Post on 07-Jul-2016
description
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… messagesyears 1993, 1998, 2008
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
be aggressive with
GLUCOSE CONTROL T1 & T2!
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 different…from 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 diabetesthat pediatricians bnever see !!!
• Eye (cataracts, retina)• Kidney (CRF, ON)• Nerve (sensory, motor) • Foot (pain, ulcer)• Amputation (BKA)• IHD • Stroke• PVD• Cirrhosis
• Early Death• Cognitive Decline• Depression• Hip Fractures• Imbalance & Frailty• Connective Tissue (shoulder)• Erectile Dysfunction• Sexual Dysfunction• Infertility/PCOS
DCCT Intervention EDIC Observation
Trai
ning
ConventionalEDIC mean 8.2%
IntensiveEDIC mean 8.0%
10
11
9
8
7
6
50 1 2 3 4 5 6 7 8 9
Year of DCCT study
Gly
cosy
late
d he
mog
lobi
n (%
)
Conventional
Intensive
1 2 3 4 5 6 7 8 9
Year of EDIC study
DCCT/EDIC: Metabolic Results
Adapted from DCCT/EDIC Research Group. N Engl J Med 1993; 329:977-86 and N Engl J Med 2005; 353:2643-53.
Cumulative incidence of a 3 step change from DCCT end of study, adjusted for EDIC baseline retinopathy
DCCT/EDIC: Metabolic Memory0.5
0.4
0.3
0.2
0.1
0.0
0 1 2 3 4 5 6 7
Cum
ulat
ive
inci
denc
e Conventional
Intensive
Year of EDIC study
169191
203222
220197
581596
158170
192218
200180
ConventionalIntensive
No. evaluated
DCCT/EDIC Research Group. JAMA 2002; 287:2563
Cum
ulat
ive
Inci
denc
e C
umul
ativ
e In
cide
nce
Years from Study EntryYears from Study Entry
Cardiovascular Events
Cumulative Incidence of First of Any EventCumulative Incidence of First of Any Event
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Number at Risk Intensive: 705 683 629 113 Conventional: 714 688 618 92
Risk reduction 42% Risk reduction 42% 95% CI: 19, 6395% CI: 19, 63Log-rank P = 0.016Log-rank P = 0.016
0.120.12
0.100.10
0.080.08
0.060.06
0.040.04
0.020.02
0.000.00
ConventionalConventional
IntensiveIntensive
DCCT/EDIC. N Engl J Med 2005; 353:2643–2653
Treatment Goals in T1 and T2DMIDF 2005
* Referenced to the nondiabetic range using a DCCT-aligned assay1
Biochemical Control Normal GoalGoalA1c* (%) <6.0 <6.5<6.5
PG fastingpreprandial (mg/dL)
<100<110
<110<110<110<110
PG 1-2 hPOSTMEAL(mg/dL)
<130 <145<145
be as normal as possiblewithout hypoglycaemia
(BG <70 mg/dl)
Question
How should we replace How should we replace insulin in subjects with Type insulin in subjects with Type
1 diabetes mellitus ?1 diabetes mellitus ?
Glu
cose
(mm
ol/l)
Glu
cose
(mm
ol/l) 9.09.0
5.05.0
160160
00
7.07.0
320320
480480
Insu
lin (p
mol
/l)In
sulin
(pm
ol/l)
Glucose HomeostasisGlucose Homeostasis
Mean ± 2SD Mean ± 2SD
07000700 12001200 18001800 24002400 0600 hrs0600 hrs
Normal SubjectsNormal Subjects
Ciofetta M., et al., Ciofetta M., et al., DIabetes Care 22:795-800, 1999DIabetes Care 22:795-800, 1999
MealsMeals
Glu
cose
(mm
ol/l)
Glu
cose
(mm
ol/l) 9.09.0
5.05.0
160160
00
7.07.0
320320
480480
Insu
lin (p
mol
/l)In
sulin
(pm
ol/l)
In Type 1 DMIn Type 1 DM
Mean ± 2SD Mean ± 2SD
07000700 12001200 18001800 24002400 0600 hrs0600 hrs
Normal SubjectsNormal Subjects
MealsMeals
Itinerary for nearnomoglycaemia
• Physiological insulin replacement (basal + prandial insulin)
• Intensive BG monitoring for insulin dose adjustment
Glu
cose
(mm
ol/l)
Glu
cose
(mm
ol/l) 9.09.0
5.05.0
160160
00
7.07.0
320320
480480
Insu
lin (p
mol
/l)In
sulin
(pm
ol/l)
07000700 12001200 18001800 24002400 0600 hrs0600 hrsCiofetta M., et al., DIABETES Care 22:795-800, 1999
Mean ± 2SD Mean ± 2SD Normal SubjectsNormal Subjects
R
~0.15 U/Kg~0.15 U/Kg
BreakfastBreakfast
Regular
~0.10 U/Kg~0.10 U/Kg
R ~0.15U/Kg ~0.15U/Kg
++NPH ~0.1 U/Kg ~0.1 U/Kg
NPH
~0.2 U/Kg~0.2 U/Kg
LunchLunch DinnerDinner Bed-timeBed-time
Intensive Insulin Regimen Intensive Insulin Regimen (1980 – 1995)(1980 – 1995)
……with human insulin…with human insulin…
R
~0.15 U/Kg~0.15 U/Kg
BreakfastBreakfast
Regular
~0.10 U/Kg~0.10 U/Kg
R ~0.15U/Kg ~0.15U/Kg
++NPH ~0.1 U/Kg ~0.1 U/Kg
NPH
~0.2 U/Kg~0.2 U/Kg
LunchLunch DinnerDinner Bed-timeBed-time
Intensive Insulin Regimen Intensive Insulin Regimen (1980 – 1995)(1980 – 1995)
the limitations of human the limitations of human insulin…insulin…
80
60
40
20
00 2 4 6 8 10 12
Pla
sma
Free
Insu
lin (µ
U/m
l)
Time (hours)
Normal post-prandial values(Mean ± SD, n=23)
S.c. injection of soluble insulinin T1 diabetics(Mean ± SEM, n=20)
Bolli G.B. et al., N.Engl.J.Med. 310:1706-11, 1984
PLASMAPLASMAINSULININSULIN
s.c.
insu
lins.
c. in
sulin
Meal
B3Lys, B29Glu : Insulin glulisine (Apidra)
INSULIN ANALOGUES‘monomeric’
‘Rapid – acting’
B28 LYS, B29 PRO : Insulin lispro(Humalog)
B28ASP : Insulin aspart (Novorapid)
80
60
40
20
00 2 4 6 8 10 12
Plas
ma
Free
Insu
lin (µ
U/m
l)
Time After Insulin Injection or Meal Ingestion (Hours)
Normal postprandial values(Mean±SD, n=23)
s.c. injection of soluble insulinin diabetic subjects(Mean ± SEM, n=20)
Bolli G.B., N.Engl.J.Med. 310:1706, 1984
PLASMAPLASMAINSULININSULIN
s.c. injection of lispro, aspart,or glulisine in diabetic subjects (Mean ± SEM, n=10)
Lower risk for latepost-prandial hypoglycaemia
s.c.
insu
lins.
c. in
sulin
MealBetter
Post-prandial BG
Glu
cose
(mm
ol/l)
Glu
cose
(mm
ol/l) 9.09.0
5.05.0
160160
00
7.07.0
320320
480480
Insu
lin (p
mol
/l)In
sulin
(pm
ol/l)
07000700 12001200 18001800 24002400 0600 hrs0600 hrsCiofetta M. et al., DIABETES Care 22:795, 1999
Mean ± 2SD Mean ± 2SD Normal SubjectsNormal Subjects
Hans Christian HagedornHans Christian Hagedorn1888-19711888-1971
HagedornHagedorn 19461946 NPHNPH
Hallas-MøllerHallas-Møller 19511951 ULTRALENTE ULTRALENTE (crystalline)(crystalline)
SEMILENTE SEMILENTE (amorphous)(amorphous)
LENTELENTE (70% (70% Ultralente Ultralente
+ 30% Semilente)+ 30% Semilente)
n=20 T1DMn=20 T1DMMean Mean ± SEM± SEM
0.3 U/Kg0.3 U/Kgs.c. NPHs.c. NPH
4.04.0
3.03.0
2.02.0
1.01.0
00
00 44 88 1212 1616 2020 2424Time (hours)Time (hours)
mg/
Kg/
min
mg/
Kg/
min
Glu
cose
Infu
sion
Rat
eG
luco
se In
fusi
on R
ate
Lepore M. et al., Diabetes 49:2142-8, 2000
5.0 5.5 6.0 6.5 7.0 7.58.08.59.0 9.5 10.010.5 HbA1c (%)
0
20
40
60
80
90
100
Rate
of s
ever
e hy
pogl
ycae
mia
(per
100
pat
ient
-yea
rs)
DCCT. N Engl J Med 1993; 329:977.
1 severe hypoevery 20 months
50% of episodeswere at night…!
Intensive treatment and severe hypoglycaemia
in 1993 – human insulin + NPH ERA
n=20 T1DMn=20 T1DMMean Mean ± SEM± SEM
0.3 U/Kg0.3 U/Kgsc insulin NPHsc insulin NPH
4.04.0
3.03.0
2.02.0
1.01.0
00
00 44 88 1212 1616 2020 2424
Time (hours)Time (hours)
mg/
Kg/
min
mg/
Kg/
min
1212
1111
1010
99
88
77
mm
ol/l
mm
ol/l
Glu
cose
Infu
sion
Rat
eG
luco
se In
fusi
on R
ate
Plas
ma
Glu
cose
Plas
ma
Glu
cose
Lepore M. et al., Diabetes 49:2142-8, 2000
•• peak effectpeak effectnocturnal hypoglycaemianocturnal hypoglycaemia
• • relatively short durationrelatively short durationfasting hyperglycaemiafasting hyperglycaemia
High variability in s.c. High variability in s.c. absorptionabsorption
wide blood glucose fluctuations fromwide blood glucose fluctuations from
day-to-dayday-to-day
Inappropriate PharmacokineticsInappropriate Pharmacokinetics
• no peak (flat, constant no peak (flat, constant activity)activity)• reproducibility of s.c. reproducibility of s.c. absorptionabsorption• long duration of actionlong duration of action
The ideal basal The ideal basal insulininsulin
n=20 T1DMn=20 T1DMMean Mean ± SEM± SEM
0.3 U/Kg0.3 U/Kgs.c. NPHs.c. NPH
4.04.0
3.03.0
2.02.0
1.01.0
00
00 44 88 1212 1616 2020 2424Time (hours)Time (hours)
mg/
Kg/
min
mg/
Kg/
min
Glu
cose
Infu
sion
Rat
eG
luco
se In
fusi
on R
ate
Lepore M. et al., Diabetes 49: 2142-8, 2000
NPH is not the ideal basal insulin
ideal peaklessbasal insulin
Insu
lin E
ffect
MEALBOLUS
Afternoon
MEALBOLUS
Evening
BASALINFUSION
Night
MEALBOLUS
Morning
Continuous Subcutaneous Insulin Infusion Continuous Subcutaneous Insulin Infusion
Analogue Fatty acidAnalogue Fatty acid DetemirDetemiracylated insulinacylated insulin (Levemir(Levemir®®, NovoNordisk), NovoNordisk)
Analogue insulin with Analogue insulin with GlargineGlargineneutral isoelectric point neutral isoelectric point (Lantus(Lantus®®, Sanofi-Aventis) , Sanofi-Aventis)
NEW CANDIDATES FOR BASAL NEW CANDIDATES FOR BASAL INSULIN REPLACEMENTINSULIN REPLACEMENT
Long-acting insulin analoguesLong-acting insulin analogues
SOLUBLESOLUBLE INSULINS INSULINS
GlargineGlargine
NPHNPH
Plasma InsulinPlasma Insulin
Time (hours)Time (hours)
3030
2525
2020
1515
1010
55
180180
150150
120120
9090
6060
303000 44 88 1212 1616 2020 2424
µµ U/m
lU
/ml
pmol
/lpm
ol/l
0.3 U/kg0.3 U/kgs.c. insulins.c. insulin n=20 T1DMn=20 T1DM
Mean Mean ± SEM± SEM
Lepore M. et al., Diabetes 49:2142-8, 2000
Glucose Infusion Rate
n=20 T1DMMean ± SEM
sc insulin
4.0
3.0
2.0
1.0
0
24
20
16
12
8
4
0
0 4 8 12 16 20 24
Time (hours)
mg/
Kg/
min
mol
/Kg/
min
µ
Lepore M. et al., Lepore M. et al., Diabetes Diabetes 49: 2142-8, 2000
NPH
Glargine
Glargine
NPH
Plasma Glucose
n=20 T1DMMean ± SEM
Time (hours)
220
200
180
160
140
120
12
11
10
9
8
7
0 4 8 12 16 20 24
mg/
dl
mm
ol/l
Lepore M. et al., Diabetes 49:2142-8, 2000
0.3 U/kg0.3 U/kgs.c. insulins.c. insulin
Hagedorn ERA in Type 1 diabetes (until June 2000)Rapid-Acting Insulin Analogue and Multiple Doses
of NPH
44 1616 2020 2424 44
BreakfastBreakfast LunchLunch DinnerDinner
Insu
lin a
ctio
n pr
ofile
Insu
lin a
ctio
n pr
ofile
88121288
Time of day (h)Time of day (h)
NPHRapid-acting insulin analogue
Physiologic insulin secretion
Average insulin
Lalli C. et al., Diabetes Care 1999;22:468-77NPH
9 June 2000 – lantus in German pharmacies
announcement…___________NPH and
NPH-based Pre-Mixesare dead !!!___________
Patients with T1DM should NOT receive NPH and/or NPH-mixtures any longer !
Glu
cose
(mm
ol/l)
Glu
cose
(mm
ol/l) 9.09.0
5.05.0
160160
00
7.07.0
320320
480480
Insu
lin (p
mol
/l)In
sulin
(pm
ol/l)
In Type 1 DMIn Type 1 DM
Mean ± 2SD Mean ± 2SD
07000700 12001200 18001800 24002400 0600 hrs0600 hrs
Normal SubjectsNormal Subjects
MealsMeals
BGBasal
R R R
CHO CHO
BG
BGBG
BGCHO
Significantly greater HbA1c reduction and less hypoglycemia with insulin glargine vs
NPH
*p<0.05 insulin glargine vs NPH; †HbA1c analysis values were not aligned with the DCCT
0 2 4 6 8 10 12Time (months)
Mean HbA1c levels during study
Mea
n H
bA1c
± S
EM (%
)
6.4
6.6
6.8
7.0
7.2
7.4
7.6
NPH + insulin lisproInsulin glargine + insulin lispro
Randomised, non-blinded study of once-daily insulin glargine versus four-times daily NPH (both + mealtime insulin lispro), 121 patients†
7.2
13.2
3.2
0
2
4
6
8
10
12
14
Mild Nocturnal
Even
ts/p
atie
nt-m
onth
Insulin glargine + insulin lispro
NPH + insulin lispro
Incidence of mild and nocturnal hypoglycemiap<0.05
p<0.05
1.2
* **
**
Hypoglycemia
Porcellati et al. Diabet Med 2004;21:1213–20. Reproduced with permission
Analogue Fatty acidAnalogue Fatty acid DetemirDetemiracylated insulinacylated insulin (Levemir(Levemir®®, NovoNordisk), NovoNordisk)
Analogue insulin with Analogue insulin with GlargineGlargineneutral isoelectric point neutral isoelectric point (Lantus(Lantus®®, Sanofi-Aventis), Sanofi-Aventis)
NEW CANDIDATES FOR BASAL NEW CANDIDATES FOR BASAL INSULIN REPLACEMENTINSULIN REPLACEMENT
Long-acting insulin analoguesLong-acting insulin analogues
SOLUBLESOLUBLE INSULINS INSULINS
GlargineGlargine
DetemirDetemir
GlargineGlargine
DetemirDetemir
Clamp 1Clamp 1 Clamp 2Clamp 2ScreeninScreeningg
Run-inRun-in4-weeks4-weeks
Period 1Period 12-weeks2-weeks
Period 2Period 22-weeks2-weeks
Wash-outWash-out2-weeks2-weeks
24 T1 DM24 T1 DM
Study DesignStudy Design
1212
1212
Porcellati F. et al., Diabetes Care 30: 2447-52, 2007
0 2 4 6 8 10 12 14 16 18 20 22 24
0.5
1.0
1.5
3
6
9
mg·
Kg-1
·min-1
·Kg-1
·min-1
GLUCOSE INFUSION RATE
s.c. insulin0.35 U/Kg
0.05
0.10
0.15
0.05
0.10
0.15
Time (hours)
mU·
Kg-1
·min-1
mU·
Kg-1
·min-1
INSULIN INFUSION RATE
Glargine (N=24)Detemir Mean±SE
0
0 0
0
mol
Porcellati F. et al., Diabetes Care 30: 2447-52, 2007
00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 242400
3333
6767
100100
00
88
1616
2424
Subj
ects
(%)
Subj
ects
(%)
Subj
ects
(N)
Subj
ects
(N)
Subjects in studySubjects in study (Plasma glucose < 180 mg/dl)(Plasma glucose < 180 mg/dl)
00
9090108108126126144144162162180180198198
00
556677889910101111
mg/
dlm
g/dl
mm
ol/l
mm
ol/l
Glargine (N=24)Detemir Mean±SE
PLASMA GLUCOSEPLASMA GLUCOSE
s.c. insulin0.35 U/Kg
Time (hours)Time (hours)
Porcellati F. et al., Diabetes Care 30: 2447-52, 2007
PLASMA FFA and PLASMA FFA and -OH -OH BUTYRATE BUTYRATE
00250250500500750750
10001000
mol
/lm
ol/l
00 44 88 1212 1616 2020 2424
-OH-Butyrate-OH-Butyrate
s.c. insulins.c. insulin0.35 U/Kg0.35 U/Kg
Time (hours)Time (hours)
Free FattyFree Fatty AcidsAcids
00
15001500
30003000
45004500
m
ol/l
mol
/lDetemirDetemir
Mean±SEMean±SE
GlargineGlargine
Porcellati F. et al., Diabetes Care 30: 2447-52, 2007
PHARMACODYNAMIC VARIABLESPHARMACODYNAMIC VARIABLES
DetDet GlaGla point point
estest(%)(%)
95% 95% CICI
PP valuevalue
AUC GIRAUC GIR00 --24h24h [mg/kg][mg/kg] 915±225915±225 1412±6621412±662 70.370.3 53.453.4; ; 92.792.7 0.0.015015
AUC GIRAUC GIR00 --12h12h [mg/kg][mg/kg]
773±200773±200 807±352807±352 97.797.7 78.5;121.678.5;121.6 0.8320.832 AUC GIRAUC GIR1212--24h24h
[mg/kg][mg/kg] 142±194142±194 605±390605±390 17.417.4 8.2;36.78.2;36.7 0.0000.000
GIR CGIR Cmaxmax
[mg/kg/[mg/kg/minmin]] 1.6±0.51.6±0.5 1.8±0.61.8±0.6 9090 78.0;103.778.0;103.7 0.1370.137
GIR TGIR Tmaxmax [h][h] 7 (2;12)7 (2;12) 4 (1;24)4 (1;24) 3.253.25 0.5;5.30.5;5.3 0.0350.035
*
**Median (min;maxMedian (min;max)) Porcellati F. et al., Diabetes Care 30: 2447-52, 2007
1 U detemir30% less potent than 1 U glargine
detemir needs greater dosesand/or 2 injections/day
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 glarginevs detemir in Type 1 diabetes confirmed
CSII vs MDI STUDYrandomized, parallel-group, open-label, multicenter (n=5)
subjects naïve to CSII and glargine
58 T1DM, 6.5<HbA1c<9%
On MDI with NPH
1 week
Run-in period
24 week
Treatment period
24 CSII (lispro)
26 Glargine + mealtime lispro
Insulin dose titration to the same BG targets: FPG 80–120 mg/dL; other preprandial BG 90–140 mg/dL; 2-h post-prandial BG <140 mg/dL; and bedtime BG 110–150 mg/dL.
2 weeks
Follow up
1 randomization error, 7 protocol violatiors
Bolli GB et al., Diabetes Care 2009; 32:1170-6
CSII vs MDI STUDY Results
Change in A1C (%) from baseline over the course of the study.
CSII
MDI
Bolli GB et al., Diabetes Care 2009; 32:1170-6
CSII vs MDI STUDY Results
Number of hypoglycemic events by visit for the two insulin regimens (safety population)
MDI
CSII
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
0
500
1000
1500
2000
2500
3000
3500
MDI CSII
Euros
Average cost per treatment during the study (Euro/24 weeks)
Bolli GB et al., Diabetes Care 2009; 32:1170-6
Basal insulin as long-acting analogue – MDI regimen
Basal insulin as CSII (the “gold standard”)
RA-IARA-IA~0.05 U/Kg~0.05 U/Kg
RA-IARA-IA~0.15 U/Kg~0.15 U/Kg
RA-IARA-IA~0.15 U/Kg~0.15 U/Kg
Glargine ONCE dailyGlargine ONCE daily~0.3-0.4 U/Kg~0.3-0.4 U/Kg
or detemir TWICE daily or detemir TWICE daily
breakfastbreakfast lunchlunch dinnerdinner
Lispro/aspart/glulisine basal rateLispro/aspart/glulisine basal rate
Lispro/aspart/glulisine (RA-IA)Lispro/aspart/glulisine (RA-IA)~0.05 U/Kg~0.05 U/Kg
RA-IARA-IA~0.10 U/Kg~0.10 U/Kg
RA-IARA-IA~0.10 U/Kg~0.10 U/Kg
breakfastbreakfast lunchlunch dinnerdinner
RA-IA~1-2 U
h 16-16:30
+30-100% basal rate
Snack? A bolus of Rapid-acting insulin Analogue any time
RA-IA~1-2 U
midmorning
in in ~~30% of30% ofsubjectssubjects
• less (nocturnal) hypoglycaemialess (nocturnal) hypoglycaemia and/or lower A1Cand/or lower A1C
• improved life-styleimproved life-style
• non-inferior vs. CSII while 3.9non-inferior vs. CSII while 3.9 times less expensive (glargine)times less expensive (glargine)
Superiority of long-acting insulin Superiority of long-acting insulin analogues vs. NPH in T1DManalogues vs. NPH in T1DM
6
6,5
7
7,5
8
8,5
HbA1c (%)
glargine + lispro NPH + HI
P<0.001
Difference 0.5 (95% C.I.-0.7,-0.3) %
A1C with insulin glargine + lispro vs NPH + human R insulin
Ashwell SG et al., Diabet.Med. 23:285-92, 2006
N=54 T1DMs4 mo, crossover
0
1
2
3
4
5
6
All symptomatic
Hypoglycaemia with insulin glargine + lispro vs NPH + human R insulin
0
0,3
0,6
0,9
1,2
1,5
Nocturnal Severe
glargine + lispro NPH + HI
P<0.001
Rate of hypoglycaemia (episodes.patient.month-1)
N=54 T1DMs4 mo, crossover
Ashwell SG et al., Diabet.Med. 23:285-92, 2006
1,00
1,10
1,20
1,30
1,40
1,50
1,60
1,70
1,80 crossovercrossover
BaselineBaseline Period 1Period 1 Period 2Period 2
Glargine+lisproGlargine+lisproNPH+Human RegularNPH+Human Regular
QoL
sco
reQ
oL s
core
Quality of Life with Insulin Quality of Life with Insulin AnaloguesAnalogues
Ashwell et al, Diabetes Care, ahead of print March 13 2008 Ashwell et al, Diabetes Care, ahead of print March 13 2008
Period 2: cross-over Period 2: cross-over to alternative treatmentto alternative treatment
5.0 5.5 6.0 6.5 7.0 7.58.08.59.0 9.5 10.010.5 HbA1c (%)
0
20
40
60
80
90
100
Rate
of s
ever
e hy
pogl
ycae
mia
(per
100
pat
ient
-yea
rs)
DCCT. N Engl J Med 1993; 329:977.
Intensive treatment and severe hypoglycaemia
in 1993 – human insulin + NPH ERA
DCCT1983
post-human insulin era
Rapid +Long-acting analogs
Impact of Intensive Therapy in Diabetes Summary of Major Clinical Impact of Intensive Therapy in Diabetes Summary of Major Clinical TrialsTrials
StudyStudy A1cA1c MicrovascularMicrovascular CVDCVD MortalityMortality
DCCT/EDIC DCCT/EDIC 9 → 9 & 7 ↓↓ ↓↓ ↔↔ ↓↓ ↔↔ ↔↔
UKPDSUKPDS 9 → 7.9 & 7 ↓↓ ↓↓ ↔↔ ↓↓ ↔↔ ↓↓
ACCORDACCORD 8.3 → 7.5 & 6.4 ↓↓ ↔↔ ↑ ↑ ??
ADVANCEADVANCE 7.5 → 7.0 & 6.4 ↓↓ ↔↔ ↔↔
VADTVADT 9.4 → 8.5 & 6.9 ↓↓ ↔↔ ↔↔
ORIGIN
6.4 → 6.5 & 6.2 ↔↔ ↔↔ ↔↔
Adapted from Bergenstal RM, Bailey C and Kendall DM. Am J Med 2010;123:374e9-e18
Baseline Study End Std Intensive
Long Term Follow-upLong Term Follow-up Initial TrialInitial Trial
Study End Std Glargine
Baseline
Time (Years Since Diagnosis)Time (Years Since Diagnosis)
A1C
(%)
A1C
(%)
9.59.59.09.08.58.58.08.07.57.57.07.06.56.56.06.0
11 22 3 3 4 4 55 6 6 7 7 88 9 9 10 10 1111 12 12 13 13 1414 15 15 16 16
Drive the risk for complications
Build up “bad” metabolic memory
The The ““Natural HistoryNatural History”” of Type 2 of Type 2 DiabetesDiabetes
Diabetes remission after intensive insulin therapy in new onset T2DM
• 382 patients with newly diagnosed type 2 DM
• CSII, MDI, or OHA until normoglycemia reached and maintained for 2 weeks
• Remission defined asFBG > 126 mg/dL or 2-hr PP > 180 mg/dL
• Initial HbA1c 9.5%-9.8%
Weng J, et al. Lancet 2008; 371:1753–60.
80
60
40
20
00 90 180 270 360 450
p = 0.0012
100
Days in remission
51.1%44.9%
26.7%
CSIIMDIIOAD
Patie
nts
in re
mis
sion
(%)
-cell function after intensive insulin therapy in new onset T2DM
p < 0.0001
CSII in the remission groupMDI in the remission groupOHA in the remission groupNon-remission group
140012001000
800600400200
0-200 Before therapy After therapy At 1 year
Acu
te in
sulin
resp
onse
(pm
ol/L
per
min
)
Weng J, et al. Lancet 2008; 371:1753–60.
*
* p < 0.05 vs each intervention in the remssion group (after treatment)
p = 0.006