Giorgio Sesti

Farmaci innovativi nella terapia del diabete

mellito di tipo 2

Università “Magna Graecia” di Catanzaro

Il Prof Giorgio Sesti dichiara di aver ricevuto negli ultimi due anni compensi o

finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche:

Novo Nordisk, Novartis, MSD, Boehringer‐Ingelheim-Lilly, Bristol-Myers Squibb,

Sanofi e Janssen-Cilag per attività di Relatore/Moderatore ad eventi.

Novo Nordisk, Intarcia, Boehringer‐Ingelheim-Lilly, MSD, Servier, Sanofi,

AstraZeneca e Janssen-Cilag per attività di Consulenza.

Potenziali conflitti di interesse

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1950 1960 1970 1980 1990 2000 2010

Vasodilators

Adrenergic neural blockers

Diuretics

Central α-2 blockers

-blockers

Peripheral α-2 blockers

Ca+ blockers ACE-I

ARBs

Sulphonylureas

Renin inhibitors

Metformin

α-glucosidase inhibitors

TZDs

Glinides

GLP-1R agonists

Amylino mimetics

DPP4-I

Bile acid sequestrants

SGTL2 Inh

Dopamine agonists

Nu

mb

er

of

Me

dic

ati

on

Cla

sse

s

Decreased Glucose Uptake

Increased Lipolysis and Adipokines

Increased HGP

Islet -cell

Increased Glucagon Secretion

Decreased Incretin Effect

Islet β-cell Impaired Insulin Secretion

HYPERGLYCEMIA

DPP-4 Inh. GLP-1R agonists

SU DPP-4 Inh.

GLP-1R agonists Insulin

DPP-4 Inh. GLP-1R agonists

Metformin TZDs

DPP-4 Inh. GLP-1R agonists

Insulin

TZDs Metformin

Insulin

TZDs Insulin

Increased Glucose Reabsorption

SGTL2 inhibitors

GLP-1 targets multiple organs to improve glucose control in T2DM

DPP-4 inhibitors

Liraglutide

Human GLP-1 analogues

Exendin-based therapies

GLP-1 receptor agonists

Incretin-based therapies: launched and in development

Incretin-based therapies

Albiglutide (Phase 3)

Dulaglutide (Phase 3)

Semaglutide (Phase 3)

Sitagliptin Linagliptin Saxagliptin Vildagliptin (Europe and Australia)

Alogliptin (US and Japan)

Teneligliptin (Japan only)

Exenatide OW Exenatide BID Lixisenatide

(Europe)

Anagliptin (Phase 3)

Gemigliptin (Phase 3)

GLP‐1 receptor agonists structural differences

Werner U, et al. Regul Pept 2010;164:58–64. Sanofi; data on file. Kim et al. Diabetes Care 2007;30:1487-93. Russell-Jones, D. Molecular and Cellular Endocrinology 297 (2009) 137–140

Short-acting and long-acting GLP-1 receptor agonists

Consider pathophysiological basis (declining beta-cell function,

glucagon secretion)

Consider efficacy

Consider side effects

Increased risk of hypoglycaemia

Weight gain

Consider effects on CV risk

Challenges in the management of type 2 diabetes

Beta-cell stimulation by saxagliptin in patients with T2D Insulin secretion rates in the postprandial state

* Values are geometric means; † Adjusted % change from baseline, geometric mean and 95% CI (represented by bar) SAXA: saxagliptin; PBO: placebo; T2D: type 2 diabetes; LOCF, last observation carried forward.

Insulin secretion rate during IV-Oral hyperglycaemic clamp: adjusted % change from baseline at Week 12

Adapted from Henry R, et al. Diabetes Obes and Metab 13: 850–858, 2011

SAXA 5 mg (n=16) PBO (n=15)

30

-10

10

20

Ge

om

etr

ic m

ea

n %

ch

an

ge

fro

m b

ase

lin

e

-20

0

-

-

-

-

-

-2.2†

15.9†

4.2

Adjusted % difference PBO (95% CI): 18.5 (1.3, 38.7)

P=0.035

Restoration of Insulin Release with Lixisenatide in Patients with Type 2 Diabetes

Adapted from Becker R et al. Diabetes 2010;59(Suppl 1):552-P

Glucagon secretion

Pancreatic cells: -cell -cell -cell

Hepatic glucose production

Insulin secretion

Eccessive hepatic glucose production

Vilda=Vildagliptin; PBO=Placebo, AUE=Area Sotto La Curva Effetto Δ si riferisce a AUE 0-840 min P<0.05 vs. PBO

Data on file, Novartis Pharmaceuticals, LAF237A2346

Singola dose orale di vildagliptin (100 mg) prima di cena

cena dose

Δ = 94% P = 0.02 *

* * * *

*

*

*

* *

* -60

-50

-40

-30

-20

-10

0

10

20

-60 0 60 120 180 240 300 360 420 480 540 600 660 720 780 840

Tempo (min)

De

lta

Glu

ca

go

ne

(n

g/L)

Placebo (16)

Vilda 100 mg (16)

Vildagliptin inibisce la secrezione di glucagone nel corso della notte

Vilda = Vildagliptin; PBO = Placebo, AUE = Area Sotto La Curva Effetto RaE velocità di comparsa del glucosio endogeno; Δ si riferisce alla AUE 0-840 min; *P<0.05 vs. PBO

Data on file, Novartis Pharmaceuticals, LAF237A2346

Singola dose orale di vildagliptin (100 mg) prima di cena

Δ = 59% P = 0.004

*

* * * * *

* * * * *

* * *

* -1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

-60 0 60 120 180 240 300 360 420 480 540 600 660 720 780 840

Tempo (min)

De

lta

EG

P (

mg

/k

g/m

in)

cena dose

Placebo (16)

Vilda 100 mg (16)

Vildagliptin sopprime la produzione endogena di glucosio nel corso della notte

Placebo BID Exenatide 0.1 µg/kg BID

Exenatide or Placebo Standardized Breakfast

Pla

sm

a G

luca

go

n (

pg

/m

L)

Time (min)

Single-blind, placebo-controlled crossover study (with two 5-d periods) of patients with T2D, n = 20 Mean ± SE; *P = 0.0123; BID indicates twice daily

Adapted from Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88:3082-3089.

0 120 180 60

50

100

150

200

• Exenatide significantly reduced AUC0-180 min

Exenatide Suppresses Inappropriately Elevated Postprandial Glucagon Secretion in T2D

Consider pathophysiological basis (declining beta-cell function,

glucagon secretion)

Consider efficacy

Consider side effects

Increased risk of hypoglycaemia

Weight gain

Consider effects on CV risk

Challenges in the management of type 2 diabetes

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

placebo: mean change from baseline in A1C

Liu S-C et al. Diabetes Obes and Metab 14: 810–820, 2012

-0,82

-0,71

-0,82

-0,66 -0,69

-1,02

-0,88

-1,07

-1,2

-1

-0,8

-0,6

-0,4

-0,2

0

SU Glinides TZDs Acarbose DPP-4 GLP-1R Basal Biphasic inhibitors agonists insulin insulin

Me

an

ch

an

ge

fro

m b

ase

lin

e i

n A

1C

le

ve

l

Efficacy of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial

Bergenstal RM et a. Lancet 376: 431-9, 2010

Consider pathophysiological basis (declining beta-cell function,

glucagon secretion)

Consider efficacy

Consider side effects

Increased risk of hypoglycaemia

Weight gain

Consider effects on CV risk

Challenges in the management of type 2 diabetes

Correlation between risk of severe hypoglycemia and cardiovascular death associated with intensive treatment: ACCORD, ADVANCE, PROACTIVE, UKPDS and VADT

meta-analysis

Mannucci E. et al. Nutr Metab Cardiovasc Dis 19:604-612, 2009

Network meta-analysis of pairwise comparisons of randomized controlled trials evaluating the use of anti-hyperglycemic agents in addition to metformin vs. placebo: At

least one event of overall hypoglycaemia (odds ratio)

Liu S-C et al. Diabetes Obes and Metab 14: 810–820, 2012

8,86

10,51

0,45 0,4 1,13 0,92

4,77

17,78

0

2

4

6

8

10

12

14

16

18

20

SU Glinides TZDs Acarbose DPP-4 GLP-1 Basal Biphasic inhibitors agonists insulin insulin

At

lea

st

on

e e

ve

nt

of

ove

rall

hyp

og

lyca

em

ia

(o

dd

s r

ati

o)

Consider pathophysiological basis (declining beta-cell function,

glucagon secretion)

Consider efficacy

Consider side effects

Increased risk of hypoglycaemia

Weight gain

Consider effects on CV risk

Challenges in the management of type 2 diabetes

Network meta-analysis of pairwise comparisons of randomized controlled trials evaluating the use of anti-hyperglycemic agents in addition to metformin vs. placebo:

Mean change from baseline in body weight

Liu S-C et al. Diabetes Obes and Metab 14: 810–820, 2012

2,17

1,4

2,46

-1,01

0,23

-1,66

1,38

3,41

-2

-1

0

1

2

3

4

SU Glinides TZDs Acarbose DPP-4 GLP-1 Basal Biphasic inhibitors agonists insulin insulin

Me

an

ch

an

ge

fro

m b

ase

lin

e i

n b

od

y w

eig

ht

Pratley RE et al. Lancet 375: 1447–1456, 2010

Liraglutide vs. sitagliptin for type 2 diabetes patients who did not have adequate glycaemic control with metformin: Change in body weight

–3.38 kg

–2.86 kg

–0.96 kg

Consider pathophysiological basis (declining beta-cell function,

glucagon secretion)

Consider efficacy and durability

Consider side effects

Increased risk of hypoglycaemia

Weight gain

Consider effects on CV risk

Challenges in the management of type 2 diabetes

Odds ratio [95% CI]

p-value

Major CV event1 0.71 [0.59, 0.86] < 0.001

Acute MI 0.64 [0.44, 0.94] 0.023

Stroke 0.77 [0.48, 1.24] 0.29

Mortality 0.60 [0.41, 0.88] 0.008

CV mortality 0.67 [0.39, 1.14] 0.14

Meta-analysis of 70 short- and medium-term trials, with 41,959 patients and mean follow-up of 44.1 weeks

DPP4 inhibitor better

Comparator better

In a large meta-analysis of CV events, DPP-4i were better than the comparator in terms of CV safety

AMI, acute myocardial infarction; CV, cardiovascular; DPP4i, dipeptidyl peptidase-4 inhibitors; MACE, major CV events.

Monami M, et al. Diabetes Obes Metab 15:112–120, 2013

0.0 1.0 10.0

FREEDOM-CVO (ITCA 650, GLP-1 in DUROS) n=2-3,000; duration ~2 yrs

end Q3 2018

Cardiovascular outcomes trials for GLP-1 and DPP4i

Source: ClinicalTrials.gov (October 2013) and LLY Investor call ADA 2013

TECOS (Sitagliptin, DPP4i)

n=14,000; duration ~4-5yrs end Q4 2014

CAROLINA (Linagliptin, DPP4i vs SU) n= 6,000; duration ~8 yrs

end Q3 2018

ELIXA (Lixisenatide, GLP-1)

n=6,000; duration ~4 yrs end Q3 2014

REWIND (Dulaglutide, QW GLP-1) n=9,622; duration ~8 yrs

end Q2 2019

SUSTAIN 6 (Semaglutide, GLP-1)

n=3,260; duration ~2.8 yrs end Q1 2016

Pre-approval Post-approval Pre + post approval

Other

LEADER (Liraglutide, GLP-1)

n=9,340; duration 3.5-5 yrs end Q1 2016

SAVOR TIMI-53 (Saxagliptin, DPP4i)

n=16,492; follow-up ~2 yrs end Q2 2013 - RESULTS

CARMELINA (Linagliptin, DPP4i)

n= 8,300; duration ~4 yrs end Q1 2018

EXAMINE (Alogliptin, DPP4i)

n=5,380; follow-up ~1.5 yrs end Q2 2013 - RESULTS

2019 2011 2015 2012 2013 2014 2016 2017 2018

EXSCEL (Exenatide QW GLP-1)

n=9,500; duration ~5.5 yrs end Q1 2017

Scirica BM et al. N Engl J Med 2013

16,492 patients, median followup 2.1 years

Saxagliptin and cardiovascular outcomes in patients with T2DM SAVOR-TIMI

White WB et al. N Engl J Med 2013

Alogliptin after acute coronary syndrome in patients with T2DM EXAMINE

5380 patients, median follow-up 18 months

Effect of GLP-1 receptor agonists on fatal and nonfatal major cardiovascular events (MACE)

Monami M et al. Diabetes Obes Metab 16: 38–47, 2014

Alterata omeostasi glucidica

Glucosuria

Alterata secrezione insulinica

Insulino-resistenza

Aumentata produzione di

glucosio 200 mg/dl

Glicemia a digiuno

<100 mg/dl

Riassorbimento del glucosio nel rene

SGLT2

90%

Glucose Sodium-glucose cotransporters 1 and 2 (SGLT1 e SGLT2)

10%

SGLT1

Escrezione di glucosio

Sodium glucose transportation

Escrezione renale del glucosio

600

400

200

0 0 200 400 600 800

Ve

locit

à d

i fi

ltra

zio

ne

de

l g

luco

sio

/

Ria

sso

rbim

en

to/E

scre

zio

ne

(m

g/m

in)

Glucosio plasmatico (mg/dL)

Glucosio

filtrato

Glucosio

escreto

Glucosio

Riassorbito

Soglia

Silverman M, Turner RJ. Handbook of Physiology. Windhager EE, ed. 1992; Oxford University Press: 2017-2038. (has graph for normal) Katsuno K, et al. J Pharm Exp Therap. 2007;320:323-330

Escrezione renale del glucosio con inibitori del SGLT2

600

400

200

0 0 200 400 600 800

Ve

locit

à d

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ne

de

l g

luco

sio

/

Ria

sso

rbim

en

to/E

scre

zio

ne

(m

g/m

in)

Glucosio plasmatico (mg/dL)

Glucosio

filtrato

Glucosio

escreto

Inibitori del SGLT2

Soglia

Silverman M, Turner RJ. Handbook of Physiology. Windhager EE, ed. 1992; Oxford University Press: 2017-2038. (has graph for normal) Katsuno K, et al. J Pharm Exp Therap. 2007;320:323-330

Glucosio

Riassorbito

Expected clinical effects of SGLT2 inhibition based on the mode of action

Increased Glucose Excretion

Increased Sodium Excretion

Reduced sodium load

Blood Pressure

Loss of energy (calories) Body weight

Reduced glycaemia FPG PPG HbA1c

Modified from Abdul-Ghani MA, et al. Endocr Rev. 2011; 32:515–31 SGLT2: sodium-glucose transporter 2

Chemical structure of SGLT2 inhibitors in late-stage clinical trials

Efficacy of Canagliflzoin on HbA1c in placebo-controlled studies*: Change from baseline

-0.26% -0.16% -0.21% -0.14% -0.09% -0.09% -0.13% ∆ 300 mg vs 100 mg

8.01% 7.94% 8.13% 7.9% 8.27% 8.35% 7.7% Baseline HbA1c

0,14

-0,17-0,13

-0,26

0,010,04

-0,03

-0,77-0,79

-0,85-0,89

-0,63

-0,7

-0,6

-1,03

-0,95

-1,06-1,03

-0,72

-0,79

-0,73

-1,2

-1

-0,8

-0,6

-0,4

-0,2

0

0,2

Hb

A1

c (%

)

PBO

CANA 100 mg

CANA 300 mg

P <0.05 vs PBO for both

CANA doses in all studies

*excluding the study in patients with chronic renal impairment

•DIA3005 •+ Diet/Ex

DIA3006 + MET

DIA3002 + MET/SU

DIA3012 + MET/Pio

DIA3008 + insulin

DIA3008 + SU

DIA3010 + Any

Changes from baseline in HbA1C in Phase 3 Dapagliflozin studies

Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224; Bailey CJ, et al. Lancet. 2010;375(9733):2223-2233.

-0,23

-0,59

-0,79

-0,89

-0,3

-0,68-0,7

-0,85

-0,12

-0,59

-0,65

-0,81

-0,3

-0,75

-0,82

-0,91

-1

-0,9

-0,8

-0,7

-0,6

-0,5

-0,4

-0,3

-0,2

-0,1

0

Placebo Dapa 2.5mg Dapa 5mg Dapa 10mg

Monotherapy

Add-on Met

Add-on SU

Add-on Insulin

Dapagliflozin: Weight loss after 24 weeks

• *p<0.05, **p<0.001 vs placebo CI, confidence interval; Dapa, dapagliflozin; PIO, pioglitazone; SU, sulphonylurea Bristol-Myers Squibb/AstraZeneca briefing document

Placebo-corrected mean weight reductions over 24 weeks ranged from 0.46 to 2.16 kg

ΔW

eig

ht

(kg

) w

ith

95

% C

I

Baseline

–4.5

–3.5

–2.5

–1.5

–0.5

0.5

1.5

2.5

–2.7*

–2.6*

–2.7*

–1.0

–3.3

–2.8 –3.2

–2.2

–2.2**

–3.0**

–2.9**

–0.9 –1.2

–1.6*

–2.3**

–0.7

0.1**

–0.1**

1.6

–1.0** –1.0**

–1.7**

0.0

Dapa 1.0 mg Dapa 2.5 mg Dapa 5.0 mg Dapa 10.0 mg Placebo

86.9 kg

Low-dose monotherapy

90.2 kg

Monotherapy

85. 9 kg

Add-on to metformin

81.1 kg

Add-on to SU

86.3 kg

Add-on to PIO

93.8 kg

Add-on to insulin

Percent Change in Body Weight (LOCF)*

45

LS

mean

% c

han

ge (

±S

E)

fro

m b

ase

lin

e

GLIM CANA 100 mg CANA 300 mg

0 8 12 18 26 36 44 52

Time point (wk)

Baseline (kg)

64 78 88 104

LS mean % change

–4.2% (–3.6 kg)

–4.1% (–3.6 kg)

0.9% (0.8 kg)

–5.1% (95% CI: –5.6, –4.5) (–4.3 kg) ([95% CI: –4.8, –3.8])

–5.2% (95% CI: –5.7, –4.6) (–4.4 kg) ([95% CI: –4.9, –3.9])

86.6 86.8 86.6

4

*N = 1,450 (Baseline); N = 1,425 (Week 4); N = 1,436 (Week 8); N = 1,438 (Weeks 12, 18, 26, 36, 44, 52, 64, 78, 88, and 104).

–6

–5

–4

–3

–2

–1

0

1

2

Cefalu WT et al. Poster presented at the 73rd Scientific sessions of the American Diabetes Association (ADA), 2013; Jun. 21-25; Chicago, (65-LB).

Proportion of subjects with documented hypoglycemia episodes through week 104

46

40,9

6,8 8,2

0

20

40

60

80

100

GLIM

CANA 100 mg

CANA 300 mg

Pe

rce

nta

ge

of

su

bje

cts

Rates of severe hypoglycemia were lower with CANA 100 and 300 mg relative to GLIM (0.6%, 0.2%, and 3.3%, respectively).

Cefalu WT et al. Poster presented at the 73rd Scientific sessions of the ADA, 2013; Jun. 21-25; Chicago, Illinois, (65-LB).

Efficacy of Canagliflozin on Systolic Blood Pressure: Change from Baseline-Placebo-controlled Phase 3 Studies

-3.7*

-5.4* -0.1

-2,2

-4.1†

-2.6*

-4.6*-5.4*

-6.6* -1.8

-1,6

-3.5† -4.4*

-7.9*-12,0

-10,0

-8,0

-6,0

-4,0

-2,0

0,0

2,0

4,0

6,0

8,0

* p<0.001; ** p<0.05 Based on ANCOVA models, data prior to rescue (LOCF)

127.7 BL Mean

SBP (mmHg) 128.2 136.2 130.5 127.2 137.8

-1.33 -0.95 -4.03 -0.16 1.02 -0.70 -0.24 -3.75 -0.53 -0.08 -1.11 -0.22

Pla

ce

bo

-su

btr

acte

d L

S M

ea

n C

ha

ng

e

in S

ysto

lic B

P (

mm

Hg

) (9

5%

CI)

-1.18 0.22

CANA 100 mg CANA 300 mg

131.1

Pulse rate (bpm) LS mean change

No clinically meaningful changes in pulse rate

Monotherapy (DIA3005)

N =584

Metformin (DIA3006) N = 1284

SU (DIA3008)

N = 127

Met/SU

(DIA3002) N = 469

Met/Pio

(DIA3012) N = 342

Insulin (DIA3008) N = 1718

Current Therapy in Older Subjects

(DIA3010) N = 714

Add-on combinations with

Vasilakou D et al Ann Intern Med 159: 262-274, 2013

Flow-chart per la terapia del diabete mellito di tipo 2

THANK YOU !

Now it’s time for discussion.

Sesti lecture