Curs Diabet Insulina

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


07000700 12001200 18001800 24002400 0600 hrs0600 hrs


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


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


•• 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


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


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


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


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


07000700 12001200 18001800 24002400 0600 hrs0600 hrs


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


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



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


Free FattyFree Fatty AcidsAcids

00

15001500

30003000

45004500

m

ol/l

mol

/lDetemirDetemir

Mean±SEMean±SE

GlargineGlargine


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


CSII vs MDI STUDY Results

Number of hypoglycemic events by visit for the two insulin regimens (safety population)

MDI

CSII


CSII vs Glargine-MDI STUDY Results

• Quality of life

• Glucose variability

NO DIFFERENCE


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)


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



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



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

Documents

Curs Diabet Insulina