David G Robertson MD

Atlanta Diabetes Associates

Atlanta, Georgia

Future Directions in Diabetes

Management

Disclosures

l Research and Grant Support to Employer: Janssen, Lilly, Pfizer, Novo Nordisk, Eisai, Agramatrix

l Consultant: Lilly

l Speaker’s Bureau: AstraZeneca, Lilly, Abbvie, Novo Nordisk, Boehringer Ingelheim

Topics

l Insulin the future

l Type 2 Diabetes: More drugs or new approaches

l Type 1 : Until Islet transplants, what options are close?

Insulin the future

l Ultra Fast Acting Prandial Insulins

– Inhaled

– Subcutaneous

– Oral

l Ultra Long Acting Basal Insulins

Insulin of the future: Oral?

l Oramed annouced 11/3/14 results of 7 days of treatment in Type 1 patients

– Small decrease in daytime glucose values

– Moderate decrease in nightime glucose values

– No increase of ypoglycemia

– Small decrease in insulin needs

l May also be able to deliver exenatide orally

Type 2 Diabetes: More drugs or new approaches

l Multidrug therapy at diagnosis

l Kidney Specific SGLT1 cotransport inhibition

l Prevention investment

l Bariatric Surgery:

– Could we actually save money?

Topics

l Insulin the future

l Type 2 Diabetes: More drugs or new approaches

l Type 1 : Until Islet transplants, what options are close?

The image shows human-embryonic-stem-cell-derived

beta cells that have formed islet-like clusters in a mouse

http://harvardmagazine.com/2014/10/melton-creates-beta-cells

Islet-like cluster of beta celss derived from stem cells

STAP stem cells: acid washing of adult cells converted to plueropotent stem cells A FRAUD

Nature 511, 5–6 (03 July 2014)

doi:10.1038/511005b

Viacyte system for insertion of embryonic beta cells into a patient fot 1 to 5 years

http://viacyte.com/products/encaptra-drug-delivery-system/

Cartoon of Cell Encapsulation

1919

• Cells implanted in environment where they are secluded from host

immune system

• Cells sense and respond to ambient metabolic conditions

"CAUTION--Investigational device. Limited by Federal (or US) law to investigational use."

Interstitial Glucose Readings

Artificial Pancreas: Fundamentals of

closed-loop systems

HCL FCLTS PLGM

Subject Burden Automation

Regulatory Ease System Complexity

Example of Threshold Suspend Cycle

22

Suspend time maximum = 2 hrs

Insulin infusion stops

Basal insulin infusion will resume even if glucose is below

Thresh Suspend limit

Basal Insulin Basal Insulin2 Hour Suspend

Insulin Suspends for 2 hours / Resumes for 4 hours

Automatically suspends insulin delivery if sensor glucose reaches the user-set limit

ASPIRE In-Home Study: Results

Study conducted with Veo pump that is not FDA approved and not commercially available in the US. Study data and final report have not been submitted to FDA.

Bergenstal RM, Klonoff DC, Garg SK, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med. 2013;369(3):224-232.

The severity and/or duration of nocturnal hypoglycemic events was lower in the Threshold Suspend Group.

1547 980 1406 1568

37.5% reduction (p<0.001)

ASPIRE In-Home Study: Results

Hypoglycemic events were less frequent in the Threshold Suspend Group.

Study conducted with Veo pump that is not FDA approved and not commercially available in the US. Study data and final report have not been submitted to FDA.

Bergenstal RM, Klonoff DC, Garg SK, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med. 2013;369(3):224-232.

30% reduction (p<0.001)

32% reduction

(p<0.001)

ASPIRE In-Home Study: Results

∆A1C was similar in the two groups. The 95% CI of the difference in ∆A1C (-0.05, 0.15) did not include the non-inferiority limit of 0.4%.

Study conducted with Veo pump that is not FDA approved and not commercially available in the US. Study data and final report have not been submitted to FDA.

Bergenstal RM, Klonoff DC, Garg SK, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med. 2013;369(3):224-232.

Predictive Low Glucose Suspend

Danne, Diab Technol Ther 2014

Predictive Low Glucose Suspend

Danne, Diab Technol Ther 2014

• N=16

• Hypoglycemia

averted in 13

Predictive Low Glucose Suspend –

Larger Scale Testing

0%

10%

20%

30%

40%

50%

< 70 < 60 < 50

Control Intervention

Maahs, Diab Care 2014

0%

10%

20%

30%

>30 min

>60 min

>120 min

>180 min

Control Intervention

Nights with Hypoglycemia Duration of Hypoglycemia

• N=45, 900+ nights

In-Home Overnight CL – Fuzzy Logic

Nimri, Pediatr Diab 2014

• N=15, 4 nights

Overnight CL – Outpatient Study

Hovorka, Diab Care 2014• N=16, 3 weeks

Overnight CL – Outpatient Study

Hovorka, Diab Care 2014

Medtronic Ambulatory Closed-Loop System Overnight CL – Feasibility

O’Grady, Diab Care 2012

• N=8, 1 night

Overnight CL – Multiple Nights

Ly, Diab Care 2014

00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:000

40

80

120

160

200

240

280

320

360

400

Glu

cose

(m

g/d

L)

Date: 1-Oct-2014

00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:000123456789

101112131415

Infu

sio

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ate

(U

/h)

Clock (HH:MM)

00:000

40

80

120

160

200

240

280

320

360

400G

luco

se (

mg

/dL

)

00:000

1

2

3

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5

6

7

8

9

10

Infu

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n R

ate

(U

/h)

18:00 20:00 22:00 00:00

18:00 20:00 22:00 00:00

00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00

Date: 1-Oct-2014

00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00

Clock (HH:MM)

00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:000

40

80

120

160

200

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280

320

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Glu

co

se (

mg

/dL

)

Date: 29-Sep-2014

00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:000123456789

101112131415

Infu

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(U

/h)

Clock (HH:MM)

UVA DiAs Ambulatory Closed-Loop System Overnight camp study

Ly, Diab Care 2014

• N=20, 5-6 nights

Del Favero, Diab Care 2014

Outpatient Full-Day Hybrid Closed-Loop

• N=6, 28 hr on CL

Boston University Dual-Hormone Delivery System with Insulin And Glucagon

Hybrid Closed-Loop – multiple hormone

(glucagon) plus standardized pre-meal bolus

Russell, Diab Care 2012• N=6, 48 hr

Bi-Hormonal Delivery in

20 Adults & 32 Adolescents

Russell SJ et al. N Engl J Med 2014;371:313-325

Full Closed-Loop – multiple hormone

(pramlintide) without meal bolus

Palau-Collazo, ADA 2013

6 9 12 15 18 21 24 27 30 330

100

200

300

Pramlintide

Control

Time (hrs)

Blo

od

G

luco

se (

mg

/dL

)

• N=10, 48 hr

Conclusions

• Sensor-augmented pump systems are becoming increasingly integrated and incrementally more automated

• Hybrid closed-loop systems with meal bolus requirements will soon be market-ready

• Fully-automated single- or multiple-hormone systems are in pipeline but more distant in product development and/or regulatory approval