PACE-CME - How to apply novel outcome data with GLP-1 ......2018/06/25 · Type 2 diabetes and recent ACS n=6,068 Treatment Lixisenatide Placebo Follow-up: 25 months (median) Impact

For internal Medical Affairs training only

Lars RydénDepartment of Medicine K2

Karolinska InstitutetStockholm, Sweden

Ljubljana April 19, 2018

How to apply

novel outcome data

with GLP-1 RA

to clinical practice

Preventing Cardiovascular Diseasein Patients with T2DM

Incretin-based glucose loweringTwo options

DPP-4 inhibition

GLP-1 receptor agonism

Effects

Insulin secretion

Glucagon secretion

Beta-cell mass

Insulin sensitivity

Gastric emptying

Satiety

Baggio LL & Drucker DJ. Gastroenterology 2007;132:2131–2157

GLP-1 receptor agonists

Requires injection

Mimics the effect of GLP-1

Reduces HbA1c by ≥1%

Causes weight loss of 2–3 kg

Low risk of hypoglycaemia

when used with metformin

Reduced risk of hypoglycaemia

if combined with insulin

GLP-1 receptor agonistsBroad approach

Drucker DJ. Cell Metab 2016;24:15–30

GLP-1

receptor

agonists

Shortacting

Longacting

Human analogues

Liraglutide QD

Semaglutide QW

Dulaglutide QW

Exendin-4 based

Exenatide BID

Lixisenatide OD

Exendin-4 based

Exenatide LARQW

ITCA 650

Meier JJ. Nat Rev Endocrinol 2012;8:728–742

Madsbad S et al. Diabetes Obes Metab 2011;13:394–407

GLP-1 receptor agonists in type 2 diabetesResults from available outcome trials

GLP-1

receptor

agonists

Shortacting

Longacting

Human analogues

Liraglutide QD

Semaglutide QW

Dulaglutide QW

Exendin-4 based

Exenatide BID

Lixisenatide OD

Exendin-4 based

Exenatide LARQW

ITCA 650

Lixisenatide

Exenatide

ITCA 650

ITCA 650 is an investigational product and not currently approved

Lixisenatide

Pfeffer MA et al. N Engl J Med 2015;373:2247–2257

Type 2 diabetes and recent ACS

n=6,068

Treatment

Lixisenatide

Placebo

Follow-up: 25 months (median)

Impact on CV death or non-fatal MI, strokeor unstable angina

HbA1c at the end of study

Lixisenatide 7.4%

Placebo 7.6%

Exenatide

Holman RR et al. N Engl J Med 2017;377:1228–1239

Type 2 diabetes with (74%) or without CVD

n=14,752

Treatment

Exenatide (2 mg once weekly)

Placebo

Follow-up: 3.2 years (median)

Impact on CV death or non-fatal MI or stroke


Exenatide 7.7%

Placebo 7.9%

GLP-1 receptor agonists in type 2 diabetesResults from available outcome trials

GLP-1

receptor

agonists

Shortacting

Longacting

Human analogues

Liraglutide QD

Semaglutide QW

Dulaglutide QW

Exendin-4 based

Exenatide BID

Lixisenatide OD

Exendin-4 based

Exenatide LARQW

ITCA 650

Lixisenatide

Liraglutide

Semaglutide

Semaglutide is an investigational product and not currently approved

Liraglutide

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

Type 2 diabetes at high risk for CVD

n=9,340

Treatment

Liraglutide (1.8 mg once daily)

Placebo




Liraglutide ~7.7%Placebo ~8.0%

Semaglutide


Type 2 diabetes at high risk for CVD

n=3,297

Treatment

Semaglutide (0.5 or 1.0 mg once daily)

Placebo




Liraglutide ~7.3%Placebo ~8.3%

SUSTAIN 6Semaglutide sc once-weekly



Liraglutide and semaglutide

Let us go into some details...



Patient characteristics at study start

0

20

40

60

80

100

W ith previous CVD

( age ≥ 5 0 )

W ith CVD risk factors

( age ≥ 6 0 )

Pe

rce

nta

ge

o

f p

ati

en

ts

Variable

Male sex (%) 64

Age (years) 64

Diabetes duration (years) 13

HbA1c 8.7

BMI (kg/m2) 32.5

Blood pressure (mmHg) 136/77

Heart failure (%) 18

Liraglutide

Placebo


75.8

50.8

3.06.3 3.8

43.7

77.1

50.6

2.66.0 3.7

45.6

0

20

40

60

80

100

M e t f o rmin Su lp h o n y lu re a s Alp h a - g lu co sida se in h ib it o rs TZ Ds Glin id e s I n su lin

Pro

po

rtio

n o

f p

ati

en

ts (

%)

SUsMet form in Alpha-glucosidase

inhib itors

TZDs Glinides I nsulin

Liraglutide Placebo

Liraglutide

Placebo

Background therapy at study start

Metformin SU AGI TZD Glinides Insulin

92.7

41.8

76.368.7

6.7

92.1

41.8

75.2

66.8

7.0

0

20

40

60

80

100

Antihypertensive therapy Diuretics Lipid-lowering drugs Platelet aggregation inhibitors Other anti-thrombotic medication

Pro

po

rtio

n o

f p

ati

en

ts (

%)

Platelet

aggregat ion

inhib itors

Ant ihypertensive

therapy

Diuret ics Lip id- lowering

drugs

Other ant i- throm bot ic

m edicat ionBP-lowering Diuretics Lipid-lowering ASA Plat stab


Treatment/guideline

Blood glucose • HbA1c ≤7.0% (individualised)

Blood pressure • Target: 130/80 mmHg

Lipids• Target LDL


H azard rat io ( 9 5 % CI )

Favou rs p laceboFavou rs lirag lu t id e

SubgroupH azard rat io

( 95% CI )

p-value for

interact ion

N o. of

pat ients

Prim ary analysis 0.87 ( 0.78 ; 0.97) 9340

Sex 0.84

Female 0.88 (0.72 ; 1.08) 3337

Male 0.86 (0.75 ; 0.98) 6003

Age 0.27

8.3% 0.84 (0.72 ; 0.98) 4572

Durat ion of diabetes 0.42≤11 years 0.82 (0.70 ; 0.97) 4429>11 years 0.90 (0.78 ; 1.04) 4892

Risk of CVD 0.04Age ≥50 years and established CVD 0.83 (0.74 ; 0.93) 7598 536/3831 (14.0) 629/3767 (16.7)

Age ≥60 years and risk factors for CVD 1.20 (0.86 ; 1.67) 1742 72/837 (8.6) 65/905 (7.2)Chronic heart fa ilure 0.53

Yes 0.94 (0.72 ; 1.21) 1305No 0.85 (0.76 ; 0.96) 8035

Antidiabet ic therapy 0.73

1 OAD 0.75 (0.58 ; 0.98) 1818

>1 OAD 0.95 (0.78 ; 1.16) 2997Insulin with OAD(s) 0.89 (0.74 ; 1.06) 3422Insulin without OAD 0.86 (0.63 ; 1.17) 737None 0.73 (0.42 ; 1.25) 366

Renal function 0.01


Primary endpoint

Heart failure hospitalisation

Cardiovascular death

Non-fatal myocardial infarction Non-fatal stroke

All-cause mortality

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

Primary outcome by insulin use at baseline

Favours placeboFavours liraglutide

Hazard ratio (95% CI)

Hazard ratio

(95% CI)

Liraglutide Placebo

N % N %

Total number of patients 4668 4672

Primary outcome 0.87 (0.78 ; 0.97) 608 13.0 694 14.9

Insulin use at baseline (Y/N)

Yes 0.88 (0.75 ; 1.03) 295 14.5 347 16.3

No 0.86 (0.74 ; 1.01) 313 11.9 347 13.7

0,5 0,75 1 1,25

Primary outcome in patients never treated with

insulin during the trial

Hazard ratio

(95% CI)

Liraglutide Placebo

N R N R

Total number of patients 4668 4672

Primary outcome 0.87 (0.78 ; 0.97) 608 3.4 694 3.9

Patients not on insulin at baseline 2630 2541

Primary outcome 0.82 (0.68 ; 0.98) 229 2.9 217 3.5

0,5 0,75 1 1,25

Favours placeboFavours liraglutide

Hazard ratio (95% CI)

Tim e from random isation ( m onths)

Liraglutide

Placebo

Pa

tie

nts

wit

h

an

ev

en

t (

%)

444

422

0 540

2

6

8

10Placebo

Liraglutide

4

4603

1589

48

4038

3921

42

4137

4030

36

4234

4134

30

4344

4260

24

4446

4373

18

4530

4504

12

4618

4631

6

4668

4672

HR 0 .8 4

(95% CI 0.73 ; 0.97)p=0.02

N o. at risk

Microvascular eventsEvent type Definit ion – one or m ore of the below

Microvascu lar

even ts

Renal

• New onset of persistent macroalbuminuria

• Persistent doubling of serum creatinine*

• Need for continuous renal replacement therapy

• Death due to renal disease

Eye

• Need for retinal photocoagulation or treatmentwith intravitreal agents

• Vitreous haemorrhage

• Diabetes-related blindness

*and eGFR ≤45 mL/min/1.73 m2 per MDRD


Time to first microvascular event

LiraglutideLiraglutide

Placebo

ETD –0.40 (95% CI: –0.45 ; 0.34)

p


Treatment diff

–0.4% 95% CI (–0.45 ; –0.34)

p

Severe hypoglycaemia

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

0

5

1 0

1 5

2 0

2 5

3 0

3 5

4 0

4 5

5 0

5 5

6 0

6 5

0 4 8 12 16 20 24 28 32 36 40 48 52 56 6044

40

35

30

25

20

15

10

5

0

45

50

55

60

65

Me

an

nu

mb

er

of

ep

iso

de

s

pe

r 1

00

0 p

ati

en

ts

Rate ratio: 0.69

95% CI: (0.51 ; 0.93) p=0.013

Time since randomisation (months)

Placebo

Liraglutide

Liraglutide Placebo

Number of patients with severe hypoglycaemia (%) 114 (2.4) 153 (3.4)

Presented at the American Diabetes Association 77th

Scientific Sessions, Session 1-AC-SY13. 11 June 2017,

San Diego, CA, USA

Marso SP et al. N Engl J Med

2016;375:311–322


In summary

3P – MACE

ARR 1.9%

RRR 13%p=0.01

CV death

–22%

p=0.04

All death

–15%

p=0.02

Microvasc

–16%

p=0.02

Renal

–22%

p=0.003

Male sex (%) 64

Age (years) 64


HbA1c 8.7

BMI (kg/m2) 32.5





Patient characteristics at study start

Male sex (%) 61

Age (years) 65


HbA1c 8.7

BMI (kg/m2) 32.8







Primary endpoint Non-fatal myocardial infarction

Cardiovascular deathNon-fatal stroke




Favours semaglutide Favours placeboSemaglutide is an investigational product and not currently approved


Glycaemic control and Body weightHbA1c

Weight


*p



Retinopathy

0

1

2

3

4

5

6

7

8

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

Subje

cts

with a

n e

vent

(%)

Time since randomisation (weeks)

Semaglutide Placebo

Semaglutide

Placebo

HR 1.76 (1.11–2.78)p=0.02


HR 1.15 (0.87–1.52)p=0.33

0.6 vs 0.5/100 patient-years


In summary

3P – MACE

ARR 2.3%

RRR 26%p=0.001

CV death

–2%

n.s.

All death

+5%

n.s.

Stroke

–39%

p=0.04

Renal

–36%

p=0.05




Why differences between

GLP-1RA trials?

GLP-1 receptor agonists in type 2 diabetes


GLP-1 receptor agonists in type 2 diabetesWhy different outcomes?

► Differences in study populationsELIXA in patients with T2DM and a recent ACS


Patient populations in different GLP-1RA trials

1. Gerstein HC et al. Diabetes Obes Metab 2017 doi: 10.1111/dom.13028. [Epub ahead of print]; 2. Pfeffer MA et al. N Engl J Med 2015;373:2247–2257;

3. Mentz RJ et al. Am Heart J 2017;187:1–9; 4. Marso SP et al. N Engl J Med 2016;375:1834–1844; 5. Marso SP et al. N Engl J Med 2016;375:311–322

REWIND1

(N=9,901)

ELIXA2

(N=6,068)

EXSCEL3

(N=14,752)

SUSTAIN 64

(N=3,297)

LEADER5

(N=9,340)

Drug tested Dulaglutide Lixisenatide Exenatide Semaglutide Liraglutide

Dosage 1.5 mg/week 20 μg*/day 2.0 mg/week0.5 or 1 mg

/week

1.2 or 1.8 mg

/day

Mean age (yrs) 66 60 63 65 64

Gender (% female) 46 31 38 39 36

Diabetes duration

(yrs)10.0 9.3 12 13.9 12.8

Prior CVD (%) 31 100 73 59 72

Mean BMI (kg/m2) 32 30 32 33 33

Mean HbA1c (%) 7.3 7.7 8.0 8.7 8.7

*Initial dose of 10 μg with down- or up-titration permitted to maximum of 20 μg/day



► Differences in the use of non-study medications

► Differences in glycaemic control



► Differences in the use of non-study medications

► Differences in glycaemic control

► GLP-1RA backboneExendin-4 vs. Human analogue GLP-1

► Duration of the GLP-1RA

GLP-1 receptor agonistsSimilarities and dissimilarities

Exenatide 2005

Liraglutide 2010

Lixisenatide 2013

Albiglutide 2014

Dulaglutide 2014

Semaglutide Under investigation

Figur 3.3: GLP-1 strukturer

Tabell 3.1: Halveringstid och tid till maximal koncentration

Kategori Substans Halveringstid Cmax

Kortverkande

GLP-1 receptor agonists in type 2 diabetesGaps in knowledge

► In less ill patientsREWIND of great interest

► Orally availablePIONEER 6 will provide insights

► In people with IGTOf interest to study

► In obese peopleOf interest to study

GLP-1 receptor agonists in type 2 diabetesImpact on guidelines (January 2018)

CVOT, cardiovascular outcomes trial

Germ any USA

I taly

Norw ay

Sw itzer land

2 0 1 6 2 0 1 7

Brazil

Hungary

Slovenia

France

Turkey

Latvia

Position Paper

Slovakia

Bosnia and

Herzegovina

Sw eden

Denm ark – Cardio

Bulgar ia

Canada

Czech

Republic

Spain

Catalonia, Andalucía

Position Paper

Greece

Poland

Scot land

Korea

GLP-1 receptor agonists in type 2 diabetesImpact on guidelines (January 2018)

In patients with type 2 diabetes and

established atherosclerotic cardiovascular disease

begin with lifestyle management and metformin

then choose

an agent proven to reduce major adverse

cardiovascular events and cardiovascular mortality

(currently empagliflozin and liraglutide)

after considering drug-specific and patient factors

Evidence level A: Supportive evidence from well conducted trials

ADA, American Diabetes Association; CVOT, cardiovascular outcomes trialAmerican Diabetes Association. Diabetes Care 2018;41(Suppl 1):S73–S85

Rydén L et al. Clin Ther 2016;38:1279–1287; ClinicalTrials.gov (accessed 15/3 2018)

Outcome trials of glucose-lowering drugs in type 2 diabetesCompleted and ongoing

GLP-1RA

FREEDOM

(ITCA 650, GLP-1RA in DUROS)

n=4000; duration ~2 yrs

Q2 2016 – RESULTS

EXSCEL

(Exenatide ER, QW GLP-1RA)

n=14,752; follow-up ~3 yrs

Q3 2017 – RESULTS

PIONEER 6

(Oral semaglutide, GLP-1RA)

n=3176; duration ~1.5 yrs

Completion Q4 2018

LEADER

(Liraglutide, GLP-1RA)

n=9340; duration 3.5–5 yrs

Q2 2016 – RESULTS

HARMONY OUTCOMES

(Albiglutide, QW GLP-1RA)

n~9400; duration ~4 yrs

Completion Q2 2018

ELIXA

(Lixisenatide, GLP-1RA)

n=6068; follow-up ~2 yrs

Q1 2015 – RESULTS

SUSTAIN 6

(Semaglutide, QW GLP-1RA)


Q3 2016 – RESULTS

REWIND

(Dulaglutide, QW GLP-1RA)


Completion Q3 2018

2015 2016 2017 2018 2019 202020142013 2021 2022

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PACE-CME - How to apply novel outcome data with GLP-1 ......2018/06/25 · Type 2 diabetes and recent ACS n=6,068 Treatment Lixisenatide Placebo Follow-up: 25 months (median) Impact