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HIGHLIGHTS ΑΠΟ ΤΑ ΜΕΓΑΛΑ ΔΙΑΒΗΤΟΛΟΓΙΚΑΣΥΝΕΔΡΙΑ

ΙΝΣΟΥΛΙΝΗ

Χαράλαμπος Α. ΜαργαριτίδηςΠαθολόγος – Επιστημονικός Συνεργάτης

Διαβητολογικού Κέντρου Α’ΠΡΠ Κλινικής Ν. ΑΧΕΠΑΘεσσαλονικη 8-11-17

τυχαιοποιημένες μελέτες

DEVOTE: trial design

Insulin degludec once daily (blinded vial) +Standard of care

IGlar U100 once daily (blinded vial) +Standard of care

Randomization

7637 patients randomized

End of treatment(633 MACE accrued)

Follow-up period

30 days

Follow-up period

Interim analysis(150 MACE accrued)

Καταληκτικά σημεία

Πρωτεύον : 3-point MACE-καρδιαγγειακός θάνατος-μη θανατηφόρο εμφράγμα-μη θανατηφορο εγκεφαλικό

Δευτερεύοντα-συχνότητα σοβαρών υπογλυκαιμικών επεισοδίων-επίπτωση σοβαρών υπογλυκαιμικών επεισοδίων

Presented at the American Diabetes Association 77th Scientific Sessions, Session 3-CT-SY22. June 12 2017, San Diego, CA, USA

Ασθενείς υψηλού καρδιαγγειακού

κινδύνου

Type 2 diabetes

Current treatment with ≥1 oral or injectable

antidiabetic agent(s)

HbA1c <7.0% and basal

insulin treatment ≥20 U/day

High cardiovascular

risk profile

HbA1c

≥7.0%OR

• cardiovascular or

chronic kidney

disease and aged ≥50

OR

• risk factors for

cardiovascular

disease and aged ≥60

U, units


DEVOTE – a global trial

KOREA

4 sites

61 patients

JAPAN

7 sites

61 patients

MALAYSIA

8 sites

102 patients

THAILAND

6 sites

68 patientsINDIA

26 sites

357 patients

SOUTH AFRICA

15 sites

194 patients

ARGENTINA

4 sites

120 patients

BRAZIL

10 sites

303 patients

UNITED STATES

269 sites

5201 patients

MEXICO

7 sites

162 patients

CANADA

6 sites

70 patients

ALGERIA

6 sites

63 patients

RUSSIAN

FEDERATION

20 sites

240 patients

SPAIN

6 sites

60 patients

GREECE

6 sites

90 patients

ROMANIA

4 sites

84 patients

UNITED KINGDOM

8 sites

80 patients

POLAND

8 sites

135 patients

ITALY

10 sites

140 patients

CROATIA

5 sites

46 patients

GLOBALLY

5 continents

20 countries

438 sites

7637 patients


Baseline characteristics

*Mean value. HbA1c and FPG measured at randomization. All other parameters measured at the screening visit

BMI, body mass index; CKD, chronic kidney disease; CV, cardiovascular; FPG, fasting plasma glucose; IGlar U100, insulin glargine U100

ParameterInsulin

degludecIGlar U100

Total number of patients, n 3818 3819

Age, years* 64.9 65.0

Sex, Male, % 62.8 62.4

Duration of diabetes, years* 16.6 16.2

CV risk profile

Established CV or CKD and age ≥50 years, % 85.5 84.9

With CV risk factors and age ≥60 years, % 14.1 14.8

BMI, kg/m2* 33.6 33.6

HbA1c, %* 8.4 8.4

FPG, mg/dL*

[mmol/L]*

169.8

[9.4]

173.5

[9.6]


Baseline medications

*Nine patients have missing initiation drug date; they are assumed to be on treatment at baseline

ParameterInsulin

degludecIGlar U100

Total number of patients, n 3818 3819

Antihyperglycemic treatment (excluding insulins),

%

Metformin 60.1 59.4

Sulfonylurea 29.3 29.1

Dipeptidyl peptidase-4 inhibitors 12.1 12.6

Glucagon-like peptide-1 receptor agonists 7.9 8.0

Thiazolidinedione 3.8 3.2

Sodium-dependent glucose transporter-2

inhibitors2.1 2.3

Alpha-glucosidase inhibitors 1.7 1.8

Others 1.3 1.8

Insulins, %

Any insulin 84.2 83.7

Basal insulin only 38.1 37.7

Basal–bolus insulin (including bolus-only and

pre-mix)46.1 46.0

Cardiovascular medications, %

Antihypertensive therapy* 93.2 93.0

Lipid-modifying medications* 82.4 81.9

Platelet aggregation inhibitors* 72.0 71.8

Anti-thrombotic medication* 8.1 7.6


Basal insulin dose (U/kg)

Full analysis set

IGlar U100, insulin glargine U100; N, number of patients; U, units

0,0

0,2

0,4

0,6

0,8

1,0

1,2

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

Ba

sal in

sulin

do

se

(U

/kg

)

Insulin

degludec (N)3724 3575 3424

329

01125 55

IGlar U100 (N) 3717 3542 3385323

91134 61

Months since randomization

Insulin degludec

IGlar U100


Similar mean HbA1c

Full analysis set

CI, confidence interval; ET, end treatment visit; ETD, estimated treatment difference

-0,86 -0,84

-1,0

-0,5

0,0

%

Observed mean change

from baseline at month 24

Insulin degludec IGlar U100

Post hoc ETD:

0.01% [-0.05; 0.07]95% CI

6,5

7,0

7,5

8,0

8,5

9,0

0 3 6 9 12 15 18 21 24 27 30

Hb

A1c (%

)

75

69

64

59

53

0

Hb

A1

c(m

mo

l/mo

l)

Insulin

degludec (N)

3774 3656 3608 3535 3525 2458 3344

IGlar U100 (N) 3776 3640 3562 3516 3500 2424 3277

0.0


ET

Insulin degludec

IGlar U100

7.55%

7.50%


0

2

4

6

8

10

12

0 3 6 9 12 15 18 21 24 27 30

Time to first 3-point MACE

Full analysis set; Cox regression analysis accounting for treatment. Analysis includes events between randomization date and follow-up date.

Patients without an event are censored at the time of last contact (phone or visit)

EAC, Event Adjudication Committee; N, number of patients at risk; PYO, patient-years of observation

HR: 0.91[0.78; 1.06]95% CI

Non-inferiority confirmed

p<0.001

Pa

tien

ts w

ith

an e

ve

nt (%

)

Insulin

degludec (N)

3818 3765 3721 3699 3611 3563 3504 2851 1767 811 217

IGlar U100 (N) 3819 3758 3703 3655 3595 3530 3472 2832 1742 811 205

Time to first EAC-confirmed event (months)

IGlar U100

Insulin degludec

356 patients

325 patients


3-point MACE, 4-point MACE and all-cause death

*CV death includes undetermined cause of death; †4-point MACE defined as cardiovascular death*, non-fatal myocardial infarction, non-fatal stroke or

unstable angina requiring hospitalization


Significant reduction of FPG with insulin degludec

compared with IGlar U100

Full analysis set

FPG, fasting plasma glucose

108

117

126

135

144

153

162

171

180

0 12 24 36

FP

G (

mg

/dL)

-2,5

-2,0

-1,5

-1,0

-0,5

0,0

-40

-30

-20

-10

0

mm

ol/Lm

g/d

L

Observed mean change

from baseline at month 24


Post hoc ETD:

-7.2 mg/dL [-10.3; -4.1]95% CI

-0.4 mmol/L [-0.6; -0.2]95% CI

ET

FP

G (m

mo

l/L)

10.0

9.5

9.0

8.0

7.5

7.0

6.5

0.0

8.5

Insulin

degludec (N)

3757 3521 2457 3345

IGlar U100 (N) 3760 3498 2425 3277

-39.9 mg/dL

-2.2 mmol/L

-34.9 mg/dL

-1.9 mmol/L

0


Insulin degludec

IGlar U100


Event Adjudication Committee-confirmed severe

hypoglycemia in this double-blinded trial

ADA, American Diabetes Association; EAC, Event Adjudication Committee

1. Seaquist et al. Diabetes Care 2013;36:1384–95

Events sent for severe

hypoglycemia adjudication

1005 events

EAC-confirmed severe hypoglycemia

752 events

Severe hypoglycemia

(ADA definition):

An episode requiring the

assistance of another person

to actively administer

carbohydrate, glucagon, or

take other corrective actions

with neurologic recovery1


Incidence of severe hypoglycemia

Full analysis set; The incidence of events is analyzed using a logistic regression model adjusted for treatment group

Time from randomization (months)

Insulin degludec

(N=3818)

IGlar U100

(N=3819)

N % N %

EAC-confirmed

episodes187 4.9 252 6.6

0

2

4

6

8

10

0 3 6 9 12 15 18 21 24 27 30

Pa

tie

nts

with

an

eve

nt (%

) Odds ratio: 0.73

[0.60; 0.89]95% CI

p<0.001

IGlar U100

Insulin degludec


Rates of severe hypoglycemia

Full analysis set; Mean number of confirmed severe hypoglycemic episodes. The number of events is analyzed using a negative binomial regression

model using a log link and the logarithm of the observation time (100 years) as offset

E, number of events; R, events per 100 patient-years of observation; PYO, patient-years of observation

0

4

8

12

16

0 3 6 9 12 15 18 21 24 27 30

Me

an

nu

mb

er

of

eve

nts

/10

0 P

YO


Insulin degludec

(N=3818)

IGlar U100

(N=3819)

E R E R

EAC-confirmed

episodes280 3.70 472 6.25

IGlar U100

Insulin degludec

Rate ratio: 0.60

[0.48; 0.76]95% CI

p<0.001


Rates of nocturnal severe

hypoglycemia

Full analysis set; Nocturnal hypoglycemia: EAC-confirmed severe hypoglycemic episode with an investigator-reported onset between 00:01 and 05:59.

Mean number of nocturnal EAC-confirmed severe hypoglycemic episodes. The number of events is analyzed using a negative binomial regression

model using a log link and the logarithm of the observation time (100 years) as offset

0

1

2

3

4

5

0 3 6 9 12 15 18 21 24 27 30

Me

an

nu

mb

er

of

eve

nts

/10

0 P

YO


Rate ratio: 0.47

[0.31; 0.73]95% CI

p<0.001

IGlar U100

Insulin degludec


• Glycemic control (insulin degludec vs. IGlar U100):

• End of treatment mean HbA1c values 7.55% vs. 7.50%

• Change in FPG levels -39.9 mg/dL vs. -34.9 mg/dL

• 27% fewer patients experienced severe hypoglycemia with insulin degludec

• 40% rate reduction of severe hypoglycemia

• 53% rate reduction of nocturnal severe hypoglycemia

Summary of glycemic control and

severe hypoglycemia


Overview of adverse events

IGlar U100, insulin glargine U100; N, number of patients

38,6

24,8

5,2

39,7

25,2

5,8

0

20

40

60

80

100

Serious Severe Leading to drugdiscontinuation

Pro

port

ion

of pa

tien

ts (

%)

N=1473 N=1517 N=945 N=962N=200 N=222

Insulin degludec

IGlar U100


Adverse events leading to permanent

discontinuation of study drugs

Full analysis set; As assessed by investigator

Discontinuation of study drug was considered permanent when patient did not resume treatment


N % E R N % E R

Number of patients 3818 3819

PYO 7568 7558

All events 200 5.2 276 3.65 222 5.8 305 4.04

Severe events 128 3.4 167 2.21 132 3.5 177 2.34

Serious events 180 4.7 241 3.18 199 5.2 265 3.51

Events related to study drugs

(probable/possible)24 0.6 30 0.39 31 0.8 39 0.51


Neoplasms by tissue type

DPT-1 : η po ινσουλίνη δεν ανέστειλε την εμφάνιση ΣΔτ1 …

N Engl J Med. 2002 May 30;346(22):1685-91

πιθανό οφέλος σε ειδικές ομάδες ασθενών

Επιδημιολογικές μελετες :ΣΔ τ1 σε Ευρώπη και Αμερική: MDI vs CSII ;

Τα οικονομικά της ινσουλινοθεραπείας

το μέλλον της ινσουλινοθεραπείας

Christof Kazda1, Jennifer Leohr1, Rong Liu1, Shobha

Reddy1, Mary Anne Dellva1, Shufen Th Lim1, Mei Teng

Loh1, Mary Pat Knadler1, Thomas Hardy1, Leona

Plum-Moerschel2

1Eli Lilly and Company, Indianapolis, USA; 2Profil, Mainz, Germany

A Novel Formulation of Insulin Lispro

Containing Citrate and Treprostinil

Shows Faster Absorption and

Improved Postprandial Glucose

Excursions vs. Humalog in Patients

with T1DM

BACKGROUND

▪ A prandial insulin with an ultra rapid on/off profile has the

potential to reduce glycemic excursions better than current

rapid-acting analogs

▪ Current rapid-acting insulins administered by pumps or

syringes are not fast enough to match carbohydrate

absorption

▪ LY is a novel formulation using the locally acting excipients

treprostinil and citrate

− Citrate increases vascular permeability at the injection site

− Treprostinil accelerates insulin lispro absorption by local

vasodilation with no measurable systemic exposure

▪ LY was developed to more closely mimic physiologic

prandial insulin secretion with the goal of improving

postprandial glucose control and allowing flexibility in the

timing of insulin administrationCopyright (C) 2017 Eli Lilly and Company. All rights reserved

BASELINE CHARACTERISTICS AND

PATIENT DISPOSITION

Demographics

▪ 30 patients with T1DM

▪ Mean age = 42.2 years

▪ Males = 24; females = 6

▪ Mean weight = 79.9 kg

Clinical Characteristics (Mean)

▪ Body mass index = 25.2 kg/m2

▪ HbA1c = 7.1%

▪ Duration of T1DM = 22 years

▪ Fasting blood glucose = 171 mg/dL

Patient Disposition

▪ All 30 randomized patients completed the 6-period crossover

Copyright (C) 2017 Eli Lilly and Company. All rights reserved

KEY RESULTS

Figure 1. Ultra rapid insulin lispro and Humalog (A) mean serum insulin lispro concentration over time (inset is time 0-1h) and (B) mean postprandial glucose

over time; Abbreviation: SE=standard error

LY900014 (LY), ultra rapid insulin lispro, showed faster, earlier insulin lispro

absorption and greater postprandial glucose reduction when

administered immediately before the test meal

Time post injection (hours)

Me

an

(+

/-S

E)

Se

rum

In

su

lin

Lis

pro

Co

nc

en

tra

tio

n (

pm

ol/

L)

Me

an

Glu

co

se

Co

nc

en

tra

tio

n (

mg

/dL

)

Time post mean (hours)

Ultra rapid insulin lispro (LY)

A B

Humalog

0 1 2 3 4 5

100

120

140

160

180

Mean

(+

/-S

E)S

eru

m I

nsu

lin

Lis

pro

Co

ncen

trati

on

(p

mo

l/L

)

Time post injection (hours)

0.00 0.25 0.50 0.75 1.00

0

100

200

300

400

500

0 1 2 3 4 5

0

100

200

300

400

500


LY ACCELERATED EARLY AND

LATE INSULIN EXPOSURE

ParameterLY

(N=30)

Humalog

(N=30)

Ratio of Geo LSM

LY:Humalog (90% CI)P value1

Early Insulin Exposure Geo LSM

Early 50% tmax, min 15.5 24.3 0.635 (0.598-.0675) <.0001

AUC(0-30min), pmol•h/L 89.1 40.1 2.23 (2.01-2.46) <.0001

AUC(0-1h), pmol•h/L 262 192 1.37 (1.28-1.46) <.0001

Late Insulin Exposure

AUC(3-5h), pmol•h/L 62.1 82.6 0.751 (0.674-0.837) <.0001

Late 50% tmax, min 124 131 0.946 (0.896-0.999) .0913

Total Insulin Exposure

Tmax, h 0.863 0.855 1.01 (0.932-1.09) .8388

Cmax, pmol/L 410 362 1.13 (1.07-1.20) .0008

AUC(0-∞), pmol•h/L 789 745 1.06 (1.00-1.12) .0848

1Predefined significance level of 0.1

Abbreviations: (0-30min)=from 0 to 30 minutes post-dose; (0-1h)=from 0 to 1 hour post-dose; (3-5h)=from 3 to 5 hour post-dose; AUC=area under the concentration vs. time curve; (0-∞)=from time 0 to

infinity CI=confidence interval; Cmax=maximalconcentration; Early 50% tmax=time to early half-maximal concentration; Geo=geometric; h=hour; Late 50% tmax=time to late half-maximal concentration;

LSM=least squares mean; min=minutes; t1/2=half life; tmax=time to maximal concentration.


LY REDUCED THE POSTPRANDIAL

GLUCOSE EXCURSION

ParameterLY (N=30)

LSM

Humalog (N=30)

LSM

Ratio1 LY : Humalog

(90% CI)P Value2

∆AUC (0-2h), mg•h/dL 35.26 58.130.61

(0.32, 0.93).0315

∆AUC (0-5h), mg•h/dL 76.37 135.540.56

(0.21, 1.04).0972

1 CI calculated using Fieller’s Therom2 P value is for the test of mean difference; predefined significance level of P=.1

Abbreviations: ∆=change from baseline (premeal); (0-2h)= from time 0 to 2 hours post-meal; (0-5h)=from time 0 to 5

hours post-meal; AUC=area under the concentration vs. time curve; CI=confidence interval; LSM=least squares mean


SAFETY

▪ Three patients reported TEAEs, 1 patient while

receiving LY (+15 min) and 2 while receiving Humalog

(0 min)

▪ TEAEs were all mild to moderate

▪ No apparent association between meal-to-dose time

and TEAE for either LY or Humalog

▪ No clinically relevant differences observed in incidence

or severity of hypoglycemia

▪ No injection site reactions or increased injection site

pain observed with single doses of up to 40 U.

▪ All treprostinil concentrations were below the lower limit

of quantification (0.010 ng/mL)


CONCLUSIONS

▪ Ultra rapid insulin lispro (LY) demonstrated

accelerated insulin lispro absorption with a 2.2 fold

increase in the insulin exposure within the first 30 min

and a 37% reduction of early 50% tmax compared with

Humalog

▪ LY reduced the total postprandial glucose excursion

by 44% relative to Humalog

▪ Treprostinil concentrations were below the

quantification limit

▪ No clinically relevant differences in local tolerability

or hypoglycemia incidence were observed

▪ These results support further evaluation of LY as an

ultra rapid mealtime insulin for the treatment of T1DM


25 άτομα με ΣΔτ1 σε σχήμα 5 ενέσεων

Συνεχιση του σχήματος ή εισπνεόμενη ινσουλίνη αντί για γευματικές για 99 μέρες

Μεγαλύτερη μείωση της HbA₁c στην ομάδα της εισπνεόμενης ινσουλίνης (0,7% vs 0,5% , p≤0,035)

per os ινσουλίνη

p.o γευματική ινσουλίνη vs SC ινσουλίνης σε παιδιά με ΣΔ τ1

Ισάξια ή και καλύτερη μεταβολική ρύθμιση

Καθοριστικός παράγοντας η συμμορφωση των ασθενών

Ευχαριστώ!!!

highlights ΑΠΟ ΤΑ ΜΕΓΑΛΑ ... - static.livemedia.gr · presented at the american diabetes...

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