ΥΠΟΓΛΥΚΑΙΜΙΑ -...

:-

A. .

-

HYPOGLYCEMIA HYPERGLYCEMIA

Insulin

Counter

regulatio

n Insulin

Counterregulation

Iatrogenic hypoglycemia is a major limiting factor in

the strict glycemic management of diabetes

Whipple:

( )

mg/dl

90

80

70

60

50

40

30

20

------ -

Mitrakou A, et al. American Journal of Physiology 1991; 260(Endocrinol. Metab. 23): E67-E74

euglycemia

hypoglycemia


euglycemia

hypoglycemia

.

Mitrakou A, et al. Journal of Clinical Endocrinology and Metabolism 1993; 76(2): 462-465

10

Prior Hypoglycemia Blunts Counterregulatory Response to Subsequent Comparable Hypoglycemia in Adults Without

Diabetes

Heller SR. Diabetes. 1991;40(2):223226. Permission pending.

Hyperinsulinemic hypoglycemic clamps on 2 consecutive mornings, with interval

afternoon clamped hypoglycemia in adults without diabetes.

**

**** ***

To

tal S

ym

pto

m S

co

re

Clock Time (h)

0

20

40

0

20

40

0915 0930 0945 1015 1030 1045

****

Glu

cag

on

Clock Time (h)

100

200

300

100

200

300

0915 0930 0945 10151030 1045

Morning before Morning after

*P

11

Matyka K et al. Diabetes Care. 1997;20(2):135141.

Change in Plasma Glucose

200

Time, min

402.0

3.0

4.0

5.0

6.0

0 40 80 120 160

Young Men Without Diabetes

Elderly Men Without Diabetes Chan

ge in

To

tal S

ym

pto

m S

co

re

0

14

12

10

8

6

4

2

Pla

sm

a G

luco

se, 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)

12

Change in Plasma Glucose

Time, min

40

Pla

sm

a G

luco

se, m

mo

l/L

2.0

3.0

4.0

5.0

6.0

0 40 80 120 160 200

Ch

an

ge in

Reactio

n T

ime, m

s

0

350

300

250

200

150

100

50

200

*

*

Matyka K et al. Diabetes Care. 1997;20(2):135141.

*

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)

Young Men Without Diabetes

Elderly Men Without Diabetes

(

100

-

)

DCCT:

(

100

-

)

Adapted from: N Engl J Med 1993;329:97786

0

2

4

6

8

10

12

0 5.5 6 6.5 7 7.5 8 8.5 9 9.5 10 10.5

120

60

0

HbA1c (%)

Normal

CDAN +

CDAN -

IMPAIRED COUNTERREGULATION in TYPE 1 DIABETES

HYPOGLYCAEMIA

(HAAF)

Insulinoma

Mitrakou A.N.Engl J Med 329: 834-839;1993

REVERSIBILITY

36

stress 610

, !!!

1

(18 )

1, problem solving;

2, learning;

3, immediate memory;

4, delayed recall;

5, spatial information;

6, attention;

7, psychomotor efficiency; and

8, motor speed

N Engl J Med 2007;356:1842-52.

Brain Activation During Working Memory in Patients With Type 1 Diabetes During Hypoglycemia

Diabetes 60:32563264, 2011

Controls Type 1 Diabetes

Does A1C tell the whole story ?

Get the complete picture

Even patients with acceptable A1C levels can

experience glycemic variability

Professional CGM vs Personal CGM

Ideal for short term blinded CGM

evaluation and retrospective analysis

Quick and easy to set up,

minimal patient training

no alarm

Can be used on all patients with

diabetes to reveal excursions and

patterns

Glucose Sensor readings are

updated every 5min on the monitor

Trend Graphs, Arrows and Alerts

help the patient avoiding lows and

highs

Patients motivation and training

are key to success

n = 272 Type 1 patients

5-Nations Study CSII A1C

Hoogma RP. et al. Diabet Med. 2006; 23:141-147.

CSII 1/4

1 Rudolph JW, Hirsch IB. Endocrine Pract 2002: 8; 401 4052 Bode, BW et al., Diabetes Care 1996, 19:325-7. 3 Boland, EA et al., Diabetes Care 1999, 22:1779 - 84. 4 Pickup JC & Sutton, AJ. Diabet Med 2008;25:765-774

1 2 3

Severe Hypoglycaemic Episodes: CSII vs MDI

New!!! Paradigm Veo

?

User settable: On/Off

Range: 40 110 mg/dLFictional illustration of Low Glucose

Suspend function in use 2

4

Reduction in Duration of Hypoglycemiaby Automatic Suspension of Insulin Delivery:

The In-Clinic ASPIRE Study

DIABETES TECHNOLOGY & THERAPEUTICS

Volume 14, Number 3, 2012

UKPDS 33: Intensive treatment and Hypoglycemiain type 2 Diabetes

(%

)

Adapted from: Lancet 1998;352:83753

50

40

30

20

10

0

0 3 6 9 12

All eventsSevere hypo

8

4

2

0

0 3 6 9 12

6

CONVENTIONAL

INTENSIVE

UKPDS 33

Insulin

InsulinInsulin

o----o Diabetics

Controls

o----o Diabetics

Controls

o----o Diabetics

Controls

o----o Diabetics

Controls

Insulin

Time (min) Time (min)

Time (min) Time (min)

Counterregulation in type 2 diabetes -normal endocrine and glycemic

Heller, et al. Diabetologia 1987; 30: 924-929

, , 2

Spyer G, et al. Lancet 2000 ; 356(9246): 1970-1974

, 2


2

insulin

normal

Oral hyp agents

Glu

ca

go

n (

pg

/ml)

Ep

ine

ph

rin

e (

pg

/ml)

( HbA1c) 2

Burakowska A. Diabetes Care 21:283-290,1998

Type 2

oControls

Poor control

oImproved control

Burakowska A. Diabetes Care 21:283-290,1998

: 2

2 .

, .

.

:

DavisS Diabetes 58:701-709,2009bA1c 10.2 to 6.7%

:

DavisS Diabetes 58:701-709,2009

Glu

ca

go

n (

pg

/ml)

Ep

ine

ph

rin

e (

pg

/ml)

After hypergl

After Hypogl

1 2

Amiel SA, et al. Diabetic Medicine 2008; 25: 245254

Proportion of patients with Type 2 and Type 1 diabetes of differing durations and receiving different regimens experiencing at least one s eve re hypog lycaemic attack during 912 monthsfollow-up. All patients were receiving insulin except the g r o u p t r e a t e d w i t h s u l p h o n y l u r e a

Proportion of patients with Type 2 and Type 1

diabetes experiencing at least one severe

hypoglycaemic attack

1 2

1 2

.. 2

.. ,

.. Addison's disease, ,

.. , ..

..

..

Moderate quality of evidence (QQQ)

Cibenzoline

Gatifloxacin *

Pentamidine

Quinine

Indomethacin ( )

Glucagon (during endoscopy)

Low quality of evidence (QQ)

Chloroquineoxaline sulfonamide

Artesunate/artemisin/artemether

IGF-I

Lithium

Propoxyphene/dextropropoxyphene

Very low quality of evidence (Q)

Drugs with 25 cases of

hypoglycemia identified

Angiotensin converting enzyme

inhibitors

Angiotensin receptor antagonists

-Adrenergic receptor antagonists

Levofloxacin

Mifepristone

Disopyramide

Trimethoprim-sulfamethoxazole*

Heparin*

6-Mercaptopurine

*

.

,

.

Bolen S, et al. Ann Intern Med 2007;147:386-399.

Reproduced with permission

A1C

0

10

20

30

40A

nnua

l ra

te (

%)

0 4 5 6 7 8 9 10 11

Most recent A1C (%)

Wright et al. J Diabetes Complications. 2006;20:395-401.

Reproduced with permission

(UKPDS)

UKPDS 33. Lancet 1998;352:837-853.

Diet Chlorpropamide Glibenclamide Insulin

Any Severe

1.2

11

17.7

36.5

0

10

20

30

40

Mean (

%)

0.1

0.4

0.6

2.3

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Mean (

%)

ADOPT Study N Engl J Med 2006;355:2427-2463.

(the ADOPT study)

38.7

11.69.8

0.6 0.1 0.10

10

20

30

40

Perc

ent

of

patients

with e

pis

odes

All hypoglycemia Severe

hypoglycemia

Glyburide Metformin Rosiglitazone Glyburide Metformin Rosiglitazone

2

9-12 6 UK

: 39% SU

7% of SU

14% SU

Patients reporting grade 2 or grade 3 hypoglycaemic events

Holman RR, et al. N Engl J Med 2007;357:1716-1730.

2

24,000

0

5

10

15

20

ACCORD ADVANCE

Intensive control

Standard control

% P

atients

with a

t le

ast

one e

ve

nt

during t

he t

rial

25

VADT

ADVANCE vs. UKPDS

UKPDS ADVANCE

0

1

2

Even

ts p

er

100 p

ati

en

ts/y

ear

0,7%

1,4%

ADVANCE collaborative group. NEJM,

2: The Fremantle Diabetes Study

:

,

< 60 ml/min per 1.73 m(2),

,

,

.

HbA1c

.

DavisClin Endocrinol Metab. 2010

ACCORD

ACCORD study. N Engl J Med 2008;358(24): 2545-2559.

16.2

5.1

10.5

3.5

0

3

6

9

12

15

18

Patients

(%

)

3

Intensive therapy

(target HbA1c

ACCORD:

1.2%

3.3%

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Never experienced SH Experienced SH

Overa

ll m

ort

alit

y r

ate

(%

)

SH = severe hypoglycaemia

The cause of the increased mortality could not be proven;

severe hypoglycaemia was implicated

(IHD,autonomic neuropathy)

/

Antecedent hypoglycemia impairs

autonomic cardiovascular function

Adler GK, Diabetes 58:360 366, 2009

Altered Ventricular Repolarization During Hypoglycaemia in

Patients with Diabetes type 2 on insulin Diabet. Med 199714: 648654

CCORD

2

.

2

ACCORD , ( HbA1C

)

.

HbA1C

4

HbA1C

.

HbA1c and Risk of SevereHypoglycemia in Type 2 Diabetes

The Diabetes and Aging StudyDiabetes Care July 2013

Intensive glucose lowering on brain structure and function in people with type 2 diabetes

(ACCORD MIND)

40

3

Poor Cognitive Function and Risk of Severe

Hypoglycemia in Type2Diabetes (ACCORD)

Diabetes Care 35:787793, 2012

B. E. de Galan Diabetologia (2009) 52:23282336

ADVANCE-ACCORD

vs

DPP4/

0

1

2

3

4

5

6

7

8

No severe hypos

Severe hypos

Media

n d

ura

tio

n o

f in

sulin

thera

py (

years

)

Type 2 diabetes Type 1 diabetes

Hepburn et al. Diabetic Med 1993; 10(3): 231-7.

2

1

.2

6 .3

15% 2 1,4

1. McAulay V, et al. Diabet Med. 2001;18:690-705.2. Amiel SA, et al. Diabetic Medicine 2008;25:245-254.

3. Gold AE, et al. Diabetes Care 1994;17:697-703.4. Leiter LA, et al. Can J Diab. 2005;29(3):186-192.

GLP-1

.

30 0 30 60 90 120 150 180 210 240 270 300 330 360

Glucose Clamp Steps

Pla

sm

a G

lucagon (

ng/L

)

0

50

100

150

200

300

250

(mmol/L): 5.0 4.0 3.2 2.7 Recovery

GLP-1=glucagon-like peptide-1

*P

Vilda and Hypo response of Glucagon

J Clin Endocrinol Metab. 2009;94:1236-1243

Vildagliptin :

Fonseca V et al. Diabetologia 2007;50:1148-1155.

No. of events No. of severe events

0

40

80

120

160

200

Placebo + insulin

Vildagliptin + insulin

0

2

4

6

8

10

Num

ber

of

severe

events

113

185

0

6

**

*

Num

ber

of

events

Severe defined as grade 2 or suspected grade 2 hypoglycaemia.

*p

vs

Basal Bolus

. 2

.

.

Adapted from Fredrickson L, et al. Optimal Pumping: A Guide to Good Health with Diabetes.

Medtronic MiniMed, Inc.; 1998.

3 AM

Bolus

Bolus Wizard calculator

bolus

15 15 15 grams

3 4 tablets

45 mL

1

15 -

1

!!!!

v2

93

v2 1 fluid ounce = 118 mlvavruh1; 30/10/2006

GlucaGenHypoKit

,

1ml

10-15

1mg(1 ml) 0,5mg(0,5

ml) 25

!!

6.5

1

73 2 .

basal-bolus A1c 6.4%.

.

sliding scale

3

62 2 10.

HbA1c

9.7%. BMI 34.

.

+

Basal bolus

DPP-4

Summary of Impaired Counterregulation

in ACCORD, hypoglycemia was judged to have a definite role in only one death, a probable role in three deaths,and a possible role in 38 deathswhich represents a role in less than 10%of the deaths recorded in the study population while the glycemic intervention was active. The investigators thus suggest that hypoglycemia at the time of death was probably not responsible for the increasedmortality rate in the intensive arm of ACCORD

that an episode of severe hypoglycemia was associated with an increased risk of subsequent mortality. In ACCORD, those who had one or more severe hypoglycemic episodes had higher rates of death than those without such episodes across both study arms (hazard ratio 1.41 [95%CI 1.031.93]) (46). One-third of all deaths were due to cardiovascular disease, and hypoglycemia was associated with higher cardiovascular mortality. In VADT, a recent severe hypoglycemic event was the strongest independent predictor of death at 90 days (3). In ADVANCE, where rates of hypoglycemia were low, a similar pattern was found (47).

ADVANCE

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