1. Blood glucose: is lower better for diabetic patients?
Nizar ALBACHE Aleppo University- Diabetes Research Unit President of Syrian Endocrine Society Vice President of Mediterranean Group for Study of Diabetes

2. Miracle of insulin
Before insulin was discovered in 1921, everyone with type 1 diabetes died within weeks to years of its onset 4

3. Chronic complications of hyperglycemia
Hyperglycaemia ??

4. Glycemic Control on Diabetic Microvascular Complications
Type 2
UKPDS
8  7%
17-21%
24-33% -
HbA1c
Retinopathy
Nephropathy
Neuropathy
Type 1
DCCT
9  7%
76%
54%
60%
Kumamoto
69%
70%
DCCT Research Group, NEJM 1993, Ohkubo et al., Diab Res Clin Pract 1995, UKPDS Group, Lancet 1998

5. UKPDS:Intensive glycemic control reduces microvascular complications
All microvascular endpoints
Cataract extraction
Retinopathy
Microalbuminuria
25%
24%
21%
33%
Reference:
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837–853.
P =
P = 0.046
P = 0.015
P =

6. Rationale for near-normoglycemia Lessons from UKPDS: Better control means fewer complications
EVERY 1%
reduction in HBA1C
REDUCED RISK* 1%
-21%
Deaths from diabetes
-14%
Heartattacks
Microvascular complications
Lessons from UKPDS: better control means fewer complications
The UKPDS has proven beyond doubt that intensive glycaemic control is strongly associated with significant clinical benefits for patients with type 2 diabetes. In an epidemiological analysis of the UKPDS cohort every 1% decrease in HbA1C was associated with clinically important reductions in the incidence of
diabetes-related death ( 21%)
myocardial infarction ( 14%)
microvascular complications ( 37%)
peripheral vascular disease ( 43%)
There is no lower limit beyond which reductions in HbA1C cease to be of benefit. Taking diabetes-related death as an example, this means that:
 HbA1C of 2% delivers a 42% reduction in risk
 HbA1C of 3% delivers a 63% reduction in risk, and so on.
Therefore, the greater the reduction in HbA1C, the greater the protection against complications.
Stratton MI Adler AI, Neil AW, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:
-37%
Peripheral vascular disorders
-43%
*p<0.0001
UKPDS 35. BMJ 2000; 321:

7. chronic complications of hyperglycemia
Hyperglycaemia ??

8. Risk of myocardial infarction is increased in type 2 diabetes* †
60%
No prior myocardial infarction
Prior myocardial infarction
40%
Risk of fatal or non-fatal myocardial infarction * †
20%
In this Finnish-based, population study involving 2,432 individuals, patients with type 2 diabetes without any previous history of myocardial infarction (MI) were found to have as high a risk of an MI as non-diabetic patients with a history of MI.
These results suggest that cardiovascular risk factors should be treated as aggressively in diabetic patients as they are in non-diabetic patients with a history of cardiovascular disease.
Haffner SM. New Engl J Med 1998; 339:229–234. 0%
Non diabetic subjects
Type 2 diabetic subjects
n = 1,
Seven-year incidence in a Finnish-based cohort
*P < vs no prior MI
†P < vs no diabetes
Adapted from Haffner SM. New Engl J Med 1998; 339:229–234.

9. Recent Studies Evaluating Effect of Glycemic Control on CVD
ACCORD
ADVANCE
VADT

10. ACCORD: Action to Control Cardiovascular Risk in Diabetes
10,251 Enrollees
60% male 40% female
Mean age 62.2
Baseline HgA1c 8.1%
BMI - 32
30% macrovascular dx
Duration DM: 10 years
Majority of intensive group on 3-5 oral agents plus insulin
Hypoglycemia 3 times greater in intensive group

11. ACCORD: Treatment effects on glucose control
Time (years)
Standard therapy
Intensive therapy 6
9.0
8.5
8.0
7.5
7.0
6.5
6.0 1 2 3 4 5
ACCORD Study Group. N Engl J Med. 2008;358:

12. ACCORD: Treatment effect on primary outcome25 20
Standard therapy
HR 0.90 ( ) P = 0.16
Patients with events (%) 15 10
Intensive therapy 5 1 2 3 4 5 6
Time (years)
Primary Outcome: NFMI, NF Stroke or CVD Death
ACCORD Study Group. N Engl J Med. 2008;358:

13. February 7, 2008
Intensive glycaemic control arm terminated in 3.5 years (instead of 5.6 years as planned for)

14. ADVANCE Treatment effect on primary macrovascular outcome
CV death, MI stroke
Follow-up (months) 25 20 15 10 5 6 12 18 24 30 36 42 48 54 60 66
HR 0.94 ( ) P = 0.32
Standard control
Intensive control
Cumulative incidence (%)
ADVANCE Collaborative Group. N Engl J Med. 2008;358:

15. VADT - Veterans Administration Diabetes Trial
Primary Endpoint: no difference in CVD outcomes
Standard: 29.3% (predicted – 40%)
Intensive: 27.4% (predicted – 31.6%)

18. The intensive approach led to confusion over the best approach
It does not result in a significantly lower number of major CVA after 5 y
It led to more death
Reasons for the higher mortality in the intensive-therapy group are unknowns
Many factors could be implicated :

19. The intensive approach led to confusion over the best approach
Many factors could be implicated :
The severe hypoglycemia ?
The degree of reduction in A1c ?
The relatively short intervention period (3.7 years) ?
The observed The role of various drugs, drug combinations
or drug interactions; weight gain ?
interaction between the blood-pressure and hyperlipidemia
and glycemia trials with respect to mortality ?
It led to more death

20. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus
Lipid Values
Figure 1. Lipid Values. Shown are mean plasma levels of total cholesterol (Panel A), low-density lipoprotein (LDL) cholesterol (Panel B), and high-density lipoprotein (HDL) cholesterol (Panel C) and median levels of triglycerides (Panel D) at baseline, 4 months, 8 months, 1 year, and annually thereafter. Nominal P values for differences between the study groups at 4 months and at the end of the study were, respectively: total cholesterol, P<0.001 and P=0.02; LDL cholesterol, P=0.11 and P=0.16; HDL cholesterol, P<0.001 and P=0.01; and triglycerides, P<0.001 for both comparisons with the use of nonparametric tests. End-of-study visits were those that occurred in early 2009 and included follow-up at years 4, 5, 6, and 7. The I bars represent 95% confidence intervals. To convert the values for cholesterol to millimoles per liter, multiply by To convert the values for triglycerides to millimoles per liter, multiply by
The ACCORD Study Group. N Engl J Med 2010; /NEJMoa

21. Mean Systolic Blood-Pressure Levels at Each Study Visit
Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus
Mean Systolic Blood-Pressure Levels at Each Study Visit
Figure 1. Mean Systolic Blood-Pressure Levels at Each Study Visit. I bars indicate 95% confidence intervals.
The ACCORD Study Group. N Engl J Med 2010; /NEJMoa

22. Survival as a function of HbA1c in people with type 2 diabetes
Currie CJ, Peters JR, Tynan A et al.:Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study. Lancet 2010; 375: 481–89

23. Cardiovascular safety of diabetes drugs
The Truth Is Not So Sweet
The goal of marely lowering blood glucose levels in diabetes is too simplistic
With respect to CVD it appears important how you lower blood sugar as well as how much
Diabetes drugs, even within the same “class” may yield dramatically different CV outcomes

24. Conclusion: is lower better for diabetic patients?
The optimal mechanism, speed, and extent of glycated hemoglobin reduction are different for differing populations
Yes
For patients with recently diagnosed diabetes, aggressive treatment will lower cardiovascular risk
No :
For patients who have diabetes of more than 15 years’ duration and are older and have other comorbidities, less aggressive treatment is indicated
And
For all patients, treatment of the dyslipidemia and hypertension that are associated with diabetes further reduces CVD risk

25. The Promise Land of diabetes therapy
Thank you
Merci
شكراً

26. Number of Participants With One or More Severe Hypoglycemia Events
Requiring Medical Assistance (n and %)
Intensive Group
Standard Group
# Events ** n % 1
400
7.8
130
2.5 2 82
1.6 34
0.7
3 to 5 43
0.8 10
0.2
>5 6
0.1
**Cumulative number of events
The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358: 26

27. No! Can we blame it all on hypoglycemia? Intensive Strategy
Higher Rates of
Hypoglycemia
Higher Mortality
Intensive Strategy
Higher Rates of
Hypoglycemia
Higher Mortality
No!
The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358: 27

29. ACCORD: Study design
N = 10,251 with T2DM and existing CVD or additional CV risk factors
BP trial (n)
Lipid trial* (n)
SBP <120 mg Hg
SBP <140 mg Hg
Group A
Group B
A1C <6%
1178
1193
1383
1374
5128
Glycemia trial
A1C 7.0%-7.9%
1184
1178
1370
1391
5123
2362
2371
2753
2765
4733
5518
*Statin + fibrate vs statin, treatment group assignment blinded until end of trial Primary outcome: CV death, MI, stroke
ACCORD Study Group. Am J Cardiol. 2007;99(suppl):21i-33i.

30. A1c Levels at Baseline, at the Intensive-Therapy Group's Transition to Standard Therapy, and After the Transition in the ACCORD Trial
Time of A1c assessment
Intensive therapy, n=5128 (%)
Standard therapy, n=5123 (%)
Baseline
8.3
At transition
6.6
7.7
After transition
7.4
7.8

31. Tight glycemic control
Any benefits
mortality
Tight glycemic control

32. Any Diabetes-related Endpoint: legacy effect
Intervention Trial Median follow-up 10.0 years
Intervention Trial + Post-trial monitoring Median follow-up 16.8 years
RR=0.88 ( )
P=0.029
Conventional
Sulfonylurea/ Insulin

33. DCCT/EDIC; Memory effect
Metabolic Results
DCCT Intervention
S t u d y Y e a r
DCCT
EDIC Observation
Training
EDIC
Conventional
EDIC mean 8.2%
Intensive
EDIC mean 8.0%
DCCT/EDIC Study Research Group, NEJM 2005

34. Outcomes Primary Secondary
First occurrence of nonfatal MI, nonfatal Stroke, or death from CV disease.
Secondary
Death from any cause.
Also measured the effect of the intervention on microvascular disease, hypoglycemia, cognition, and quality of life.
cardiovascular causes included death from myocardial infarction, heart failure, arrhythmia, invasive cardiovascular interventions, cardiovascular causes after noncardiovascular surgery, stroke, unexpected death presumed to be from ischemic cardiovascular disease occurring within 24 hours after the onset of symptoms, and death from other vascular diseases
The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:

35. Observations
Targeting HbAIC levels below 6.0% increased the rate of death from any cause after a mean of 3.5 years
Magnitude of reduction
Speed of reduction
Rate of hypoglycaemia
Adverse drug interactions at high doses
compared with a strategy targeting levels of 7.0 to 7.9% in patients with a median glycated hemoglobin level of 8.1% and either previous cardiovascular events or multiple cardiovascular risk factors.
The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358: 35

36. The intensive approach led to confusion over the best approach
Many factors could be implicated :
The patients selection ?

37. The intensive approach led to confusion over the best approach
Many factors could be implicated :
The patients selection ?
The severe hypoglycemia ?

38. The intensive approach led to confusion over the best approach
Many factors could be implicated :
The patients selection ?
The severe hypoglycemia ?
The degree of reduction in A1c ?

39. ACCORD: Treatment effects on glucose control
Time (years)
Standard therapy
Intensive therapy 6
9.0
8.5
8.0
7.5
7.0
6.5
6.0 1 2 3 4 5
ACCORD Study Group. N Engl J Med. 2008;358:

40. The intensive approach led to confusion over the best approach
Many factors could be implicated :
The patients selection ?
The severe hypoglycemia ?
The degree of reduction in A1c ?
The relatively short intervention period (3.7 years) ?

41. The intensive approach led to confusion over the best approach
Many factors could be implicated :
The patients selection ?
The severe hypoglycemia ?
The degree of reduction in A1c ?
The relatively short intervention period (3.7 years) ?
The observed The role of various drugs, drug combinations, or drug interactions; weight gain ? to

43. ACCORD: Treatment effect on all-cause mortality
Time (years) 25 20 15 10 5 1 2 3 4 6
Standard therapy
Intensive therapy
HR 1.22 ( ) P = 0.04
CVD Death:
HR 1.35 (1.04–1.76)
P=0.02
Patients with events (%)
ACCORD Study Group. N Engl J Med. 2008;358:

44. ADVANCE: Action in Diabetes and Vascular Disease
Goal: To examine effects of reducing HgA1c to < 6.5% and routine use of fixed dose ACE-thiazide combination in >55 y/o Type 2 DM
11,140 Enrollees
60% male 40% female
Mean age 66
50% macrovascular dx
10% microvascular
Baseline HgA1c: 7.51%
“standard” : 7.30% Intensive: 6.53%

45. ADVANCE Treatment effect on glucose control
Follow-up (months)
Standard control
Intensive control
10.0
9.0
8.0
7.0
6.0
5.0
0.0 6 12 18 24 30 36 42 48 54 60 66
P < 0.001
Mean A1C (%)
ADVANCE Collaborative Group. N Engl J Med. 2008;358:

46. ADVANCE 11,140 Patients, Age ~66, With Type 2 DM, And High CV Risk
Intensive (A1c 6.4%) vs Conventional (A1c 7.3%)
Benefit with regard to microvascular complications
No Excess Mortality In Intensive Group

47. VADT - Veterans Administration Diabetes Trial
BMI 31.3
Majority had multiple CV risk factors
72% HTN
40% macrovascular dx
62% retinopathy
43% neuropathy
1742 Enrollees
97% male
Mean age 60.4

48. confusion over the best approach to cardiovascular risk reduction

49. Patients selection in ACCORD & UKPDS
Duration DM: 10 years
30% macrovascular dx
Majority of intensive group on 3-5 oral agents plus insulin
UKPDS
Newly diagnosed
Less CVD
Less therapeutic combinations

50. What HbA1c goal should we try to achieve?
In newly diagnosed diabetes, the goal is clear:
treat to a target HbA1c =6.5-7% (Take advantage of the legacy effect and metabolic memory)
In older patients with multiple comorbidities and diabetes of long duration;
The HbA1c =7.5% and 8% may be more appropriate
To reduce the CVD, treat the dyslipidemia and hypertension
In some patients who have had diabetes for more than 10 years:
may not be able to sense hypoglycemiaglucose monitoring
In patients whose hyperglycemia is not coming down despite our best efforts (multiple antihyperglycemic agents):
it may be appropriate to try to determine the cause of the inadequate response