TERAPIA CON ANALOGHI DEL GLP-1 · 2018. 5. 2. · S.B. Solerte Università di Pavia [email protected] TERAPIA CON ANALOGHI DEL GLP-1 4.0 Protezione CV e renale Uso negli anziani

SB Solerte

Universitagrave di Pavia

brunosolerteunipvit

TERAPIA CON ANALOGHI DEL GLP-1

SB Solerte


brunosolerteunipvit


40

SB Solerte


brunosolerteunipvit


40 Protezione CV e renale

Uso negli anziani + 75 anni

Uso fino a GFR 15 mlmin

In sostituzione del BasalBolus

insulinico

Neuroprotezione

Recupero della massa magra

PREVENZIONE PRIMORDIALE

PREVENZIONE PRIMARIA

PREVENZIONE SECONDARIA

PREVENZIONE TERZIARIA Binomio

GLICEMIAINSULINA

RISCHIO ANGIOMETABOLICO SISTEMICO

Il binomio glicemiainsulina

egrave superato

helliphellipdagli anni rsquo70

ma non ce ne siamo accorti

Grimelius L Capella C Buffa R PolakJM Pearse AG Solcia E

Cytochemical and ultrastructural differentiation of enteroglucagon and pancreatic-type glucagon cells of

gastrointestinal tract

Virchows Arch Cell Pathol 20217-2281976

Ohneda A Horigome K Kay Y Habashi H Ishii S Yagamata S

Purification of canine gut glucagon-like immunoreactivity (GLI) and its insulin releasing activity

Horm Metab Res 8170-1741976





PREVENZIONE TERZIARIA

Gut Brain Pancreas

System






Gut Brain Pancreas

System PREMORBILITArsquo

COMORBILITArsquo

COMPLICANZA

Holst JJ Physiol Rev 87 1409ndash1439 2007

The physiology of Glucagon-like Peptide 1

Prohormone convertase 2


Epithelial cell regeneration

(barrier function in intestine)

Satiety

bull Satiety (15 min max 40 ndash 90 min)

bull GI transient reduction

bull Insulin secretion INSL5 colonic L-cells

upregulated by CR and in germ-free mice

orexogenic hormone hepatic glucose production

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins

confirmed Incretin and

enteroinsular

axis further

defined

HISTORY OF GLP-1-RA PREHISTORY OF GLP-1

2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

GLP-1 RECEPTOR IS EXPRESSED IN MIOCARDIOCYTES AND VASCULAR CELLS

Miocardiocytes Endocardium Endothelium + VSMC

Ban K Circulation 1172340 2008

Potential indirect cardiovascular effects of GLP-1R agonists

Ussher JR et al Circ Res 1141788-1803 2014

Endocrine 2017 Sep 11 doi 101007s12020-017-1418-y [Epub ahead of print]

TYPE 2 DIABETES AND CARDIOVASCULAR PREVENTION THE DOGMAS DISPUTED Giugliano D Maiorino M Bellastella G Esposito K

Section of Endocrinology and Diabetes Department of Medical Surgical Neurological Metabolic Sciences and

Aging L Vanvitelli University Naples Italy dariogiuglianounicampaniait


Aging L Vanvitelli University Naples Italy

The drugs used to reduce glucose levels in patients with

type 2 diabetes seem important for the ultimate

cardiovascular outcome the combination of intensive

glycemic control when safely attainable with newer

diabetes drugs (empagliflozin canagliflozin liraglutide

and semaglutide) may decrease the incidence of MACE

nephropathy and retinopathy Moreover depending on the

drug used CV mortality and heart failure may also be

reduced

Date

7

37

9

Lys

DPP-IV

His Ala Thr Thr Ser Phe Glu Gly Asp

Val

Ser

Ser Tyr Leu Glu Gly Ala Ala Gln Lys

Phe

Glu

Ile Ala Trp Leu Gly Val Gly Arg

Adapted from Vilsboslashll et al J Clin Endocrinol Metab 200388220ndash224

Healthy individuals (n=6)

Inta

ct

GL

P-1

(p

mo

ll)

500

1000

tfrac12 = 15ndash21 minutes

(iv bolus 25ndash250

nmoll)

Enzymatic cleavage

High clearance (4ndash9 lmin)

NATIVE GLP-1 HAS LIMITED CLINICAL VALUE BECAUSE OF ITS SHORT HALF-LIFE

Human ileum

GLP-1 producing

L-cells

Capillaries

Di-Peptidyl

Peptidase-IV

(DPP-IV)

His Gly Thr Thr Ser Phe Glu Gly Asp

Leu

Ser

Lys Gln Met Glu Glu Ala Val Glu Arg

Phe

Leu

Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys Lys Lys Lys Lys

bull 50 amino acid homology to human GLP-1

bull T12 27ndash43 hours

Lixisenatide1

GLP-1 glucagon-like peptide-1

1 Lyxumia Summary of Product Characteristics 2 Victoza Summary of Product Characteristics 3 Christensen et al IDrugs 200912503ndash513


bull T12 13 hours

Liraglutide23


Val

Ser


Phe

Glu


Glu

Arg

C-16

Fatty acid

7

37

9

Lys

DPP-IV

His Ala Thr Thr Ser Phe Glu Gly Asp Val

Ser


Phe

Glu


GLP1 nativo

LIRAGLUTIDE HAS MULTIPLE DIRECT EFFECTS ON HUMAN PHYSIOLOGY1

Insulin secretion (glucose-dependent) and β-cell sensitivity

Insulin synthesis

Glucagon secretion (glucose-dependent)

Pancreas2ndash4

Liver4

Hepatic glucose output

Brain56

Satiety

Energy intake

Cardiovascular system78

Systolic blood pressure

Heart rate

1 Holst JJ et al Trends Mol Med 200814161ndash168 2 Flint A et al Adv Ther 201128213ndash226 3 Degn K et al Diabetes 2004531187ndash1194 4 Baggio LL Drucker DJ Gastroenterology 20071322131‒2157 5

Horowitz M et al Diabetes Res Clin Pract 201297258‒266 6 Niswender K et al Diabetes Obes Metab 20131542‒54 7 Fonseca V et al Diabetes 201059(Suppl 1)A79 (296-OR) 8 Meier JJ et al Nat Rev

Endocrinol 20128728ndash742

Marso SP et al N Engl J Med 2016375311ndash322

Presented at ADA June 13 2016 Published in NEJM June 13 2016

Baseline characteristics (mean plusmn SD unless stated)

Heart failure includes New York Heart Association class I II and III

BMI body mass index HbA1c glycated hemoglobin SD standard deviation






ANZIANI eo FRAGILI

Chhetri JK et Al

The prevalence and incidence of frailty in pre-

diabetic and diabetic community-dwelling older

population

BMC Geriatr 17472017

20 di diabetici anziani sono fragili

Heterogeneity in health status among patients with diabetes based on data from the Health

and Retirement Study of people over age 50 People with known diabetes were assigned to

one of four mutually exclusive categories

A Very Healthy group with no comorbidities A Healthy Intermediate group with

comorbidities constrained to osteoarthritis and hypertension and with no functional

impairments A group for whom intensive diabetes management would be Difficult to

Implement andor any one of the following mild cognitive impairment poor vision two or

more minor functional due to multiple comorbidities impairments and a group with

Uncertain Benefit from intensive diabetes management due to having the poorest health

status with one or more of the following moderate-to-severe cognitive impairment two or

more major functional dependencies andor residence in a long-term nursing facility

As the Health and Retirement Study is a US population-based survey the y-axis estimates the

total number of people in the US over age 50 with diabetes in each category

JB Halter et Al

Diabetes 2014 Aug 63(8) 2578ndash2589

N Engl J Med 2016 Jul 28375(4)311-22

LIRAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES LEADER CLINICAL TRIAL Marso SP Daniels GH Brown-Frandsen K Kristensen P Mann JF Nauck MA Nissen SE Pocock S Poulter NR Ravn LS Steinberg WM Stockner M

Zinman B Bergenstal RM Buse JB LEADER Steering Committee LEADER Trial Investigators Collaborators (2255)

BACKGROUND

The cardiovascular effect of liraglutide a glucagon-like peptide 1 analogue when added to standard care in patients with type 2 diabetes

remains unknown

METHODS

In this double-blind trial we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo

The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes nonfatal myocardial

infarction or nonfatal stroke The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome

with a margin of 130 for the upper boundary of the 95 confidence interval of the hazard ratio No adjustments for multiplicity were

performed for the prespecified exploratory outcomes

RESULTS

A total of 9340 patients underwent randomization The median follow-up was 38 years The primary outcome occurred in significantly fewer

patients in the liraglutide group (608 of 4668 patients [130]) than in the placebo group (694 of 4672 [149]) (hazard ratio 087 95

confidence interval [CI] 078 to 097 Plt0001 for noninferiority P=001 for superiority) Fewer patients died from cardiovascular causes in the

liraglutide group (219 patients [47]) than in the placebo group (278 [60]) (hazard ratio 078 95 CI 066 to 093 P=0007) The rate of

death from any cause was lower in the liraglutide group (381 patients [82]) than in the placebo group (447 [96]) (hazard ratio 085 95

CI 074 to 097 P=002) The rates of nonfatal myocardial infarction nonfatal stroke and hospitalization for heart failure were nonsignificantly

lower in the liraglutide group than in the placebo group The most common adverse events leading to the discontinuation of liraglutide were

gastrointestinal events The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group

CONCLUSIONS

In the time-to-event analysis the rate of the first occurrence of death from cardiovascular causes nonfatal myocardial infarction or

nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo

(Funded by Novo Nordisk and the National Institutes of Health LEADER ClinicalTrialsgov number NCT01179048)

Severe hypoglycemia over time

Full analysis set Mean number of severe hypoglycemic episodes Number of events analyzed using a

negative binomial regression model using a log link and the logarithm of the observation time (100 years)

as offset Treatment sex region and antidiabetic therapy at baseline included as fixed effects and age at

baseline included as covariates

CI confidence interval

Presented at the American Diabetes Association 77th Scientific Sessions Session 1-AC-SY13 June 11 2017 San Diego CA USA

Primary outcome CV death non-fatal myocardial infarction or non-fatal stroke

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard

ratios with the use of the Cox proportional-hazards regression model The data analyses are truncated at

54 months because less than 10 of the patients had an observation time beyond 54 months

CI confidence interval CV cardiovascular HR hazard ratio



liraglutide liraglutide

liraglutide

liraglutide

liraglutide

Mann JFE et al N Eng J Med 2017 August 377839-848

- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470

Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on

Glycemic Control in Patients With Type 2 Diabetes A Randomized Clinical Trial

Davies M Pieber TR Hartoft-Nielsen ML Hansen OKH Jabbour S Rosenstock J

COMPLEMENTARY ACTIONS OF BASAL INSULIN AND A GLP-1 RA TARGET THE UNDERLYING PATHOPHYSIOLOGY OF TYPE 2 DIABETES

BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE

Decreased energy intake

Increased satiety

GLP-1 RA

Glucose-dependent insulin

and glucagon secretion

Insulin synthesis

GLP-1 RA

Inhibits gastric emptying GLP-1 RA

Inhibition of hepatic

glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin

Increased glucose disposal Basal insulin

Basal insulin Inhibition of hepatic

glucose production

GLP-1 RA glucagon-like peptide-1 receptor agonist

1 Baggio amp Drucker Gastroenterol 20071322131ndash57 2 Niswender Postgrad Med 201112327ndash37

LIRAGLUTIDE amp INSULINA DEGLUDEC (PRIMA DELLrsquoINIEZIONE SC)

IDegLira puograve consentire di

ottimizzare al meglio il regime insulinico basale nellrsquoanziano

Risultati dal Protocollo DUAL V

DUAL V HBA1C OVER TIME

55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00

Mean observed values with error bars (standard error mean) based on full analysis set and LOCF imputed data

Treatment difference is estimated from an ANCOVA analysis while ∆ values are observed LOCF

---ADAEASD HbA1c target lt70 AACE HbA1c target le65

AACE American Association of Clinical Endocrinologists ADA American Diabetes Association EASD European Association for the Study of Diabetes

Lingvay et al JAMA 2016315(9)898ndash907

0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)

At EOT approximately 40 of subjects

on IDegLira received the maximum 50

dose steps of which 68 achieved

HbA1c lt7

Mean insulin dose over time with error bars (95 CI) and change from baseline (delta) are based on observed values with missing data imputed by LOCF for SAS IDegLira dose

capped at 50 dose steps there was no maximum dose for IGlar

ETD was estimated from an ANCOVA analysis based on FAS

ANCOVA analysis of covariance CI confidence interval ETD estimated treatment difference EOT end of treatment FAS full analysis set HbA1c glycosylated haemoglobin

IDegLira insulin degludecliraglutide combination IGlar insulin glargine LOCF last observation carried forward SAS safety analysis set


41 U

66 U

ETD ndash2547 U

[ndash2890 ndash2205]95 CI

plt0001

DUAL V DAILY INSULIN DOSE

IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)

Mean cumulative function based on SAS

Treatment ratio is estimated from a negative binomial model based on FAS

Nocturnal was defined as the time from 0001ndash0559 (both inclusive)

FAS full analysis set IDegLira insulin degludecliraglutide IGlar insulin glargine SAS safety analysis set

Lingvay et al JAMA 2016315898ndash907

DUAL V NOCTURNAL CONFIRMED HYPOGLYCAEMIA OVER TIME

IDegLira (n=278)

IGlar (n=279) IDegLira IGlar

HbA1c at week 26 66 71


sostituire il regime insulinico basal bolus (4 iniezioni)

nellrsquoanziano

Risultati dal Protocollo DUAL VII

CHANGE IN HBA1C OVER TIME DUAL VII

55

60

65

70

75

80

85

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

67

67 HbA

1c (

)

Time (weeks) Mean observed values with error bars (standard error of the mean) based on full analysis set ETD is based on LSMeans from

full analysis set using mixed model for repeated measurement ---ADAEASD HbA1c target lt70 and AACE HbA1c target le65

AACE American Association of Clinical Endocrinologists ADA American Diabetes Association CI confidence interval EASD European

Association for the Study of Diabetes HbA1c glycated haemoglobin IAsp insulin aspart IDegLira insulin degludecliraglutide combination

ETD estimated treatment difference IGlar U100 insulin glargine 100 unitsmL LSMean least square mean

ETD

-002 [-016 012]95 CI

plt00001 for test for non-inferiority by 03

IDegLira (n=252)

IGlar U100 + IAsp (n=254)

DAILY TOTAL INSULIN DOSE OVER TIME DUAL VII

404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001

Mean observed values with error bars (standard error of the mean) based on safety analysis set ETD is based on observed data

using MMRM with treatment region and visit as factors and insulin dose at screening and baseline HbA1c as covariates

ETD estimated treatment difference CI confidence interval HbA1c glycated haemoglobin IAsp insulin aspart

IDegLira insulin degludecliraglutide combination IGlar U100 insulin glargine 100 unitsmL MMRM mixed model repeated measurement

IDegLira (n=252)


Time (weeks)

Dose (

units)

SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCAEMIA OVER TIME

DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct

Mean cumulative function based on safety analysis set Severe or BG-confirmed symptomatic an episode that is severe according to the ADA

classification or BG-confirmed by a plasma glucose value lt31 mmolL (lt56 mgdL) with symptoms consistent with hypoglycaemia

ADA American Diabetes Association BG blood glucose CI confidence interval IAsp insulin aspart IDegLira insulin degludecliraglutide

combination IGlar U100 insulin glargine 100 unitsmL

Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)


Diabetes Technol Ther 2017 19(4)255-264

A FIXED RATIO COMBINATION OF INSULIN DEGLUDEC AND LIRAGLUTIDE (IDEGLIRA) REDUCES GLYCEMIC FLUCTUATION AND

BRINGS MORE PATIENTS WITH TYPE 2 DIABETES WITHIN BLOOD GLUCOSE TARGET RANGES

KING AB1 PHILIS-TSIMIKAS A2 KILPATRICK ES3 LANGBAKKE IH4 BEGTRUP K4 VILSBOslashLL T5

BACKGROUND

Reducing glycemic fluctuation is important for optimal diabetes management This post hoc analysis examined glycemic

fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of

insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone

METHODS

We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients

with type 2 diabetes (T2D) and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess

glycemic fluctuation and day-to-day variability

RESULTS

Compared with IDeg IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (39-

90thinspmmolL) than IDeg for all pre- and postprandial values and for the full nine-point profile (Pthinspltthinsp005 for all) IDegLira also

resulted in a greater reduction in the range of SMBG values over 24thinsph than IDeg (Pthinsplethinsp00001) CGM data showed that IDegLira

provided greater reductions in interstitial glucose (IG) fluctuation (Pthinsp=thinsp00018) and postprandial IG increment (Pthinsp=thinsp00288)

compared with IDeg Compared with liraglutide IDegLira brought a higher proportion of subjects within SMBG target ranges (all

pre- and all postprandial values and the full nine-point profile Pthinspltthinsp001 for all) and resulted in a greater reduction of time outside

the IG target range (Pthinsp=thinsp00072) IDegLira also reduced mean IG more than liraglutide (Pthinspltthinsp00001)

CONCLUSIONS

Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than

either IDeg or liraglutide alone

Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078

Waist circumference (cm) - 2

Body weight (g) - 2000

Fat mass (g) - 1498

Free Fat Mass (g) + 9

SMI (Kgm2) + 003

PASE score (point) - 1164

9 pazienti studiati con DXA trattati con liraglutide 3 gdie per 24 settimane Al basale Etagrave media 6822 A1c 79 BMI 3234 PASE 9450

Aging Clin Exp Res 2016

hellip 24 weeks liraglutide in a dose up to 30 mg treatment in overweight and obese elderly patients with T2DM is safe well tolerated and facilitates the fat mass loss particularly in android fat mass

ANALOGO GLP1 LIRAGLUTIDE

effetti su

CARDIOTOSSICITArsquo

ATEROGENESI

NEUROGENERAZIONE ALZHEIMER

- 29 + 1 - 36 - 4

Obesity 2017

Diabetes 2015 Apr64(4)1395-406 doi 102337db14-1149 Epub 2014 Oct 16

SIRTUIN 6 EXPRESSION AND INFLAMMATORY ACTIVITY IN DIABETIC

ATHEROSCLEROTIC PLAQUES EFFECTS OF INCRETIN TREATMENT Balestrieri ML Rizzo MR Barbieri M Paolisso P DOnofrio N Giovane A Siniscalchi M Minicucci F Sardu C DAndrea D

Mauro C Ferraraccio F Servillo L Chirico F Caiazzo P5 Paolisso G Marfella R

Abstract

The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic

patients is unknown We evaluated SIRT6 expression and the effect

of incretin-based therapies in carotid plaques of asymptomatic diabetic

and nondiabetic patients Plaques were obtained from 52 type 2

diabetic and 30 nondiabetic patients undergoing carotid endarterectomy

Twenty-two diabetic patients were treated with drugs that work on the

incretin system GLP-1 receptor agonists and dipeptidyl peptidase-4

inhibitors for 26 plusmn 8 months before undergoing the endarterectomy

Compared with nondiabetic plaques diabetic plaques had more inflammation

and oxidative stress along with a lesser SIRT6 expression and collagen

content Compared with non-GLP-1 therapy-treated plaques GLP-1 therapy

-treated plaques presented greater SIRT6 expression and collagen content and less inflammation and oxidative stress

indicating a more stable plaque phenotype These results were supported by in vitro observations on endothelial

progenitor cells (EPCs) and endothelial cells (ECs) Indeed both EPCs and ECs treated with high glucose (25 mmolL) in

the presence of GLP-1 (100 nmolL liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression

compared with cells treated only with high glucose These findings establish the involvement of SIRT6 in the inflammatory

pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin the effect of which is

associated with morphological and compositional characteristics of a potential stable plaque phenotype

Expert Rev Neurother 2017 Jan17(1)59-75

MODULATION OF GLP-1 SIGNALING AS A NOVEL THERAPEUTIC APPROACH

IN THE TREATMENT OF ALZHEIMERS DISEASE PATHOLOGY Tramutola A Arena A Cini C Butterfield DA Barone E

Clinical studies suggest a link between peripheral insulin resistance and

cognitive dysfunction Post-mortem analyses of Alzheimer disease (AD)

subjects revealed insulin resistance in the brain suggesting a role of this

condition in cognitive deficits observed in AD In this review we focus on the

glucagon-like peptide-1 (GLP-1) signaling pathway whose role in the brain

is collecting increasing attention because of its association with insulin

signaling activation Areas covered The role of GLP-1-mediated effects in the

brain and how they are affected along the progression of AD pathology is

discussed Furthermore we provide a comprehensive discussion about the use

of GLP-1 mimetics drugs which have been developed as a treatment for T2DM

but seem to possess a number of other physiological properties including

neuroprotective and anti-inflammatory effects that may be useful to slow AD

progression Expert commentary The repurposing of antidiabetic drugs for

the modulation of brain insulin resistance in AD appears to be of great interest

The beneficial effects on synaptogenesis neurogenesis and cell repair as well

as the reduction of the chronic inflammatory response and most importantly

the reduction of amyloid plaques in the brain indicate that these drugs have

promise as novel treatments for AD

Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta

Neuronal IRIGF-1R and GLP-1R mediated

intracellular signaling transduction

pathways show several overlapping

downstream targets Activation of these

pathways may mediate several biological

responses in the central nervous system

such as control of cell metabolism and

energy homeostasis inhibition of

apoptosis reduction of inflammatory

responses modulation of synaptic

neurotransmission regulation of gene

transcription cell growth synapse growth

cell repair and regeneration facilitation of

long-term potentiation and memory

formation

World J Diabetes 2015 Jun 256(6)807-27

GUT-BRAIN CONNECTION THE NEUROPROTECTIVE EFFECTS OF THE ANTI-DIABETIC DRUG LIRAGLUTIDE

Candeias EM1 Sebastiatildeo IC1 Cardoso SM1 Correia SC1 Carvalho CI1 Plaacutecido AI1 Santos MS1 Oliveira CR1 Moreira PI1 Duarte AI1

Postgrad Med 2017 Sep129(7)686-697 doi 1010800032548120171342509 Epub 2017 Jun 28

COMBINATION SGLT2 INHIBITOR AND GLP-1 RECEPTOR AGONIST THERAPY A

COMPLEMENTARY APPROACH TO THE TREATMENT OF TYPE 2 DIABETES

Busch RS Kane MP

Albany Medical Center Division of Community Endocrinology Department of Pharmacy Practice Albany

College of Pharmacy and Health Sciences Albany NY USA

Associazione INCRETINE E GLICOSURICI

EMPAGLIFLOZIN AND LIRAGLUTIDE

CV cardiovascular HR hazard ratio MI myocardial infarction

1 Zinman B et al N Engl J Med 20153732117-2128 2 Marso SP et al N Eng J Med 2016 DOI 101056NEJMoa1603827

0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()

Time from randomisation (months)

Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)

EMPA-REG OUTCOME1 LEADER2 CV death non-fatal MI or non-fatal stroke CV death non-fatal MI or non-fatal stroke

plt0001 for non-inferiority

p=001 for superiority



SACCO RL STROKE 2007

Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk

Dalla diabetologia dellrsquoaging al paradosso di

Waterloo

Contrastare

lrsquoipoglicemia iperglicemia

SB Solerte


brunosolerteunipvit


40

SB Solerte


brunosolerteunipvit






insulinico

Neuroprotezione






GLICEMIAINSULINA



egrave superato















Gut Brain Pancreas

System






Gut Brain Pancreas


COMORBILITArsquo

COMPLICANZA







Satiety






2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d




















reduced

Date

7

37

9

Lys

DPP-IV


Val

Ser


Phe

Glu




Inta

ct

GL

P-1

(p

mo

ll)

500

1000



nmoll)

Enzymatic cleavage



Human ileum

GLP-1 producing

L-cells

Capillaries

Di-Peptidyl

Peptidase-IV

(DPP-IV)


Leu

Ser


Phe

Leu




Lixisenatide1




bull T12 13 hours

Liraglutide23


Val

Ser


Phe

Glu


Glu

Arg

C-16

Fatty acid

7

37

9

Lys

DPP-IV


Ser


Phe

Glu


GLP1 nativo



Insulin synthesis


Pancreas2ndash4

Liver4


Brain56

Satiety

Energy intake



Heart rate














ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare


SB Solerte


brunosolerteunipvit






insulinico

Neuroprotezione






GLICEMIAINSULINA



egrave superato















Gut Brain Pancreas

System






Gut Brain Pancreas


COMORBILITArsquo

COMPLICANZA







Satiety






2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d




















reduced

Date

7

37

9

Lys

DPP-IV


Val

Ser


Phe

Glu




Inta

ct

GL

P-1

(p

mo

ll)

500

1000



nmoll)

Enzymatic cleavage



Human ileum

GLP-1 producing

L-cells

Capillaries

Di-Peptidyl

Peptidase-IV

(DPP-IV)


Leu

Ser


Phe

Leu




Lixisenatide1




bull T12 13 hours

Liraglutide23


Val

Ser


Phe

Glu


Glu

Arg

C-16

Fatty acid

7

37

9

Lys

DPP-IV


Ser


Phe

Glu


GLP1 nativo



Insulin synthesis


Pancreas2ndash4

Liver4


Brain56

Satiety

Energy intake



Heart rate














ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare






GLICEMIAINSULINA



egrave superato















Gut Brain Pancreas

System






Gut Brain Pancreas


COMORBILITArsquo

COMPLICANZA







Satiety






2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d




















reduced

Date

7

37

9

Lys

DPP-IV


Val

Ser


Phe

Glu




Inta

ct

GL

P-1

(p

mo

ll)

500

1000



nmoll)

Enzymatic cleavage



Human ileum

GLP-1 producing

L-cells

Capillaries

Di-Peptidyl

Peptidase-IV

(DPP-IV)


Leu

Ser


Phe

Leu




Lixisenatide1




bull T12 13 hours

Liraglutide23


Val

Ser


Phe

Glu


Glu

Arg

C-16

Fatty acid

7

37

9

Lys

DPP-IV


Ser


Phe

Glu


GLP1 nativo



Insulin synthesis


Pancreas2ndash4

Liver4


Brain56

Satiety

Energy intake



Heart rate














ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare



egrave superato















Gut Brain Pancreas

System






Gut Brain Pancreas


COMORBILITArsquo

COMPLICANZA







Satiety






2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d




















reduced

Date

7

37

9

Lys

DPP-IV


Val

Ser


Phe

Glu




Inta

ct

GL

P-1

(p

mo

ll)

500

1000



nmoll)

Enzymatic cleavage



Human ileum

GLP-1 producing

L-cells

Capillaries

Di-Peptidyl

Peptidase-IV

(DPP-IV)


Leu

Ser


Phe

Leu




Lixisenatide1




bull T12 13 hours

Liraglutide23


Val

Ser


Phe

Glu


Glu

Arg

C-16

Fatty acid

7

37

9

Lys

DPP-IV


Ser


Phe

Glu


GLP1 nativo



Insulin synthesis


Pancreas2ndash4

Liver4


Brain56

Satiety

Energy intake



Heart rate














ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare







Gut Brain Pancreas

System






Gut Brain Pancreas


COMORBILITArsquo

COMPLICANZA







Satiety






2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d




















reduced

Date

7

37

9

Lys

DPP-IV


Val

Ser


Phe

Glu




Inta

ct

GL

P-1

(p

mo

ll)

500

1000



nmoll)

Enzymatic cleavage



Human ileum

GLP-1 producing

L-cells

Capillaries

Di-Peptidyl

Peptidase-IV

(DPP-IV)


Leu

Ser


Phe

Leu




Lixisenatide1




bull T12 13 hours

Liraglutide23


Val

Ser


Phe

Glu


Glu

Arg

C-16

Fatty acid

7

37

9

Lys

DPP-IV


Ser


Phe

Glu


GLP1 nativo



Insulin synthesis


Pancreas2ndash4

Liver4


Brain56

Satiety

Energy intake



Heart rate














ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare







Gut Brain Pancreas


COMORBILITArsquo

COMPLICANZA







Satiety






2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d




















reduced

Date

7

37

9

Lys

DPP-IV


Val

Ser


Phe

Glu




Inta

ct

GL

P-1

(p

mo

ll)

500

1000



nmoll)

Enzymatic cleavage



Human ileum

GLP-1 producing

L-cells

Capillaries

Di-Peptidyl

Peptidase-IV

(DPP-IV)


Leu

Ser


Phe

Leu




Lixisenatide1




bull T12 13 hours

Liraglutide23


Val

Ser


Phe

Glu


Glu

Arg

C-16

Fatty acid

7

37

9

Lys

DPP-IV


Ser


Phe

Glu


GLP1 nativo



Insulin synthesis


Pancreas2ndash4

Liver4


Brain56

Satiety

Energy intake



Heart rate














ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare








Satiety






2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d




















reduced

Date

7

37

9

Lys

DPP-IV


Val

Ser


Phe

Glu




Inta

ct

GL

P-1

(p

mo

ll)

500

1000



nmoll)

Enzymatic cleavage



Human ileum

GLP-1 producing

L-cells

Capillaries

Di-Peptidyl

Peptidase-IV

(DPP-IV)


Leu

Ser


Phe

Leu




Lixisenatide1




bull T12 13 hours

Liraglutide23


Val

Ser


Phe

Glu


Glu

Arg

C-16

Fatty acid

7

37

9

Lys

DPP-IV


Ser


Phe

Glu


GLP1 nativo



Insulin synthesis


Pancreas2ndash4

Liver4


Brain56

Satiety

Energy intake



Heart rate














ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare


2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d




















reduced

Date

7

37

9

Lys

DPP-IV


Val

Ser


Phe

Glu




Inta

ct

GL

P-1

(p

mo

ll)

500

1000



nmoll)

Enzymatic cleavage



Human ileum

GLP-1 producing

L-cells

Capillaries

Di-Peptidyl

Peptidase-IV

(DPP-IV)


Leu

Ser


Phe

Leu




Lixisenatide1




bull T12 13 hours

Liraglutide23


Val

Ser


Phe

Glu


Glu

Arg

C-16

Fatty acid

7

37

9

Lys

DPP-IV


Ser


Phe

Glu


GLP1 nativo



Insulin synthesis


Pancreas2ndash4

Liver4


Brain56

Satiety

Energy intake



Heart rate














ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare





















reduced

Date

7

37

9

Lys

DPP-IV


Val

Ser


Phe

Glu




Inta

ct

GL

P-1

(p

mo

ll)

500

1000



nmoll)

Enzymatic cleavage



Human ileum

GLP-1 producing

L-cells

Capillaries

Di-Peptidyl

Peptidase-IV

(DPP-IV)


Leu

Ser


Phe

Leu




Lixisenatide1




bull T12 13 hours

Liraglutide23


Val

Ser


Phe

Glu


Glu

Arg

C-16

Fatty acid

7

37

9

Lys

DPP-IV


Ser


Phe

Glu


GLP1 nativo



Insulin synthesis


Pancreas2ndash4

Liver4


Brain56

Satiety

Energy intake



Heart rate














ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare


















reduced

Date

7

37

9

Lys

DPP-IV


Val

Ser


Phe

Glu




Inta

ct

GL

P-1

(p

mo

ll)

500

1000



nmoll)

Enzymatic cleavage



Human ileum

GLP-1 producing

L-cells

Capillaries

Di-Peptidyl

Peptidase-IV

(DPP-IV)


Leu

Ser


Phe

Leu




Lixisenatide1




bull T12 13 hours

Liraglutide23


Val

Ser


Phe

Glu


Glu

Arg

C-16

Fatty acid

7

37

9

Lys

DPP-IV


Ser


Phe

Glu


GLP1 nativo



Insulin synthesis


Pancreas2ndash4

Liver4


Brain56

Satiety

Energy intake



Heart rate














ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare
















reduced

Date

7

37

9

Lys

DPP-IV


Val

Ser


Phe

Glu




Inta

ct

GL

P-1

(p

mo

ll)

500

1000



nmoll)

Enzymatic cleavage



Human ileum

GLP-1 producing

L-cells

Capillaries

Di-Peptidyl

Peptidase-IV

(DPP-IV)


Leu

Ser


Phe

Leu




Lixisenatide1




bull T12 13 hours

Liraglutide23


Val

Ser


Phe

Glu


Glu

Arg

C-16

Fatty acid

7

37

9

Lys

DPP-IV


Ser


Phe

Glu


GLP1 nativo



Insulin synthesis


Pancreas2ndash4

Liver4


Brain56

Satiety

Energy intake



Heart rate














ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare


Date

7

37

9

Lys

DPP-IV


Val

Ser


Phe

Glu




Inta

ct

GL

P-1

(p

mo

ll)

500

1000



nmoll)

Enzymatic cleavage



Human ileum

GLP-1 producing

L-cells

Capillaries

Di-Peptidyl

Peptidase-IV

(DPP-IV)


Leu

Ser


Phe

Leu




Lixisenatide1




bull T12 13 hours

Liraglutide23


Val

Ser


Phe

Glu


Glu

Arg

C-16

Fatty acid

7

37

9

Lys

DPP-IV


Ser


Phe

Glu


GLP1 nativo



Insulin synthesis


Pancreas2ndash4

Liver4


Brain56

Satiety

Energy intake



Heart rate














ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare


7

37

9

Lys

DPP-IV


Val

Ser


Phe

Glu




Inta

ct

GL

P-1

(p

mo

ll)

500

1000



nmoll)

Enzymatic cleavage



Human ileum

GLP-1 producing

L-cells

Capillaries

Di-Peptidyl

Peptidase-IV

(DPP-IV)


Leu

Ser


Phe

Leu




Lixisenatide1




bull T12 13 hours

Liraglutide23


Val

Ser


Phe

Glu


Glu

Arg

C-16

Fatty acid

7

37

9

Lys

DPP-IV


Ser


Phe

Glu


GLP1 nativo



Insulin synthesis


Pancreas2ndash4

Liver4


Brain56

Satiety

Energy intake



Heart rate














ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare



Leu

Ser


Phe

Leu




Lixisenatide1




bull T12 13 hours

Liraglutide23


Val

Ser


Phe

Glu


Glu

Arg

C-16

Fatty acid

7

37

9

Lys

DPP-IV


Ser


Phe

Glu


GLP1 nativo



Insulin synthesis


Pancreas2ndash4

Liver4


Brain56

Satiety

Energy intake



Heart rate














ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare




Insulin synthesis


Pancreas2ndash4

Liver4


Brain56

Satiety

Energy intake



Heart rate














ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare












ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare










ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare






ANZIANI eo FRAGILI

Chhetri JK et Al



population
















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare















JB Halter et Al


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare


N Engl J Med 2016 Jul 28375(4)311-22



BACKGROUND


remains unknown

METHODS






RESULTS









CONCLUSIONS



















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare

















liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare










liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare




liraglutide

liraglutide

liraglutide


- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare



- 22 - 26


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare



JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare


JAMA 2017 Oct 17318(15)1460-1470





BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare



BRAIN

PANCREAS

GI TRACT

LIVER

ADIPOSE TISSUE

SKELETAL MUSCLE


Increased satiety

GLP-1 RA



Insulin synthesis

GLP-1 RA



glucose production

GLP-1 RA

Insulin receptor

activation

Basal insulin



glucose production








55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare







55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare






55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare



55

60

65

70

75

80

85

90

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

71

66 HbA

1c (

)

Time (weeks)

IDegLira (n=278)

IGlar (n=279)

EOT

Treatment

difference

ndash059

plt0001

∆HbA1C

ndash181

ndash113

00






0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare


0

10

20

30

40

50

60

70

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

Time (weeks)

Dose (

units)




HbA1c lt7







41 U

66 U

ETD ndash2547 U


plt0001


IDegLira (n=278)

IGlar (n=279)

00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare


00

01

02

03

04

05

06

07

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

Treatment ratio 017

plt0001

Num

ber

of epis

odes p

er

subje

ct

Time (weeks)







IDegLira (n=278)





nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare




nellrsquoanziano



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare



55

60

65

70

75

80

85

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

67

67 HbA

1c (

)






ETD

-002 [-016 012]95 CI


IDegLira (n=252)



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare



404 units

841 units

0

20

40

60

80

100

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

ETD

-4450 units

[-4830 -4071]95 CI

plt00001





IDegLira (n=252)


Time (weeks)

Dose (

units)


DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare



DUAL VII

00

05

10

15

20

25

30

35

40

45

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

Num

ber

of

epis

odes

per

subje

ct





Treatment ratio

011

[008 017]95CI

plt00001

Time (weeks)

IDegLira (n=252)






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare






BACKGROUND




METHODS




RESULTS








CONCLUSIONS



Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare


Variabile Mediana

A1c () - 08

BMI (Kgm2) - 078



Fat mass (g) - 1498


SMI (Kgm2) + 003






effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare



effetti su


ATEROGENESI


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare


- 29 + 1 - 36 - 4

Obesity 2017





Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare






Abstract








































Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare























Aumento neurogenesi

Ridotta insulino

resistenza

Ridotta

Neuroinfiammazione

Decremento placche

Abeta















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare
















formation







Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare





Busch RS Kane MP







0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare





0 6 12 18 30 24 42 36 48

20

10

5

0

15

Pa

tie

nts

wit

h a

n e

ve

nt

()


Placebo

Empagliflozin

Patients at risk

Empagliflozin

Placebo

4687

2333

4455

2194

4328

2112

3851

1875

2821

1380

2359

1161

1534

741

370

166

4580

2256

HR 086

9502 CI (074 ndash 099)

Pa

tie

nts

wit

h a

n e

ve

nt

()

Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

Placebo

Liraglutide

HR 087

95 CI (078 ndash 097)







Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare



Strategic Group

2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare


2000 1960

lsquoEnteroinsular

axisrsquo named

Incretin

defined

Discovered as

proglucagon

gene product

Receptor

cloned

1930 1980 1970 1990

Normalisation

of BG in type 2

diabetes

GLP1 mimetics and

analogues

(exenatide

liraglutide)

Insulinotropic

action of

incretins


enteroinsular

axis further

defined


2010

Prevention of

CV risk and

death in type 2

diabetes

Liraglutid

e

LEADER

2020 2030

PubMe

d

Semaglutid

eSUSTAIN

Primary

prevention of

type 2 diabetes

and CV global risk


Waterloo

Contrastare



Waterloo

Contrastare


Documents

TERAPIA CON ANALOGHI DEL GLP-1 · 2018. 5. 2. · S.B. Solerte Università di Pavia [email protected] TERAPIA CON ANALOGHI DEL GLP-1 4.0 Protezione CV e renale Uso negli anziani