Type 1 diabetes & nieuwe mogelijkheden in 2016

Type 1 diabetes &

nieuwe mogelijkheden in 2016

Christophe De Block, Diabetologie & Endocrinologie, UA & UZA

Voorzitter Diabetes Liga

Inhoud

• Nieuwigheden in de behandeling anno 2016

– Farmaca

• GLP1-RA

• SGLT2-i

• Nieuwe insulines

– Technologie:

• CGM & SAP

• Flash glucose monitoring

• Artificial pancreas

Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr Diab Rep 2003;3:365–

372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.

Incretins Regulate Glucose Homeostasis Through Effects

on Islet Cell Function

glycaemic

effects

non-glycaemic effects

Reduced

FPG & PPG

1.0 to 1.5 %

HbA1C

2 to 3 kg

weight Loss

Satiety, fullness,

gastric motlity

↑ natriuresis 3 to 5 mm Hg

BP

GLP1 receptor agonisten bij type 2 DM

↑ heart rate (2-5

bpm)

low risk of

hypoglycaemia

Improved lipid

profile

GLP1-RA + Basal Insulin: HbA1c

Balena et al, Diabetes, Obesity and Metabolism 15: 485–502, 2013.

GLP1-RA + Basal Insulin: weight


GLP1-RA + Basal Insulin: insulin dose


LEADER: Primary outcome CV death, non-fatal myocardial infarction, or non-fatal stroke

The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal

myocardial infarction, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the

hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less

than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio.

Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

GLP1-receptor agonists in T1DM

Frandsen et al. Lancet Diabetes Endocrinol 2016; 4: 766–80

x3

x10

GLP1-receptor agonists in T1DM: ADJUNCT-ONE

OBJECTIVE

• To investigate whether liraglutide added to treat-to-target insulin

improves glycemic control and reduces insulin requirements and

body weight in subjects with type 1 diabetes

RESEARCH DESIGN AND METHODS

• A 52-week, double-blind, treat-to-target trial involving 1,398

adults randomized 3:1 to receive once-daily subcutaneous

injections of liraglutide (1.8, 1.2, or 0.6 mg) or placebo added to

insulin.

Mathieu C et al. Diabetes Care 2016;39:1702–1710


CONCLUSIONS:

• Liraglutide added to insulin therapy reduced

– HbA1c levels,

– total insulin dose, and

– body weight

• but increased rates of

– symptomatic hypoglycemia and

– hyperglycemia with ketosis,

thereby limiting clinical use in this group


SGLT-2 inhibitor bij type 1 DM

• Potential:

– hemoglobin A1c reduction

– weight loss

– potential to reduce insulin doses

– and lower hypoglycemia risk

Glomerulus Proximal tubule

S1 S2

S3

Collecting duct

Adapted from Bays H. Curr Med Res Opin 2009;25(3):671–681.

GLUCOSE REABSORPTION

GLUCOSE FILTRATION

The kidneys filter and reabsorb 180 g of glucose per day

Minimal glucose excetion

SGLT2 ~90%

SGLT1 ~10%

Special transporters in the kidneys are responsible for the reabsorption of glucose

(180-200 L/day) (900 mg/L) =162-180 g/day

SGLT2 Reduced glucose

reabsorption

Increased urinary

excretion of excess

glucose

(~70 g/day,

corresponding to 280

kcal/day)

Proximal tubule

Glucose

filtration

Gliflozins: A novel insulin-independent approach to

remove excess glucose1–3

1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18.

2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35.

3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14–21.

SGLT2

Glucose

Gliflozin

Gliflozin

Gliflozins selectively inhibit SGLT2 in the renal proximal tubule

Clinical Effects of SGLT2 Inhibition Based on the Mode

of Action in T2DM

Increased Glucose

Excretion

Increased Sodium Excretion

Reduced

FPG & PPG

0.6 to 1 % HbA1C

2 to 3 kg

Weight Loss Loss of Energy

Calories

Reduced

Sodium Load 3 to 5 mmHg

BP

no hypoglycemia

Zinman B, NEJM 2015

SGLT2-inhibitors in T1DM: dapagliflozin

Henry et al. Diabetes Care 2015;38:412–419

SGLT2-inhibitors in T1DM: EASE-1 study

Pieber et al Diabetes, Obesity and Metabolism 17: 928–935, 2015

HbA1c insulin dose

Cascade of clinical events and metabolic changes that contribute sequentially to euDKA.

New Insulins

Less than 50% of insulin-treated patients are at their glycemic target1,2 due to

key unmet needs and challenges

Remaining unmet needs and challenges with

current basal insulin therapy

1. Davis KL et al. Curr Med Res Opin. 2013;29:1083-91; 2. Baser O et al. Clinicoecon Outcomes Res 2013;5:497-505;

3. Maiorino MI et al. Expert Opin Biol Ther. 2014;14:799-808; 4. Ahrén B. Vasc Health Risk Man. 2013;9:155-163; 5. Wei W et al. Endocr Pract.

2014;20:52-61

Sub-optimal doses

and early treatment

discontinuation4,5

Fear of

hypoglycemia and

insulin-associated

weight gain4

Hypoglycemia

has important

short- and

long-term

consequences4

Intra-patient

glucose variability3

Behavioral challenges PK/PD Incidence of

hypoglycemia

28

Insulin glargine U300

More constant and stable PK/PD profile with

Gla-300 vs Gla-100

Becker RH et al. Diabetes Care. 2014

3

2

1

0

20

10

0

0 6 12 18 24 30 36

0 6 12 18 24 30 36

Insu

lin c

on

ce

ntr

atio

n,

µU

/mL

Glu

co

se

in

fusio

n r

ate

,

mg

/kg

/min

25

15

5 LLOQ

30 LLOQ, lower limit of quantification

Time, hours

Gla-300 0.4 U/kg, n=16

Gla-100 0.4 U/kg, n=17

Primary endpoint was successfully achieved

in all EDITION trials

LS

M H

bA

1c

ch

an

ge

fro

m b

as

eli

ne

, %

Gla-100

Gla-300

31 Primary endpoint: non-inferiority in HbA1c change with Gla-300 vs Gla-100 at Month 6

RR 1.00

(0.95 to 1.04) RR 0.98

(0.92 to 1.04) RR 0.98

(0.91 to 1.06)

EDITION 4 EDITION JP 1

Data on file, saf_hypo_ph2_3, pg 219, 273; Home PD et al. Poster presentation at ADA 2014; Abstract 80-LB;

Data on file, JP1-efc12449_15_3_1_ae_data, pg 7, 9; Matsuhisa M et al. Poster presentation at EASD 2014; Abstract 975

Part

icip

an

ts w

ith

≥1 c

on

firm

ed

(≤70 m

g/d

L [

3.9

mm

ol/L

])

an

d/o

r sev

ere

hyp

og

lycem

ia (

%)

Gla-100 Gla-300

At any time (24 h) Nocturnal (00:00–05:59 h) At any time (24 h) Nocturnal (00:00–05:59 h)

RR 0.98

(0.88 to 1.09)

RR 0.82

(0.70 to 0.96)

RR 1.06

(0.92 to 1.23)

RR 0.99

(0.95 to 1.04) RR 0.91

(0.84 to 0.99) RR 1.01

(0.95 to 1.08)

RR 0.85

(0.73 to 0.99)

RR 0.71

(0.56 to 0.91)

RR 0.84

(0.70 to 1.00)

Relative risk (95% CI)

32

Incidence of confirmed (≤70 mg/dL [3.9 mmol/L]) or severe

hypoglycemia in T1DM studies

Neither study was designed and powered to test the difference in hypoglycemia risk

between Gla-300 and Gla-100 as pre-specified endpoint

Weight changes with Gla-300 vs Gla-100 at Month 6

33

Basal insulin doses at Month 6

Data on file, E19_Insulin dose_Absolute and Relative differences_M12_2014-09-03.doc, pg 6, 12, 14, 22, 38, 44 1US Prescribing Information, 27 Feb 2015

Basal insulin dose at Month 6, U/kg

T1DM studies

EDITION 4 EDITION JP 1

Gla-300 0.47 0.36

Gla-100 0.40 0.29

Relative

difference for

Gla-300 vs

Gla-100, %

+17.51 +22.47

34

T1

ABASAGLAR® PK profile is similar to that of EU Lantus®

ABASAGLAR®

EU Lantus®

Time (hours)

Mean

C-p

ep

tid

e-c

orr

ecte

d

ins

uli

n c

on

ce

ntr

ati

on

± S

D (

pm

ol/

L)

For the key PK and PD parameters, the criteria for bioequivalence were met.

The 90% CI for AUC and Cmax were completely contained in the pre-specified limit of 0.8 to

1.25

36

FIAsp

Freestyle Libre

& AGP

Christophe De Block

Hoe glucose wordt gemeten en bewaard

Na het scannen, verschijnen 3 belangrijke data

1. Heden

Huidige glucosemeting

2. Verleden

8-uur geschiedenis

3. Toekomst

Trendpijl

De trendindicatoren geven de richting

van uw glucose aan.

AGP (Ambulatory Glucose Profile) AGP is een visueel rapport dat alle glucose metingen van verschillende dagen of weken samenvat

alsof ze voorvielen in een enkele 24-u periode, wat het makkelijker maakt glycemie patronen* te

visualizeren

* Mazze RS. Making sense of glucose monitoring technologies from SMBG to CGM. Diabetes Technology and Therapeutics 2005;7(5):784-7

AGP grafiek is gebaseerd op glucose metingen, idealiter over een periode van 14 dagen.

Mediaan

25e en 75e Percentiel

Curves 10e en 90e Percentiel

Curves

AGP

• Offers standardized reporting and analysis to create a universal

template in which data are represented in a predictable, easy-to-

view format

– Target range

– Glucose variability

– Hypoglycemia

– Hyperglycemia

• Enhances quality of care through pattern recognitions, improves

practice efficiency with minimal disruption of workflow, and

engages patients

Estimated A1c

(Gemidd glyc + 50) / 30 = HbA1c

Casus 1

Rather wide 25-75 percentile range, particularly in the evening – irregular life style (meetings, time

of dinner, type of dinner, …)

What would you propose as therapeutic changes?

Casus 1 real time total period

Combination of AGP (educational aspects, pattern recognition, areas of importance)

and real-time offers help

AGP shows much narrower 25-75 percentile ranges

Bolinder et al. Lancet 2016

Steineck et al. BMJ 2015;350:h3234

pump therapy: why ?

Pickup J et al. BMJ 2011

Pickup J et al. BMJ 2011

Fig 4 Individual patient data two step meta-analysis of difference in ln area under the curve of

hypoglycaemia during continuous glucose monitoring compared with self monitoring of blood glucose

Threshold-Based Insulin-Pump Interruption for

Reduction of Hypoglycemia

Bergenstal et al. NEJM 2013;369:224-32.

Impact on clinical outcomes of a Belgian

reimbursement system for real-time

continuous glucose monitoring:

the RESCUE trial

http://www.medgadget.com/archives/img/Minilink-with-sensor.jpg

Evolution of Haemoglobin A1c

4 Results – Impact on glycaemic control

No at risk 545 485 355 282

*** p < 0.001

Evolution of hypoglycaemia

4 Results – Impact on glycaemic control

No at risk 359 389 389 274 200

*** p < 0.001

The future:

closed loop

no more excuses

Type 1 diabetes & nieuwe mogelijkheden in 2016

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