Updates in Type 1 Diabetes - PowerPoint Presentation

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Updates in Type 1

Diabetes

Rodica

Busui MD, PhDProfessor of Internal Medicine,Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI

Slide2

No Disclosures

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The

Diabetes Control and Complications Trial

Rate/100

pt-yrs.

N

Engl

J Med, 1993

Diabetologia

, 1995

CAN

Intensive Glucose Control

Reduces Risk of all complications

AT THE COST OF:

Severe Hypoglycemia

62 vs. 19 incidents per 100py16 vs. 5 coma/seizure per 100py

Overweight >120

% IBW

13

vs

. 9

incidents per 100py

(mean excess 4.6kg)

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Long-Term Adherence to Glycemic Control in the

DCCT/EDIC

DCCT/EDIC Research Group. N Engl J Med. 2000;342:381-9.

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CURRENT STATE OF AFFAIRS IN THE U.S.:

A1c and Age Distribution in the T1D Exchange Cohort

~25% of youth/young adults with T1DM achieve A1c targets.

Wood et al. T1D Exchange Clinic Network. Diabetes Care 36:2035–2037, 2013

How do we reconcile the problem of long-term adherence to glycemic control?

Miller et al, Diabetes Care 2015,38: 971-978

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Putative Strategies for Targeting Glycemic Control in T1D

*

Aschner

P et al. Global Partnership for Effective Diabetes Management.

Int

J

Clin

Pract

2001c

Develop new means

to

implement and intensify the

b

asal-bolus insulin regimen– pumps, CGM.Reconcile psychosocial barriers*Advance and complete the journey towards the artificial pancreas technologies

Slide7

Putative Strategies for Targeting Glycemic Control in T1D

*

Aschner

P et al. Global Partnership for Effective Diabetes Management.

Int

J

Clin

Pract

2001c

Develop new means

to

implement and intensify the

b

asal-bolus insulin regimen– pumps, CGM.Reconcile psychosocial barriers*Advance and complete the journey towards the artificial pancreas technologies

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Insulin Pumps

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Progress with Insulin PumpsMore

adjustableFiner dose adjustments (as low as 0.025 units)Improved boluses (extended, dual wave etc.)

Multiple doses for a meal if extra food is eatenMultiple basal rates (dawn phenomenon, active day, etc.) and patterns (Sat-Sun vs M-F)Temporary changes in basal ratesLower after exercise, alcohol

Higher with stress, illness, inactivity, pre-menstrual

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Bolus calculatorsProgrammed with insulin to carbohydrate ratio (ICR) and correction factor (CF)- minimized mistakes

in dose calculationInsulin on Board Feature: eliminate insulin dose stackingLower temporary basal rates with exercise

Lower rates of hypoglycemiaProgress with Insulin Pumps

Less weight gain Decrease insulin with exercise (vs. extra food)

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Insulin dosing in a pump (setting basal)Adults: 50% basal, 50% bolus

Children: 35-40% basal, 60-65% bolusIf on NPH, calculate previous total daily dose (TDD), subtract 20% to generate a starting pump TDDOr use a dose per kg/d: 0.5-1.0 u/kg/d Lean or athletic, start near the lower endAs much as 1 u/kg/d in growing teenagers

If on MDI, you can take the Lantus dose and subtract 0-20%, divide by 24

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Insulin dosing in a pump (setting boluses)

Carb Ratio (ICR):Start with the predicted the total daily dose (TDD)Use the “450 rule” (450/TDD=ICR)Young children (<8) need more insulin for food coverage, use the 300 ruleThese are starting doses if the patient did not have a previous ICR with multiple daily injections

Correction Factor (CF-also called sensitivity factor or ISF)Start with the predicted the total daily dose (TDD)Use the “1800 rule” (1800/TDD=CF)May need less in the youngest children (2200 rule)

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Pump Therapy vs. MDI Trials in T1D: Outcome A1c

Misso ML et al, Cochrane Database Syst

Rev. 2010 Jan

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Insulin Pumps- not enough!DKA risk

Always attachedPrivacySkin irritationMust carry supplies if the site gets pulled outCost !

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CGM Systems

Medtronic

Dexcom

(Freestyle

Libre

)

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Effect of CGM Alone (patients with A1c 7-10%)

Insignificant

effect of CGM on younger subgroups (n=224

)

A

separate report of 129 subjects with A1c <7.0% showed substantial benefit in a composite outcome including

hypoglycemic

events

−0.53%, P<0.001

JDRF Continuous Glucose Monitoring Study Group. N

Engl

J Med. 2008

JDRF Continuous Glucose Monitoring Study Group

. Diabetes Care 2009

6 month study, N=322.

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Treat to target*

RealTrend*

Current

Evidence Supports a Moderate Independent Effect of CGM on A1c Reduction

Langendan

M et al. CGM systems for T1DM (Systematic Review). Cochrane Database 2012

.

Battelino

Diabetologia

. 2012

-0.43% (-0.32 to -0.55; P<0.001)

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Putative Strategies for Targeting Glycemic Control in T1D

*

Aschner

P et al. Global Partnership for Effective Diabetes Management.

Int

J

Clin

Pract

2001c

Develop new means

to

implement and intensify the

b

asal-bolus insulin regimen– pumps, CGM.Reconcile psychosocial barriers*Advance and complete the journey towards the artificial pancreas technologies

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Artificial Pancreas: a long journey

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“Closed-Loop” Concepts: Intravenous Sensor withIntraperitoneal

Insulin Delivery

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The Goal

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2) Sensor- Augmented

Pump

Two Therapy Groups:

1) Multiple Daily Injections

(

glargine

,

aspart

)

Sensor Augmented Pump Therapy

STAR

3

Trial

Bergenstal

, et al. N

Engl

J Med. 2010

All Patients (N = 485)

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= MDI

= SAP

n = 244

n = 241

7.0%

7.5%

8.0%

8.5%

0

3

6

9

12

A1C

Primary Endpoint: A1C Reduction

Comparisons between SAP group and MDI group are significant for each time period (P<0.001).

Months

8.3%

7.3%

7.5%

7.5%

7.5%

8.0%

8.0%

8.1%

8.1%

∆ -0.2

∆ -0.8

- 0.6

P<0.001

Bergenstal

, et al. N

Engl

J Med. 2010

Maximal A1C reduction was correlated with sensor use in post-hoc analysis

A1c reduction durable to 18 months in a non-randomized continuation phase

Bergenstal

, et al. Diabetes Care 2011

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AUC for Hyper- and Hypoglycemia

Hypoglycemia AUC

(< 70 mg/dL or <4mM)

p =0.54

Hyperglycemia AUC

(>180 mg/dL or >10mM)

= MDI

= SAP

n = 247

n = 248

p<0.001

Extent & duration of hyperglycemia in SAP was a third lower compared to MDI –

without excess hypoglycemia

.

Comparisons between SAP group and MDI group

were significant

for

each time period (P<0.001).

Bergenstal

, et al. N

Engl

J Med. 2010;363:311-20.

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Overall

(n=153)

Adult (n=81)

Pediatric (n=72)

*p<0.0001

*

Battelino

Diabetologia

. 2012

Effect

of CGM Alone

vs. SAP

-

“

SWITCH STUDY

”

N=153 in 4 European Centers, pump patients with inclusion criteria otherwise similar to STAR 3

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The ASPIRE In-Home trial (Automation to Simulate Pancreatic Insulin Response)

Design

:

3-month (2w run-in) randomized, controlled, multi-center, open-label trial N= 247.

Patients:

27years

of T1DM, A1c 7.2%, no recent severe

hypo/DKA, wore

a sensor ≥80%

Primary

Endpoint (Efficacy)

:

AUC

10p-8a HYPO

INTERVENTIONSAP with Low Glucose Suspend LGS set at < 3.9 mmol/LCONTROLStandard SAP

No LGS

Bergenstal RM et al for the ASPIRE In-Home Study Group. N

Engl

J Med 2013;369:224-32

.

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Extent & duration of hyperglycemia in LGS/TS was a third (38%) lower compared to Control

Safety

Efficacy

Bergenstal RM et al for the ASPIRE In-Home Study Group. N

Engl

J Med 2013;369:224-32

.

Number of Discrete Events decreased by 30%:

Nocturnal 1.5 vs. 2.2 events per

patient∙week

Combined 3.3 vs. 4.7 events per

patient∙

week

Severe hypoglycemia: 0 vs. 4 total events in the control.The ASPIRE In-Home trial (Automation to Simulate Pancreatic Insulin Response)

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Sensor Glucose Values Before, During and After the 2-Hour Nocturnal Suspends

Bergenstal RM, Klonoff DC, Garg SK, et al for the ASPIRE In-Home Study Group. Threshold-based insulin-pump interruption for reduction of hypogylycemia. N Engl J Med 2013;369:224-32.

3.9

mmol/L

5.1

mmol

/L

9.4

mmol

/L

There were no DKA events

A separate study of 95 T1D

subjets with NEAR-TOTAL LOSS OF HYPOGLYCEMIA AWARENESS demonstrated 70% reduction (9.5

vs 34 incidents per patient-months)* Bergenstal RM et al for the ASPIRE In-Home Study Group. N Engl J Med 2013;369:224-32.*Ly et al. JAMA Sept 26, 2013Low risk of severe rebound hyperglycemia with LGS

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Ly et al, Diabetes Care 2014, 37: 2310

Glucose Control During Overnight Closed Loop

Closed loop

SAP

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Medtronic Closed-Loop Camp Study

Ly et al, Diabetes Care, 2015, 38: 1205-11

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Medtronic Closed-Loop Camp Study

Ly et al, Diabetes Care, 2015, 38: 1205-11

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The MD-Logic Closed Loop System- at Camp

N Engl

J Med 2013; 368:824-833

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12-Week Outpatient Single Hormone Artificial Pancreas

Thabit

/

Hovorka (University of Cambridge group) and the AP@Home Consortium NEJM 2015N=5833 adults25 children/adol

.

2 separate trials

vs. SAP

Run-in period

Carb count

SMBG

24h Support Hotline

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12-Week Outpatient Single Hormone Artificial Pancreas

Thabit

/Hovorka

and the AP@Home Consortium NEJM 2015Also: Hood T et al., Lancet Diabetes Endocrinol.

2014;

Leelarathna

L et al.,

Diabetes Care.

2014

Hovorka

R et al.,

Diabetes Care.

2014;37:1204–1211

ADULTS

10% greater time-in-targetMean glucose 0.6mM lower (8.7 vs. 9.3)% time in hypo 2.9 vs. 3.0 %A1c 0.3% lowerCHILDREN/ADOL.10% greater time-in-targetMean glucose 0.6mM lower (9.5 vs. 10.1)% time in hypo 3.1 vs. 3.8 %A1c 0.3% lowerClosed-loop Control DifferenceClosed-loop Control Difference

Single Hormone AP - Summary

Automated outpatient trials



Night and 24h trials



Adults & pediatrics



Compared to sensor augmented pump therapy

Glucose time in target:

+10–15%

Mean blood glucose:

-0.8

mmol

/L

Hypoglycemia:

possible reduction

A1c reduction:

Yes

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Bionic Pancreas

Russel

SJ et al. NEJM. 2014;371(4):313–325.Also:

Haider A et al. CMAJ. 2013

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Mean Glucose Levels in Adults

Russel

SJ et al.

NEJM

. 2014;371(4):313–325.

Also:

Haider

A et al.

CMAJ

. 2013

Mean Glucose 7.4 vs. 8.8 mmol/l,

P<0.001

Time in Target

4-10

80% vs 59%, p<0.001Time in Hypoglycemia 4.1% vs. 7.3%, P = 0.01Similar findings in the adolescents5d “outpatient” intervention in 20 adults and 32 adolescents

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Single-hormone AP

Insulin only

Dual-hormone AP

Insulin & Glucagon

FUNDAMENTAL RESEARCH GAP:

DIRECT COMPARISON BETWEEN SINGLE- and DUAL-HORMONE AP

Artificial Pancreas: still unanswered questions?

If ultra-rapid insulin is available, glucagon may not be needed

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Artificial Pancreas: still unanswered questions?

Increased CGM Accuracy (replacement of finger sticks) REPLACE BG trialCritical Question: When will the CGM be accurate enough to control insulin/

glucagon for patients not in research studies?

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The Artificial Pancreas is Close but Not Quite Ready for Prime Time…

Rapidly progressing field

Extremely promising short-term results especially for overnight

Daytime/Postprandial AP strategies require urgent research attentionInterest inadjunctive-to-insulin therapy, faster-acting insulin

If dual, then stable glucagon and

dual-chamber pump

Will need step-by-step market introduction (first version will likely require meal & exercise announcements)

KEY RESEARCH NEEDS:

Longer-term comparative trials with

standard outcomes and reporting.

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Thank You !