1. Comprehensive Glycaemic Control
Prof. ADEL A EL-SAYED MD
Chair Elect
Middle East and North Africa (MENA) Region
International Diabetes Federation (IDF)
Professor of Internal Medicine
Sohag Faculty of Medicine
Sohag-EGYPT
422HQ10PM039

2. Glycaemic targets are going unmet with current
treatments
80 P<.001
Shortcomings
70
of current treatments
Treatment Goal at 8 y, %
60
Patients Obtaining
P=.001
50
• Glucose control is difficult 40
even with intensification of
30
therapy P=.06
20
• Treatment related trade-offs 10
• Weight gain 0
HbA1c Systolic BP Cholesterol
• Hypoglycaemia <6.5% <130 mm Hg <4.5 mmol/L
Intensive (n=63) Conventional (n=67)
Conventional therapy was according to 2000 revised Danish Medical Association guidelines (diet alone, oral hypoglycaemic drugs,
and/or insulin);
intenassive therapy added behaviour modification and pharmacologic therapy that targeted hyperglycaemia, hypertension,
dyslipidaemia, and microalbuminuria, and added aspirin for secondary prevention of cardiovascular disease

3. Current management often fails to achieve
glycaemic targets
EUROPE LATIN AMERICA
(CODE-2)1 (DEAL)2
31%
HbA1c ≤6.5% 43% HbA1c ≤7%
69% 57%
CANADA USA
(DRIVE)3 (NHANES)4
53% 37%
HbA1c ≤7% HbA1c <7%
47% 63%
HbA1c above target HbA1c at or below target
1. Liebl A, et al. Diabetologia. 2002;45:S23-S28. 2. Lopez Stewart G, et al. Rev Panam Salud Publica. 2007;22:12-20. 3. Braga M, et
al. Presented at ADA 68th Scientific Sessions; 2008: Poster 1189-P. 4. Saydah SH, et al. JAMA. 2004;291:335-42.

4. Disease progression ultimately overwhelms
current medications
10
9
HbA1c (%)
8
7
6
Duration of diabetes
Del Prato S, et al. Int J Clin Pract. 2005,59:1345-55.

5. Early achievement and maintenance of glycaemic control
reduces the incidence of long-term complications
UKPDS: Early intensive therapy in newly diagnosed type 2 diabetes significantly
reduces long-term complications
Kaplan-Meier plots for cumulative incidence of clinical outcomes
Myocardial infarction Microvascular Disease
1.0 1.0
Proportion with event
Proportion with event
P=0.01 P=0.001
0.8 0.8
0.6 0.6
Conventional Conventional
therapy therapy
0.4 0.4
0.2 0.2
Sulphonylurea- Sulphonylurea-
insulin insulin
0.0 0.0
0 5 10 15 20 25 0 5 10 15 20 25
Years since randomisation Years since randomisation
No. At Risk
Conventional
therapy 1138 1013 857 578 221 20 1138 1018 844 508 172 13
Sulphonylurea-
insulin 2729 2488 2097 1459 577 66 2729 2465 2076 1368 488 53
Holman R, et al. N Engl J Med. 2008;359:1577-89.

6. Achieving comprehensive glycaemic control
requires 1 an action on both FPG and PPG
HbA1c= Fasting Glucose + Postprandial Glucose
Relative contributions of postprandial and fasting hyperglycemia (%) to the
overall diurnal hyperglycemia
FPG PPG
100
80
Contribution (%)
60
40
20
0
<7.3 7.3-8.4 8.5-9.2 9.3-10.2 >10.2
n=58 n=58 n=58 n=58 n=58
HbA1c (%)
Monnier L, et al. Diabetes Care. 2003;26:881-5.

7. Need for comprehensive glycaemic control
2 Excessive fluctuations in daily glucose levels contribute to symptoms,
complications and impaired QoL
glucose level
Daily plasma
1. Kleefstra N, et al. Neth J Med. 2005;63:215-21. 2. Monnier L, et al. JAMA. 2006;295:1681-7. 3.
Cerriello A, et al. Nutr Metab Cardiovasc Dis. 2006;16:453-6. 4. Mitri J, Hamdy O. Expert Opin Drug Saf.
2009;8:573-84. 5. Marrett E, et al. Diabetes Obes Metab. 2009;11:1138-44.

8. Inter-relationship between overweight/obesity, diabetes and
CV risk: potential impact of treatment-related weight gain
+
Weight gain/
obesity
Treatment-
related weight +
gain, and/or
weight gain
through Diabetes CV risk
“defensive
snacking”
because of
-
hypoglycaemia
Glucose-
lowering
therapy
Increases CV risk Decreases CV risk

9. The incidence of severe hypoglycaemic episodes
increases with duration of treatment
episode of severe hypoglycaemia
Proportion reporting at least one
Type 2 DM sulphonylureas (n= 103)
0.6 Type 2 DM <2 years insulin (n= 85)
Type 2 DM >5 years insulin (n= 75)
Type 1 DM <5 years (n= 46)
Type 1 DM >15 years (n= 54)
0.4
Annual
0.2 Prevalence
= 7%
0.0
Treated with <2 yrs >5 yrs <5 yrs >15 yrs
sulphonylurea of insulin treatment of insulin treatment
Type 2 diabetes Type 1 diabetes
Error bars, 95% confidence interval.
 The proportion of patients with type 2 diabetes experiencing severe hypoglycaemia was
similar for those treated with sulphonylureas or insulin for <2 years (7% in both
groups)
UK Hypoglycaemia Study Group. Diabetologia. 2007;50:1140-7.

10. ‘Defensive snacking’ as a potential mechanism
for weight gain in diabetes
 In the DCCT, insulin-treated patients with severe hypoglycaemia had a
significantly (P<0.05) greater increase in weight than those without severe
hypoglycaemia during the study1
Patients
with severe +6.8 kg
hypoglycaemia
Patients
without severe +4.6 kg
hypoglycaemia
0 2 4 6 8
Weight gain (kg)
 A potential explanation for this is “defensive snacking” - an increase in a
patient’s carbohydrate intake following hypoglycaemia due to their fear of
further events2
1. DCCT Research Group. Diabetes Care 1988;11:567-73. 2. Russell-Jones D, Khan R. Diabetes Obes
Metab. 2007;9:799-812.

11. Most current therapies result in weight gain
over time
UKPDS: up to 8 kg ADOPT: up to 4.8 kg
in 12 years1 in 5 years2
8 100 Annualised slope (95% CI)
Insulin (n=409)
Rosiglitazone, 0.7 (0.6 to 0.8)
7 Metformin, -0.3 (-0.4 to -0.2)
Glibenclamide, -0.2 (-0.3 to 0.0)
6
Change in weight (kg)
96
5
Weight (kg)
Glibenclamide (n=277)
4
92
3
Conventional (n=411)*
2
88
Treatment difference (95% CI)
1 Rosiglitazone vs metformin
6.9 (6.3 to 7.4); P<0.001
Metformin (n=342) Rosiglitazone vs glibenclamide,
0 2.5 (2.0 to 3.1); P<0.001
0
0 3 6 9 12 0 1 2 3 4 5
Years Years
* Conventional treatment; diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/L (>270 mg/dL)
n=at baseline
1. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-65. 2. Kahn SE, et al (ADOPT).
N Engl J Med. 2006;355:2427-43.

12. Oral anti hyperglycaemia drugs and their effect
on HbA1c and weight change
Weight loss
Metformin
DPP-4 Inhibitors
HbA1c increase HbA1c decrease
TZDs
Weight gain
Sulphonylureas

13. Injectable anti hyperglycaemic drugs and their
effect on HbA1c and weight change
Weight loss
GLP-1 analogues
HbA1c increase HbA1c decrease
Weight gain
Insulin

14. Summary
• Diabetes treatment usually fails with time. So, it
requires a more proactive approach
• HbA1c is important but does not accurately reflect
glycaemic fluctuations
• Hypoglycaemia and weight gain may be barriers to
tight glycaemic control
• Drugs need to be chosen with a view to achieve tight
glycaemic control with a low propensity for
hypoglycaemia and/or weight gain