Rimonabant: A new approach to multiple cardiometabolic risk factors

Rimonabant: A new approach to multiple cardiometabolic risk factors

Version 1.1

29 April 2005

RIO programme

RIO: Rimonabant In Overweight/Obesity

RIO-North America: 2-year treatmentRIO-Europe: 2-year treatmentRIO-Lipids: 1-year treatmentRIO-Diabetes: 1-year treatment

(>6600 patients enrolled)

Study Population Design

Obese or overweight with/without comorbidities (excluding diabetes)

3040 1+1 yearRe-randomized

Obese or overweight with/without comorbidities (excluding diabetes)

1507 2 years

Obese or overweight with untreated dyslipidaemia(excluding diabetes)

1033 1 year

Obese or overweight with type 2 diabetesTo be released at the ADA 2005

1047 1 year

Rimonabant In Overweight/Obesity

N=6627

Pi-Sunyer. Obes Res 2004, 12(Suppl)108-OR, A27

RIO programme study design

Rimonabant 20 mg

Rimonabant 5 mg

Placebo

Placebo

Week 104Week 52 InclusionRandomization

Week 0InclusionRandomization

Week - 4Week - 6

Mild hypocaloric diet, reduced by 600 kcal/day

ScreeningPlacebo run-in

Single-blindTreatment period: 1 or 2 years double-blind

Re-randomization: RIO-NA

Rimonabant 20 mg

Rimonabant 5 mg

Placebo

Placebo

Placebo

Pi-Sunyer. Obes Res 2004, 12(Suppl)108-OR, A27

RIO programme study populations

Ratio women/men (%): 80/20 (RIO-North America & RIO-Europe) ~50/50 (RIO-Lipids & RIO-Diabetes)

80–95% of patients had a waist circumference >88 cm (women) or 102 cm (men)Mean body weight: 94–104 kg Mean BMI: 33–38 kg/m2 >1300 patients with BMI >40 (RIO-North America &

RIO-Europe)50–70% completed 12 months

Data on file

Associated medical conditionsindicated at baseline or screening

Dyslipidaemia (%)* 62.7 60.8 100

Metabolic syndrome (%)

ATP III34.7 41.4 54.0

Hypertension (%)** 30.4 40.9 27.2

Smoking (%) 9.3 19.8 16.7

* Patients treated for dyslipidaemia or untreated patients with LDL-C ≥3.36 mmol/L and/or HDL-C<1.03 mmol/L and/or TG ≥1.69 mmol/L

** Patients treated for hypertension or untreated patients with supine SBP ≥140 mmHg and/or DBP ≥90 mmHg

N.B. Patients with type 1 or type 2 diabetes were not included in these trials

Pi-Sunyer X. ,2004, IASO, Sun City, South Africa, 2831 October

Rimonabant induces consistent changes in:Waist circumference

Weight change

Consistent Changes in Waist Circumference Completers

-10

-8

-6

-4

-2

0

0 4 8 1216202428323640444852 LOCFWai

st c

ircu

mfe

ren

ce c

han

ge

(cm

)

Weeks

Placebo

R 20 mg

PlaceboR 20 mg

Placebo

R 20 mg

-4.5cm*

-8.5cm*

L.Van Gaal, Lancet 2005; 365: 1389-97, X. Pi-Sunyer, Circulation 2005:111(13);1727Circulation 2005, JP. Després, Int J. Obes. Relat Metab Disod 2004, 28 (Suppl1) pS28; T5:O2-005

Consistent weight change at 1 year

Completers

PlaceboRimonabant

20 mg

PlaceboRimonabant

20 mg

PlaceboRimonabant

20 mg

-10

-8

-6

-4

-2

0

0 16 32 48

Wei

gh

t ch

ang

e (k

g)

Weeks

L.Van Gaal, Lancet 2005; 365: 1389-97, X. Pi-Sunyer, Circulation 2005:111(13);1727Circulation 2005, JP. Després, Int J. Obes. Relat Metab Disod 2004, 28 (Suppl1) pS28; T5:O2-005

Changes in weight & waist circumference at 1-year: RIO-Europe

Placebo

Rimonabant 5 mg Rimonabant 20 mg

Completers

Wai

st c

ircu

mfe

ren

ce c

han

ge

(cm

)

- 4.5 - 5.3

- 8.5

p<0.001

WeeksITT LOCF

placebo: - 2.4 cm 5 mg: - 3.9 cm (p=0.002 vs placebo) 20 mg: - 6.5 cm (p<0.001 vs placebo)

Waist (cm)Waist (cm)

Wei

gh

t ch

ang

e (k

g)

Weight (kg)Weight (kg)

- 3.6

- 4.8p=0.042

- 8.6p<0.001

Weeks

ITT LOCF placebo: - 1.8 kg 5 mg: - 3.4 kg (p=0.002 vs placebo) 20 mg: - 6.6 kg (p<0.001 vs placebo)

L.Van Gaal, Lancet 2005; 365: 1389-97

Weight loss ≥ 10% at 1-yearCompleters

Placebo Rimonabant 20 mg

12.4%10.3%

39.0%

44.3%

0

5

10

15

20

25

30

35

40

45

50

RIO~Europe RIO~Lipids

Per

cent

(%

) p<0.001

p<0.001

13.6%

38.2%p<0.001

L.Van Gaal, Lancet 2005; 365: 1389-97, X. Pi-Sunyer, Circulation 2005:111(13);1727, N. Finer , Poster presented at IASO congress 2004

Rimonabant produces consistent change in

metabolic parameters:

1 year results

• Lipids (triglycerides, HDL)

• Insulin resistance (HOMA)

Change in HDL-cholesterol and triglycerides:RIO-Europe

TriglyceridesTriglycerides

Weeks


Rimonabant 20 mg

ITT LOCF Placebo : 8.3%

5 mg : 5.7% (ns vs placebo) 20 mg : - 6.8% (p<0.001 vs placebo)

ITT LOCF Placebo : 13.4%

5 mg : 16.2% (p=0.048 vs placebo) 20 mg : 22.3% (p<0.001 vs placebo)

Completers

6.6%4.9%

-10.6%

p<0.001

HDL-cholesterol HDL-cholesterol

Weeks

0

5

10

15

20

25

30

0 4 8 12 14 20 24 28 32 36 40 44 48 52

27.0%

19.0% 17.3%

p<0.001

% c

han

ge

% c

han

ge

L.Van Gaal, Lancet 2005; 365: 1389-97

Improvements in lipids adjusted forweight loss: RIO-North America

20 mg vs placebop=0.008

20 mg vs placebop<0.001

TG

Weight-independenteffect

47%

Weight-dependent effect

53%

Overall effect: - 13.2%

44%Weight-dependent effect

HDL-C

56%Weight-independent effectO

vera

ll ef

fect

: +

7.2

%

% c

han

ge

-10

0

5

10

-5

-15

X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

0.0

Improvement in fasting insulin and insulin resistance adjusted for weight loss:

RIO-North AmericaO

verall effect - 0.80*

- 0.8

- 0.6

- 0.4

- 0.2

2

50%Weight-

dependenteffect

50%Weight-

independent effect

- 3.0

- 2.5

- 2.0

- 1.5

- 1.0

- 0.5

0.0

FASTING INSULIN 20 mg vs Placebo

*p<0.001

HOMA-IR 20 mg vs Placebo

*p<0.001

Ch

ang

e in H

OM

A (%

)C

han

ge

in f

asti

ng

insu

lin (

µU

/mL

) 51%Weight-

independent effect

49% Weight-

dependent effectO

vera

ll ef

fect

- 2

.8*

1 Year Analysis


Insulin during OGTT among patients with/without metabolic syndrome (MS) at baseline:

RIO-LipidsITT-LOCF

010

Time

2030405060708090

100110

0 mn 30 mn 60 mn 90 mn 120 mn

ulU

/mL

Placebo

0

Rimonabant

20mg

102030405060708090

100110

0 mn 30 mn 60 mn 90 mn 120 mnTime

ulU

/mL

AU

Cu

lU/m

L*m

inWithMS

WithoutMS

AU

Cu

lU/m

L*m

in

WithMS

WithoutMS

Year 1 with MSYear 1 without MS

Baseline with MSBaseline without MS

R, Després J-P. Presented at the ACC congress, March 2004, Abstr. 409-1

Effect on HOMA-derived insulin resistance: RIO-Europe

ITT LOCF 5 mg vs placebo: ns 20 mg vs placebo:

p=0.003

Baseline 1 year

Completers - 0.7 0.3

p=0.005

2.4

2.6

2.8

3.0

3.2

HO

MA

(%

)

2.8

3.1 3.13.0

3.1

2.6


Rimonabant 5 mg

L.Van Gaal, Lancet 2005; 365: 1389-97

Changes in leptin and adiponectin: RIO-Lipids

Lep

tin

leve

ls (

ng

/mL

)

- 3.8 ng/mL

p<0.001

1.6 g/mL

p=0.001

Ad

ipo

nec

tin

leve

ls (g

/mL

)

ITT-LOCF

Placebo Rimonabant 20 mg Placebo Rimonabant 20 mg

18 18 18

14

5.96.7

5.8

8.2

10

12

14

16

18

20

22

0

2

4

6

8

10

Baseline 1 Year

41%41%

Leptin Adiponectin

JP. Després, presented as a poster in ENDO congress 2004, Abst P1-345

Metabolic syndrome NCEP-ATP IIICriteria

Abdominal obesity: men: waist circumference >102 cm, women: waist circumference >88 cm

Hypertension: 130/85 mmHg

Hypertriglyceridaemia: 150 mg/dl

Low HDL-cholesterol: men: <40 mg/dl, women: <50 mg/dl

Abnormal fasting glucose: 110 mg/dl

To fulfill the diagnostic criteria for the metabolic syndrome patients must meet three of the following criteria:

NCEP-ATP-III, JAMA 2001, 285: 2486-2497

Reduction in metabolic syndrome


ITT

- 60

- 50

- 40

- 30

- 20

- 10

0

- 21%

- 53%

p<0.001

- 21%

- 51%

p<0.001

Red

uct

ion

in m

etab

olic

syn

dro

me

(%)

- 8%

- 39%

p<0.001

1 year

L.Van Gaal, Lancet 2005; 365: 1389-97, X. Pi-Sunyer, Circulation 2005:111(13);1727, JP. Després, Int J. Obes. Relat Metab Disod 2004, 28 (Suppl1) pS28; T5:O2-005

Rimonabant

induces improvement

in atherogenic parameters

LDL peak particle size: RIO-Lipids

ITT-LOCF

1.2 Å

p<0.001


LD

L p

eak

par

ticl

e si

ze (

Å)

259.3258.4

259.1 259.4

250

252

254

256

258

260

262

Baseline 1 YearData on file

Change in proportion of small and large LDL particles: RIO-Lipids

Baseline 1 Year

Proportion of small LDL particles

ITT-LOCF


- 4.7%

p=0.002

26.2

29.5

25.824.4

20

22

24

26

28

30

32

34

% s

mal

l LD

L p

arti

cles

Proportion of large LDL particles


6.3%

p<0.00140.2

35.1

40.041.2

20

25

30

35

40

45

% la

rge

LD

L p

arti

cles


C-reactive protein : RIO-Lipids

ITT-LOCF

Baseline 1 Year

CR

P le

vels

(m

g/L

)*

- 0.6 mg/L

p=0.007


3.63.2

3.7

2.7

0

1

2

3

4

5

27%27%

* Excluding values>10mg/L


Rimonabant maintains metabolic benefits

over 2 years

Waist circumference maintenance over 2 years in re-randomized patients:

RIO-North AmericaITT-LOCF

Waist circumference (cm) change from baseline at 2 years (Mean + SEM)

Wai

st c

ircu

mfe

ren

ce (

cm)

LOCF

- 7.6 ± 0.4 cm

- 3.4 ± 0.5 cm

- 3.8 ± 0.4 cm

- 10

- 8

- 6

- 4

- 2

0

52 68 84 100

Weeks PlaceboRimonabant 20 mg/Placebo Rimonabant 20 mg/20 mg


Prevention of weight regain by chronic therapy: RIO-North America

ITT-LOCF

Weight (kg) Change from Baseline at 2 Years (Mean + SEM)

LOCF

- 7.4 ± 0.4 kg

- 2.3 ± 0.5 kg

- 3.2 ± 0.4 kg

- 12

- 9

- 6

- 3

0

52 60 68 76 84 92 100

Weeks

Wei

gh

t ch

ang

e (k

g)

PlaceboRimonabant 20 mg/Placebo Rimonabant 20 mg/20 mg


Consistent Waist Circumference Changes in RIO Studies

Van Gaal L., . Presented at the ACC congress, March 2005, presentation 410-13

20 mg vs. placebo: -4.2cm (p<0.001)

RIO~NA

ITT (LOCF)

0

-2

-4

-6

-8

-10

-12

0 4 12 20 28 36 44 52 60 68 76 84 92 104 LOCF

Wai

st (

cm)

Weeks

Placebo

Rimonabant 20 mg

Placebo

Rimonabant 20 mg

20 mg vs. placebo: -4.1cm (p<0.001)

RIO~EUCOMPLETERS COMPLETERS

-12,0

-10,0

-8,0

-6,0

-4,0

-2,0

0,0

0 2 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96100104 LO

Weight loss in completers on the same treatment for 2 years: RIO-North America

>5% weight loss>5% weight loss >10% weight loss>10% weight loss

ITT LOCFPlacebo: 19.3% 5 mg: 19.0% (ns vs placebo) 20 mg: 39.7% (p<0.001 vs placebo)

ITT LOCFPlacebo: 8.3% 5 mg: 8.5% (ns vs placebo) 20 mg: 16.5% (p<0.001 vs placebo)

*p<0.001

Placebo Rimonabant5 mg

Rimonabant20 mg

33.2% 36.7%

62.5%*

0

20

40

60

80

% o

f p

atie

nts

32.8%*

20.0%16.4%

0

20

40

60

80*p<0.001


Rimonabant20 mg

% o

f p

atie

nts


Change in metabolic syndrome statusat 2 years: RIO-North America

ITT, LOCF

Pat

ien

ts (

%)

Baseline

2 years of treatment

Rimonabant20 mg

Rimonabant5 mg

0

10

20

30

40

Placebo

31.7%

29.2%

34.7%

29.9%

34.8%

22.5%p<0.001


Consistent Reduction in Metabolic Syndrome at 2 Years

COMPLETERS

Reduction in Metabolic Syndrome (%)



-34 %

-57 %

-28 %

-54 %

OR= 0.599 (p<0.05)OR= 0.483 (p<0.05)

-60

-50

-40

-30

-20

-10

0

-54% -57%

Van Gaal L., . Presented at the ACC congress, March 2005, presentation 410-1X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

HDL-cholesterol over 2 years: RIO-North America

ITT-LOCF 5 mg vs placebo: ns20 mg vs placebo: p<0.001

Placebo Rimonabant 5 mg Rimonabant 20 mg

24.5%

15.6%

13.8%

0

5

10

15

20

25

30

0 12 24 36 52 64 76 88 104

Weeks

HD

L-C

(%

ch

ang

e)Completers

Data on file

Fasting insulin over 2 years by visit: RIO-North America

20 mg vs Placebo: - 1.8 ± 0.7 µIU/ml; p=0.014

Placebo Rimonabant 5 mg Rimonabant 20 mg

13.1

15.0

15.3

9

11

13

15

0 12 24 36 52 64 76 88 104 LOCF

Weeks

Fas

tin

g in

sulin

(µ

IU/m

l)

ITT-LOCF

Data on file

Rimonabantimproves quality of life

Improvement in quality-of-life scale

- 4

- 2

0

2

4

6

8

10

12

14

16

Physicalfunction

Self-esteem

Sexuallife

Publiccomfort

Work Totalscore

Mea

n

PlaceboRimonabant 20 mg

Impr

ovem

ent

Mean IW-quality of life scorechange from baseline to year 1

JP. Després, Obes Res 2004, 12 (suppl) 231-P, A 61

Safety and tolerability of rimonabant

RIO programme pooled 1-year overall safety

Pooled year 1 data: RIO-LIPIDS, RIO-EUROPE, RIO-NORTH AMERICA

13.6%8.9%7.7%Subjects discontinued due to adverse event

RimonabantPlacebo

5.6%5.0%4.1%Subjects with any serious adverse event

86.1%83.0%82.5%Subjects with any adverse event

20 mg

N=2164

5 mg

N=2162N=1254

Rimonabant

Deaths n=1 n=2 n=1

Data on file

RIO programme pooled 1-year overall safety: AEs leading to discontinuation

Placebo Rimonabant

(N=1254)n (%)

5 mg(N=2162)

n (%)

20 mg(N=2164)

n (%)

Psychiatric disorders 40 (3.2) 79 (3.7) 146 (6.7)

Depressed mood disorders 19 (1.5) 48 (2.2) 63 (2.9)

Anxiety 5 (0.4) 8 (0.4) 24 (1.1)

Irritability 2 (0.2) 4 (0.2) 10 (0.5)

Nervous system disorders 14 (1.1) 25 (1.2) 46 (2.1)

Headache 5 (0.4) 7 (0.3) 10 (0.5)

Dizziness 1 (<0.1) 4 (0.2) 14 (0.6)

Gastrointestinal disorders 5 (0.4) 18 (0.8) 49 (2.3)

Nausea 1 (<0.1) 5 (0.2) 29 (1.3)

According to MedDRA code, 0.5% in any rimonabant group: in the 3 main system organ class.

Data on file

RIO programme pooled 1-yearcardiovascular safety


N

subjects

Mean

(SD)N

subjects

Mean

(SD)

Blood pressure (mmHg) (ITT)

Supine SBP change

Supine DBP change

Heart rate change (bpm)

Mean QTcB changes

1225

1052

1052

2130

1850

1850

- 0.1 (11.6) - 0.8 (12.3)

- 0.2 (8.1) - 0.7 (8.4)

- 0.1 (7.9) 0.6 (8.2)

- 2.0 (19.7) - 0.6 (19.5)

Data on file

RIO~Europe Overall Safety

Van Gaal L., . Presented at the ACC congress, March 2005, presentation 410-13

14.5 %8.3 %9.2 %Year 1

18.9 %10.9 %13.1 %

Subjects discontinued due to adverse eventYr 1 and Yr 2

Rimonabant 20mg

n=599n=305 n=603

Rimonabant 5mgPlacebo

Year 2

3.9 % 2.6 % 4.4 %

Conclusions

Consistent results were replicated in 3 large studies

Rimonabant 20 mg consistently produced: Significant reductions in waist circumference and weight Significant improvement in metabolic profile:

• Increased HDL-cholesterol and decreased triglyceride levels

• Improved insulin sensitivity (HOMA) Significant decrease in % of subjects with metabolic

syndrome Weight-independent effect of rimonabant on several

metabolic variables suggestive of a direct pharmacological effect beyond weight loss alone

Conclusions II

Rimonabant 20 mg:

Improved other metabolic and cardiovascular risk factors:

Increased plasma adiponectin and decreased plasma

leptin

Decreased CRP, a marker of inflammation

Improved small dense LDL particles profile

Achieved efficacy at year 1 which was maintained over

year 2 with chronic therapy

Improved quality of life

Is well tolerated

DISCLAIMER

Rimonabant is not yet licensedThis information is provided for

medical information purpose

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Rimonabant: A new approach to multiple cardiometabolic risk factors