clamp (t=150 min)
ACCORD?
Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.

23. 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

24. Conclusions-Cont.
• 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)

25. Thank you