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