Post on 18-Dec-2014
description
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
Glycaemic targets are going unmet with current treatments
Shortcomings
of current treatments
• Glucose control is difficult
even with intensification of therapy
• Treatment related trade-offs
• Weight gain
• Hypoglycaemia
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
Pat
ien
ts O
bta
inin
g Tr
eat
me
nt
Go
al a
t 8
y, %
80
70
60
50
40
30
20
10
0
P<.001
P=.001
P=.06
HbA1c
<6.5% Systolic BP
<130 mm Hg Cholesterol
<4.5 mmol/L
Intensive (n=63) Conventional (n=67)
EUROPE (CODE-2)1
HbA1c ≤6.5%
69%
31%
37%
63%
57%
43%
47%
53%
Current management often fails to achieve glycaemic targets
LATIN AMERICA (DEAL)2
HbA1c ≤7%
CANADA (DRIVE)3
HbA1c ≤7%
USA (NHANES)4
HbA1c <7%
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.
Duration of diabetes
10
9
8
7
6
HbA
1c (
%)
Disease progression ultimately overwhelms current medications
Del Prato S, et al. Int J Clin Pract. 2005,59:1345-55.
Early achievement and maintenance of glycaemic control reduces the incidence of long-term complications
Kaplan-Meier plots for cumulative incidence of clinical outcomes
Sulphonylurea-insulin
Myocardial infarction
Pro
port
ion w
ith e
vent
Years since randomisation
P=0.01
0.0
0.4
0.8
0.6
0.2
1.0
5 10 0 15 20 25
Conventional therapy
Microvascular Disease
Pro
port
ion w
ith e
vent
Years since randomisation
P=0.001
0.0
0.4
0.8
0.6
0.2
1.0
5 10 0 15 20 25
Conventional therapy
Sulphonylurea-insulin
Holman R, et al. N Engl J Med. 2008;359:1577-89.
No. At Risk Conventional therapy 1138 1013 857 578 221 20
Sulphonylurea-insulin 2729 2488 2097 1459 577 66
UKPDS: Early intensive therapy in newly diagnosed type 2 diabetes significantly
reduces long-term complications
1138 1018 844 508 172 13
2729 2465 2076 1368 488 53
HbA1c= Fasting Glucose Postprandial Glucose +
Achieving comprehensive glycaemic control
requires 1 an action on both FPG and PPG
PPG FPG
Relative contributions of postprandial and fasting hyperglycemia (%) to the overall diurnal hyperglycemia
Monnier L, et al. Diabetes Care. 2003;26:881-5.
0
20
40
60
80
100
<7.3 n=58
7.3-8.4 n=58
8.5-9.2 n=58
9.3-10.2 n=58
>10.2 n=58
Contr
ibution (
%)
HbA1c (%)
Need for comprehensive glycaemic control D
aily p
lasm
a
glu
cose level
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.
2 Excessive fluctuations in daily glucose levels contribute to symptoms,
complications and impaired QoL
Treatment-related weight gain, and/or weight gain through “defensive snacking” because of hypoglycaemia
Increases CV risk Decreases CV risk
Weight gain/ obesity
Diabetes
Glucose- lowering therapy
CV risk
+
-
+
Inter-relationship between overweight/obesity, diabetes and CV risk: potential impact of treatment-related weight gain
UK Hypoglycaemia Study Group. Diabetologia. 2007;50:1140-7.
Pro
port
ion r
eport
ing a
t le
ast
one
epis
ode o
f severe
hypogly
caem
ia
Error bars, 95% confidence interval.
The incidence of severe hypoglycaemic episodes increases with duration of treatment
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)
0.0
0.4
0.2
0.6 Type 2 DM sulphonylureas (n= 103) 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)
Annual Prevalence = 7%
Treated with sulphonylurea
<2 yrs >5 yrs <5 yrs >15 yrs of insulin treatment of insulin treatment
Type 2 diabetes Type 1 diabetes
Patients with severe
hypoglycaemia
Patients without severe hypoglycaemia
0 2 4 6 8 Weight gain (kg)
+6.8 kg
+4.6 kg
‘Defensive snacking’ as a potential mechanism for weight gain in diabetes
1. DCCT Research Group. Diabetes Care 1988;11:567-73. 2. Russell-Jones D, Khan R. Diabetes Obes Metab. 2007;9:799-812.
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
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
Years
Insulin (n=409)
0
1
5
0 3 6 9 12
8
7
6
4
3
2 Conventional (n=411)*
* Conventional treatment; diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/L (>270 mg/dL) n=at baseline
UKPDS: up to 8 kg in 12 years1
ADOPT: up to 4.8 kg in 5 years2
Annualised slope (95% CI) Rosiglitazone, 0.7 (0.6 to 0.8) Metformin, -0.3 (-0.4 to -0.2) Glibenclamide, -0.2 (-0.3 to 0.0)
Glibenclamide (n=277)
Metformin (n=342)
Treatment difference (95% CI) Rosiglitazone vs metformin 6.9 (6.3 to 7.4); P<0.001 Rosiglitazone vs glibenclamide, 2.5 (2.0 to 3.1); P<0.001
Weig
ht
(kg)
Years
96
92
88
0
100
0 1 2 3 4 5
Change in w
eig
ht
(kg)
Most current therapies result in weight gain over time
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.
We
igh
t g
ain
W
eig
ht
los
s
HbA1c increase HbA1c decrease
Oral anti hyperglycaemia drugs and their effect on HbA1c and weight change
Sulphonylureas
TZDs
DPP-4 Inhibitors
Metformin
We
igh
t g
ain
W
eig
ht
los
s
HbA1c increase HbA1c decrease
Injectable anti hyperglycaemic drugs and their effect on HbA1c and weight change
GLP-1 analogues
Insulin
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