Insulin Analogues versus Pump Insulin Analogues versus Pump

Therapy in Type 2 Diabetes:Therapy in Type 2 Diabetes:

Benefits from Pump TherapyBenefits from Pump Therapy

Eric RENARD, MD, PhDEric RENARD, MD, PhD

Endocrinology Dept, Endocrinology Dept, LapeyronieLapeyronie HospitalHospital

Montpellier, FranceMontpellier, France

ee--renard@churenard@chu--montpellier.frmontpellier.fr

Type 2 Diabetes Burnout : What is the Type 2 Diabetes Burnout : What is the

Remedy and for Whom ? Remedy and for Whom ?

Needles ?Needles ?Or Pump ?Or Pump ?

What is the Current Experience of Glucose What is the Current Experience of Glucose

Control with Insulin Injections in Type 2 Control with Insulin Injections in Type 2

Diabetes ?Diabetes ?

Insulin Therapy in Type 2 Diabetes Insulin Therapy in Type 2 Diabetes

and Outcomes on HbA1cand Outcomes on HbA1c

9,3

7,9

7,4 7,4

6,9

6

6,5

7

7,5

8

8,5

9

9,5

OHA+/-

INS

Bedtime

INS

Bedtime

INS+SU

INS x 2/d INS x 3-4/d

AbrairaAbraira et al, VA CSDM, Diabetes Care, 1995, 18: 1113et al, VA CSDM, Diabetes Care, 1995, 18: 1113--2323

FollowFollow--up of intensively treated group (75 patients)up of intensively treated group (75 patients)

p < 0.05p < 0.05HbA1c HbA1c

(%)(%)

BASALBASAL--BOLUS BOLUS isis finallyfinally requestedrequested to to reachreach targettarget

23

61 64

116133

20

40

60

80

100

120

140

OHA +/-

INS

Bedtime

INS

Bedtime

INS+SU

INS x

2/d

INS x 3-

4/d

p < 0.05p < 0.05

InsulinInsulin

(IU/day)(IU/day)

HIGH INSULIN DOSES are HIGH INSULIN DOSES are oftenoften neededneeded to to reachreach targettarget

Insulin Therapy in Type 2 Diabetes and Outcomes on Insulin Therapy in Type 2 Diabetes and Outcomes on

Insulin Daily DosesInsulin Daily Doses

AbrairaAbraira et al, VA CSDM, Diabetes Care, 1995, 18: 1113et al, VA CSDM, Diabetes Care, 1995, 18: 1113--2323

FollowFollow--up of intensively treated group (75 patients, mean BMI = 30.7)up of intensively treated group (75 patients, mean BMI = 30.7)

Fat Mass, Distribution and Liver Determine Necessary Fat Mass, Distribution and Liver Determine Necessary

Insulin Doses to Reach TargetInsulin Doses to Reach Target

Correlations with Correlations with

insulin absorption insulin absorption

�� Visceral fat (ml)Visceral fat (ml) --0,73 0,73 p<0,0004 p<0,0004

�� SC fat (ml) SC fat (ml) --0,60 0,60 p<0,0072p<0,0072

�� BMIBMI --0,59 0,59 p<0,006p<0,006

Correlations with insulin dose to Correlations with insulin dose to

suppress endogenous glucose suppress endogenous glucose

productionproduction

�� Liver Liver steatosissteatosis (%) (%) 0,72 0,72 p<0,0013p<0,0013

�� SC fat (ml) SC fat (ml) 0,67 0,67 p<0,0065p<0,0065

�� Body fat mass (kg) Body fat mass (kg) 0,60 0,60 p<0,01p<0,01

RyysyRyysy et al, Diabetes, 2000, 49: 749et al, Diabetes, 2000, 49: 749--58.58.

20 Type 2 patients insulin treated for > 1 year,20 Type 2 patients insulin treated for > 1 year, HbA1c: 7.6 HbA1c: 7.6 ++ 0.2%0.2%

Doses: 10 Doses: 10 -- 176 IU/d176 IU/d (Bedtime NPH + (Bedtime NPH + metforminmetformin), ), Weight: 67 Weight: 67 -- 127 kg127 kg

Insulin doses needed to reach glucose control Insulin doses needed to reach glucose control depends on : depends on :

1) Liver 1) Liver steatosissteatosis (r=0,76; p<0,0004)(r=0,76; p<0,0004)

2) waist/hip ratio (r=0,69; p<0,0008) 2) waist/hip ratio (r=0,69; p<0,0008)

3) BMI (r=0,68; p<0,0009)3) BMI (r=0,68; p<0,0009)

GlargineGlargine vs. 1vs. 1--2 Daily NPH in Type 2 Diabetes: 2 Daily NPH in Type 2 Diabetes:

MetaMeta--AnalysisAnalysis

RosenstockRosenstock et al, Diabetes Care, 2005et al, Diabetes Care, 2005

0

10

20

30

40

50

60

Hypoglycemia Nocturnal Hypos Severe Hypos Noct. Severe Hypos

GlargineGlargine (n=1142) vs. 1(n=1142) vs. 1--2 daily NPH (n=1162)2 daily NPH (n=1162)

HbA1c < 7% : 30,8 % vs. 32,1 % (NS)HbA1c < 7% : 30,8 % vs. 32,1 % (NS)% %

reduction reduction

of hyposof hypos

P = 0.0006P = 0.0006 P < 0.0001P < 0.0001 P = 0.0442P = 0.0442 P = 0.0231P = 0.0231

[[GlulisineGlulisine vs. Regular Insulin] + NPH Twice Daily in vs. Regular Insulin] + NPH Twice Daily in

Type 2 DiabetesType 2 Diabetes

Dailey et al, Diabetes Care, 2004Dailey et al, Diabetes Care, 2004

876 patients, 26 weeks follow876 patients, 26 weeks follow--upup

154154

(p<0.05)(p<0.05)

163163PostPost--dinner blood dinner blood

glucose (mg/dl)glucose (mg/dl)

156156

(p<0.05)(p<0.05)

162162PostPost--breakfast breakfast

blood glucose blood glucose

(mg/dl)(mg/dl)

0.46 %0.46 %

(p=0.0029)(p=0.0029)

0.3 %0.3 %HbA1c decrease HbA1c decrease

from baseline (%)from baseline (%)

GlulisineGlulisine + NPH + NPH

x 2/dayx 2/dayRegular + NPH Regular + NPH

x 2/dayx 2/day

Hypoglycemia and weight = no differenceHypoglycemia and weight = no difference

[NPH vs. DETEMIR] + ASPART in Type 2 Diabetes[NPH vs. DETEMIR] + ASPART in Type 2 Diabetes

HaakHaak et al, Diabetes et al, Diabetes ObesObes MetabMetab, 2005, 2005

505 patients, 26 weeks follow505 patients, 26 weeks follow--upup

+1.00+1.00

(p=0.017)(p=0.017)

+ 1.80+ 1.80Weight gain (kg)Weight gain (kg)

LowerLower

(p=0.021)(p=0.021)

HigherHigher

BetweenBetween--day day

intraintra--subject subject

blood glucose blood glucose

variabilityvariability

0.2%0.2%

(p=0.004)(p=0.004)

0.4 %0.4 %

(p=0.0001)(p=0.0001)

HbA1c decrease HbA1c decrease

from baseline from baseline

(%)(%)

DETEMIR + DETEMIR +

ASPARTASPARTNPH + ASPARTNPH + ASPART

[[NPH+RegularNPH+Regular] vs. [] vs. [Detemir+AspartDetemir+Aspart] in Type 2 ] in Type 2

Diabetes MellitusDiabetes Mellitus

RaslovaRaslova et al, Diabetes et al, Diabetes ResRes ClinClin PractPract, 2004, 2004

395 patients, 22 weeks follow395 patients, 22 weeks follow--upup

0.510.51

(p = 0.038)(p = 0.038)

1.131.13Weight gain (kg)Weight gain (kg)

1.201.20

(p<0.001)(p<0.001)

1.541.54BetweenBetween--day intraday intra--

sujectsuject blood blood

glucose variability glucose variability

((mmol/lmmol/l))

0.650.650.580.58HbA1c decrease HbA1c decrease

from baseline (%)from baseline (%)

DetemirDetemir + +

((AspartAspart x 3/day)x 3/day)

NPH + NPH +

(Regular x 3/day)(Regular x 3/day)

No significant difference on hyposNo significant difference on hypos

Screening Baseline 6 12 24

SC insulin (n=149)Inhaled insulin (n=149)

55

6

7

8

9

10

��

Duration of treatment (weeks)

MeanA1c(%)

Hollander et al., Diabetes Care 2004;27:2356-62.

Effectiveness of Inhaled Insulin Effectiveness of Inhaled Insulin ExuberaExuberaTMTM

in Type 2 Diabetesin Type 2 Diabetes

Inhaled SC

Mean weightchange

(kg)

0.0

0.5

1.0

1.5

2.0

ExuberaExuberaTMTM in Type 2 Diabetes:in Type 2 Diabetes:

Change in Body Weight (6 Months)Change in Body Weight (6 Months)

Hollander et al., Diabetes Care 2004;27:2356-62.

Current Experience of Glucose Control with Current Experience of Glucose Control with

Insulin Injections in Type 2 DiabetesInsulin Injections in Type 2 Diabetes

�� Evolution of insulin therapy toward Evolution of insulin therapy toward basalbasal--bolusbolus is is needed to reach target.needed to reach target.

�� High insulin dosesHigh insulin doses are commonly requested, are commonly requested, according to according to fat distribution and liver fat distribution and liver steatosissteatosis..

�� Insulin analoguesInsulin analogues decrease occurrence of hypos, decrease occurrence of hypos, improve glucose stability, may reduce weight improve glucose stability, may reduce weight gain but gain but often fail in further lowering of HbA1coften fail in further lowering of HbA1c..

�� Expected benefit of Expected benefit of inhaled insulininhaled insulin looks looks minor, minor, except for the acceptance of insulin and except for the acceptance of insulin and perhaps perhaps for weight controlfor weight control..

What Can We Expect from Insulin Pumps in What Can We Expect from Insulin Pumps in

Type 2 Diabetes ?Type 2 Diabetes ?

IV Insulin Infusion Followed by OneIV Insulin Infusion Followed by One--year year

CSII in 8 Severely Resistant Type 2 PatientsCSII in 8 Severely Resistant Type 2 Patients

PouwelsPouwels et al, Diabetic Medicine, 2003et al, Diabetic Medicine, 2003

6

7

8

9

10

11

12

Baseline 6 months 9 months 12 months

FollowFollow--up of HbA1c up of HbA1c

using CSII for 1 yearusing CSII for 1 year

With Weight stabilityWith Weight stabilityp < 0.0005 vs. Baselinep < 0.0005 vs. Baseline

p < 0.001 vs. Baselinep < 0.001 vs. Baseline

Effects of 4 weeks with IV insulin infusionEffects of 4 weeks with IV insulin infusion

FortyForty--week Experience with CSII in 10 week Experience with CSII in 10

Severely Obese Type 2 PatientsSeverely Obese Type 2 Patients

WainsteinWainstein et al, Diabetes Care, 2001et al, Diabetes Care, 2001

9.56 +/9.56 +/-- 0.760.7612.34 +/12.34 +/-- 1.741.74HbA1cHbA1c

(%)(%)

93.4 +/93.4 +/-- 12.712.795.9 +/95.9 +/-- 13.213.2Weight Weight

(kg)(kg)

1.19 +/1.19 +/-- 0.420.421.46 +/1.46 +/-- 0.430.43Daily Insulin Daily Insulin

Dose (IU/kg)Dose (IU/kg)

After 40 weeksAfter 40 weeksBaselineBaseline

Does it mean

that insulin

pump is only

good for me ?

No Sir, we

shall perform

randomized

studies now !

CSII [CSII [AspartAspart] vs. ] vs. Multiple Multiple DailyDaily InsulinInsulin InjectionsInjections

[[AspartAspart + NPH]+ NPH] in Type 2 in Type 2 DiabetesDiabetes: :

a a RandomizedRandomized, , ParallelParallel--GroupGroup, 24, 24--week week StudyStudy

RaskinRaskin P et P et alal, , DiabetesDiabetes Care 2003, 26: 2598Care 2003, 26: 2598--603.603.

7

7,2

7,4

7,6

7,8

8

8,2

Baseline 24 weeks

CSII

MDI

P<0.05 vs. P<0.05 vs. baselinebaseline

HbA1c (%)HbA1c (%)

Baseline and EndBaseline and End--ofof--Study Eight Point Study Eight Point

Blood Glucose Profiles (ITT)Blood Glucose Profiles (ITT)

* p = 0.02* p = 0.02

ChangeChange--fromfrom--Baseline Improvements in Baseline Improvements in

Patient Satisfaction Patient Satisfaction SubscoresSubscores

at the End of Studyat the End of Study

* p<0.025* p<0.025 ** p<0.01** p<0.01 *** p<0.001*** p<0.001

For sure,

they will

never try

to

randomize

me…

Don’t be

so

negative,

it may

happen !

… and

for now,

don’t

move !!

Insulin [Insulin [lisprolispro] Pump Therapy vs. Multiple Daily Injections ] Pump Therapy vs. Multiple Daily Injections

[Regular + NPH] in Obese Type 2 Diabetic Patients[Regular + NPH] in Obese Type 2 Diabetic Patients

J J WainsteinWainstein et al, Diabetic Medicine, 2005et al, Diabetic Medicine, 2005

4040 Type 2 insulinType 2 insulin--treated patients (treated patients (BMI: 30BMI: 30--4545; HbA1c > 8.5%; ; HbA1c > 8.5%;

insulin doses > 1 insulin doses > 1 iu/kg/diu/kg/d; ; metforminmetformin), 2 x ), 2 x 1818--weekweek randomized randomized

crosscross--overover study, study, 1212--week washweek wash--outout b/w periods, b/w periods, 29 completers29 completers

Direct treatment effect by group, ITT analysisDirect treatment effect by group, ITT analysis

Take your hands Take your hands

away of my pump !!!away of my pump !!!

The Results of this Study The Results of this Study FavourFavour Pump Therapy for Pump Therapy for

hardhard--toto--control Type 2 Obese Patientscontrol Type 2 Obese Patients

Gee ! ThatGee ! That’’s s

fun. Can I be fun. Can I be

randomized, randomized,

too ?too ?

CSII [CSII [lisprolispro] vs. Multiple Daily Injections [] vs. Multiple Daily Injections [lisprolispro

+ + glargineglargine] in Adults older than 60 years] in Adults older than 60 years

Herman WH et al, Diabetes Care, 2005Herman WH et al, Diabetes Care, 2005

107107 Type 2 insulinType 2 insulin--treated patients (treated patients (Age > 60Age > 60; ; BMI: 32BMI: 32; ; HbA1c: 8.2%HbA1c: 8.2%), ),

1212--month randomizedmonth randomized parallelparallel study, study, 98 completers98 completers

--11 00 11 22 44 66 88 1010 1212

HbA1c HbA1c

(%)(%)

Study monthStudy month

�� CSII CSII

oo MDIMDI

No difference in weight gain, incidence of hypos, daily insulin No difference in weight gain, incidence of hypos, daily insulin doses, doses, QoLQoL indicesindices

OK for oldies, but what

about us, playing rugby ?

Don’t look for

my pump, it’s

internal !

What is an ‘Internal’ Insulin Pump ? What is an ‘Internal’ Insulin Pump ?

CathCatheterter

Telemetry Telemetry

ProgrammerProgrammer

Central Port

Sideport

MODEL…

SN…Subcutaneous Part

Anchoring Flange

Intraperitoneal

Part

Anchoring

hoops

) )

) )

)) ) ) ) )

Titanium case

(81 x 20 mm, 146 g)

MedtronicMedtronic--MiniMedMiniMed Implantable Pump, model 2007Implantable Pump, model 2007

RandomizedRandomized, , ControlledControlled, Prospective , Prospective StudyStudy: Implantable : Implantable

PumpPump vs. MDI in 122 Type 2 Patientsvs. MDI in 122 Type 2 Patients

SaudekSaudek et et alal, JAMA 1996, JAMA 1996

8,85

7,54

8,77

7,34

5

6

7

8

9

10

MDI IMP PUMP

97,8

101,4

9392

90

100

110

MDI IMP PUMP

53

4650

34,5

20

30

40

50

60

MDI IMP PUMP

p < 0,001 vs initialp < 0,001 vs initial

SD

BG

(m

g/d

l)S

D B

G (

mg

/dl)

initialinitial

12 12 monthsmonths

p < 0,01 vs MDIp < 0,01 vs MDI p < 0,001 vs MDIp < 0,001 vs MDIW

eig

ht

(kg

)W

eig

ht

(kg

)

Hb

A1

c (

%)

Hb

A1

c (

%)

What Can We Expect from Insulin Pumps in What Can We Expect from Insulin Pumps in

Type 2 Diabetes ?Type 2 Diabetes ?

�� Insulin pumps are usable Insulin pumps are usable at any ageat any age with with at least at least similar effectivenesssimilar effectiveness, , no further weight gainno further weight gain, , no no more acute eventsmore acute events when compared with MDI when compared with MDI using analogues or not.using analogues or not.

�� They They may provide better satisfactionmay provide better satisfaction because of because of increased flexibility of use and avoidance of increased flexibility of use and avoidance of injections, injections, as they do in type 1as they do in type 1 diabetic patients.diabetic patients.

�� They may help in They may help in more efficientmore efficient glucose control glucose control in in severely resistant, obeseseverely resistant, obese patients.patients.

�� Further studies are needed to Further studies are needed to assess costassess cost--effectiveness and effectiveness and ––benefitbenefit..

Insulin Pump Therapy in Type 2 DiabetesInsulin Pump Therapy in Type 2 Diabetes

Yes, when glucose control with MDI looks as an

‘impossible mission’.

No, there is no reason for

any ‘diktat’ against pump in these patients.

We will probably have to think more of using pumps in the

future: younger patients, QoLissues, glucose sensors…

BeBe WelcomeWelcome in Montpellier to in Montpellier to KnowKnow More More

about about TheThe Future Future ofof DiabetesDiabetes TherapyTherapy !!

1st EuropeanDiabetes

Technology andTransplantation

Meeting