reduction in hypoglycemia and no increase in a1c with ... · a1c with threshold-based...

Reduction in Hypoglycemia and No Increase in A1C with Threshold-Based Sensor-Augmented

Pump (SAP) Insulin Suspension:ASPIRE In-Home

Richard M. Bergenstal1, David C. Klonoff2, Bruce W. Bode3, Satish Garg4, Andrew Ahmann5, Robert Slover4, Melissa Meredith6, Francine R. Kaufman7, ASPIRE In-Home Study Group

1, International Diabetes Center at Park Nicollet, Minneapolis, MN; 2, Mills-Peninsula Health Services, San Mateo, CA; 3, Atlanta Diabetes Associates, Atlanta, GA; 4, Barbara Davis Center for Childhood Diabetes, Aurora, CO; 5, Oregon Health and Sciences University, Portland, OR; 6, University of Wisconsin, Madison, WI; 7, Medtronic, Inc., Northridge, CA

Late Breaking Poster 48Available Saturday June 22 at 10 AM Presented Sunday June 23 at Noon‐2PM

Published on June 22, 2013 at NEJM.org

N Engl J Med 2013DOI: 10.0156/NEJMoa1303576

Reducing the Risk of Complications Intensive Glycemic Control in Type 1 Diabetes

0

2

4

6

8

10

12

66 77 88 99 1010 11110

20

40

60

80

100

120

Severe Hypoglycem

ia(per 100 patient-years)

Rat

e of

Ret

inop

athy

(per

100

pat

ient

-yea

rs)

A1C (%)A1C (%)

The Diabetes Control and Complications Research Group The Diabetes Control and Complications Research Group N Engl J Med N Engl J Med 329:977, 1993329:977, 1993

Highlights from the American Diabetes Association 70th

Scientific Sessions l October 2010 l 4

Bergenstal RM, Tamborlane WV, Ahmann A et al. N Engl J Med. 2010;363:311-320.

Sensor-

Augmented

Pump

Two Therapy Groups

Multiple Daily Injections

(2 typesof insulin)

STAR 3

Presented at ADA 2010 and published NEJM 2010

STAR 3: A1C at 3, 6, 9, 12 months: All Patients

7.3%7.5% 7.5% 7.5%

8.0%8.0%

8.1%8.1%

Values are means ±

SE. Asterisks denote P<0.001 for comparisons between SAP group and MDI group at each time point.

Adapted from Bergenstal RM, Tamborlane WV, Ahmann A et al. N Engl J Med. 2010;363:311‐320.

Adapted from Figure 5B of: DCCT. N Engl J Med. 1993;329:977-986. JDRF data from: JDRF CGM Study Group. N Engl J Med.

2008;359:1465-1476. Bergenstal RM, Tamborlane WV, Ahmann A, et al. [published online

ahead of print June 29, 2010]. N Engl J Med. doi: [].

Severe Hypoglycemia and A1C DCCT (1993),

JDRF

(2008), STAR 3 (2010) & ASPIRE in Home (2013) Studies

DCCT

(intensive therapy):62 per 100 pt-yrs, A1C(6.5 yr): 9.0% 7.2%

Severe ReactionEvery: 1.6 yrs.

JDRF CGM

(adults, 1 subject excluded):20.0 per 100 pt-yrs;A1C (6 mo): 7.5% 7.1%

5 yrs.

STAR 3 SAP

(all ages): 13.3 per 100 pt-yrs; A1C (1 yr): 8.3% 7.5%

STAR 3 MDI

(all ages): 13.5 per 100 pt-yrs; A1C (1 yr): 8.3% 8.1%7.5 yrs.

Ideal None

Sensor Augmented Pump (SAP) Sensor Augmented Pump + Threshold Suspend (SAP + TS)

ParticipantsScreen failures

or withdrawals (94)

Withdrawals or did notmeet randomization

criteria (73) which included

at least one episode of nocturnal hypoglycemia in 2 weeks

BaselineEnrollment

(414)

Run-in Phase(2 weeks)

(320)

Randomized(247)

Threshold Suspend (121) Control (126)

Early withdrawals(5 Threshold

Suspend, 2 Control)

Threshold Suspend Control

Age 41.6 ±

12.8 44.8 ±

13.8

% Male 38 39.7

Diabetes Duration 27.1 ±

12.5 26.7 ±

12.7

BMI, kg/m2 27.6 ±

4.7 27.1 ±

4.3

A1C and Nocturnal Hypoglycemia AUC

Study Phase (3 months)

Background

Presentation Number 984-PClinical Therapeutics/New Technology –

Insulin Delivery SystemsSunday, June 23, 2013

Noon –

2:00 PM

Predictors of Nocturnal Hypoglycemia During the Run‐In Phase of the ASPIRE‐2 StudyBruce W. Bode1, Scott W. Lee2, Francine R. Kaufman2, ASPIRE In‐Home Study Group

1, Atlanta Diabetes Associates, Atlanta, GA; 2, Medtronic, Inc.,

Northridge, CA

AMCR Institute, Escondido, CA: T. Bailey; Atlanta Diabetes Associates, Atlanta, GA: B.

Bode; Rainier Clinical Research Center, Renton, WA: R. Brazg; Texas Diabetes and

Endocrinology, Austin, TX: L. Casaubon; University of Colorado Denver and the Barbara

Davis Center, Aurora, CO: S. Garg, R. Slover; Palm Beach Diabetes and Endocrine

Specialists, West Palm Beach, FL: B. Horowitz; Diabetes Research

Institute Mills‐

Peninsula Health Services, San Mateo, CA: D. Klonoff; Rocky Mountain Diabetes and

Osteoporosis Center, Idaho Falls, ID: D. Liljenquist; Physicians

Research Associates, LLC,

Lawrenceville, GA: O. Odugbesan; Endocrine Research Solutions, Inc., Roswell, GA: J.

Reed; Ohio University Diabetes Center, Athens, OH: F. Schwartz; Arkansas Diabetes Clinic

and Research Center, Little Rock, AR: J. Thrasher; Oregon Health

and Science University,

Portland, OR: A. Ahmann; International Diabetes Center at Park Nicollet, Minneapolis,

MN: R. Bergenstal; Iowa Diabetes and Endocrinology Center (IDEC), Des Moines, IA: A.

Bhargava; The Naomi Berrie Diabetes Center, Columbia University,

New York, NY: R.

Goland; The Board of Regents of the University of Wisconsin Madison, Madison, WI: M.

Meredith; Joslin Diabetes Center (Syracuse University), Syracuse, NY: R. Weinstock.

Summary

ASPIRE In‐Home Study Group

Methods

Results (updated after study completion)

The rate of NH events was 0.3 per patient‐night. The tables show variables examined in association with the

mean (±SD) number of NH events per patient per 2‐week interval. N, number of NH events in each patient

category. The total number of NH events was 314. GV, glycemic variability.

•

The incidence of NH was higher in

patients with lower baseline A1C

values and higher glycemic

variability (GV).

•

The findings of higher rates of NH in

younger patients, patients with

shorter diabetes duration, and

patients with lower BMI appears to

result from greater GV in these

patients.

•

Gender and race had no effect on

NH.

There was no effect of gender (P=0.77) or race (P=0.13).

Baseline A1C N NH Events

≤

7% 92 5.05 ±

3.39> 7% 222 3.80 ±

2.66P value <0.001

P value (adjusted for GV) <0.001

Coefficient of Variation (a measure

of glycemic variability)

N NH Events

≤

40% 154 2.90 ±

2.19> 40% 160 5.39 ±

3.06P value <0.001

Screen failures

or withdrawals

(94)

Withdrawals and

RandomizationFailures (73)

Screened(414)

Entered Run‐in Phase(2 weeks)(320)

Randomized(247)

•

In an attempt to mitigate hypoglycemia, particularly that

which occurs at night, sensor‐augmented pump systems

have been developed that allow for automatic insulin

suspension at a preset sensor glucose threshold (Threshold

Suspend, TS, previously referred to as Low Glucose

Suspend).

•

Previous studies have shown the benefit of the TS feature

in mitigating hypoglycemia. The present study was

conducted to examine the safety and efficacy of the TS

feature in a randomized, controlled study in which the

study patient population was enhanced for nocturnal

hypoglycemia.

•

Data from those who completed the run‐in period of this

study were used to examine predictors of hypoglycemia.

Basal:Bolus Ratio N NH EventsBasal ≤

Bolus 165 4.05 ±

2.95Basal > Bolus 149 4.30 ±

2.95P value 0.27

P value (adjusted for GV) 0.12

Diabetes Duration N NH Events≤

15 years 63 5.10 ±

3.46> 15 years 245 3.94 ±

2.77P value < 0.001


Age N NH Events≤

50 years 207 4.43 ±

2.95> 50 years 107 3.67 ±

2.88P value 0.002


Conclusion

In an attempt to identify patients

potentially most at risk for NH, the

use of glycemic variability coupled

with A1C might be useful in clinical

practice or to define a study cohort

at risk.

Study Visit Schedule

Completed Run‐In Phase

(314)

BMI N NH Events

< 25 kg/m2 96 4.46 ±

2.85≥

25 kg/m2 218 4.04 ±

2.98P value 0.098


Patient Characteristics

(N=314 patients who completed the Run-In Phase)

•

Age, 43.6 ±

13.83 years (range, 16-

70)

•

Sex, 60.2% female

•

Race, 96.5% white

•

Height, 169.9 ±

9.76 cm (range, 137.2-195.6)

•

Weight, 79.5 ±

16.01 kg (range, 48.7-137.3)

•

BMI, 27.5 ±

4.82 kg/m2

(range, 19.2-

51.5)

•

Diabetes duration, 26.9 ±

12.69 years (range, 2.4-61.8)

•

More than 3 months CGM: 56.7%

•

A1C at screening visit, 7.6 ±

0.9% (range, 5.8-10.0)

Continuous Variable P value P value (adjusted for GV)

Baseline A1C <0.001 <0.001Coefficient of Variation <0.001 N/A

Basal:Bolus Ratio 0.76 0.20Age <0.001 0.26

Diabetes Duration <0.001 0.92BMI 0.026 0.39

See Poster LB‐48 for study results.

Nocturnal Hypoglycemia (NH)•SG <

65 mg/dL for > 20 min.

•From 10PM to 8AM •No patient intervention •Each pt >

2 events over 2 wks.

Rates NH •0.3 events per pt night •Approx 2.1 NH events per

patient per wk

15

NH Something We Need to Fix Now

Buckingham data published in Kowalski review: DTT 2009

ParticipantsScreen failures

or withdrawals (94)

Withdrawals or did notmeet randomization

criteria (73) which included

at least one episode of nocturnal hypoglycemia in 2 weeks

BaselineEnrollment

(414)

Run-in Phase(2 weeks)

(320)

Randomized(247)

Threshold Suspend (121) Control (126)

Early withdrawals(5 Threshold

Suspend, 2 Control)

Threshold Suspend Control

Age 41.6 ±

12.8 44.8 ±

13.8

% Male 38 39.7

Diabetes Duration 27.1 ±

12.5 26.7 ±

12.7

BMI, kg/m2 27.6 ±

4.7 27.1 ±

4.3

A1C and Nocturnal Hypoglycemia AUC

Study Phase (3 months)

Sensor Augmented Pump (SAP) Sensor Augmented Pump + Threshold Suspend (SAP + TS)

ResultsReduction in hypoglycemia (duration and

severity) in the Threshold Suspend Group

The mean AUC of NH events was 38% lower in the Threshold Suspend Group. SD values are shown in parentheses.

0200400600800

10001200140016001800

ThresholdSuspend

Control

AUC

(mg/

dL ×

min

)

Mean AUC of Nocturnal Hypoglycemia Events

Run-In Phase

Study Phase

38% reductionp<0.001

1547(2035)

980(1200)

1406(1950)

1568(1995)

ResultsReduction in hypoglycemia events in the Threshold Suspend Group

Hypoglycemia events were less frequent in the Threshold Suspend Group. SD values are shown in parentheses.

0

1

2

3

4

5

6

ThresholdSuspend

Control ThresholdSuspend

Control

Even

ts p

er P

atie

nt-W

eek

Hypoglycemia Events per Patient-Week

Run-In

Study


5.0(2.8) 3.3

(2.0)5.1(3.0)

4.7(2.7)

Nocturnal Combined Day and Night

2.4(1.2)

1.5(1.0)

2.5(1.5)

2.2(1.3)


ResultsCharacterization of Threshold

Suspend events lasting 2 Hours

0

50

100

150

200

250

300

-180 -150 -120 -90 -60 -30 0 30 60 90 120 150 180 210 240 270 300 330 360

Sens

or G

luco

se (m

g/dL

)

Time from TS Event Start (min)

Insulin Suspended

Mean ±

SD of sensor glucose values surrounding 2-hour TS events. The dotted line is at 70 mg/dL.

n=1438

ResultsNo significant between-group difference in ∆A1C

∆

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%.

6

6.5

7

7.5

8

8.5

9

9.5

10

ThresholdSuspend

Control

A1C

(%

)A1C

Randomization

3-month∆

= 0.00±0.44

7.26(0.71)

7.24(0.67)

7.21(0.77)

7.14(0.77)

∆

= -0.04±0.42

Summary•

The TS feature improves upon SAP therapy by significantly reducing NH.–

Reduction in mean event AUC.

–

Reduced percentage of time spent with SG values in the hypoglycemic range.

–

Decreased number of NH events per week•

No deterioration in A1C with TS use.

•

Low risk of severe rebound hyperglycemia following 2-hour TS events.

•

No severe hypoglycemia in TS feature group

Conclusion

Automating insulin delivery appears to be an effective and safe strategy to reduce hypoglycemia.

Adapted from Figure 5B of: DCCT. N Engl J Med. 1993;329:977-986. JDRF data from: JDRF CGM Study Group. N Engl J Med.

2008;359:1465-1476. Bergenstal RM, Tamborlane WV, Ahmann A, et al. [published online

ahead of print June 29, 2010]. N Engl J Med. doi: [].

Severe Hypoglycemia and A1C DCCT (1993),

JDRF

(2008), STAR 3 (2010) & ASPIRE in Home (2013) Studies

JDRF CGM

(adults, 1 subject excluded):20.0 per 100 pt-yrs;A1C (6 mo): 7.5% 7.1%

DCCT

(intensive therapy):62 per 100 pt-yrs, A1C(6.5 yr): 9.0% 7.2%

STAR 3 SAP


STAR 3 MDI


Future AP system

Severe ReactionEvery: 1.6 yrs.

5 yrs.

7.5yrs.

ASPIRE SAP13.0 per 100 pt-yrs; A1C (3mo.): 7.2% 7.1%

7.7yrs.

ASPIRE SAP + TS0.0 per 100 pt-yrs; A1C (3mo.): 7.3% 7.2%

Never

26

AP Strategy – Iterative Increases in Automation

Bode 984 P

Bergenstal

LB 48

Trang, Jones

Australia 228 OR

Danne

357 OR

Russell, Nathan, Damiano

OR 15

Buckingham 37 LB

Castle, Ward 14OR

Zisser

11OR

Nimir, Phillip, Battelino

13OR

Cameron

9 OR

Finan

10OR

Lee, Renard

16OR

Artificial Pancreas presentations at ADA Scientific Sessions 2013

addressing the various strategies of AP development

reduction in hypoglycemia and no increase in a1c with ... · a1c with threshold-based...

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