Geremia B. BolliDepartment of Medicine

Perugia University Medical School, Italy, EUROPE

31st Panhellenic Annual Congress of the Hellenic Association

for the Study & Education of Diabetes Mellitus

Thessaloniki, 9 November 2017

THE PIVOTAL ROLE OF BASAL INSULIN REPLACEMENT

IN THE TREATMENT OF DIABETES MELLITUS

Geremia B.Bolli

CONFLICT OF INTERESTover past two years

Sanofi

Eli Lilly

Menarini

agenda

➢Fasting and inter-prandial plasma glucose

concentration as major determinant of mean daily

glycaemia and A1C

➢Role of basal insulin

➢Type 2 diabetes as endocrine disease with insulin

deficiency

➢How to replace and titrate basal insulin as early as

possible

➢Insulin preparations

3

Glu

co

se

(m

mo

l/l) 9.0

5.0

160

0

7.0

320

480

Ins

ulin

(p

mo

l/l)

Mean ± 2SD

0700 1200 1800 2400 0600 hrs

Normal SubjectsMeals

Ciofetta M. et al., DIabetes Care 22:795-800, 1999

Physiology of Glucose Homeostasis known only since 1980

4 h 5 h 9 h total 18 hPG controlby basalinsulin

ADA-EASD 2015

\

???

Natural history of Type 2 DM

NGT IGT/IFG T2D

Diet OHGAs OHGAs

+ Insulin

Insulin sensitivity remains low

Time (years)IFG: Impaired fasting glucose; IGT: Impaired glucose tolerance;

NGT: Normal glucose tolerance; OHGA: Oral hypoglycaemic agent.

Initiation of basal insulin is usually delayed

Freemantle et al. DOM 2012;14:901-909;

Zilov AV, et al. Diabetes 2011;60 (Suppl.1):2485

Use of insulin is delayed until 7–15 years from diagnosis,when HbA1c is 9.0–10.3%

0 4 8 16 years

Japan

Eastern Europe

Southern Europe

Canada

South Asia

East Asia

China

Middle East

North Africa

Latin America

Northern Europe

N=511

N=252

N=1032

N=1073

N=460

N=735

N=3623

N=11971

N=21107

N=9062

N=9493

9.9%

9.3%

9.0%

9.3%

9.1%

9.7%

9.6%

9.5%

10.3%

9.5%

9.5%

A1c

6.7

7.9

10.2

9.0

8.0

12.0

12.0

11.4

15.5

11.0

12

12.5

Start of therapy with basal Insulins

Caratteristiche Media±ds

o %

Età (anni) 62.1±11.2

Maschi (%) 53.4%

Durata diabete (anni) 10.9±8.3

BMI (Kg/m2) 29.3±5.4

HbA1c (%) 8.9±1.6

HbA1c <=7% (%) 11.5%

HbA1c >8% (%) 68.6%

Pressione sistolica (mmHg) 140±20

Pressione diastolica (mmHg) 79±10

Colesterolo totale (mg/dl) 186±43

Colesterolo HDL (mg/dl) 48±13

Colesterolo LDL (mg/dl) 106±35

Trigliceridi (mg/dl) 166±129

Caratteristiche dei pazienti per cui è stata avviata una terapia con analoghi lenti dell’insulina.

Combinazioni di farmaci Tutti

(%)

HbA1c

<=7.0%

(%)

HbA1c

>7.0%

(%)

Insulina+Metformina+SU 47.9 28.6 52.2

Insulina+Glinidi 12.5 16.6 10.7

Insulina+Metformina 11.2 17.2 9.5

Insulina+Metformina+Glinidi 6.9 6.0 7.0

Insulina+SU 6.6 6.8 6.6

Insulina 5.2 16.7 3.7

Insulina+Metformina+SU+Glinidi 1.6 1.5 1.7

Insulina+Metformina+SU+Acarbose 1.6 0.8 1.8

Insulina+Metformina+SU+DPP-IV 1.1 1.1 1.1

Pattern terapeutici più utilizzati al momento dell’avvio della terapia con analoghi lenti dell’insulina.

• Durante l’intero periodo di osservazione 2004-2011, un totale di 57.920 pazienti precedentemente in terapia con ipoglicemizzanti orali hanno avuto un cambiamento della terapia ed inizio di insulina.

• i pazienti passati da terapia orale ad insulina basale sono relativamente giovani e con una durata media di malattia di 10.9 anni. È da notare che al cambio di terapia quasi il 70% dei pazienti presentava valori di HbA1c maggiori di 8.0%, mentre un decimo presentava valori <=7.0%.

• Il 53.8% presentava valori >8% un anno prima del cambio di terapia e il 47.3% già due anni prima.

• Anche dopo l’inizio della terapia insulinica la metformina e i farmaci secretagoghi rimangono i farmaci più utilizzati .

• L’analisi dei pattern prescrittivi mostra come in quasi la metà dei casi l’utilizzo di analoghi lenti avvenga in concomitanza con terapia dual oral (metformina + secretagogo), mentre più raramente si associa a tripla terapia orale

Le Monografie degli Annali AMD : focus su «Cambiamento delle terapie» Cimino et al.2013

24-Hour Plasma Glucose in failure to OHA

Time of Day

22.2

16.6

11.1

5.5

0

0600 06001000 1400 1800 2200 0200

courtesy of Jay Skyler

adapted from Polonsky et al, N Engl J Med 1988

Glucose

(mmol/L)

Diabetic

T2

Normal

Effect of treatment with basal insulin

6

7

8

9

0 4 8 12 16 20 24

Weeks of treatment

8.6 8.6

6.9, 6.9 %

Mean A1c%

58% ≤ 7%

Riddle MC et al. Diabetes Care 2003;26: 3080-86

NPH vs glargineThe Treat-to-Target Trial

Glargine NPH

Consistent achievement of A1C 7.0%

with basal insulin

1. Riddle M, et al. Diabetes Care 2003;26:3080–6. 2. Yki-Järvinen H, et al. Diabetes Care 2006;49:442–51.3. Bretzel RG, et al. Lancet 2008;371:1073−84. 4. Janka H, et al. Diabetes Care 2005;28:254−9.

5. Rosenstock J, et al. Diabetes Care 2006;29:554–9. 6. Yki-Järvinen H, et al. Diabetes Care 2007;30:1364–69.

Hb

A1

cc

ha

ng

es

(%

)

TTT1 LANMET2 APOLLO3 LAPTOP4 Triple Therapy5 INITIATE6

Baseline Study endpoint (after insulin glargine treatment)

10

45

0

10

20

30

40

50

0 2 4 6 8 12 18 24 weeks

Units : Starting dose 10 units

To

tal D

aily

Do

se

(u

nits)

Both Treatment Groups

0

2.7

5.5

8.3

11.1

8.6

6.9

6.5

7.0

7.5

8.0

8.5

9.0

HbA1c

%

FBG

mmol/l

6.5

11

Rosenstock J, et al. Diabetes. 2001;50(suppl 2):A520.

Proof of Concept: Initial Report on the Treat To Target Study

Combination Oral Agents + Glargine vs NPH

0.4-0.5 units/Kg

titration of basal insulin in practice

• prefer semplicity, safety, empowerment

of patients

measure fasting BG every morning,

after 3 days take the mean/median:

if BG is >110 mg/dl, add 2 U

if BG = 110 mg/dl, continue same dose

if BG is <110 mg/dl, decrease 2 U

Educate a nurse

Answer telephone, use telemedicine

No need for patient to come to the clinic

1. Riddle M et al. Diabetes Care 2003;26:3080–862. Janka H et al. Diabetes Care 2005;28:254–259

3. Rosenstock J et al. Diabetes Care 2006 4. Gerstein HC et al. Diab. Med. 2006

5. Rosenstock J et al. Diabetologia, 2008

Basal + OHA studies in Type 2 DM

TTT2003

Triple Therapy2006

Rosenstock2008

Glargine

Comparator

Insight2005

0

10

20

30

40

50

60

70

Laptop2005

% o

f p

atie

nts

wh

o d

o

no

t re

ach

tar

get

A1

c

after intensive treatment and near-normal fasting PG,

it is post-prandial hyperglycaemia the cause

of A1C >7.0%

Woerle JH et al, Diab Res Clin Pract, 2007

A1C 7.60.1

A1C 6.20.4

relative contribution of post-prandial

hyperglycemia to A1C

Woerle JH et al, Diab Res Clin Pract, 2007

Diabetes Care, Diabetologia. 19 April 2012

Beyond basal Insulin in T2 DM

Insu

lin

Eff

ect

meal mealmeal bedtime

basal

• lispro• aspart• glulisine

• or GLP-1 RA

{

Glu

co

se

(m

mo

l/l) 9.0

5.0

160

0

7.0

320

480

Ins

ulin

(p

mo

l/l)

Mean ± 2SD

0700 1200 1800 2400 0600 hrs

Normal Subjects

Meals

30-60 pmol/l

5-10 mU/L

Ideal Basal Insulin

• Flat PK/PD, long (24 h and a little beyond) –

mimicking CSII*

• Low within-subject, within-day and day-to-day

variability

• Flexible dosing

• Available to all patients at a sustainable price

*CSII: continuous subcutaneous insulin infusion

basal insulin preparations

➢NPH

➢Gla-100 (and biosimilars, copies outside EU/USA)

➢Detemir

➢Degludec

➢Gla-300

21

NPH Insulin needs resuspension

prior to injection

NPH Insulin needs resuspension prior to injection

95

150

205

95

150

205

Pla

sm

a G

luc

os

e

mg

/dl

NPH

0 2 4 6 8 10 12 14 16 18 20 22 24

1

2

3

4

0

Time (hours)

Glu

co

se

Infu

sio

nR

ate

mg

/Kg

/min INSULIN ACTION

Subjects with Type 1 DMMean±SE

NPH

basal insulin

s.c. injection

Rossetti P. et al., Arch. Physiol. Biochem., 114:3-10, 2008

Limitations of NPH

NPH limitations

• peak at 4-6 hours post-injection (riskhypoglycaemia)

• Day-to-day high variability in PK/PD ifnot properley re-suspended

Variability of NPH Insulin

in Type 1 Diabetes

O R+

▼R- down

▲R- up

■R- horizontal

Lucidi P. et al., Diabetes Care 2015

Within subjects C.V.

62%

Variability of NPH Insulin

in Type 1 Diabetes

O R+

▼R- down

▲R- up

■R- horizontal

Lucidi P. et al., Diabetes Care 2015

Within subjects C.V.

62%

NPH limitations

• peak at 4-6 hours post-injection (riskhypoglycaemia)

• Day-to-day high variability in PK/PD ifnot properley re-suspended

the insoluble NPHshould not be used,

neither the pre-mixed

Never in type 1 DM

Neither in type 2 DM

prefer alternatives(soluble insulins)

NPH in vials and cartridgesLucidi P. et al.,

Diabetes Metab, 2017

Re-suspended

Not re-suspended

Not re-suspended

95

150

205

95

150

205

Pla

sm

a G

luco

se

mg

/dl

glargine

detemir

NPH

0 2 4 6 8 10 12 14 16 18 20 22 24

1

2

3

4

0

Time (hours)

Glu

co

se

Infu

sio

nR

ate

mg

/Kg

/min INSULIN ACTION

Subjects with Type 1 DMMean±SE

NPH

glarginedetemir

basal insulin

s.c. injection

Rossetti P. et al., Arch. Physiol. Biochem. 2008

physiology

0

0.2

0.4

0.6

0.8

1

1.2

1.4

20 21 22 23 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Time of day

Glargine

NPHInsulin

injection

NPH vs glargineHypoglycemia by time of day in the Treat-to-Target Trial

Confirmed events per patient-year

*

*

*

*

*

*

*

* p <0.05

Riddle MC et al. Diabetes Care 2003;26: 3080-86

Riddle MC et al. Diabetes Care 2003;26: 3080-86

Events per pt-yr confirmed < 4 mmol/L

NPH Glargine % lower

Anytime of day-night 12.9 9.2 29

Nocturnal 5.5 3.1 44

Events per pt-yr confirmed < 3.1 mmol/L

NPH Glargine % lower

Anytime of day-night 5.1 3.0 41

Nocturnal 2.5 1.3 48

NPH vs glargineThe Treat-to-Target Trial

basal insulin preparations

➢NPH

➢Gla-100 (and biosimilars, copies outside EU/USA)

➢Detemir

➢Degludec

➢Gla-300

31

questions

➢Why new basal insulins?

➢How do they work?

➢What benefit for the patient?

➢Which one is the best?

32

NH

O

OH

O NH

O

OH

OHexadecandioyl

L-γ-Glu

desB30 Insulin

Glutamic acid ‘spacer’

C16 Fatty diacid side chain

DesB30

Thr

Des(B30) LysB29(γ-Glu Nε-hexadecandioyl) human insulin

Insulin Degludec Molecular Structure

s

A1

B1

A21

s s

s

s

s

T YG EE CYCC NLQLSISQVI NC

PTYY FFF GGG REE CC VLLAVLHSLHQNV Lys

Jonassen I et al. Pharm Res 2012 (DOI 10.1007/s11095-012-0739-z)

B29

Insulin Degludec: Mode of Absorption

Jonassen I et al. Pharm Res 2012 (DOI 10.1007/s11095-012-0739-z)

Heise T et al, Expert Opin Drug Metab Toxicol 2015

PD of acylated insulin Degludec vs Gla-U100

Glargine Gla300

a new version of Gla100

Gla300Gla100

Reduction of volume by 2/3

Reduction of depot surface by 1/2

Gla300

Same amount of units

Gla100

32

*red3 2

preredprered ))(6.3

(36)(*36**)(

cF

tPkVkSAk

dt

tdP

Reinhard Becker

PK/PD of Gla-U300 vs Gla-U100

Becker RHA et al, Diabetes Care 2015

basal insulin preparations

➢NPH

➢Gla-100 (and biosimilars, copies outside EU/USA)

➢Detemir

➢Degludec

➢Gla-300

38

IDeg and Gla-300, when compared to Gla-100, both:• Are non-inferior (A1C lowering)• Reduce the risk for hypoglycemia (primarily nocturnal) because of flatter action profile

Hypoglycemia with degludec and glargine U-300

compared with glargine U-100 (courtesy of Matt Riddle)

Ratner RE et al. Diab Obes Metab 2013;15: 175-184 Ritzel R et al. Diab Obes Metab 2015;17: 859-867

Meta-analyses of phase 3 clinical studies of type 2 diabetes

Degludec (Ratner et al) Glargine U-300 (Ritzel et al)

N of studies 5 3

N of participants 3372 2496

Definition of confirmed <3.1 mmol/L ≤3.9 mmol/L

hypoglycemia or severe or severe

Rate Ratio (95% CI)

Anytime events 0.83 (0.74-0.94 0.86 (0.77-0.97)

Nocturnal events 0.68 (0.57-0.82) 0.69 (0.57-0.84)

With both new insulins, ~15% fewer overall and ~30% fewer nocturnal events

QUESTION in year 2017

difference between IDeg and Gla-U300

degludec vs glargine U-300acylated, forms multihexamers s.c. iso-electic pH, precipitates s.c.

longer? Half-life 18 h

Titration time: similar

Flexibility: similar

A1C lowering: similar

Risk Reduction Hypoglycemia: similar

? Variability ?

COST: different

Head-to-head studies needed

PK and PD of clinical doses ofGla-300 vs Gla-100 in type 1 DM (N=18)

Porcellati F et al.,

Diabetes 2017 (abs)

Head-to-head trial in T2DM:Gla-300 vs. IDeg

Outcomes: HbA1cHypoglycemia

24-week, multicenter, randomized, open-label, parallel-group study

ClinicalTrials.gov. NCT02738151. Available at: https://clinicaltrials.gov/ct2/show/02738151. Last accessed September 2017.

Heise T et al., Diabetes Obes Metab 2017

0.4 U/kg fixed dose 1/day for 12 days (evening)

Gla-300 vs IDegl in type 1 diabetes mellitusGIR (insulin activity)

Heise T et al., Diabetes Obes Metab 2017

Lower variability of IDegl explained by failure of the

clamp which is not euglycemic with Gla-300

Heise T et al., Diabetes Obes Metab 2017

Lower within-day variability of GIR profiles with Gla-300 vs

IDeg-100 at 0.4 U/kg/day

For GIR data a smoothing factor (LOESS factor 0.15) was applied.

CI, confidence interval; GIR, glucose infusion rate; GIR-smFL0–24, fluctuation of the smoothed GIR curve over 24 hours

Results

• Within-day variability of the smoothed GIR (GIR-smFL0–24) was significantly lower (20%)

with Gla-300 vs Deg-100 at the 0.4 U/kg/day dose

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

0 2 4 6 8 10 12 18 20 22 24 26 28 30 16 14

Me

an

GIR

(m

g/m

in/k

g)

Gla-300 (0.4 U/kg)

Deg-100 (0.4 U/kg)

Time after dosing on day 8 (h)

GIR-smFL0–24 treatment ratio

0.80 (90% CI: 0.66 to 0.96)

p=0.047

Bailey T et al., in preparation 2017

0.4 U/kg fixed dose 1/day for 8 days (morning)

CONCLUSIONS

• The new insulins IDeg and Gla-U300 have the potential of more

physiological PK/PD vs Gla-100 and detemir

• They are indicated especially in Type 1 DM (total B-cell failure)

however…

• We need more experience in its use, to get the benefits and

avoid the risks for patients (hypoglycemia from prolonged

fasting, exercise)

• We also need more studies head-to-head in Type 1 DM to

understand differences and similarities

• A new approach to compare Gla-300 to IDeg at clinical doses in

individual patients (cross-over study) is underway

IN T2 DMUSE BASAL INSULIN…

…according to the rule of the

5 M

• MORE (in more patients)

• MORE EARLY (at diagnosis, or shortly after)

• MORE PHYSIOLOGICALLY (prefer basal insulin first, add prandial later as needed – do not mix…)

• MORE AGGRESSIVELY (treat to target) and

• MORE SAFELY (minimize hypoglycaemia)

IN T2 DM, USE BASALINSULIN…

INSULIN…

…a natural hormone created by Nature, not by drug companies !!!

…exactly what it is missing in people with diabetes!!!

THANK YOUfrom Torgiano!