LES NOVES INSULINES RÀPIDES I EL CONTROL DE … › files › 425-14696-DOCUMENT › Perez...LES NOVES INSULINES RÀPIDES I EL CONTROL DE LA GLICÈMIA POSTPRANDIAL Dr Manuel Pérez

LES NOVES INSULINES RÀPIDES I EL CONTROL DE LA GLICÈMIA POSTPRANDIAL

Dr Manuel Pérez Maraver Servei dÉndocrinologia i Nutrició Hospital Universitari de Bellvitge

Conflicto de intereses: -Ensayos clínicos: Sanofi, Novo Nordisk -Advisory boards: Sanofi, Novo Nordisk, AZ, Lilly, Boehringer, Abbott -Formación continuada: Novo Nordisk, Lilly, Sanofi, AZ, Boehringer, MSD, Novartis, Menarini -Empleado por: Institut Català de la Salut -Profesor asociado de Medicina en la Universitat de Barcelona

1- Importància de la glicèmia postprandial

2- La HbA1c com a factor de risc CV: dades actuals (breu)

3- Insulina Faster Aspart

4- Conclusions

Fast-acting insulin aspart is approved in Europe and it has not been launched in Spain

Postprandial hyperglycaemia results from loss of early insulin release

Mitrakou et al. Diabetes 1990;39:1381–90.

Estudio Comienzo

Localización

No. de pacient

es

Duración

(años)

Chicago Peoples Gas Company Study

1992 EE.UU 873 19

Oslo Study 1995 EE.UU 873 19

Diabetes Intervention Study

1996 Alemania 1139 11

Chicago Heart Association Detection Project

1997 EE.UU 12220 22

Paris Prospective and Helsinki Policemen Studies

1998 – 7260 20

Rancho Bernardo Study 1998 EE.UU 1858 7

Funagata Diabetes Study 1999 Japón 2534 6

Honolulu Heart Program 1999 Hawaii 8006 23

Hoorn Study 1999 Países Bajos 2363 8

Mauritius-Fiji-Nauru Study 1999 – 9179 8–12

Estudio Comien

zo Localizació

n

No. de pacient

es

Duración (años)

DECODE 1999 EU 22514 8.8

Saydah, Diabetes Care 2001 EE.UU 3092 16

Framingham Offspring Study 2002 EE.UU 3370 4

Cardiovascular Health Study 2002 EE.UU 4014 8.5

Qiao, Eur Heart J 2002 Finlandia 6766 7–10

DECODA 2004 Asia 6817 5

San Luigi Gonzaga Study 2006 Italia 529 5

Whitehall Study 2006 Reino Unido

17869 33

AusDiab Study 2009 Australia 10026 7

Israel Study of Glucose Intolerance, Obesity and Hypertension

2016 Israel 2138 33

Observación consistente Correlación significativa entre la hiperglucemia postprandial y la mortalidad CV o eventos CV

Datos epidemiológicos que correlacionan GPP con enfermedades CV

CV: cardiovascular; CVD: enfermedad cardiovascular; GPP: glucosa plasmática postprandial. Standl et al. Diabetes Care 2011;34 (Suppl. 2):120–7; Bergman et al. Diabet Med 2016;33:1060–6

Raz I et al. Diabetes Care 2009; 32: 381-85



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Relationship between fasting and postprandial glucose with HbA1c

HbA1c

PPG FPG PPG has a stronger correlation with

HbA1c than FPG3

PPG is the predominant contributor in patients with satisfactory to good control of diabetes, whereas the

contribution of FPG increases with worsening diabetes2

A recent meta-analysis found that:

Increased PPG and FPG drive increase in HbA1c

1

1. Monnier et al. Diabetes Care 2007;30:263–9; 2. Monnier et al. Endocr Pract 2006;12:S1:42–6; 3. Ketema et al. Arch Public Health 2015;73:43

FPG, fasting plasma glucose; PPG, postprandial plasma glucose

Woerle et al. /Diabetes Research and Clinical Practice 77 (2007) 280–285

Only 64% of patients achieving FPG targets of <100 mg/dl achieved an HbA1c target of <7% whereas 94% of patients achieving the postprandial target of <140 mg/dl did.

A1c >7%, TA >140/80 mm Hg, fumador, LDL >97 mg/dl, EUA +. N Engl J Med 2018; 379: 633-44

N Engl J Med 2018; 379: 633-44

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Ultra-fast insulin: approaching a physiological insulin profile even further

Rapid-acting insulin

Time (h)

Insulin a

ction (

at

mealtim

e)*

From the normal pancreas

‘Ultra-fast’ insulin

Regular human insulin

Ultra-fast insulin should:

• Better approach physiological insulin secretion in T1D

• Replace early insulin secretion in T2D

• Have a better profile for pump therapy

*Schematic representation T1D, type 1 diabetes; T2D, type 2 diabetes Adapted from Home. Diabetes Obes Metab 2015;17:1011–20

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Designing an ultra-fast-acting insulin

• Sprinkler needle • Pulmonary

Administration

• Additives e.g.: • EDTA/citric acid • Magnesium • Bio-chaperone • Niacinamide

Formulation

• Application of heat • Hyaluronidase

Injection site

EDTA, ethylenediaminetetra-acetic acid

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2015 Insulin glargine U300

Glucose-sensitive insulin

BioChaperone lispro

Liver-selective prandial insulin

Oral insulin

Lo

ng

-acti

ng

Goal of insulin development: approach endogenous insulin secretion by healthy pancreatic beta-cells

Future

First clinical use of insulin 1922

Biosynthetic human insulin

1982

Rapid-acting insulin analogue

1996

Exubera inhaled insulin (withdrawn 2007) 2006

Afrezza inhaled insulin

2015

Sh

ort-

acti

ng

1950 NPH insulin

1953 Lente insulin

2000 Insulin glargine

U100

2013 Insulin degludec

1920 1940 1960 1980 2000

Ult

ra-f

ast-

acti

ng

2005 Insulin detemir

Faster aspart 2017

2017

Adapted from Cahn et al. Lancet Diabetes Endocrinol 2015;3:638–52; Eli Lilly. Patent application, 12 November 2015; Eli Lilly. Press release, 4 December 2015; Novo Nordisk. Capital Markets Day R&D update, 19 November 2015

Faster aspart, fast-acting insulin aspart; NPH, neutral protamine Hagedorn

Trepostinil lispro (LY900014)

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Niacinamide: absorption modifier

Vitamin B3

L-Arginine: added for stability

Naturally occurring amino acid

FDA. Inactive Ingredient Search for Approved Drug Products database. www.accessdata.fda.gov/scripts/cder/iig/index.cfm. Accessed June 2016.

Insulin aspart

Changing the formulation: faster aspart is insulin aspart in a new formulation

Faster aspart, fast-acting insulin aspart

http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm

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Niacinamide increases monomer fraction and permeation rate of insulin aspart Rate of increase similar as leap from human insulin to insulin aspart

Monomer fraction

+35%

Permeation rate across HDMEC cell monolayers

0.00

0.01

0.02

0.03

0.04

0.05

Human insulin

Insulin aspart

Faster aspart†

0

2x10-06

4x10-06

6x10-06

Papp (

cm

/s)

+27%

Volu

me fra

ction o

f m

onom

ers

in b

uff

er

Human insulin

Insulin aspart

Faster aspart†

Buckley et al. ATTD 2016 (ATTD-0083); Novo Nordisk. Data on file

†Concentration of niacinamide simulating subcutaneous environment after injection HDMEC, human dermal microvascular endothelial cells

Dissociation of insulin hexamers Increasing early monomer fraction after injection

Schematic representation

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Faster aspart vs. insulin aspart via sc injection

Twice as fast onset of appearance in the bloodstream

Two-fold higher insulin exposure within the first 30 min

74% greater insulin action within the first 30 min

Compared with insulin aspart, faster aspart has:

Pooled analysis of NN1218 trials 3887, 3888, 3889, 3891, 3921, 3978. Faster aspart, fast-acting insulin aspart; GIR, glucose infusion rate; IAsp, insulin aspart; sc, subcutaneous

Faster aspart Insulin aspart

0 30 60 Time (min)

0

50

100

150

200

250

300

IAsp s

eru

m c

onc. (p

mol/

L)

9 4

0 30 60

GIR

(m

g/k

g/m

in)

0

2

4

6

8

Time (min) Heise et al. Clin Pharmacokinet 2017;56:551–9


PD: Early glucose-lowering effect Cross-trial indirect comparison: Comparable improvement with fast-acting insulin aspart over insulin aspart as insulin aspart over human insulin

aIn healthy volunteers; bIn patients with type 1 diabetes. AUC, area under the curve; GIR, glucose infusion rate. Modified from: Heinemann L et al. Exp Clin Endocrinol Diabetes 1997;105:140–4; Heise et al. Clin Pharmacokinet 2017; 56:551–9.

Overview of the onset programme for fast-acting insulin aspart

MDI, multiple daily injections; T1D, type 1 diabetes; T2D, type 2 diabetes

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onset 1: trial design A randomised, treat-to-target trial in T1D

Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771; Mathieu et al. ADA 2017. Poster 992-P

Key endpoints from baseline to week 26

• Change in HbA1c

• Change in PPG increment (meal test)

• Number of treatment-emergent hypoglycaemic episodes

• Number of treatment-emergent AEs

Faster aspart (mealtime) + detemir

Faster aspart (post-meal) + detemir

Insulin aspart (mealtime) + detemir

26 weeks

Randomisation (1:1:1) Primary endpoint for 26-week trial

8 weeks

Run-in

26 weeks

EOT

Insulin aspart + insulin detemir

FUa

Double-blind

This trial is registered at ClinicalTrials.gov: NCT01831765. aFU (7–30 days) AE, adverse event; BMI, body mass index; DBL, database lock; faster aspart, fast-acting insulin aspart; FU, follow-up; PPG, postprandial plasma glucose; T1D, type 1 diabetes

n=381

n=380

n=382

Key endpoints from baseline to week 52

• Number of hypoglycaemic episodes


• Change in HbA1c from baseline at 52 weeks

• PPG regulation (based on meal test)

• Change in body weight from baseline at 52 weeks

FUa

•

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Faster aspart (mealtime)

n=381

Insulin aspart (mealtime)

n=380

Faster aspart (post-meal)*

n=382

Age, years 46.1 (13.8) 43.7 (14.0) 43.5 (13.7)

Male, n (%) 215 (56) 238 (63) 219 (57)

BMI, kg/m2 26.4 (3.8) 26.7 (3.7) 26.9 (4.1)

Body weight, kg lb

78.6 (14.9) 173.2 (32.8)

80.2 (15.2) 176.7 (33.5)

80.5 (15.9) 177.5 (35.1)

Duration of diabetes, years 20.9 (12.9) 19.3 (11.8) 19.5 (12.1)

HbA1c, % mmol/mol

7.6 (0.7) 59.7 (7.7)

7.6 (0.7) 59.3 (7.5)

7.6 (0.7) 59.9 (7.9)

FPG, mmol/L mg/dL

8.4 (3.1) 151.4 (55.8)

7.9 (2.8) 141.8 (50.2)

8.1 (3.2) 145.6 (56.9)

onset 1: baseline characteristics at randomisation

*Faster aspart (post-meal) arm was not continued in the additional treatment period. Data are presented as mean (SD) unless stated otherwise BMI, body mass index; faster aspart, fast-acting insulin aspart; FPG, fasting plasma glucose; SD, standard deviation

Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771; Russell-Jones et al. Diabetes 2016;65(Suppl. 1):A77

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onset 1: mean HbA1c over time

HbA

1c (m

mol/m

ol)

8.0

8.2

7.6

7.8

7.2

7.4

64

66

60

62

56

58

HbA

1c (

%)



Faster aspart (post-meal)

0 8 4 12 16 20 24 26 -5 -10 -1 34 40 46 52

Basal optimisation

Bolus intensification

Error bars: ± standard error (mean) EOT, end of treatment; faster aspart, fast-acting insulin aspart


HbA1c 7.5%

HbA1c 7.4%

HbA1c 7.3%

EOT HbA1c 7.6%

EOT HbA1c 7.5%

Time since randomisation (weeks)

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onset 1: PPG increment at week 26 Standardised meal test: mealtime comparison

Faster aspart (mealtime) Insulin aspart (mealtime)

*p<0.0001; P-values are 2-sided. ETD represents PPG changes from baseline estimates. Changes from baseline in PPG increments were analysed based on an ANOVA model.

0

18

36

54

72

90

108

126

0

1

2

3

4

5

6

7

0

Week 26

PPG

incre

ment

(mg/d

L)

Time (min) Bolus dose 0.1 U/kg

PPG

incre

ment

(mm

ol/

L)

0 60 120 180 240

108

126

72

90

36

54

18

0

6

7

4

5

2

3

1

0

PPG

incre

ment (m

g/d

L)

2-h ETD**: –0.67 mmol/L [95% CI: –1.29; –0.04] –12.0 mg/dL [95% CI: –23.3; –0.7]

**

1-h ETD*: –1.18 mmol/L [95% CI: –1.65; –0.71] –21.2 mg/dL [95% CI –29.7; –12.8]

*

**p=0.0375.

aCompared with mealtime insulin aspart. ANOVA, analysis of variance; CI, confidence interval; ETD, estimated treatment difference (faster aspart–insulin aspart); PPG, postprandial plasma glucose

Error bars: ± standard error (mean). *p<0.0001; **p=0.0375.

Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771

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Week 52

Error bars: ± standard error (mean). P-values are 2-sided. ETD represents PPG changes from baseline estimates. Changes from baseline in PPG increments were analysed based on an ANOVA model

onset 1: PPG increment at week 52 Standardised meal test: mealtime comparison

ANOVA, analysis of variance; CI, confidence interval; ETD, estimated treatment difference (faster aspart–insulin aspart); faster aspart, fast-acting insulin aspart; PPG, postprandial plasma glucose

Mathieu et al. ADA 2017. Poster 992-P

0

1-h ETD*: −0.91 mmol/L (95% CI: −1.40;−0.43) −16.5 mg/dL (95% CI: −25.2;−7.8)

*

*p=0.0002

Bolus dose 0.1 U/kg

2-h ETD: −0.42 mmol/L (95% CI: −1.11;0.27)

−7.6 mg/dL (95% CI: −20.0;4.8)

Faster aspart (mealtime) Insulin aspart (mealtime)

0

6

7

4

5

2

3

1

0 0 60 120 180 240

PPG

incre

ment

(mm

ol/

L)

PPG

incre

ment

(mg/d

L)

108

126

72

90

36

54

18

0

PPG

incre

ment (m

g/d

L)

Time (min)

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0

10

20

30

40

50

60

70

80

Week 26 Week 52

Severe

or

BG

-confirm

ed h

ypogly

caem

ic e

pis

odes p

er

patient-

year

of exposure

NS

NS

Week 261 Week 522

Estimated ratio

95% CI Estimated

ratio 95% CI

Faster aspart (mealtime)/ insulin aspart (mealtime)

1.01 0.88;1.15 1.01 0.88;1.15

Faster aspart (post-meal)/ insulin aspart (mealtime)

0.92 0.81;1.06 n/a n/a

The analysis was based on a negative binomial regression model. Treatment-emergent was defined as an event that has onset up to 1 day after last day of randomised treatment and excluding the events occurring in the run-in period. Estimated treatment ratios (faster aspart/insulin aspart) are presented with 95% CIs BG-confirmed: PG value <3.1 mmol/L (56 mg/dL) BG, blood glucose; CI, confidence interval; faster aspart, fast-acting insulin aspart; PG, plasma glucose; NS, non-significant

onset 1: treatment-emergent hypoglycaemia



Faster aspart (post-meal)

1. Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771; 2. Mathieu et al. ADA 2017. Poster 992-P

NS

No difference in the overall rates of severe or BG-confirmed hypoglycaemia between treatment arms

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onset 1: conclusions

Faster aspart, fast-acting insulin aspart; PPG, postprandial plasma glucose; T1D, type 1 diabetes

Faster aspart effectively improved glycaemic control in subjects with T1D

• Non-inferiority in HbA1c reduction (mealtime and post-meal) to insulin aspart was confirmed after 26 weeks

• The reduction in HbA1c with faster aspart (mealtime) was statistically significantly larger than with insulin aspart.

• Statistically significantly greater reduction in HbA1c was maintained at week 52 with faster aspart (mealtime) vs. insulin aspart

At week 26, superior PPG control with mealtime faster aspart vs. insulin aspart (2-h PPG increment at meal test) was observed • At week 52, a statistically significant difference was observed only for 1-h PPG increment

No statistically significant difference in the overall rate of hypoglycaemia

Similar overall safety profiles, and as expected for insulin aspart


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8 weeks 1 week/30 days Follow-up

onset 2: trial design A double-blind, treat-to-target trial in T2D

Faster aspart + insulin glargine U100 + metformin

Insulin aspart + insulin glargine U100 + metformin

26 weeks

Patients with T2D on basal insulin and metformin ± other OADs

Randomisation (1:1)

End of treatment

Insulin glargine U100 + metformin

Run-in

This trial is registered at ClinicalTrials.gov: NCT01819129 AE, adverse event; BMI, body mass index; faster aspart, fast-acting insulin aspart; OAD, oral antidiabetic drug; PPG, postprandial plasma glucose; T2D, type 2 diabetes

n=345

n=344

Key inclusion criteria

• T2D for ≥6 months and age ≥18 years

• Basal insulin for ≥3 months

• Metformin ± OADs for ≥3 months

• HbA1c

• Metformin/basal insulin only: 7.0–9.5% (53–80 mmol/mol) or

• Metformin/basal insulin + OAD: 7.0–9.0% (53–75 mmol/mol)

• BMI <40 kg/m2

Key endpoints

• Change in HbA1c

• Change in PPG increment (meal test)

• Change in body weight

• Number of treatment-emergent hypoglycaemic episodes


Basal insulin dose optimisation

Bolus intensification

Bowering et al. Diabetes Care 2017;doi:10.2337/dc16-1770

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Faster aspart n=345

Insulin aspart n=344

Age, years 59.6 (9.3) 59.4 (9.6)

Male, n (%) 163 (47) 173 (50)

BMI, kg/m2 31.5 (4.7) 31.0 (4.5)

Body weight, kg lb

89.0 (16.9) 196.3 (37.3)

88.3 (16.7) 194.7 (36.9)

Duration of diabetes, years 13.2 (6.7) 12.3 (6.3)

HbA1c, % mmol/mol

8.0 (0.7) 63.5 (7.5)

7.9 (0.7) 62.7 (7.7)

FPG, mmol/L mg/dL

6.8 (1.8) 121.7 (32.7)

6.8 (2.0) 122.7 (35.1)

onset 2: baseline characteristics at randomisation

Data are presented as mean (SD) unless stated otherwise BMI, body mass index; faster aspart, fast-acting insulin aspart; FPG, fasting plasma glucose; SD, standard deviation


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onset 2: mean HbA1c over time1

Faster aspart

Insulin aspart

8.5

7.5

8.0

6.5

7.0

6.0

5.5

26 -1 -5 -10

0 0.0

HbA

1c (

%)


HbA

1c (m

mol/m

ol)

64

69

53

58

42

48

8 4 12 16 20 0

37

8.2%

8.1%

8.0%

7.9% EOT 6.6%

EOT 6.6% ETD: –0.02%

(95% CI: –0.15;0.10)

Non-inferiority was confirmed

Error bars: ± standard error (mean) BMI, body mass index; CI, confidence interval; EOT, end of trial; ETD, estimated treatment difference (faster aspart–insulin aspart); faster aspart, fast-acting insulin aspart

Change from baseline in HbA1c was analysed using a mixed-effect model for repeated measurements

Baseline

Basal optimisation Bolus intensification

1. Bowering et al. Diabetes Care 2017;doi:10.2337/dc16-1770

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2-h ETD:† −0.36 mmol/L (95% CI: −0.81;0.08)

−6.6 mg/dL (95% CI: −14.5;1.4)

1-h ETD:* −0.59 mmol/L (95% CI: −1.09;−0.09) −10.6 mg/dL (95% CI: −19.6;−1.7)

PPG

incre

ment (m

g/d

L)

90

72

54

36

18

0

PPG

incre

ment

(mm

ol/

L)

5

4

3

2

1

0

Time (min) Median bolus dose: 0.16 U/kg

Week 26

**

*

0 60 120 180 240

onset 2: PPG increment at week 26 Significantly greater reduction at 1 h with faster aspart vs. insulin aspart

Faster aspart

Insulin aspart

Error bars: ± standard error (mean). ANOVA, analysis of variance; CI, confidence interval; ETD, estimated treatment difference (faster aspart–insulin aspart); faster aspart, fast-acting insulin aspart; PPG, postprandial plasma glucose

*p=0.0198.

ETD represents PPG change from baseline estimates. The analysis was based on an ANOVA model

†Confirmatory secondary endpoint, not statistically significant


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onset 2: mean body weight over time

Faster aspart

Insulin aspart

Body w

eig

ht (lb

)


87

89

91

93

95

Body w

eig

ht

(kg)

192

196

201

205

209

0 12 26

Error bars: ± standard error (mean) CI, confidence interval; ETD, estimated treatment difference (faster aspart–insulin aspart); faster aspart, fast-acting insulin aspart

ETD: 0.00 kg (95% CI: −0.60;0.61)

2.7 kg weight gain for both groups

*p=0.0198.

ETD represents PPG change from baseline estimates. The analysis was based on an ANOVA model


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onset 2: treatment-emergent hypoglycaemia No difference in rates of severe or BG-confirmed hypoglycaemia

0

5

10

15

20

25

Severe

or

BG

-confirm

ed h

ypogly

caem

ic e

pis

odes p

er

patient-

year

of

exposure

NS

Estimated ratio

95% CI

Faster aspart/ insulin aspart

1.09 0.88;1.36

The analysis was based on a negative binomial regression model. Treatment-emergent was defined as an event that has onset up to 1 day after last day of randomised treatment and excluding the events occurring in the run-in period. Estimated treatment ratios (faster aspart/insulin aspart) are presented with 95% confidence intervals. BG-confirmed: PG value <3.1 mmol/L (56 mg/dL) BG, blood glucose; CI, confidence interval; faster aspart, fast-acting insulin aspart; PG, plasma glucose; NS, non-significant




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onset 2: conclusions

†Confirmatory secondary endpoint BG, blood glucose; CI, confidence interval; EOT, end of trial; ETD, estimated treatment difference (faster aspart–insulin aspart); faster aspart, fast-acting insulin aspart; PPG, postprandial plasma glucose; T2D, type 2 diabetes

PPG regulation (meal test): • 1-h PPG increment significantly improved vs. insulin aspart

(ETD [95% CI]:−0.59 mmol/L [−1.09;−0.09]; −10.6 mg/dL [−19.6;−1.7]) • 2-h PPG increment† not significantly improved vs. insulin aspart

(ETD [95% CI]: −0.36 mmol/L [−0.81;0.08]; −6.6 mg/dL [−14.5;1.4])

Faster aspart effectively improved glycaemic control (EOT HbA1c = 6.6%) in subjects with T2D previously on basal insulin only • HbA1c reduction: non-inferior to insulin aspart

No statistically significant difference was seen in overall rate of severe or BG-confirmed hypoglycaemic episodes

Similar overall safety profile with faster aspart and insulin aspart


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Randomised, double-blind, crossover trial evaluating the PK/PD properties of faster aspart, under glucose clamp conditions, during CSII in 48 patients with T1D receiving faster aspart or insulin aspart as a CSII bolus dose on top of basal CSII

Inclusion criteria

• T1D for ≥12 months

• Treatment with MDI or CSII for ≥12 months

• BMI 18.5–28.0 kg/m2

• HbA1c ≤8.5%

PK/PD study in CSII Comparing faster aspart with insulin aspart

3–12 days washout period

Dosing 1 day

Follow-up 7–21 days

Screening 3–21 days

Dosing 1 day

Faster aspart basal 0.02 U/kg/h bolus 0.15 U/kg

Insulin aspart basal 0.02 U/kg/h bolus 0.15 U/kg

Insulin aspart basal 0.02 U/kg/h bolus 0.15 U/kg

Faster aspart basal 0.02 U/kg/h bolus 0.15 U/kg

N=48 Primary endpoint

• AUCIAsp, 0–30 min (pmol*h/L)

Heise et al. Diabetes Obes Metab 2017;19(2):208–215

This trial is registered at ClinicalTrials.gov: NCT01992588. AUC, area under the curve; BMI, body mass index; CSII, continuous subcutaneous insulin infusion; faster aspart, fast-acting insulin aspart; IAsp, insulin asaprt; MDI, multiple daily injections; PK/PD, pharmacokinetic/pharmacodynamic; T1D, type 1 diabetes


PK: Early insulin exposure ~3-fold higher insulin exposure within the first 30 min with fast-acting insulin aspart vs. IAsp

*p<0.001. Treatment ratios (fast-acting insulin aspart / insulin aspart) and 95% CI. AUC, area under the curve; CI, confidence interval; CSII, continuous subcutaneous insulin infusion; IAsp, insulin aspart; LLoQ, lower limit of quantification; PK, pharmacokinetic. Heise T et al. Diabetes Obes Metab 2017;19:208–15.

3890


Trial design A randomised exploratory crossover pump trial with meal test

CSII, continuous subcutaneous insulin infusion; BMI, body mass index; CGM, continuous glucose monitoring; PG, plasma glucose. Bode B et al. Diabetes Technol Ther 2017;19:25–33.

3930

Faste

r Aspart

Core

Scie

nce 0

8032017 V

6 0

PPG in CSII with faster aspart Improved PPG after a meal test in CSII with faster aspart vs. insulin aspart

Time (min)

0 120 180 240 60

0

8

2

4

6

Baseline-a

dju

ste

d p

lasm

a g

lucose

(mm

ol/

L)

Insulin aspart

Faster aspart

∆PG0–1 ha

–0.50 (–1.07;0.07) mmol/Lb

∆PG0–2 ha

–0.99 (–1.95;–0.03) mmol/Lb*

Bode et al. Diabetes Technol Ther 2017;19:25–33

*p<0.05 aPGav,0–1 (2)h was calculated as AUCPG,0-2 h/2 h – PGPre-dose where AUCPG,0-2h was the area under the plasma glucose concentration time profile based on observed

values and actual measurement times in relation to time of injection between 0 and 2 h; btreatment difference, 95% CI AUC, area under the curve; CI, confidence interval; CSII, continuous subcutaneous insulin infusion; faster aspart, fast-acting insulin aspart; PG, plasma glucose; PPG, postprandial plasma glucose


Trial design

*Follow-up (7 and 30 days). 1,5-AG, 1,5-anhydroglucitol; AE, adverse event; BMI, body mass index; CGM, continuous glucose monitoring; CSII, continuous subcutaneous insulin infusion; FU, follow-up; IG, interstitial glucose; PPG, postprandial glucose. 1. NN1218-3854. Klonoff D et al. Diabetes Technol Ther 2018; 20(Suppl 1): A32–3.

onset 5


Baseline characteristics at randomisation

Data are mean unless otherwise stated. BMI, body mass index; FPG, fasting plasma glucose; n, number of randomised subjects. 1. NN1218-3854. Klonoff D et al. Diabetes Technol Ther 2018; 20(Suppl 1): A32–3.

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Mean HbA1c over time

*Non-inferiority confirmed at 0.4% level p-value for non-inferiority p<0.001, **p=0.022. Error bars: ± standard error (mean). Primary estimand. All available information regardless of treatment discontinuation was used. Change from baseline in HbA1c was analysed using a multiple imputation model. ETD represents fast-acting insulin aspart minus insulin aspart values. CI, confidence interval; ETD, estimated treatment difference. 1. NN1218-3854. Klonoff D et al. Diabetes Technol Ther 2018; 20(Suppl 1): A32–3.

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PPG increment at baseline and week 16

*p<0.001, **p=0.001, ***p=0.01. Error bars: ± standard error (mean). Primary estimand. All available information regardless of treatment discontinuation was used. The conversion factor between mmol/L and mg/dL is 0.0555 Change from baseline in PPG increment was analysed using a multiple imputation model. CI, confidence interval; ETD, estimated treatment difference [fast-acting insulin aspart – insulin aspart] for PG changes from baseline; PG, plasma glucose; PPG, postprandial glucose. 1. NN1218-3854. Klonoff D et al. Diabetes Technol Ther 2018; 20(Suppl 1): A32–3.

onset 5

Meal test


Treatment-emergent hypoglycaemia after 16 weeks

Treatment-emergent is defined as an event that has onset up to 1 day after last day of randomised treatment and excluding the events occurring in the run-in period BG-confirmed: PG value <3.1 mmol/L (56 mg/dL). Statistical analysis is based on a negative binomial regression model. BG, blood glucose; N, number of subjects with at least one event; %, percentage of subjects; E, number of events; R, number of events per patient-year of exposure. 1. NN1218-3854. Klonoff D et al. Diabetes Technol Ther 2018; 20(Suppl 1): A32–3.

onset 5


Why was the HbA1c reduction with fast-acting insulin aspart vs. IAsp lower, despite of improved PPG profile?

IAsp, insulin aspart.

Examination of CGM profiles for fast-acting insulin aspart vs. IAsp, showed:


Fast-acting insulin aspart vs. IAsp treatment with CSII has benefits for patients:

How can we interpret findings from onset 5?

BG, blood glucose; CSII, continuous subcutaneous insulin infusion; IAsp, insulin aspart; PPG, postprandial glucose.


1- La glicèmia postprandial és un element molt important del control glicèmic

2- Faster Aspart presenta una PK/PD més fisiològica que els anàlegs actuals

3- Faster Aspart presenta un millor control glicèmic postprandial

4- Límpacte sobre el control glicèmic global és encara limitat: aspecte pràctic

de la flexibilitat dádministració valorable

5- Hem de tenir més dades déstudis per definir bé lábast del seu benefici i

disposar déstratègies per maximitzar-ho.


Treatment-emergent AEs during 16 weeks

Treatment emergent is defined as an event that has onset up to 7 days after last day of randomised treatment and excluding the events occurring in the run-in period. AE, adverse event; E, number of events; ECG, electrocardiogram; N, number of subjects with at least one event; R, number of events per patient-year of exposure; %, percentage of subjects. 1. NN1218-3854. Klonoff D et al. Diabetes Technol Ther 2018; 20(Suppl 1): A32–3.

onset 5

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LES NOVES INSULINES RÀPIDES I EL CONTROL DE … › files › 425-14696-DOCUMENT › Perez...LES NOVES INSULINES RÀPIDES I EL CONTROL DE LA GLICÈMIA POSTPRANDIAL Dr Manuel Pérez