INSULINOTERAPIA IN TRATAMENTUL

DIABETULUI ZAHARAT

Dr. Tinu Anna Maria

 GLUCOSE
IS A VASCULAR POISON !

for everybody
any hyperglycaemia
T1, T2, seconday diabetes, etc
the DCCT-EDIC, UKPDS, STENO 2 messages
years 1993, 1998, 2008

be aggressive with
GLUCOSE CONTROL T1 & T2!

keep A1C <7.0%

since clinical onset of diabetes, life-long
primarily in young, middle-age subjects free of
vascular complications
but individualize A1C and prevent hypoglycaemia in
elderly people with CV disease
 wrong messages from last century
only 20-30 years ago

Hyperglycaemia is not dangerous in children,

especially before puberty
Children do not develop micro-/macrovascular
complications
Children are differentfrom adults
It is not possible to maintain normoglycaemia
in children
Intensive therapy is a dangerous psichological
stress for children
Use 1 or 2 injections of premixed insulins/day
and avoid hypoglycaemia
etc.
 Chronic Consequences of Type 1 diabetes
that pediatricians bnever see !!!
Eye (cataracts, retina) Early Death
Kidney (CRF, ON) Cognitive Decline
Nerve (sensory, motor) Depression
Foot (pain, ulcer) Hip Fractures
Amputation (BKA) Imbalance & Frailty
IHD Connective Tissue (shoulder)
Stroke Erectile Dysfunction
PVD Sexual Dysfunction
Cirrhosis Infertility/PCOS
 DCCT/EDIC: Metabolic Results
DCCT Intervention EDIC Observation
11

Training
Conventional
Glycosylated hemoglobin (%)

10
Conventional
EDIC mean 8.2%
9

Intensive
7 EDIC mean 8.0%

6 Intensive

5
0 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9

Year of DCCT study Year of EDIC study

Adapted from DCCT/EDIC Research Group.
N Engl J Med 1993; 329:977-86 and N Engl J Med 2005; 353:2643-53.
 DCCT/EDIC: Metabolic Memory
0.5
Cumulative incidence of a 3 step change
0.4 from DCCT end of study, adjusted for
Cumulative incidence

Conventional
EDIC baseline retinopathy
0.3

0.2

0.1
Intensive
0.0
0 1 2 3 4 5 6 7

No. evaluated
Year of EDIC study
Conventional 169 203 220 581 158 192 200
Intensive 191 222 197 596 170 218 180

DCCT/EDIC Research Group. JAMA 2002; 287:2563

Cardiovascular Events

Cumulative Incidence of First of Any Event

0.12
Cumulative Incidence

0.10
Risk reduction 42% Conventional
0.08
95% CI: 19, 63
0.06 Log-rank P = 0.016
0.04
Intensive
0.02

0.00
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Years from Study Entry

Number at Risk
Intensive: 705 683 629 113
Conventional: 714 688 618 92

DCCT/EDIC. N Engl J Med 2005; 353:26432653

Treatment Goals in T1 and T2DM
IDF 2005
Biochemical Control Normal Goal
A1c* (%) <6.0 <6.5

PG fasting
<100
be as normal <110
as possible
preprandial
without hypoglycaemia
(mg/dL) <110 <110
(BG <70 mg/dl)
PG 1-2 h
POSTMEAL <130 <145
(mg/dL)
* Referenced to the nondiabetic range using a DCCT-aligned assay1
 Question

How should we replace

insulin in subjects with Type
1 diabetes mellitus ?
 Glucose Homeostasis
9.0

Glucose (mmol/l)
Meals
7.0

5.0

480
Insulin (pmol/l)

320 Normal Subjects

Mean 2SD
160

0
0700 1200 1800 2400 0600 hrs
Ciofetta M., et al., DIabetes Care 22:795-800, 1999
 In Type 1 DM
9.0

Glucose (mmol/l)
Meals
7.0

5.0

480
Insulin (pmol/l)

320 Normal Subjects

Mean 2SD
160

0700 1200 1800 2400 0600 hrs

Itinerary for nearnomoglycaemia

Physiological insulin
replacement (basal + prandial
insulin)

Intensive BG monitoring for

insulin dose adjustment
 9.0

Glucose (mmol/l)
7.0

5.0

480
Insulin (pmol/l)

320 Normal Subjects

Mean 2SD
160

0
0700 1200 1800 2400 0600 hrs
Ciofetta M., et al., DIABETES Care 22:795-800, 1999
 Intensive Insulin Regimen
(1980 1995)

Regular R ~0.15U/Kg R NPH

~0.10 U/Kg +NPH ~0.1 U/Kg ~0.15 U/Kg ~0.2 U/Kg

Breakfast Lunch Dinner Bed-time

with human insulin

 Intensive Insulin Regimen
(1980 1995)

Regular R ~0.15U/Kg R NPH

~0.10 U/Kg +NPH ~0.1 U/Kg ~0.15 U/Kg ~0.2 U/Kg

Breakfast Lunch Dinner Bed-time

the limitations of human insulin

 Normal post-prandial values
Plasma Free Insulin (U/ml) 80 Meal (Mean SD, n=23)

S.c. injection of soluble insulin

60
PLASMA in T1 diabetics
INSULIN (Mean SEM, n=20)
s.c. insulin

40

20

0
0 2 4 6 8 10 12

Time (hours)

Bolli G.B. et al., N.Engl.J.Med. 310:1706-11, 1984

 INSULIN ANALOGUES
monomeric
Rapid acting

B28 LYS, B29 PRO : Insulin lispro

(Humalog)

B28ASP : Insulin aspart (Novorapid)

B3Lys, B29Glu : Insulin glulisine

(Apidra)
 Better Normal postprandial values
80 Meal
Post-prandial BG
Plasma Free Insulin (U/ml)
(MeanSD, n=23)

s.c. injection of soluble insulin

60
PLASMA in diabetic subjects
INSULIN (Mean SEM, n=20)
s.c. insulin

s.c. injection of lispro, aspart,

40 or glulisine in diabetic subjects
(Mean SEM, n=10)

20

0
0 2 4 6 8 10 12

Timerisk
Lower After Insulin
for late Injection or Meal Ingestion (Hours)
post-prandial hypoglycaemia
Bolli G.B., N.Engl.J.Med. 310:1706, 1984
 9.0

Glucose (mmol/l)
7.0

5.0

480
Insulin (pmol/l)

320 Normal Subjects

Mean 2SD
160

0
0700 1200 1800 2400 0600 hrs
Ciofetta M. et al., DIABETES Care 22:795, 1999
Hans Christian Hagedorn
1888-1971
Hagedorn 1946 NPH

Hallas-Mller 1951 ULTRALENTE (crystalline)

SEMILENTE (amorphous)

LENTE (70% Ultralente

+ 30% Semilente)
 0.3 U/Kg
s.c. NPH n=20 T1DM
Mean SEM
Glucose Infusion Rate

4.0

3.0
mg/Kg/min

2.0

1.0

0 4 8 12 16 20 24
Time (hours)
Lepore M. et al., Diabetes 49:2142-8, 2000
Intensive treatment and severe hypoglycaemia
in 1993 human insulin + NPH ERA

100 1 severe hypo

Rate of severe hypoglycaemia

every 20 months
90
(per 100 patient-years)

80 50% of episodes
were at night!
60

40

20

0
5.0 5.5 6.0 6.5 7.0 7.58.0 8.5 9.0 9.5 10.0 10.5
HbA1c (%)

DCCT. N Engl J Med 1993; 329:977.

 0.3 U/Kg
sc insulin NPH n=20 T1DM
Mean SEM
12
Glucose Infusion Rate

4.0

Plasma Glucose
11
3.0
mg/Kg/min

mmol/l
10
2.0
9

1.0 8

0 7

0 4 8 12 16 20 24
Time (hours)
Lepore M. et al., Diabetes 49:2142-8, 2000
Inappropriate Pharmacokinetics
peak effect
nocturnal hypoglycaemia

relatively short duration

fasting hyperglycaemia

High variability in s.c. absorption

wide blood glucose fluctuations from

day-to-day
 The ideal basal insulin
no peak (flat, constant activity)
reproducibility of s.c. absorption
long duration of action
 NPH is not the ideal basal insulin
0.3 U/Kg
s.c. NPH n=20 T1DM
Mean SEM
Glucose Infusion Rate
4.0

3.0
mg/Kg/min

2.0
ideal peakless
basal insulin
1.0

0 4 8 12 16 20 24
Time (hours)
Lepore M. et al., Diabetes 49: 2142-8, 2000
 Continuous Subcutaneous Insulin Infusion

Morning Afternoon Evening Night

Insulin Effect

MEAL MEAL MEAL

BOLUS BOLUS BOLUS
BASAL
INFUSION
 NEW CANDIDATES FOR BASAL INSULIN
REPLACEMENT
Long-acting insulin analogues

SOLUBLE INSULINS

Analogue Fatty acid Detemir

acylated insulin (Levemir, NovoNordisk)

Analogue insulin with Glargine

neutral isoelectric point (Lantus, Sanofi-Aventis)
 Plasma Insulin
0.3 U/kg
s.c. insulin n=20 T1DM
30 Mean SEM 180

25 150

20 Glargine 120

pmol/l
U/ml

15 90

10 60

NPH
5 30
0 4 8 12 16 20 24
Time (hours)

Lepore M. et al., Diabetes 49:2142-8, 2000

 Glucose Infusion Rate

sc insulin n=20 T1DM

Mean SEM
4.0 24
NPH
20
3.0

mol/Kg/min
mg/Kg/min

16

2.0 12
Glargine
8
1.0
4

0 0

0 4 8 12 16 20 24
Time (hours)

Lepore M. et al., Diabetes 49: 2142-8, 2000

 Plasma Glucose
0.3 U/kg
s.c. insulin n=20 T1DM
220 Mean SEM 12

NPH
200 11

mmol/l
10
mg/dl

180

9
160
Glargine
8
140
7
120

0 4 8 12 16 20 24
Time (hours)
Lepore M. et al., Diabetes 49:2142-8, 2000
 Hagedorn ERA in Type 1 diabetes (until June 2000)
Rapid-Acting Insulin Analogue and Multiple Doses of NPH

Breakfast Lunch Dinner

Physiologic insulin secretion
Insulin action profile

NPH
Rapid-acting insulin analogue
Average insulin

4 8 12 16 20 24 4 8

NPH Time of day (h)

Lalli C. et al., Diabetes Care 1999;22:468-77
 9 June 2000 lantus in German pharmacies

___________
announcement

NPH and
NPH-based Pre-Mixes
are dead !!!
___________
Patients with T1DM should NOT receive NPH and/or
NPH-mixtures any longer !
 In Type 1 DM
9.0

Glucose (mmol/l)
Meals
7.0

5.0 BG
480 R R BG R CHO
Insulin (pmol/l)

CHO CHO Basal BG

BG
320 Normal Subjects
BG
Mean 2SD
160

0700 1200 1800 2400 0600 hrs

 Significantly greater HbA1c reduction and less
hypoglycemia with insulin glargine vs NPH

Randomised, non-blinded study of once-daily insulin glargine versus

four-times daily NPH (both + mealtime insulin lispro), 121 patients
Mean HbA1c levels during study Incidence of mild and nocturnal hypoglycemia
14 p<0.05
7.6 13.2 Insulin glargine +
Insulin glargine + insulin lispro 12 insulin lispro
Mean HbA1c SEM (%)

7.4 NPH + insulin lispro

Events/patient-month
10 NPH + insulin lispro
7.2
8
7.0 7.2
6
6.8 * * p<0.05
* * 4
6.6 * 3.2
2
6.4 1.2
0 2 4 6 8 10 12 0
Time (months) Mild Nocturnal
Hypoglycemia
*p<0.05 insulin glargine vs NPH; HbA1c analysis values were not aligned with the DCCT
Porcellati et al. Diabet Med 2004;21:121320. Reproduced with permission
 NEW CANDIDATES FOR BASAL INSULIN
REPLACEMENT
Long-acting insulin analogues

SOLUBLE INSULINS

Analogue Fatty acid Detemir

acylated insulin (Levemir, NovoNordisk)

Analogue insulin with Glargine

neutral isoelectric point (Lantus, Sanofi-Aventis)
 Study Design

Screening Clamp 1 Clamp 2

12

Glargine Glargine
24 T1 DM

Detemir Detemir

12

Run-in Period 1 Wash-out Period 2

4-weeks 2-weeks 2-weeks 2-weeks
Porcellati F. et al., Diabetes Care 30: 2447-52, 2007
 s.c. insulin
0.15 0.35 U/Kg Glargine (N=24) 0.15
Detemir MeanSE

mUKg-1 min-1
mUKg-1 min-1
0.10 0.10
INSULIN INFUSION RATE
0.05 0.05

0 0

1.5 9
mgKg -1 min-1

mmol Kg -1 min-1
1.0 6

0.5 3
GLUCOSE
INFUSION RATE
0 0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)

Porcellati F. et al., Diabetes Care 30: 2447-52, 2007

Porcellati F. et al., Diabetes Care 30: 2447-52, 2007

198 s.c. insulin Glargine (N=24) 11

0.35 U/Kg Detemir MeanSE
180 10
162 9
PLASMA GLUCOSE

mmol/l
144 8
mg/dl

126 7
108 6
90 5

0 0

100 24

Subjects (N)
Subjects (%)

67 16
Subjects in study
(Plasma glucose < 180 mg/dl)
33 8

0 0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)
 PLASMA FFA and b-OH BUTYRATE

s.c. insulin
0.35 U/Kg
1000
Glargine
750 Free Fatty
Detemir
m mol/l
500
Acids
250

0 MeanSE
4500
m mol/l

3000 b-OH-Butyrate
1500

0
0 4 8 12 16 20 24

Time (hours)
Porcellati F. et al., Diabetes Care 30: 2447-52, 2007
 PHARMACODYNAMIC VARIABLES

Det Gla point 95%

est CI P value
(%)

AUC GIR0-24h 915225 1412662 70.3 53.4;92.7 0.015

[mg/kg]

AUC GIR0-12h 807352 97.7 78.5;121.6 0.832

773200
[mg/kg]
1 U detemir
30% less potent than 17.4
142194 605390
AUC GIR12-24h 1 U glargine
8.2;36.7 0.000
[mg/kg]

GIR Cmax 90 78.0;103.7 0.137

detemir1.60.5
[mg/kg/ min ]
needs1.80.6
greater doses
GIR T [h] *
and/or 2 injections/day
7 (2;12) 4 (1;24) 3.25 0.5;5.3 0.035
max
*Median (min;max)
Porcellati F. et al., Diabetes Care 30: 2447-52, 2007
 S. Heller et al, Clin.Ther. 31:10:2086-97, 2009
N = 443 persons with Type 1 DM

randomized to: glargine 1/day

or detemir 1 or 2/day for 1 year
(+ mealtime aspart in both)

RESULTS:

- same A1C (~7.5%)

- same hypoglycaemia

- with detemir: 2 daily doses in 66% of subjects

21-42% greater dose vs glargine

the 2007 results of Porcellati et al. on PK/PD glargine

vs detemir in Type 1 diabetes confirmed
 CSII vs MDI STUDY
randomized, parallel-group, open-label, multicenter (n=5)
subjects nave to CSII and glargine

24 CSII (lispro)

Insulin dose titration to the same BG targets:

58 T1DM, 6.5<HbA1c<9% FPG 80120 mg/dL; other preprandial BG 90140
mg/dL; 2-h post-prandial BG <140 mg/dL; and
On MDI with NPH bedtime BG 110150 mg/dL.

1 randomization error, 7
protocol violatiors
26 Glargine + mealtime lispro

1 week 24 week 2 weeks

Run-in period Treatment period Follow up

Bolli GB et al., Diabetes Care 2009; 32:1170-6

 CSII vs MDI STUDY
Results

MDI

CSII

Change in A1C (%) from baseline over the course of the study.
Bolli GB et al., Diabetes Care 2009; 32:1170-6
 CSII vs MDI STUDY
Results

CSII

MDI

Number of hypoglycemic events by visit for the two insulin regimens (safety
population)
Bolli GB et al., Diabetes Care 2009; 32:1170-6
 CSII vs Glargine-MDI STUDY
Results

Quality of life
Glucose variability

NO DIFFERENCE

Bolli GB et al., Diabetes Care 2009; 32:1170-6

 CSII vs Glargine-MDI STUDY
Results
Average cost per treatment during the study
(Euro/24 weeks)

3500

3000

2500

2000
Euros
1500

1000

500

0
MDI CSII

Bolli GB et al., Diabetes Care 2009; 32:1170-6

Basal insulin as CSII (the gold standard)

+30-100% basal rate

Lispro/aspart/glulisine basal rate

Lispro/aspart/glulisine (RA-IA) RA-IA RA-IA

~0.05 U/Kg ~0.10 U/Kg ~0.10 U/Kg

breakfast lunch dinner

Snack? A bolus of
Rapid-acting insulin Analogue any time

Basal insulin as long-acting analogue MDI regimen

in ~30% of Glargine ONCE daily
subjects ~0.3-0.4 U/Kg
RA-IA RA-IA RA-IA RA-IA RA-IA
~0.15 U/Kg ~0.15 U/Kg or detemir TWICE daily
~0.05 U/Kg ~1-2 U ~1-2 U

breakfast midmorning lunch h 16-16:30 dinner

Superiority of long-acting insulin
analogues vs. NPH in T1DM

less (nocturnal) hypoglycaemia

and/or lower A1C

improved life-style

non-inferior vs. CSII while 3.9

times less expensive (glargine)
 A1C with insulin glargine + lispro
vs NPH + human R insulin
N=54 T1DMs
4 mo, crossover
Difference 0.5 (95% C.I.-0.7,-0.3) %

8,5 P<0.001

7,5
HbA1c
(%)
7

6,5

6
Ashwell SG et al.,
Diabet.Med. 23:285-92, 2006 glargine + lispro NPH + HI
 Hypoglycaemia with
insulin glargine + lispro vs NPH + human R insulin
Rate of hypoglycaemia N=54 T1DMs
4 mo, crossover
(episodes.patient.month-1)

6 1,5 P<0.001

5 1,2

4
0,9
3
0,6
2
0,3
1

0 0
All symptomatic Nocturnal Severe
Ashwell SG et al.,
Diabet.Med. 23:285-92, 2006 glargine + lispro NPH + HI
 Quality of Life with Insulin Analogues

Glargine+lispro
NPH+Human Regular
1,80 crossover
1,70
1,60
QoL score

1,50
1,40
1,30
1,20
Period 2: cross-over
1,10 to alternative treatment

1,00
Baseline Period 1 Period 2

Ashwell et al, Diabetes Care, ahead of print March 13 2008

Intensive treatment and severe hypoglycaemia
in 1993 human insulin + NPH ERA

100 DCCT
Rate of severe hypoglycaemia

1983
90
(per 100 patient-years)

80
post-human insulin era
60
Rapid +
40 Long-acting analogs

20

0
5.0 5.5 6.0 6.5 7.0 7.58.0 8.5 9.0 9.5 10.0 10.5
HbA1c (%)

DCCT. N Engl J Med 1993; 329:977.

Impact of Intensive Therapy in Diabetes Summary of Major Clinical Trials

Study A1c Microvascular CVD Mortality

Study End
Baseline
Std Intensive

DCCT/EDIC 9 9 & 7

UKPDS 9 7.9 & 7

ACCORD 8.3 7.5 & 6.4 ?

ADVANCE 7.5 7.0 & 6.4

VADT 9.4 8.5 & 6.9

Baseline Study End
ORIGIN Std Glargine
6.4 6.5 & 6.2
Initial Trial Long Term Follow-up
Adapted from Bergenstal RM, Bailey C and Kendall DM. Am J Med 2010;123:374e9-e18
 The Natural History of Type 2 Diabetes

Build up bad
metabolic
memory Drive the risk
9.5 for
9.0 complications
8.5
A1C (%)

8.0
7.5
7.0
6.5
6.0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Time (Years Since Diagnosis)
 Diabetes remission after intensive
insulin therapy in new onset T2DM

100 CSII 382 patients with newly

diagnosed type 2 DM
Patients in remission (%)

MDII
80
OAD CSII, MDI, or OHA until
p = 0.0012 normoglycemia reached
60 and maintained for 2 weeks
51.1%
44.9%
Remission defined as
40
FBG > 126 mg/dL or
26.7% 2-hr PP > 180 mg/dL
20
Initial HbA1c 9.5%-9.8%
0
0 90 180 270 360 450
Days in remission

Weng J, et al. Lancet 2008; 371:175360.

 b-cell function after intensive insulin
therapy in new onset T2DM
CSII in the remission group
MDI in the remission group
OHA in the remission group
Non-remission group
p < 0.0001
1400
Acute insulin response

1200
(pmol/L per min)

p = 0.006
1000
800
600
*
400
200
0
-200 Before therapy After therapy At 1 year

* p < 0.05 vs each intervention in the

remssion group (after treatment) Weng J, et al. Lancet 2008; 371:175360.