VANTAGGI E LIMITI DELLA TERAPIA INSULINICAMarco Giorgio BaroniDipartimento di Medicina SperimentaleUniversità Sapienza di Roma

Roma, 31 ottobre 2017

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Dichiaro di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti

Aziende Farmaceutiche e/o Diagnostiche:

SanofiNovo Nordisk

Abbott

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Diabetes is a progressive disease that requires reassessment to reach target

Canada(DICE)2

HbA1c

Controllo glicemico nei pazienti italianicon diabete tipo 2

Annali AMD 2012

Andamento per classi dell’HbA1c (normalizzata a 6,0)

Il 43.8% dei pazienti presenta valori 8%

Il 12% ha valori < 6%

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Diabete di tipo 2: durata dell’efficacia dei singoli farmaci

33

45

57

0 10 20 30 40 50 60

Glyburide

Metformin

Rosiglitazone

RosiglitazoneMetforminGlyburide

mesi

Kahn SE et al. NEJM 2006; 355: 2427–2443

Durata del ControlloGlicemico: tempo da intendersi Hba1c< 7% (ADOPT)

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Diagramm1

Glyburide

Metformin

Rosiglitazone

mesi

Months

33

45

57

Tabelle1

Months

Glyburide33

Metformin45

Rosiglitazone57

Ziehen Sie zum Ändern der Größe des Diagrammdatenbereichs die untere rechte Ecke des Bereichs.

UKPDS1

(n=3867)ADVANCE2

(n=11,140)ACCORD3

(n=10,251)VADT4

(n=1791)

Duration of diabetes (years) 0* 8 10 11.5

Mean baseline HbA1c (%)

7.1 7.5 8.3 9.4

Mean baseline FPG (mmol/L) 8.0 8.5 9.7 11.4

Mean age (years) 53 66 62 60

MicrovascularMacrovascular

=±

==

1UKPDS Group. Lancet 1998; 352:837. 2ADVANCE Collaborative Group. N Engl J Med 2008; 358:25603ACCORD Study Group. N Engl J Med 2008; 358:2545. 4Duckworth et al N Engl J Med 2009; 360:129

*Newly diagnosed patients with no previous history of CVD; FPG: fasting plasma glucose

Disease progression

Early vs late glycemic intervention: UKPDS enrolled newly diagnosed patients

Intervento precoce ed individualizzazione della terapia

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Insulin therapy in T2DM

ADVANTAGES

The defect in insulin secretion is a

primary one. The primary defect in

insulin secretion is reverted by insulin

treatment

LIMITATIONS

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UKPDS 16. Diabetes 1995;44:1249–58; Lebovitz 1999;7:139–53

Years from diagnosis

β-ce

ll fu

nctio

n (%

, HOM

A)

Diabetes diagnosis

β-cell function progressively declines

ADOPTUKPDS

0

20

40

60

80

100

Diet (n=110)Sulphonylurea (n=511)

Metformin (n=159)

–5 –4 –3 –2 –1 0 1 2 3 4 5 6

Extrapolation of β-cell function prior to diagnosis

0 1 2 3 4 50

60

70

80

90

100

Rosiglitazone, −2.0 (−2.6 to −1.3)Metformin, −3.1 (−3.8 to −2.5)Glyburide, −6.1 (−6.8 to −5.4)

Annualised slope (95% CI)

Treatment difference (95% CI)Rosiglitazone vs. metformin, 5.8 (1.9 to 9.8); p=0.003Rosiglitazone vs. glyburide, −0.8 (−4.7 to 3.1)); p=0.67

Time (y)

β-ce

ll fu

nctio

n (%

)

Kahn et al. N Engl J Med 2006;355:2427–43

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-60 0 60 120 180 240

360

330300270240110

80

140130120110100

90

120906030

0

Glucose (mg/dl)

Insulin (μU/ml)

Glucagon (pg/ml)

Meal

(minutes)

Type 2 diabetes(n=12)

Normals (n=11)

Delayed/depressedinsulin response

Non-suppressed glucagon

Adapted from Muller WA et al. N Engl J Med. 1970;283:109

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Yoneda S et al. J Clin Endocrinol Metab 98: 2053–2061, 2013

Relative β-cell area to entire pancreatic section in NGT, IGT, newly diagnosed DM and longstanding T2DM

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Yoneda S et al. J Clin Endocrinol Metab 98: 2053–2061, 2013

T2DM had a significantly increased β-cell apoptosis compared with the NGT

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Insulin prevents apoptosis induced by serum deprivation for 24 h in human pancreatic islets

Modified from Federici M al. FASEB J 15: 22-24, 2001

0

5

10

15

20

25

30

% a

popt

osis

Basal) Serum deprived Insulin(100 nm)

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The insulin receptor is localized in insulin secretory vescicles in human pancreatic β-cells

Hribal et al. FASEB J 17: 1340-1342, 2003

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Insulin stimulates its biosynthesis in human pancreatic islets

Modified from Andreozzi F et al. Endocrinology 145: 2845–2857, 2004

200

230

0

50

100

150

200

250

Insu

linbi

osyn

thes

is(%

ove

rbas

al)

Glucose(3 mm)

Glucose(16.7 mm)

Insulin(100 nm)

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Effetto della terapia insulinica intensiva sulla funzione -cellulare e sul controllo glicemico in diabetici tipo 2 di nuova diagnosi

Lancet 2008; 371: 1753-1760

51.1%

44.9%

26.7%

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First-phase and second-phase insulin secretion in response to IVGTT in 14 patients with type 2 diabetes before and after 8 weeks of

insulin glargine treatment add-on to metformin

Pennartz C et al. Diabetes Care 34:2048–2053, 2011

The mean diabetes duration was 4.6±3.0 years

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Insulin therapy in T2DM

ADVANTAGES

The primary defect in insulin secretion is

reverted by insulin treatment

Insulin treatment reverted defects in

hepatic glucose production.

LIMITATIONS

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Key Pathogenetic Defects in T2DM:The Ominous Octet

IMPAIRED INSULIN SECRETION

INAPPROPRIATE GLUCAGON SECRETION

REDUCED GLUCOSE UPTAKE

REDUCED GLP-1Altered Adipòcyte Metabolism

Altered Brain Signalling

Increased RenalGlucose Reabsorption

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Islet β-cell

ImpairedInsulin Secretion

12.6%

HYPERGLYCEMIA

Groop L et al. Am J Med 87:183-190, 1989Mod. da Gerich JE, Diabetes,Obesity and Metabolism 2:345-350, 2000

Relative contributions of HGP and glucose disposal to secondary failure to oral agents in Finnish diabetic

patients

IncreasedHGP

26.1% Decreased GlucoseUptake17.3%

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Excessive hepatic glucose production

Glucagon secretion

Pancreatic cells: β-cell α-cell δ-cell

Hepatic glucose production

Insulin secretion

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Henquin JC et al. Diabetologia 54:1720–1725, 2011

Ratio of alpha cell/beta cell areas in 52 non-diabetic subjects (ND) and 50 type 2 diabetic (T2D) subjects

P < 0.0001

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Linn T et al. J Clin Endocrinol Metab 93: 3839–3846, 2008

* * *

20.0

0

21.0

0

22.0

0

23.0

0

0.0

0

1.0

0

2.0

0

3.0

0

4.0

0

5.0

0

6.0

0

7.0

0

8.0

0

9.0

0

10.0

0

** *

Nocturnal Hepatic Glucose Production after Bedtime Injection of Glargine or NPH Insulin in Patients with Type 2 Diabetes

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Insulin therapy in T2DM

ADVANTAGES

The primary defect in insulin secretion is

reverted by insulin treatment

Insulin treatment reverted defects in

hepatic glucose production.

Insulin therapy is not associated with

atherogenesis and increased risk of CV

events.

LIMITATIONS

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ORIGIN Trial Investigators, N Engl J Med 367: 319-28, 2012

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ORIGINPrimary & Secondary Outcomes & their Components

HR (95% CI) P Insulin Standard/100 py /100 py

1st Coprimary 1.02 (0.94, 1.11) 0.63 2.94 2.852nd Coprimary 1.04 (0.97, 1.11) 0.27 5.52 5.28

Microvascular 0.97 (0.90, 1.05) 0.43 3.87 3.99Death 0.98 (0.90, 1.08) 0.70 2.57 2.60

MI 1.02 (0.88, 1.19) 0.75 0.93 0.90Stroke 1.03 (0.89, 1.21) 0.69 0.91 0.88CV Death 1.00 (0.89, 1.13) 0.98 1.57 1.55CHF Hospital 0.90 (0.77, 1.05) 0.16 0.85 0.95Revascularized 1.06 (0.96, 1.16) 0.24 2.69 2.52

0,5 1 2 Favors StandardFavors Insulin

HR

ORIGIN Trial Investigators, N Engl J Med 367: 319-28, 2012

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Marso SP et al. N Engl J Med. 377(8):723-732, 2017

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DEVOTE Kaplan–Meier Analysis of the Composite Primary Outcome

Marso SP et al. N Engl J Med. 377(8):723-732, 2017

Rate:4.71/100 PYO

Rate:4.29/100 PYO

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Devote Primary Endpoints: 3-Point MACE, 4-Point MACE, and All-Cause Mortality

Marso SP et al. N Engl J Med. 377(8):723-732, 2017

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Insulin therapy in T2DM

ADVANTAGES

The primary defect in insulin secretion is

reverted by insulin treatment

Insulin treatment reverted defects in

hepatic glucose production.

Insulin therapy is not associated with

atherogenesis and increased risk of CV

events.

Basal insulin is easy to use : one insulin,

once daily injection, one glucose target

(FPG), and easy dose titration (FPG).

LIMITATIONS

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Titration algorithm: insulin degludec and insulin glargine

Meneghini L et al. Diabetes Care 36:858–864, 2013

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Insulin therapy in T2DM

ADVANTAGES

The primary defect in insulin secretion is

reverted by insulin treatment

Insulin treatment reverted defects in

hepatic glucose production.

Insulin therapy is not associated with

atherogenesis and increased risk of CV

events.

Basal insulin is easy to use : one insulin,

once daily injection, one glucose target

(FPG), and easy dose titration (FPG).

LIMITATIONS

Treatment with insulin is associated with body

weight gain.

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Type 2 diabetes –weight gain over time is associated with insulin and oral antidiabetic therapies

These major trials have shown weight gain over time:

– UKPDS, significant mean increase of 3.1 kg in weight in the intensive treatment (sulphonylurea or insulin) group compared with the conventional treatment (diet and exercise) group1

– Action to Control Cardiovascular Risk in Diabetes (ACCORD), where patients receiving intensive therapy (targeting an HbA1c 10 kg3

– In A Diabetes Outcome Progression Trial (ADOPT), patients receiving glibenclamidegained an average of 1.6 kg over a median treatment duration of3.3 years4

1. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837–53; 2. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854–65;3. Members of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group. N Engl J Med 2008;358:2545–59; 4. Kahn SE, Haffner SM, Heise MA, et al. for the ADOPT Study Group. N Engl J Med 2006;355:2427–43.

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In the UKPDS, insulin-treated patients with type 2 diabetes gained the most weight

UKPDS 34. Lancet 1998:352:854–865.

insulinconventional chlorpropamideglibenclamide

Chan

ge in

wei

ght (

kg)

Years from randomisation

10

0

2.5

5

7.5

0 3 6 9 12

metformin

While patients on all therapies gained weight, patients receiving insulin gained the most (up to 8 kg after 12 years of insulin therapy)

–2.5Diapos

itiva pre

parata d

a MARC

O BARO

NI e ced

uta alla

Società

Italiana

di Diabe

tologia.

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Insulin and weight

• Reduced glycosuria

• Anabolic action of insulin

• Fluid retention

• Hypoglycaemia and increased calorie consumption

• Excess insulin administrationDiapositiv

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Network meta-analysis of pairwise comparisons of randomised controlled trials evaluating the use of anti-hyperglycaemic agents in addition to metformin vs.

placebo: Mean change from baseline in body weight

3,41

2,462,17

1,4 1,38

0,23

-1,01

-1,66-2

-3

-2

-1

0

1

2

3

4

Mea

n ch

ange

from

bas

elin

e in

bod

y w

eigh

t

Biphasic TZDs SU Glinides Basal DPP-4 Acarbose GLP-1R SGLT2*Insulin Insulin inhibitors agonists inhibitors

Liu S-C et al. Diabetes Obes and Metab 2012; 14: 810-820b Fujita Y et al. J Diabetes Investing 2014; 5: 265-275

*An estimate of body weight reduction; SGLT2 inhibitors were not included in the network analysis

DPP-4, dipeptidyl peptidase-4; SGLT2, sodium glucose cotransporter-2; TZDs, thiazolidinediones; GLP-1R, glucagon-like peptide 1 receptor; SU, sulphonylurea

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Insulin therapy in T2DM

ADVANTAGES

The primary defect in insulin secretion is

reverted by insulin treatment

Insulin treatment reverted defects in

hepatic glucose production.

Insulin therapy is not associated with

atherogenesis and increased risk of CV

events.

Basal insulin is easy to use : one insulin,

once daily injection, one glucose target

(FPG), and easy dose titration (FPG).

LIMITATIONS

Treatment with insulin is associated with

body weight gain.

Treatment with insulin is associated with

increased risk for hypoglycemia.

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Yki-Jarvinen et al. Ann Int Med 1999

Hypoglycaemia limits further reduction of FPG with basal insulin

Mea

n Hb

A 1c

[%]

Mean annual fasting blood glucose [mmol/l]

12

Freq

uenc

y of

Hyp

ogly

caem

ic

Episo

des [

%]

10

8

6

4

40

30

20

10

0

3 4 5 6 7 8 9 10 11

3 4 5 6 7 8 9 10 11

n = 13,072

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Thomas R. Pieber et al Diabetologia 2017

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Network meta-analysis of pairwise comparisons of randomised controlled trials evaluating the use of anti-hyperglycaemic agents in addition to metformin vs.

placebo: At least one event of overall hypoglycaemia (odds ratio)

17,78

10,51

8,86

4,77

1,13 0,92 0,45 0,41,1

0

2

4

6

8

10

12

14

16

18

20

Biphasic Glinides SU Basal DPP-4 GLP-1R TZDs Acarbose SGLT2*Insulin Insulin inhibitors agonists inhibitors

At le

ast o

ne e

vent

of o

vera

ll hy

pogl

ycae

mia

(odd

s ra

tio)

*An estimate of hypoglycaemia risk; SGLT2 inhibitors were not included in the network analysis b

Liu S-C et al. Diabetes Obes and Metab 2012; 14: 810-820b Fujita Y et al. J Diabetes Investing 2014; 5: 265-275

DPP-4, dipeptidyl peptidase-4; SGLT2, sodium glucose cotransporter-2; TZDs, thiazolidinediones; GLP-1R, glucagon-like peptide 1 receptor; SU, sulphonylurea

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4T Study: Glycated Hemoglobin Level, Hypoglycemia, and Increase in Body Weight at 1 Year and 3 Years

N Engl J Med 361;18, 2009

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Black box denotes both treatment arms switching to NPH for 1 week then resuming IDeg or IGlar to allow for antibody measurement

Zinman et al. Diab Care 35:2464–71, 2012; Rodbard et al. Diabetic Med 30:1298–304, 2013

CoreCore0,0

0,2

0,4

0,6

0,8

1,0

52 65 78 91 104

Nocturnal confirm

ed hypoglycaemia

(cumulative events per patient)

0,0

0,2

0,4

0,6

0,8

1,0

0 13 26 39 52

Noc

turn

al c

onfir

med

hyp

ogly

caem

ia(c

umul

ativ

e ev

ents

per

pat

ient

)

0

1

2

3

4

5

52 65 78 91 104

Confirmed hypoglycaem

ia(cum

ulative events per patient)

0

1

2

3

4

5

0 13 26 39 52

Conf

irm

ed h

ypog

lyca

emia

(c

umul

ativ

e ev

ents

per

pat

ient

)

5,0

5,5

6,0

6,5

7,0

7,5

8,0

8,5

9,0

0 4 8 1216202428323640444852

HbA

1c(%

)

3

4

5

6

7

8

9

10

11

0 4 8 1216202428323640444852

FPG

(m

mol

/L)

HbA1c FPG

Confirmed hypoglycaemia Nocturnal confirmed hypoglycaemia

18% lower rate with IDeg (ns)

Extension

16% lower rate with IDeg (ns)

Extension

43% lower rate with IDeg, p=0.002

5,0

5,5

6,0

6,5

7,0

7,5

8,0

8,5

9,0

525660646872768084889296100104

HbA

1c (%)

0.0

Treatment difference:

non-inferior

26

Extension0.0

Treatment difference:

0.12%-points (ns)

65 79 91 104Time (weeks)

Core3

4

5

6

7

8

9

10

11

525660646872768084889296100104

FPG (m

mol/L)

0

Treatment difference:

–0.43 mmol/L, p=0.005

26

Core Extension0

Treatment difference:

–0.38 mmol/L, p=0.019

65 79 91 104Time (weeks)

Time (weeks) Time (weeks)

36% lower rate with IDeg, p=0.038

IDeg OD I Glar OD

Insulin-naïve T2D: study designBEGIN ONCE LONG – 2 years

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Marso SP et al. N Engl J Med. 377(8):723-732, 2017

Devote Secondary Endpoints: Rates of severe hypoglycaemia

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Marso SP et al. N Engl J Med. 377(8):723-732, 2017

Devote Secondary Endpoints: Rates of nocturnal severe hypoglycaemia

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Insulin therapy in T2DM

ADVANTAGES

The primary defect in insulin secretion is

reverted by insulin treatment

Insulin treatment reverted defects in

hepatic glucose production.

Insulin therapy is not associated with

atherogenesis and increased risk of CV

events.

Basal insulin is easy to use : one insulin,

once daily injection, one glucose target

(FPG), and easy dose titration (FPG).

LIMITATIONS

Treatment with insulin is associated with

body weight gain.

Treatment with insulin is associated with

increased risk for hypoglycemia.

Insulin therapy needs to control both

FPG and post-prandial PG.

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Comparison of 24-hour plasma glucose levels in healthy subjects vs patients with diabetes (p

Insulin therapy needs to control both FPG and post-prandial PG

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Glycaemic control (%) in patients with T2DM initiating basal insulin in Europe and the USA

Mauricio D et al. Diabetes Obes Metab 19:1155–1164, 2017

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Insulin therapy in T2DM

ADVANTAGES

The primary defect in insulin secretion is

reverted by insulin treatment

Insulin treatment reverted defects in

hepatic glucose production.

Insulin therapy is not associated with

atherogenesis and increased risk of CV

events.

Basal insulin is easy to use : one insulin,

once daily injection, one glucose target

(FPG), and easy dose titration (FPG).

LIMITATIONS

Treatment with insulin is associated with

body weight gain.

Treatment with insulin is associated with

increased risk for hypoglycemia.

Insulin therapy needs to control both

FPG and post-prandial PG.

Insulin treatment may be refused by the

patient barriers.

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Reasons why health-care professionals and patients might refrain from starting insulin

treatment

Cahn A et al. Lancet 2015

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Patient-cited issues with insulin treatment

66,7%

59,8%

54,4%

81,4%

23,1%

27,6%

0% 20% 40% 60% 80% 100%

Insulin-treated diabetes controls their life

Insulin regimen can be restrictive

Hard to live normal life while managingdiabetes

Wish insulin regimen would fit daily lifechanges

Number of daily injections

Taking insulin at prescribed time/mealseveryday

Percentage

Peyrot et al. Diabetic Med 29:682–9, 2012

GAPP™• A global internet survey of patient

and physician beliefs regarding insulin therapy

• n=1530 insulin treated patients with diabetes

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Insulin therapy in T2DM

ADVANTAGES

The primary defect in insulin secretion is

reverted by insulin treatment

Insulin treatment reverted defects in

hepatic glucose production.

Insulin therapy is not associated with

atherogenesis and increased risk of CV

events.

Basal insulin is easy to use : one insulin,

once daily injection, one glucose target

(FPG), and easy dose titration (FPG).

LIMITATIONS

Treatment with insulin is associated with

body weight gain.

Treatment with insulin is associated with

increased risk for hypoglycemia.

Insulin therapy needs to control both

FPG and post-prandial PG.

Insulin treatment may be refused by the

patient barriers.

Insulin treatment is associated with

clinical inertia.

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Median time to intensification and mean HbA1c at intensification in patients with T2DM currently treated with 1-2 OADs with intensification to 3 OADs or insulin

Khunti et al. Diabetes Care 36:3411-7, 2013

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Consequences of delayed intervention in patients with T2DM

Paul, SK et al. Cardiovasc. Diabetol. 14: 100, 2015

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Modified from Raccah d et al. Diabetes Metab Res Rev 23: 257-264, 2007

??

Diet and exercise

Oral mono-or

combinationtherapy

Basal insulinOnce-daily

?

HbA1cuncontrolled

Time

HbA1c uncontrolled,FBG on target, PPBG >160 mg/dl

What next?

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Modified from Raccah d et al. Diabetes Metab Res Rev 23: 257-264, 2007

??

Diet and exercise

Oral mono-or

combinationtherapy

Basal insulinOnce-daily

Basal Bolus

3 prandial

HbA1cuncontrolled

Time

HbA1c uncontrolled,FBG on target, PPBG >160 mg/dl

Basal Plus

2 prandial for largest

glucoseexcurtions

Basal Plus

One prandial for largest

glucoseexcurtion

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Arguments in favor of timely insulin use in T2DM

• The defect in insulin secretion is a primary one.• Insulin treatment reverted defects in insulin secretion and

hepatic glucose production.

• Early insulin initiation is associated with reduced CVD risk• Treatment with insulin has high efficacy and is indicated in

certain clinical condition (pregnancy, hospitalized patients, critically ill patients).

• Increase in body weight and the risk for hypoglycemia may be minimized.

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What are the real unmet needs in insulin therapy

• Early recognition of failure of oral therapy• Strong positive recommendation of benefits of

insulin treatment to patients• Reassurance concerning potential negative

consequences in therapy• Intense support to optimise insulin dosage• Regular expert clinic review to identify problems

with insulin therapyDiapos

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O BARO

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Need for personalized care

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Grazie

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Vantaggi e limiti della terapia insulinicaDichiaro di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche:� �Sanofi�Novo Nordisk�Abbott�Diabetes is a progressive disease that requires reassessment to reach targetDiapositiva numero 4Diapositiva numero 5Early vs late glycemic intervention: �UKPDS enrolled newly diagnosed patientsDiapositiva numero 7Insulin therapy in T2DMDiapositiva numero 9Insulin and glucagon dynamics in response to meals are abnormal in type 2 diabetes�Diapositiva numero 12Diapositiva numero 13Diapositiva numero 14Diapositiva numero 15Diapositiva numero 16Effetto della terapia insulinica intensiva sulla funzione -cellulare e sul controllo glicemico in diabetici tipo 2 di nuova diagnosi�Diapositiva numero 18Insulin therapy in T2DMKey Pathogenetic Defects in T2DM:�The Ominous OctetDiapositiva numero 21Diapositiva numero 22Diapositiva numero 23Diapositiva numero 24Insulin therapy in T2DMDiapositiva numero 26ORIGIN�Primary & Secondary Outcomes & their ComponentsDiapositiva numero 28DEVOTE �Kaplan–Meier Analysis of the Composite Primary OutcomeDEVOTE Primary Endpoints:�3-Point MACE, 4-Point MACE, and All-Cause DeathInsulin therapy in T2DMTitration algorithm: insulin degludec and insulin glargineInsulin therapy in T2DMType 2 diabetes –weight gain over time is associated with insulin and oral antidiabetic therapiesIn the UKPDS, insulin-treated patients �with type 2 diabetes gained the most weightDiapositiva numero 36Diapositiva numero 37Insulin therapy in T2DMHypoglycaemia limits further reduction of FPG with basal insulinDiapositiva numero 41Diapositiva numero 424T Study: Glycated Hemoglobin Level, Hypoglycemia, and Increase in Body Weight at 1 Year and 3 YearsInsulin-naïve T2D: study design�BEGIN ONCE LONG – 2 yearsDEVOTE Secondary Endpoints:�Rates of Severe HypoglycemiaDEVOTE Secondary Endpoints:�Rates of Nocturnal Severe HypoglycemiaInsulin therapy in T2DM24-hour plasma glucose profile in T2DM and healthy subjectsThe Importance of Controlling PPGDiapositiva numero 50Insulin therapy in T2DMReasons why health-care professionals and patients might refrain from starting insulin treatmentPatient-cited issues with insulin treatmentInsulin therapy in T2DMClinical Inertia With Insulin TherapyDiapositiva numero 57Diapositiva numero 59Diapositiva numero 60Diapositiva numero 61Arguments in favor of timely insulin use in T2DMWhat are the real unmet needs in insulin therapyNeed for Personalized Care Diapositiva numero 65Diapositiva numero 66