Innovazione Terapeutica - SIE · Obiettivi di riduzione del peso. Mantenimento della perdita di...

UNIVERSITÀ DI ROMA

“TOR VERGATA”Dipartimento di Medicina dei Sistemi

UOC di Medicina Interna

Centro per la Cura dell’Obesità

Policlinico Tor Vergata

FONDAZIONEFONDAZIONE

Innovazione Terapeutica

nell’Obesità

PAOLO SBRACCIA

Obiettivi di riduzione del peso. Mantenimento della perdita di peso. Contro-risposte fisiologiche al calo ponderale. Controllo ipotalamico del bilancio energetico,

regolazione omeostatica e ed edonicadell’appetito.

Determinanti dell’obesità. Nuovi farmaci disponibili sul mercato. Innovazione farmacologica futura. L’obesità è una malattia cronica che richiede un

trattamento cronico.

INDICE

Natural historyof body weight

< 5 % weight lossMay reduce risk(Unsatisfactory)

Stable weight(Population Goal)

> 15 % weight losswith significnt riskreduction(Excellent)

Weightnormalization(Ideal but rare)

Bray G & Greenway F, Endo Rev, 1999

Years of Observation

20

Normal

>25

>30

Obese

BMI

Weight Loss Maintenance

Face-to-face

or web-basedIntervention

Diet

PhysicalActivity

Drugs

EducationalGroups

BariatricSurgery

WHAT MULTIDISCIPLINARY MEANS?

Cognitive Behavioural

Therapy

Mann et al. Am Psychol 2007

Weig

ht

chan

ge (

kg)

Anderson et al.

Fosteret al.

Graham et al.

Hensrudet al.

Jordanet al.

Krameret al.

Lantzet al.

Murphyet al.

Stalonaset al.

Waddenet al.

Walsh &Flynn

Wadden & Frey

Pekkarinen & Mustajoki

Stunkard & Penik

Mean change from baseline to end of diet (kg)

MAINTENANCE OF WEIGHT LOSS IS CHALLENGINGDiets Are Not the Answer?

Follow up range from 4 to 7 years

Mean change from baseline to follow-up (kg)

-30

-25

-20

-15

-10

-5

0

5

Knowler et al. Lancet 2009;374:1677–86

10-YEAR FOLLOW-UP OF DIABETES INCIDENCE AND WEIGHT LOSS IN THE DPP OUTCOMES STUDY

DietPhysicalActivity

EducationalGroups


Therapy

CV EFFECTS OF INTENSIVE LIFESTYLE INTERVENTION IN T2DTHE LOOK AHEAD STUDY

The Look AHEAD Research Group, New Engl J Med, 2013

DietPhysicalActivity

EducationalGroups


Therapy

WHAT IS THE DEFINITION OF WEIGHT LOSS MAINTENANCE?

Lifelong weight reduction!

Sjöström L, New Engl J Med 2004

Hunger Desire to

eat

Pancreas

Resting energy expenditure

Energy intake

Schwartz et al. Obes Rev 2010. Sumithran et al. N Engl J Med 2011

PHYSIOLOGICAL RESPONSES TO WEIGHT LOSS FAVOR WEIGHT REGAIN

GLP-1, CCK, PYY, GhrelinGut

Adipose tissue

Leptin

InsulinPancreas

Hypothalamic control of energy homeostasis

• AgRP, agouti-related peptide; CART, cocaine- and amphetamine-regulated transcript; LHA, lateral hypothalamic area; MC4R, melanocortin-4 receptor;α-MSH, α-melanocyte-stimulating hormone; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; PVN, paraventricular nucleus

• Adapted from: Badman MK and Flier JS. Science 2005;307:1909–1914; Seo S et al. Endocr J 2008;55:867–874

Arcuate

POMC-MSHCART

PVN

Energy intake Energy expenditure

Adipose tissueMC4R

Peripheral signals

NPY/AgRP LHA

Energy intake Energy expenditure

Adipose tissue

Homeostatic regulation of appetite

• α-MSH, α-melanocyte stimulating hormone; AgRP, Agouti-related peptide; CART, cocaine- and amphetamine-regulated transcript; GLP-1, glucagon-like peptide-1; MC3/4R, melanocortin 3/4 receptor; NPY, neuropeptide Y; OXM, oxyntomodulin; POMC, pro-opiomelanocortin; PP, pancreatic polypeptide; PYY, peptide YY; Y1/Y5R, Y1/Y5 receptor

• Adapted from: Badman et al. Science 2005;307:1909–14; Seo et al. Endocr J 2008;55:867–74; Secher et al. J Clin Invest 2014;124:4473–88

Effectors

Hypothalamus

FeedingGastric emptyingMetabolic rate

Brainstem regions

Nucleus

tractus

solitarius

HungerSatietySecond-order neurons

MC3/4R Y1/Y5RAgRP

α-MSH

Arcuate nucleus First-order neurons

NPY/

AgRP

POMC/

CART

AppetiteAppetite

Area

postrema

Satiety peptides

Amylin GLP-1Vagal afferents

Satiety peptidesPYY GLP-1

PP OXM

Adiposity signalsLeptin Insulin

Hunger signalGhrelin

Homeostatic and hedonic

• Yu YH et al. Obes Rev 2015;16:234–247; Sorenson LB et al. Int J Obes Relat Metab Disord 2003;27:1152–1166

• Palatability

• Taste

• Texture

• Smell

• Genetics

• Epigenetics

Social factors Reward/pleasure

Food cuesEmotion

Homeostatic

signals

Obesity is a complex disease: Drivers of obesity

BMI, body mass index1. Sharma AM et al. Obes Rev 2010;11:362–370; 2. Chesi A et al. Trends Endocrinol Metab 2015;26:711–721

• Central nervous system pathways

– Hunger and reward

• Neuroendocrine signals– Long-term

– Short-term

• High heritability of body weight, especially at BMI extremes

• Genes in hypothalamus leptin-melanocortin pathway

• Single genetic mutations leading to obesity are rare, but variations in many genes may predispose to obesity

• Socio-cultural factors– Traditions, belief systems,

peer pressure

• Socio-economic factors– Education level

– Affordability of healthy food

• Food environment– Availability of inexpensive,

highly palatable food with high fat, sugar and salt content

MISMATCH EVOLUZIONISTICO

Daniel E. Lieberman, The story of the human body. Evolution, Health and Diseases, Pantheon Book, New York, 2013

2 yr re-randomisation trial shows need for continued drug use

Placebo Rim 20mg/Placebo Rim 20mg/20mg

Baseline mean (SD) 103.7 (21.1) Kg

- 7.9 kg

- 2.8 kg

0 8 16 24 32 40 48 56 64 72 80 88 96 104 LOCF

Weeks

-10

-8

-6

-4

-2

0

Wei

ght

chan

ge (

Kg)

(Mean ± SEM)

X. Pi-Sunyer, Circulation 2005:111(13);1727

- 2.8 kg

Wadden et al. N Engl J Med 2005

PHARMACOTHERAPY IN ADDITION TO DIET AND EXERCISE CAN HELP PATIENTS ACHIEVE CLINICALLY

RELEVANT WEIGHT LOSS

Lifestyle modification aloneSibutramine alone

Combined therapy

Sibutramine+ brief lifestyle modification

0

2

4

6

8

10

12

16

14

Weig

ht

loss (

kg)

Weeks0 3 6 10 18 40 52

+ Drugs

1. Obesity Drug Outcome Measures: A Consensus Report of Considerations Regarding Pharmacologic Intervention. Available at: http://sphhs.gwu.edu/pdf/releases/obesitydrugmeasures.pdf; 2. Jensen et al. Circulation 2014;129(25 Suppl 2):S102–38; 3. Courcoulas et al. JAMA 2013;310:2416–25; 4. LABS consortium. N Engl J Med 2009;361:445–54

Treatment options for people with obesity

Lifestyle modification

Gastric band

Gastric bypass

Pharmacotherapy plus lifestyle modification

0% 3% 8% 32%16%

Percent weight loss

“A treatment gap exists for those patients who do not respond sufficiently to behavioural and lifestyleinterventions and who are not viable candidates for, or do not wish to undergo, bariatric surgery. Such patientsneed additional options for treatment. Used appropriately, effective prescription drugs could potentially help fillthat gap”1.

FDA Drugs: http://www.fda.gov/Drugs/default.htm; EMA Medicines: http://www.ema.europa.eu/

Orlistat(Xenical®/Alli®)

PhenterminePhentermine/ Topiramate

(Qsymia®)

Lorcaserin(Belviq®)

Naltrexone / bupropion

(Mysimba®, Contrave®)

Liraglutide3.0 mg

(Saxenda®)

Status (EU)Approved

(Rx and OTC)Not approved Rejected Rejected Approved Approved

Status (US)Approved

(Rx and OTC)

Only approved for short term

useApproved Approved Approved Approved

Mechanismof action

Lipase inhibitor

Noradrenaline and dopamine/

serotoninreuptake inhibitor

Noradrenaline and dopamine/

serotoninreuptake inhibitor

Selective 5HT2c receptor

agonist

Noradrenaline and dopamine

reuptake inhibitor/µ-

opioid receptor antagonist

GLP-1 receptoragonist

Indications

Adjunct to diet for obesity, including weight loss and maintenance

Adjunct to diet and physical activity for chronic weight management in a) obese BMI≥30 and b) overweight BMI≥27 with comorbidity

A limited number of pharmacological treatment options are currently available

Naltrexone – Bupropione

EFFECT OF NALTREXONE PLUS BUPROPION ON WEIGHT LOSS IN OVERWEIGHT AND OBESE ADULTS

(COR-I TRIAL)

Greenway et al, Lancet 2010

%

Effect of Naltrexone-Bupropion on Major AdverseCardiovascular Events in Overweight and Obese Patients

With Cardiovascular Risk Factors

Nissen et al, JAMA 2016

Effect of Naltrexone-Bupropion on Major AdverseCardiovascular Events in Overweight and Obese Patients

With Cardiovascular Risk Factors

Nissen et al, JAMA 2016

COMMON ADVERSE REACTIONS REPORTED WITH NALTREXONE/BUPROPION

Adverse ReactionNB

N=2545PlaceboN=1515

Nausea 32.5 6.7

Constipation 19.2 7.2

Headache 17.6 10.4

Vomiting 10.7 2.9

Dizziness 9.9 3.4

Insomnia 9.2 5.9

Dry mouth 8.1 2.3

Diarrhea 7.1 5.2

*Adverse events occurring in greater than 5% of patients are shownData from Integrated Primary Data Set. Source: US Package Insert for CONTRAVE.

CONTROINDICAZIONI

• History of bipolar disorder.• Uncontrolled hypertension.• Seizure disorders.• Anorexia nervosa or bulimia.• Drug or alcohol withdrawal.• MAO inhibitors.• Current dependency on chronic opioids or opiate

agonists, or opiate withdrawal.

DOSAGGIO1 cp: Naltrexone SR/Bupropion SR, 8 mg/90 mg

Liraglutide

ArcuateNucleus

POMC/CART

NPY/AgRP

NPY/AgRPHunger

POMC/CARTSatiety

Liraglutide

Secher A, et al. J Clin Invest 2014;124:4473-88

AgRP, Agouti-related protein

CART, cocaine and amphetamine-regulated transcript

NPY, Neuropeptide Y

POMC, pro-opiomelanocortin

+ -

LIRAGLUTIDE EFFECTS ON HYPOTHALAMIC NEURONS INVOLVED IN APPETITE REGULATION

THE ARCUATE NUCLEUS MEDIATES GLP-1 RECEPTOR AGONIST LIRAGLUTIDE-DEPENDENT WEIGHT LOSS

Secher et al, J Clin Invest, 2014

Normal mice

GLP-1R -/- mice

Fluorescently labeledliraglutide in the mouse brain

GLP-1 caused membrane depolarization and increased firing rate of spontaneous action potentials in POMC/CART cells

• GLP-1R expression

– Absent on NPY/AgRP

– Present on POMC/CART

Liraglutide is not approved for weight management outside Canada, EU and US

*P<0.05 compared with saline treatment, same genotype unless otherwise indicated

Adapted from: Sisley et al. J Clin Invest 2014;124:2456–63

Body w

eig

ht

change (

%)

5

0

-5

-10

Saline Liraglutide

* *

Brain GLP-1 receptors mediate the body weight lowering effect of liraglutide

Peripheral nervous system GLP-1R-/-

Brain GLP-1R-/-

Control


GLP-1 mediated regulation of GABAergic effects on POMC neurons

IPSC frequency (%) from voltage clamp recordings of POMC neurons showed an increased GABAergic IPSC frequency in the presence of GLP-1(7-36)amide. GLP-1, glucagon-like peptide-1; IPSC, inhibitory postsynaptic current; POMC, pro-opiomelanocortin; GABAergic, gamma-aminobutyric acid-ergic; GLP-1(7-36)amide, glucagon-like peptide-1(7-36)amide

10007505002500-250

100

200

300

400

Time (s)

Norm

alised I

PSC

frequency (

%)

Secher et al. J Clin Invest 2014;124:4473–88

GABA

Arcuate nucleus

GLP-1R

NPY POMC

+

?

GLP-1R ?

+

+

–

Liraglutide Modulates Appetite and Body Weight ThroughGlucagon-Like Peptide 1 Receptor–Expressing

Glutamatergic Neurons

Adams et al, Diabetes, 2018

Saline-Lira Saline-Lira Saline-Lira

(GABAERGIC) (GLUTAMATERGIC)

Hedonic Regulation of Appetite is Another Important Aspect of Food Intake

Billes SK, et al Pharmacol Res 2014;84:1–11

Prefrontal cortex

AmyAmigdala

V ralTVentral Tegmental Area

Hypothalamus (homeostatic regulation))

Substantia Nigra

Nucleus Accumbens

Striatum

Am gdala

The y-axis represents effect size of the activation (z scores). Blood oxygen level-dependent contrasts are superimposed on a T1 structural image inneurological orientation. The colour bar represents voxel T value

Farr et al. Diabetologia 2016;59:954-65

Liraglutide 1.8 mg decreased activation of the: Parietal cortex in response to highly desirable food images

Insula and putamen, areas involved in the reward system

0.5

0.3

0.1

-0.1

-0.3

-0.5

Left

insula

0.5

0.3

0.1

-0.1

-0.3

-0.7

Puta

men

-0.5

Liraglutide 1.8 mg

Placebo

Liraglutide 3.0 mgn=212

Placebon=210

SCALE Maintenance (1923) 3


Placebon=179

SCALE Sleep Apnea (3970) 4

SCALE Obesity and Prediabetes (1839) 1


Placebon=212

Liraglutide 1.8 mg n=211

SCALE Diabetes (1922) 2

Liraglutide 3.0 mg n=2487

Placebo n=1244

Weight management in type 2 diabetes

Weight management & delayed onset of diabetes

Prevention ofweight regain

Effect of liraglutide in subjects with obesity and moderate to severe OSA

SCALE Phase 3a Clinical Trial ProgramSCALE, Satiety and Clinical Adiposity Liraglutide Evidence in non-diabetic and diabetic individuals

OSA, Obstructive Sleep Apnea

1. Pi-Sunyer X, et al. NEJM 2015;373:11-22; 2. Davies MJ, et al. JAMA 2015;314:687-99; 3. Wadden TA, et al. Int J Obes 2013;37:1443-51, 4. Blackman A, et al. Int J Obes 2016;40:1310-9

Baseline Characteristics of the Patients

Pi-Sunyer et al. , New Engl J Med, 2015

SCALE Obesity and Prediabetes

61.2% had prediabetes

Inclusion criteria:• BMI: ≥30 kg/m2, or

≥27 kg/m2 + comorbidities*

• Stable body weight, and preceding failed dietary effort

0.6 mg

1.2 mg

1.8 mg

2.4 mg

Trial design

16040–2Week

Screening

Liraglutide 3.0 mg/day

Placebo

Randomisation2:1 (lira:pbo)

Dose escalation

56

EOS

68


Placebo


Placebo

Withoutprediabetes

With Prediabetes

0.6 mg

1.2 mg

1.8 mg

2.4 mgObservational

follow-up

172

Re-randomisation1:1 EOS**

*Treated or untreated hypertension or dyslipidaemia according to ATP-III; **Treatment ends at week 68 for the population without prediabetes and is followed by an off-treatment follow-up period of 2 weeks. EOS end of study; EOT, end of treatment. NN8022-1839 3yr data. ClinicalTrials.gov Identifier: NCT01272219. Pi-Sunyer et al. NEJM 2015;373:11–22

All arms included lifestyle intervention: −500 kcal/day hypocaloric diet + 150 min./week increased physical activity

Obs. follow-

up

70

EOT

http://www.clinicaltrials.gov/ct2/show/NCT01272219?term=NN8022-1839&rank=1


Mean weight loss (%) from baseline to week 56Change in w

eig

ht

(%)

Week

-12

-10

-8

-6

-4

-2

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

FAS, fasting visit data only. Line graphs are observed means (±SE). Circles are observed means LOCF. Statistical analysis is ANCOVA. FAS, full analysis set; LOCF, last observation carried forward; SE, standard error.

-8.0%

-2.6%

p<0.0001


Liraglutide 3.0 mgObserved mean LOCF

PlaceboObserved mean LOCF



Cumulative distribution of changes in body weight after 56 weeks of treatment

Weight change (%)

Liraglutide 3.0 mg Placebo

0

20

40

60

80

100

-45 -40 -35 -30 -25 -20 -15 -10 -5 0 5 10 15 20

63%

33%

14%

92%

100

80

60

40

20

0

65%

27%

11%

4%

Pro

po

rti

on

of

ind

ivid

uals

(%

)

Pi-Sunyer X, et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. NEJM 2015;373:11-22

Inclusion criteria:• BMI: ≥30 kg/m2, or

≥27 kg/m2 + comorbidities*

• Stable body weight, and preceding failed dietary effort

Trial design

16040–2Week

Screening

Placebo

Randomisation2:1 (lira:pbo)

Dose escalation

56

EOS

68


With Prediabetes

0.6 mg

1.2 mg

1.8 mg

2.4 mgObservational

follow-up

172

Re-randomisation1:1 EOS**

All arms included lifestyle intervention: −500 kcal/day hypocaloric diet + 150 min./week increased physical activity

70

EOT

le Roux CW et al. Lancet 2017 (Published Online 22 February 2017). DOI: http://dx.doi.org/10.1016/S0140-6736(17)30069–7.

Liraglutide 3.0 mg: WL and progression to T2DSCALE Obesity and Prediabetes: 3 years

-12

-10

-8

-6

-4

-2

0

0 16 28 40 56 68 80 92 104 116 128 140 152 160 172

Liraglutide 3.0 mg: WL and progression to T2DSCALE Obesity and Prediabetes: 3 years

le Roux CW et al. Lancet 2017 (Published Online 22 February 2017). DOI: http://dx.doi.org/10.1016/S0140-6736(17)30069–7.

Full analysis set, fasting-visit data only. Line graphs are observed means (±SE).

-2.1%

-5.2%

Change in w

eig

ht

(%)

Off-drug follow-up Off-drug follow-up


Week

-7.1%

-2.7%

0

2

4

6

8

10

12

0 16 32 48 64 80 96 112 128 144 160

Part

icip

ants

(%

)

80% risk reduction47

31

172

46

26

*Derived from the primary Weibull analysis. ETD, estimated treatment difference; LOCF, last observation carried forward; SCALE, Satiety and Clinical Adiposity –Liraglutide Evidence in individuals with and without diabetes; SE, standard error; T2D, type 2 diabetes; WL, weight loss.

Week

Full analysis set. Numbers in the figure correspond to the accumulated number of diagnosed participants.

-9.2%

-3.5%


Adverse events reported in ≥5% of participants0–56 weeks

Liraglutide 3.0 mg%

Placebo%

20.0 8.7

9.5 3.1

Constipation

Dyspepsia

40.2 14.7Nausea

10.8 3.1Decreased appetite16.3 4.1Vomiting

20.9 9.3Diarrhoea

5.2 3.55.7 3.5

Abdominal painAbdominal pain upper

% of subjects

0 10 20 30 40 50

17.2 18.8Nasopharyngitis8.6 9.8Upper respiratory tract infection

5.2 5.95.8 5.3

SinusitisInfluenza

13.2 12.4Headache

6.7 4.87.5 5.2

DizzinessFatigue

11.9 3.3Hypoglycaemia

5.0 5.75.7 7.56.9 8.5

ArthralgiaInjection site haematomaBack pain


Safety analysis set



• Safety profile was generally consistent with that of previous clinical trials with liraglutide 3.0 mg1,2 and liraglutide 1.8 mg in individuals with T2D3

• Liraglutide 3.0 mg was generally well tolerated; nausea, diarrhoea and constipation were the most commonly reported adverse events

• Incidence of gallbladder disorders and acute pancreatitis was low, but more frequent with liraglutide 3.0 mg:

• Gallbladder disorders: 2.5 vs. 1.0 events/100 PYE (n=54 vs. 9)*

• Acute pancreatitis: 0.3 vs. 0.1 events/100 PYE (n=7 vs. 1)†

• Acute pancreatitis: no consistent mode of presentation or latency period, majority mild according to revised Atlanta criteria

Overall summary and conclusions (2/2)SCALE Obesity and Prediabetes



• Gallbladder-related adverse events and events of confirmed acute pancreatitis were low, but more frequent with liraglutide 3.0 mg vs. placebo

Gallbladder and pancreatic safety

PYO, patient years of observation

le Roux et al. Obesity Week 2015, 2–6 November 2015, Poster T-P-LB-3843


2.9

0.29

1.2

0.13

0

1

2

3

4

5

Gallbladder-related events Acute pancreatitis events

Events

per

100 P

YO

0,0

0,5

1,0

1,5

2,0

2,5

3,0

1. Novo Nordisk Briefing Document: Liraglutide 3.0 mg for weight management NDA 206-321; 2. FDA Endocrinologic and Metabolic Drugs Advisory Committee Meeting September 11, 2014

Data are from the NN8022-1839, -1922, -3970, -1923, -1807 and -1807-ext-1 trials. Full analysis set; last observation carried forward at end of trial; mean*Events of cholecystitis and cholecystitis acute, grouped as cholecystitis%, percentages based on total n; n, number of participants; WG, weight gain; WL, weight loss

• The incidence is higher in liraglutide 3.0 mg vs placebo at any given weight-loss category1,2

• Weight-loss independent factors in addition to weight loss per se with liraglutide involved1,2

Gallbladder-related events across weight-loss categories

Cholelithiasis

Liraglutide 3.0 mgPlacebo

n=

WG 0–4.9 5–9.9 ≥10

WL (%)

291 1020 958 1031 665 763 297 165

WG 0–4.9 5–9.9 ≥10

WL (%)

Pro

port

ion o

f part

icip

ants

(%

)

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0

0 .0

0 .1

0 .2

0 .3

0 .4

0 .5

0 .6

Time to acute pancreatitis in the LEADER trial

Steinberg et al. Diabetes Care 2017;40:966–972

Full analysis set. Kaplan–Meier plot of time to first EAC-confirmed acute pancreatitis index event. Hazard ratio calculated using Cox analysisCI, confidence interval; EAC, event adjudication committee; HR, hazard ratio; NS, non-significant

Pati

en

ts w

ith

an

even

t (%

)

Subjects at risk

Liraglutide 4668 4641 4596 4554 4496 4434 4369 4309 1719 483 10

Placebo 4672 4644 4595 4537 4471 4394 4321 4250 1699 464 15

Placebo

Liraglutide 1.8 mg

HR: 0.78(95% CI: 0.42 ; 1.44); p=NS

Time since randomisation (months)

Liraglutide 1.8 mg is not approved for weight management


Early responders, individuals who achieved ≥5% weight loss from baseline at 16 weeks; early non-responders, individuals who achieved <5% weight loss from baseline at 16 weeks.Week 56 completers, FAS, fasting visit data only. Line graphs are observed means (±95% CI). CI, confidence interval; FAS, full analysis set

Week

Change in w

eig

ht

(%)

-12

-10

-8

-6

-4

-2

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

−11.5%

−3.8%

−3.6%

−9.3%

Early non-responders


Early responders

SCALE Diabetes

Blüher et al. IDF 2015. 30 November–4 December 2015, Vancouver, Canada. Poster 0208-P.

Change in body weight for early responders and non-respondersBaseline to week 56

5% stopping rule

47

31

0

2

4

6

8

10

12

0 16 32 48 64 80 96 112 128 144 160

le Roux et al. Lancet 2017;389:1399–1409

Full analysis set. Numbers in the figure correspond to the accumulated number of diagnosed participantsT2D, type 2 diabetes

Time course for incident T2DSCALE Obesity and Prediabetes – Kaplan–Meier plot: 0–160 weeks

504

205

Week160

1472 1313 1204 1135 1060 977 910 830 799863738 636 569 523 468 422 376 328 310350

n=

n=776

296

172

46

26


Part

icip

ants

(%

)

Placebo: 11%Liraglutide 3.0 mg: 3%

3-year data from SCALE Obesity and Prediabetes are only included in the labels in the EU, US and Canada

LEADER: MACE analysis – primary outcomeCV death, non-fatal myocardial infarction or non-fatal stroke

Marso et al. N Engl J Med 2016;375:311–322

The primary composite outcome in the time-to-event analysis was the first occurrence of death from CV causes, non-fatal myocardial infarction or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard 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; MACE, major adverse cardiovascular events

0 6 18 24 30 36 42 48 540

5

10

15

20

12

HR: 0.87(95% CI: 0.78 ; 0.97)

p<0.001 for non-inferiorityp=0.01 for superiority

Time from randomisation (months)

Liraglutide 1.8 mgPlacebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

Patients at riskLiraglutide

Placebo

Patients

with a

n e

vent

(%)

Liraglutide 1.8 mg is not approved for weight management


30

35

40

45

50

55

-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

Change in AHI (events/h)0–32 weeks

AH

I (e

vents

/h)

Week

FAS. Line graphs are observed means (±SE). Circles are observed means LOCF. Statistical analysis is ANCOVA. AHI, apnoea–hypopnoea index, FAS, full analysis set; LOCF, last observation carried forward; SE, standard error

36.8

44.0

p=0.0150

Blackman et al., Int J Obes, 2016

LOCF week 32

Liraglutide 3.0 mg

Placebo

LOCF week 32

SCALE Sleep Apnoea

Liraglutide safety and efficacy in patients with NASH (LEAN):

a multicentre, double-blind, randomizedplacebo-controlled phase 2 study

Armstrong MJ et al., Lancet, 2015

ALT GT

Nine (39%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of defi nite non-alcoholicsteatohepatitis compared with two (9%) of 22 such patients in the placebogroup (relative risk 4∙3 [95% CI 1∙0–17∙7]; p=0∙019).

PIPELINES

Velneperit: Neuropeptide Y5 receptor inhibitor, appetite suppression, Phase II

Successful proof-of-concept study butdiscontinued from development after little weight loss.

Other drugs in development stages:

central hypothalamic pathways (e.g. RM-493, amelanocortin type 4 receptor agonist – Setmelanotide-, Tesofensine)

peripheral metabolism (e.g. Beloranib, increases fatoxidation), Phase III trial aborted in December 2015 after 2ndreported patient death in Prader-Willi trial.

inhibitors of intestinal fat absorbtion: Cetilistat

PEPTIDI MULTIFUNZIONALI

Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised,

placebo-controlled and active comparator-controlled phase 2 trial

Frias et al, Lancet, 2018

Efficacy and safety of semaglutide compared with liraglutide for weight loss in patients with obesity

O’Neil et al, Lancet, 2018

1. Obesity Drug Outcome Measures: A Consensus Report of Considerations Regarding Pharmacologic Intervention. Available at: http://sphhs.gwu.edu/pdf/releases/obesitydrugmeasures.pdf; 2. Jensen et al. Circulation 2014;129(25 Suppl 2):S102–38; 3. Courcoulas et al. JAMA 2013;310:2416–25; 4. LABS consortium. N Engl J Med 2009;361:445–54

Treatment options for people with obesity

Lifestyle modification

Gastric band

Gastric bypass

Pharmacotherapy plus lifestyle modification

0% 3% 8% 32%16%

Percent weight loss

“A treatment gap exists for those patients who do not respond sufficiently to behavioural and lifestyleinterventions and who are not viable candidates for, or do not wish to undergo, bariatric surgery. Such patientsneed additional options for treatment. Used appropriately, effective prescription drugs could potentially help fillthat gap”1.

Natural historyof body weight

< 5 % weight lossMay reduce risk(Unsatisfactory)

Stable weight(Population Goal)

> 15 % weight losswith significnt riskreduction(Excellent)

Weightnormalization(Ideal but rare)

Bray G & Greenway F, Endo Rev, 1999

Years of Observation

20

Normal

>25

>30

Obese

BMI

Weightnormalization

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