13th Meeting of the Mediterranean Group for the Study of Diabetes

Satellite Symposium: Diamicron MR 60 mg “Protect the

kidney to save the heart“

HbA1c target: how low should we go?

Angelo Avogaro. University of Padova. Italy

Patient 1, Male

Patient 2, Female

Patient 3, Female

Age (yrs) 45 65 82

BMI (Kg/m2) 28 30 24

Duration of the disease (yrs)

1 10 18

CVD No Yes Yes

Kidney disease (eGFR ml/min)

95 35 25

Retinopathy No Yes Yes

Patient 1, Male

Patient 2, Female

Patient 3, Female

Age (yrs) 45 65 82

BMI (Kg/m2) 28 30 24

Duration of the disease (yrs)

1 10 18

CVD No Yes Yes (st

Kidney disease (eGFR ml/min)

95 35 25

Retinopathy No Yes Yes

UKPDS Epidemiologic Data in Type 2 Diabetes: No A1C Threshold

0%

10%

20%

30%

40%

50%

60%

70%

80%

5 6 7 8 9 10 11

Adjusted incidence per 1000 person-years Myocardial infarction

Microvascular endpoints

Updated mean A1C (%)

Stratton IM, et al. BMJ. 2000;321:405-412.

Myocardial infarction

Source: adapted from http://www.dtu.ox.ac.uk

SU/Insulin vs. Conventional Metformin vs. Conventional

What are appropriate goals for this patient?

•HbA1c

•FPG

•2 hr PPG

•Normalization of Glycemia

PPG Contributes more to HbA1c at low HbA1c values

Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments

to the overall diurnal hyperglycaemia of type 2 diabetic patients. Diabetes Care 2003;26.

Co

ntr

ibu

tio

n (

%)

(<7.3) (7.3-8.4) (9.5-9.2) (9.3-10.2) (>10.2)

HbA1c quintiles

0

20

40

60

80

1 2 3 4 5

Postprandial

Fasting Hyperglycemia

Hyperglycemia is a continuous risk factor for CVD...

Therefore normality should be the goal if it can be safely achieved

ADA: “...for patients in general is an A1C<7%....for the individual patient is an A1C as close to normal (<6.0%) as

possible without significant hypoglycemia..”

ADA, Diabetes Care 29:S4-S42, 2006. CDA, Can J Diabetes 27:S1-S151, 2003

Mortality Primary outcome (composite nonfatal

MI, nonfatal stroke, CVD death)

Source: www.accordtrial.org

Pozzilli P, Diabetes Metab Res Rev, 2010

9%

Personalized approach: proposed intervention strategy for recently diagnosed patients with type 2 diabetes

Patient 1, Male

Patient 2, Female

Patient 3, Female

Age (yrs) 45 65 82

BMI (Kg/m2) 28 30 24

Duration of the disease (yrs)

1 10 18

CVD No Yes Yes

Kidney disease (eGFR ml/min)

95 35 25

Retinopathy No Yes Yes

Lower A1C

Targets (achieved median)

<6% (6.4%) vs 7-7.9% (7.5%)

Greater use of medications:

More multiple oral meds

More insulin

More combination orals + insulin

70% vs 45% on 3-5 oral classes

77% vs 55% on insulin

62% vs 18% on 3-5 orals + insulin

More consequences of therapy:

Severe hypoglycemia

Weight gain

More SAEs

10.5% vs 3.5% w/ hypoglycemia event requiring medical assistance

28% vs 14% >10 kg gain

2.2% vs 1.6% w non-hypo SAE

ACCORD: Compared with the standard

strategy, the intensive strategy had:

Source: www.accordtrial.org

Association of hypoglycemia and cardiac ischemia. A study based upon continuous glucose monitoring

and EKG monitoring (Desouza et al; Diabetes Care 26: 1485, 2003)

Total episodes Episodes with

cardiac pain

Episodes with

EKG

abnormalities

Hypoglycemia 54 10 6

Asymptomatic 28 - 2

Symptomatic 26 10 4

Normoglycemia - 0 0

Hyperglycemia 59 1 0

Glucose

increase >100

mg in 1 h

50 9 2

ACCORD2

ADVANCE3

Intensive Control

Standard Control

Pati

en

ts e

xp

eri

en

cin

g a

t le

ast

on

e

severe

hyp

og

lycem

ic e

ven

t (%

)

0

5

10

15

20

25

VADT1

2.7% 1.5%

16.2%

5.1%

21.2%

9.9%

P<0.001 P<0.001 HR=1.86

(95% CI 1.40-2.40)

Comparison of severe hypoglycemia in morbimortality trials in diabetes

% HbA1c at study end 7.3 6.4 6.9

% change from baseline -0.2 -1.7 -2.5

8.4

-1.0

7.5

-0.6

6.5

-1.0

1. VADT Investigators. N Engl J Med. 2009;360:129-139. 2. Bonds DE, et al, BMJ. 2010;340:b4909. 3. ADVANCE Study Group. N

Engl J Med. 2008;358(24):2560-2572.

VADT Study: Mean A1C ± IQR

Source: Adapted from ADA 2008 presentation

CV Death

Standard Intensive

29 36

Sudden Death

Standard Intensive

4 11

Source: Adapted from ADA 2008 presentation

Predictors of Cardiovascular Death

VADT

Prior Event

HbA1c

HDL

Age

3.116 (1.744, 5567)

1.213 (1.038,1.417)

0.699 (0.536, 0.910)

2.090 (1.518, 2877)

Hypoglycemia 4.042 (1.449,11.276) 0.01

<0.01

0.02

0.01

<0.01

12 0 2 4 6 8 10

P Value

Hazard Ratio

(HR lower CL,

HR upper CL)

Pozzilli P, Diabetes Metab Res Rev, 2010

9%

Personalized approach: proposed intervention strategy for recently diagnosed patients with type 2 diabetes

Patient 1, Male

Patient 2, Female

Patient 3, Female

Age (yrs) 45 65 82

BMI (Kg/m2) 28 30 24

Duration of the disease (yrs)

1 10 18

CVD No Yes Yes

Kidney disease (eGFR ml/min)

95 35 25

Retinopathy No Yes Yes

Diabetes increases the risk of hypoglycaemia in patients with chronic kidney disease

Risk for hypoglycaemia of varying severity and adjusted incidence rate ratio classified by presence or absence of CKD and diabetes

Moef MF, et al. Clin J Am Soc Nephrol. 2009;4:1121-7.

Inci

den

t ra

te r

atio

s

+CKD, +diabetes

-CKD, +diabetes

Ref: -CKD, -diabetes

Glucose <70 and ≥60 mg/dl

Glucose <60 and ≥50 mg/dl

Glucose <50 mg/dl

9

0

N=243,222

Mean age of patients with CKD, 73 years

8

7

6

5

4

3

2

1

+CKD, -diabetes

3.28

7.21

8.43

1.66 1.53 1

1

1

1.58

1.62

4.09

3.56

DIHC: drug-induced hypoglycaemic coma

17–20

Age range (years)

Num

ber

of

subje

cts

30

35

40

20

15

0

25

10

5

21–30 31–40 41–50 51–60 61–70 71–80 81–90

45

Hypoglycaemic coma requiring hospitalisation is more common in the elderly

Ben-Ami H, et al. Arch Intern Med. 1999;159:281-4.

Retrospective medical record review of individuals with diabetes who were admitted with DIHC or developed DIHC during hospitalisation

24

In a Hypoglycemic Clamp Study of Healthy Men,

Symptom Recognition of Hypoglycemia

Was Lower Among Older Men

Change in Plasma Glucose

200

Time, min

–40

2.0

3.0

4.0

5.0

6.0

0 40 80 120 160

Young Men Without Diabetes

Elderly Men Without Diabetes Ch

an

ge

in T

ota

l Sym

pto

m S

co

re

0

14

12

10

8

6

4

2

Pla

sm

a G

luc

os

e, m

mo

l/L

Glucose

Infusion

maintained at

5 mmol/L

(90 mg/dL)

Glucose Infusion

reduced stepwise from

5 mmol/L to 2.4 mmol/L

(90 mg/dL to 43 mg/dL)

Glucose

Infusion

restored to

5 mmol/L

(90 mg/dL)

Copyright ©1997 American Diabetes Association. Matyka K et al. Diabetes Care. 1997;20(2):135–141. Adapted with permission from The American Diabetes Association.

Reducing average glycaemia without reducing variability may be dangerous

• Reduction in average glycaemia without reducing glucose variability is indicated by downward shift of the glucose profile from the upper panel to the lower panel

• This results in increased occurrence and severity of hypoglycaemic episodes

Kovatchev et al. J Diabetes Sci Technol 2009;3:1058–65

A: Relationship between MMSE and MAGE. B: Relationship between cognitive composite score and

MAGE.

Rizzo M R et al. Dia Care 2010;33:2169-2174

Hypoglycemia due to glibenclamide was associated

with higher prevalence of coma and longer duration

than hypoglycemia due to insulin.

Glibenclamide use was also associated with a longer

hospital stay.

Pozzilli P, Diabetes Metab Res Rev, 2010

9%

Personalized approach: proposed intervention strategy for recently diagnosed patients with type 2 diabetes