Does Insulin Pump Therapy Have A Role in Type 2 … · Does Insulin Pump Therapy Have A Role in...

Does Insulin Pump Therapy Have

A Role in Type 2 Diabetes?

Bruce W. Bode, MD, FACE

Atlanta Diabetes Associates

Atlanta, Georgia

Disclosures

Consultant: CellNovo, JNJ, Novo Nordisk,

Medtronic, Sanofi, Tandem, Valeritas

Speaker’s Bureau: Insulet, Lilly, Novo Nordisk,

Medtronic, Sanofi

Grant and Research Support: Lilly, Novo Nordisk,

Medtronic, Sanofi, Valeritas

Question 1:

How many type 2 patients are on the insulin

pump in the USA?

a. <25,000

b. 25,000 to 50,000

c. 50,000 to 100,000

d. >100,000

Insulin Therapy Segmentation (US) – 2008

T2 Conventional

3,080,160(69%)

T1 Conventional

368,160 (48%)T1 MDI

398,840 (52%)T1 Pump Therapy

361,000

T2 Pump Therapy

37,000

T2 MDI

1,383,840 (31%)

4.5 Million Type 2 (T2)

>5.6 Million = 1.2 Million Type 1 (T1)

>31% Penetrationin Type 1

<1% Penetrationin Type 2

Source: Medtronic with 78% of the market

Insulin Therapy:

4.5 Million Type 2 Patients are on Insulin

Overall, 71% of intensive therapy pt’s DO NOT inject outside the home

69% of T1 patients DO NOT inject outside the home

89% of T2 patients DO NOT inject outside the home

35%

25%

15% Intensive Tx (3 shots or >)

Premix +/- OAD

Long-Acting +/- OAD

Intermediate +/- OAD

25%Source: Roper Starch 2006 (n=2025; T1DM = 105; T2DM = 1,922)

N=790 on Insulin; n=705 insulin injectors; n=85 on pump therapy.

Graph: Type 2 Diabetes Patients only; excludes patients on CSII therapy.

Type 2 Patients Insulin Needs

Effective (glucose reduction)

Simplicity

Discretion (keep disease to themselves)

Cost effective

Low risk of hypoglycemia

Qualitative market research

Polonsky KS et al. N Engl J Med. 1988;318:1231-1239

0600 0600

Time of day

20

40

60

80

100B L D

Normal Daily Plasma Insulin Profile

B=breakfast; L=lunch; D=dinner

0800 18001200 2400

U/mL GOAL of therapy:

To mimic this

physiologic pattern

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Time

Glargineor

Detemir

Pla

sm

a i

ns

uli

nBasal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs

Aspart,

Lispro

or

Glulisine

Aspart,

Lispro

or

Glulisine

Aspart,

Lispro

or

Glulisine

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Time

Basal infusion

Bolus Bolus Bolus

Pla

sm

a i

nsu

lin

Variable Basal Rate: CSII Program

Major Suppliers of Insulin Pumps in the US

Animas 2020/One Touch Ping Insulet: Omnipod

Roche: Accucheck Spirit

Medtronic/Minimed Paradigm 522/722

Current Pump Therapy Indications

Need to normalize blood glucose (BG)

–A1C > 6.5% or 7%

–Glycemic excursions

Hypoglycemia or Hypoglycemia unawareness

Need for a flexible insulin regimen

Medicare requires: Fasting C-peptide to be ≤110% lower limit of normal

or ≤200% lower limit of normal if CrCl ≤50 ml/min with concurrent FPG ≤225 mg/dL;

or Beta Cell autoantibody positive (+ICA or +GAD antibodies)

T2 CSII Literature Review Summary

2 large RCTs comparing CSII vs MDI - no difference in A1C

3 smaller RCTs comparing CSII vs MDI - improvement in A1C

Longitudinal Data with Labrousse-Lhermine et al.

– n=59

– Sustained A1c reduction (baseline = 9.45%, 1 year = 7.8%, 2 year = 8.0% and 3 year 8.3%)

Parkner et al.

– n= 21

– Intra subject variability was 41% lower with CSII versus MDI (P = .012)

Parkner et al Insulin and glucose profiles During CSII and long acting insulin. Diabetic Medicine 25, 585-591

Labrousse-Lhermine Longer term treatment CSII in type 2 diabetes. Diabetes and Metabolism 33 (2007) 253-260

CSII versus MDI in Type 2 Diabetes14 Center Randomized Parallel Group Study

Dose

adjustment

Maintenance

period

Week 0 Week 8 Week 24

Insulin aspart in CSII (n = 66)

Insulin aspart/NPH in MDI (n = 61)

Screen:

DM 2 >2 years

On insulin >6 months

A1C > 7.5%;

Stop OHA

Raskin et al. Diabetes Care 26(9): 2598-2603, 2003

Target FBG 80 -120 mg/dl

CSII MDI

Design: Multi-center (14) Randomized, parallel group, 24 week study

N 66 61

Participant age (mean) 55.1 + 10.2 56.0 + 8.18

Years with T2DM 13.8 + 7.9 11.9 + 6.4

BMI (kg/m2) 32.2 + 4.2 32.2 + 5.1

Insulin regimen Inclusion Criteria 1 or more injections

Insulin treatment years 5.9 + 5.0 4.6 + 5.1

Insulin requirements at enrollment 0.75 + 0.46 units/kg 0.69 + 0.39 units/kg

Insulin in combination with OAD 27 22

MDI = aspart and NPH

CSII = aspart

Raskin P et al. CSII vs MDI in type 2 diabetes Diabetes Care 26, 9 2003

CSII versus MDI in Type 2 Diabetes

14 Center Randomized Parallel Group Study


8.28

7.6 7.5

6

6.5

7

7.5

8

8.5

9

Pump MDI

Baseline

24 weeks

A1C


Differences in Glucose Profile and Patient Preference

93 % preferred CSII

Difference in 90 min post BF Glucose


Change in scores (raw units) from baseline to endpoint

-5 0 5 10 15 20 25 30 35

Convenience

Less burden

Less hassle

Advocacy

Preference

General satisfaction

Flexibility

Less life interference

Less pain

Fewer social limitations

MDICSII


Testa et al. Diabetes. 2001;50(suppl 2):1781


CSII vs MDI in Older Adults with Type 2 Diabetes2 Center Randomized Parallel Group Study

Dose adjustment

Week 0 Week 52

Insulin lispro in CSII (n = 53)

Insulin lispro/glargine in MDI (n = 54)

Screen:

DM 2

On insulin

Age > 60yo

Herman W et al. CSII versus MDI in Older Adults type 2 DM Diabetes Care 28, 7, July 2005

CSII versus MDI in DM 2 patients > age 60 yrs

CSII MDI

Design: 2 center 12 month randomized controlled clinical trial

N 53 54

Participant age (mean) 66.6 + 5.9 66.2 + 4.5

Years with T2DM 16.9 + 9.0 15.4 + 8.9

BMI (kg/m2) 32.5 + 5.8 31.8 + 5.8

Insulin regimen Inclusion Criteria 1 or more injections

Insulin treatment years 8.1 + 8.3 8.2 + 7.7

Insulin requirements at study

end 108 + 63 units/ day 108 + 62 units/ day

Insulin in combination with OAD 23 21

MDI = lispro and glargine

CSII = lispro


CSII vs MDI in Older Adults with Type 2 Diabetes

2 Center Randomized Parallel Group Study

A1C


Objectives

To better understand the most effective insulin dosing regimens and

the specific pump feature-set required to meet the needs of patients

with type 2 diabetes

To provide data that will help design/power future, larger-scale

controlled trials

Data on file, Animas CorporationEdelman et al. DT&T 2010: 12(8): 628-33

Pump used in Type 2 DM trial

16-week, open-label, uncontrolled, multi-center pilot study

Type 2 DM; Insulin pump naïve (n=60)

OAs (n=20) or Basal insulin ± OAs (n=20) or MDI ± OAs (n=20)

A1C 7.0-11.5%

Study Design

Wk 16

(V11)

Pump* (rapid-acting analog**) ± metformin

Pump (rapid-acting analog) ± metformin

Pump (rapid-acting analog) ± metformin

Cohort A:≥ 2 OAs

Cohort B:Basal Insulin ±

OA(s)

Cohort C:Basal-Bolus Insulin ±

OA(s)

Wk 8

(V8)

Wk 12

(V9)

Screening

(V1)

D -7

(V2)

Wk 1

(V4)

Wk 2

(V5)

Wk 3

(V6)

Wk 4

(V7)

D 1

(V3)

Wk 15

(V10)

CGM CGM

(Wk 6) (Wk 10) (Wk 14) *Animas® 2020 insulin pump

**Insulin glulisine (Apidra®)

Cohort A(n=18)

Cohort B(n=17)

Cohort C(n=21)

All Cohorts(n=56)

Age (y) 57.3 ± 7.3 55.4 ± 8.3 57.0 ± 12.7 56.6 ± 9.8

Female (n) 6 (33.3%) 10 (58.8%) 12 (57.1%) 28 (50.0%)

Weight (kg) 103.3 ± 20.5 95.6 ± 16.3 97.5 ± 19.9 98.8 ± 19.0

BMI (kg/m2) 34.9 ± 5.1 34.3 ± 4.7 33.8 ± 5.3 34.3 ± 5.0

DM Duration (y) 10.7 ± 6.2 14.1 ± 6.1 15.1 ± 6.2 13.4 ± 6.3

A1C (%) 8.2 ± 1.2 8.8 ± 1.5 8.6 ± 1.4 8.5 ± 1.4

FPG (mg/dl) 169 ± 51 170 ± 53 165 ± 58 168 ± 53

C-Peptide (ng/dl) 3.1 ± 1.6 2.5 ± 1.8 1.7 ± 1.4 2.4 ± 1.7

Daily Total Insulin Dose (U) 0 31.5 ± 19.7 99.2 ± 65.3 -

Demographics and Baseline Characteristics

Data on file, Animas CorporationAll data Mean ± SD Edelman et al. DT&T 2010: 12(8): 628-33

Cohort A(n=18)

Cohort B(n=17)

Cohort C(n=21)

All Cohorts(n=56)

Long-acting Analog 0 17 (100%) 19 (90.5%) 36 (64.3%)

Rapid-acting Analog 0 0 20 (95.2%) 20 (35.7%)

Intermediate-Acting 0 0 3 (14.3%) 3 (5.4%)

Regular Human Insulin 0 0 1 (4.8%) 1 (1.8%)

Baseline Diabetes Therapy Insulin Agents

Data on file, Animas CorporationEdelman et al. DT&T 2010: 12(8): 628-33

Patient Disposition

Cohort A Cohort B Cohort C All Cohorts

Enrolled (n) 18 18 22 58

Intent-to-Treat (n) 18 (100%) 17 (94%) 21 (96%) 56 (97%)

Evaluable (n) 17 (94%) 17 (94%) 20 (91%) 54 (93%)

Withdrew (n) 1 (5.6%) 1 (5.6%) 2 (9.1%) 4 (6.9%)

Intent-to-Treat (ITT) population: All patients who received at least one dose on insulin via the insulin pump subsequent to Visit 2 (Baseline).

Evaluable population: All ITT patients who completed the study procedures through study termination (Visit 11/Week 16).

2 patients enrolled in the study (Visit 2), but withdrew prior to initiating pump therapy at Visit 3 (Day 1)

Only 2 patients (one from Cohort A and 1 from Cohort B) withdrew from

the 16-week study after initiating pump therapy.

Data on file, Animas Corporation

For all cohorts combined (n=56) at Week 16:

Mean total daily insulin dose was 95±59U (0.93±0.49U per kg) (Mean SD)

Mean ratio of basal-to-bolus insulin was 55% (basal) to 45% (bolus) per day

~90% of patients were treated with one (70%) or two (18%) basal rates per day

Total Daily Insulin Dose

ITT Population: Cohort A n=18; Cohort B n=17; Cohort C n=21; All Cohorts n=56

0

25

50

75

100

125

150

Baseline Day 1 Wk 4 Wk 8 Wk 12 Wk 16

Cohort A Cohort B Cohort C

Total Daily

Insulin Dose (U)

99 14 U/day

32 5 U/day

124 16 U/day*

67 6 U/day*

88 12 U/day*

Mean ± SE

* P<0.001 compared to Baseline


Number of Daily Basal Rates at Week 16

Approximately 90% of patients were treated with 1 or 2

daily basal rates at Week 16

70%

18%

6%6%

1 Basal Rate per Day

2 Basal Rates per Day

3 Basal Rates per Day

≥4 Basal Rates per Day

% of subjects treated with:

ITT Population: All Cohorts n=56ITT Population: All Cohorts n=56 Data on file, Animas Corporation

Change in A1C at Week 16


All values Mean ± SD

> Each cohort had a significant reduction in A1C from baseline (*p<0.001)

> A1C <7.0 and <6.5% achieved by 45% and 28% of patients, respectively

> Change in A1C in patients with baseline A1C >8.5% was -2.1±1.2%

8.2 1.3

8.8 1.5

8.4 1.0 8.4 1.3

7.1 0.9*

7.3 0.9*7.2 1.0* 7.2 0.9*

6.5

7

7.5

8

8.5

9


A1

C (

%)

Pre-Pump (Baseline) Week 16


* All values Mean ± SD, P<0.001 from Baseline Data on file, Animas Corporation

6.5

7

7.5

8

8.5

9

Baseline Wk 4 Wk 8 Wk 12 Wk 16

A1C

(%

)

ITT Population: All Cohorts n=56

Change from Baseline at Wk 16 = -1.2±1.2%

P<0.001

8.4±1.3%

7.2±0.9%*

8.0±1.0%*

7.6±0.8%*

7.4±0.8%*

* All values Mean±SD, P<0.001 from Baseline

Change in A1C All Cohorts (n=56)


Change in A1C Patients with Baseline A1C >8.5% (n=23)

9.6

8.7

8.0

7.67.4

6.5

7

7.5

8

8.5

9

9.5

10

Baseline Wk 4 Wk 8 Wk 12 Wk 16

A1C

(%

)

ITT Population with A1C >8.5 at Baseline: All Cohorts n=23

Change from Baseline at Wk 16 = -2.1±1.2%

P<0.001


DM 2 Pump Study: Change in A1C and Mean BG based on Baseline Data

Pre-pump (Baseline) Week 16

Continuous Glucose MonitoringPercent of Values Within Glycemic Ranges at Baseline and Week 16

Blinded CGM* for 5-7 Days at Baseline and During Week 16

2%

59%

39%

<70 mg/dL 70-180 mg/dL >180 mg/dL

4%

69%

27%

<70 mg/dL 70-180 mg/dL >180 mg/dL

P<0.001

P<0.001

P<0.05


*DexCom™ SEVEN®


Hypoglycemia

Cohort A (n=18)

Cohort B (n=17)

Cohort C (n=21)

All Cohorts (n=56)

Incidence of Hypoglycemic AEs 8 (44.4%) 8 (47.1%) 17 (81.0%) 33 (58.9%)

Incidence of Severe Hypoglycemic AEs 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)

Mean (SD) Hypoglycemic episodes per 30 days 0.96 (2.03) 0.95 (1.96) 1.75 (2.70) 1.22 (2.64)



Change in Body Weight at Week 16

= +0.8±3.5 kgp=0.4

= +1.8±3.6 kg p=0.06

= +2.8±2.6 kgp<0.001

= +1.9±3.3 kg p<0.001


All values Mean ± SD

103±21

94±1698±21 98±20

106±20

96±15101±22 101±19

0

20

40

60

80

100

120


Bo

dy W

eig

ht (K

g)




Mean±SD

Patient Reported Outcomes (DMSRQ/IDSRQ)

Cohort A Cohort B

ITT Population: Cohort A n=18; Cohort B n=17; Cohort C n=21

Cohort C

P=0.2

P<0.005

P=0.2

P=0.4

P=0.8

P<0.001

P=0.3

P<0.01

P<0.005

P<0.05

P=0.07

P<0.05

P<0.001

P=0.7

P<0.001

P<0.001

P=0.07

P<0.001

P<0.05

P<0.001

P=0.4


Lane W et al. Endocrine Practice 2009; 15:71-79

Case 1: Patient CG

57 yo female with DM 2 since age 44

Developed non alcoholic fatty liver disease age 50.

Placed on pump age 51 for poor control A1C 9.2%

Received liver transplant age 56

Control suboptimal; A1C 7.9%

Patient CG

Case 1: Patient CG

Case 1: Patient CG

QUESTION 2:

What would you do?

Options:

a. Send back to CDE/DM training class

b. Place on retrospective/blinded/professional CGM

c. Place on real-time/personal CGM

d. Tell her to monitor her BG 4 times per day

Patient CG

Case 1: Patient CG

Patient CG

Patient CG

Patient CG

Case 1: Patient CG

A1C now 6.3%

No severe hypoglycemia

Loves CGM

Recommendations:

- no major changes

- continue to wear CGM

Case 2: 13 yo girl on pump with weight gain

Diagnosed at age 11: polys without weight loss

BG 364; trace urine ketones; A1C 10.4%

Weight 165 pounds; HT 63”

No family history of DM

GAD negative; ICA negative

Placed on pump at age 12 due to A1C 7.9%


A1C is 6.9% but child now weighs 195 pounds

Insulin requirement 65 units per day

What would you do now?

I chose to check current c-peptide: 4.4 ng/ml

QUESTION #3:

Now what do you do?

a. Pramlintide

b. Metformin

c. GLP-1

d. MNT intervention


A1C is 6.9% but child now weighs 195 pounds

Insulin requirement 65 units per day

Current c-peptide: 4.4 ng/ml

• Started liraglutide per label; titrated to 1.8 mg/day

• Returned post 3 months:

- weight 159 pounds

- mean BG 93 mg/dl

- A1C 5.3%

- off basal; on 1 unit per 10 grams ~11 units per day

- still on pump: easier to give meal bolus

Future Directions: Meeting the needs The Start-ups

Valeritas h-PatchDebiotech Insulin

Nanopump (MEMS)

NiliMEDIX

Starbridge

Starlet PATCH

Danfoss Bionics

Others: M2, SteadyMed, Thomas & Thomas

TheraFuse

Medingo

Medsolve

http://www.cozmore.com/about-cozmonitor

http://www.starbridgesystems.co.uk/03_products_1-patch.htm

Conclusion 1:

Pump therapy in type 2 diabetes is associated with:

- Improvement in glucose levels

- Improvement in quality of life and satisfaction

measures

Conclusion 2:

Further research is needed to determine the

appropriate candidates for pump therapy and

determine the cost effectiveness of such therapy

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