Clinical evaluation of CB1 receptor blockade

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Clinical evaluation of CB1 receptor blockade

• Rimonabant clinical trial program

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Rimonabant In Obesity (RIO) program
Randomized, double-blind, placebo-controlled
trials
Study Population N Follow-up (years)
RIO-Europe BMI 30 kg/m2 orgt27 kg/m2 with comorbidity 1507 2
RIO-Lipids BMI 2740 kg/m2 with dyslipidemia 1033 1
RIO-Diabetes BMI 2740 kg/m2 with T2DM 1045 1
RIO-N Am BMI 30 kg/m2 or gt27 kg/m2 with comorbidity 3045 2
Van Gaal LF et al. Lancet. 2005. Després J-P et
al. N Engl J Med. 2005.Pi-Sunyer FX et al. JAMA.
2006. Scheen AJ et al. Lancet. 2006.
Hypertension and/or dyslipidemia
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RIO program Improved cardiometabolic risk
factors at 1 year
Rimonabant 20 mg placebo-corrected changes from
baseline
Waist circumference
HDL-C




cm





TG
Systolic BP
NS
mm Hg

NS






RIO-North America
RIO-Europe
RIO-Lipids
RIO-Diabetes
Van Gaal LF et al. Lancet. 2005. Després J-P et
al. N Engl J Med. 2005.Pi-Sunyer FX et al. JAMA.
2006. Scheen AJ et al. Lancet. 2006.
P lt 0.001, P lt 0.0001, P lt 0.05 vs placebo
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RIO program Decreased metabolic syndrome
incidence
Rimonabant 20 mg
RIO-Lipids
RIO-N Am
RIO-Diabetes
RIO-Europe
(n 346)
(n 1222)
(n 339)
(n 599)
Baseline
1 year
Van Gaal LF et al. Lancet. 2005. Després J-P et
al. N Engl J Med. 2005.Pi-Sunyer FX et al. JAMA.
2006. Scheen AJ et al. Lancet. 2006.
ATP III criteria
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RIO program Safety and tolerability
Rimonabant 20 mg

• CNS adverse effects
• Dizziness (5.610.4)
• Insomnia (5.86.4)
• Anxiety (58.7)
• Depressed mood (5.2)
• GI adverse effects
• Nausea (11.212.9)
• Diarrhea (5.37.2)
• Adverse effect-related discontinuation rates
• Rimonabant (12.815)
• Placebo (59.2)
• Overall discontinuation rates
• Rimonabant (3244.9)
• Placebo (33.649.1)

Van Gaal LF et al. Lancet. 2005. Després J-P et
al. N Engl J Med. 2005.Pi-Sunyer FX et al. JAMA.
2006. Scheen AJ et al. Lancet. 2006.
Most common
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RIO program No significant effect on mood
Hospital Anxiety and Depression (HAD) scale
Scores at 1 year
Placebo Rimonabant 20 mg
RIO-Europe Anxiety Depression 4.42.7 5.6 3.4
RIO-Lipids Anxiety Depression 5.23.2 5.6 3.1
RIO-Diabetes Anxiety Depression 4.92.9 5.53.3
RIO-N Am Anxiety Depression 5.23.1 5.63.0
Van Gaal LF et al. Lancet. 2005. Després J-P et
al. N Engl J Med. 2005.Pi-Sunyer FX et al. JAMA.
2006. Scheen AJ et al. Lancet. 2006. Zigmond AS,
Snaith RP. Acta Psychiatr Scand. 1983.
HAD scale 07 normal810 borderline
symptoms 11 significant symptoms
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RIO program Mood at 1 year
n 1545 in rimonabant 20 mg group
0-7
8-10
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Baseline HAD depression score
No impairment Improved
Impairment
HAD scores 0-7 normal, 8-10 borderline
symptoms, 11 significant symptoms
Pi-Sunyer FX. JAMA. 2006296650-651.
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RIO clinical trial program efficacy summary
Rimonabant 20 mg combined with diet over 1 year
Significant decreases in weight and waist
circumference 11.716.4 lbs absolute loss
8.712.0 lbs placebo-corrected loss
Improved cardiometabolic risk factor profile
Weight loss only partially accounted for changes
in lipids, glucose, and adipokines, consistent
with direct actions in peripheral tissues
Van Gaal LF et al. Lancet. 2005. Després J-P et
al. N Engl J Med. 2005.Pi-Sunyer FX et al. JAMA.
2006. Scheen AJ et al. Lancet. 2006.
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SERENADE Study design
Study Evaluating Rimonabant Efficacy in
drug-NAïve DiabEtic patients
N 278 T2DM (drug naïve) -600 kcal/day
advised to ?PA
PlaceboEnrolled 140 Completed 125
Rimonabant 20 mgEnrolled 138 Completed 111
Primary endpoint Change in A1CSecondary
endpoints ? weight and waist circumference, FG,
insulin, C-peptide, HOMA-IR, HDL-C, TG, BP
Follow-up 6 months
Iranmanesh A et al. Diabet Med. 200623(suppl
4)230.NIH. www.clinicaltrials.gov.

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SERENADE Change in A1C at 6 months
Placebo
Rimonabant 20 mg
P 0.0002
Baseline A1C 7.9
Iranmanesh A et al. Diabet Med. 200623(suppl
4)230.
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Summary

• Multiple cardiometabolic risk factors ?CVD risk
• Abdominal adiposity, ?HDL-C, ?TG, ?BP, ?glucose
• Moderate weight loss ?cardiometabolic risk
• Significantly improves cardiometabolic risk
  factors
• Encourages continued health-promoting behaviors
  and adherence to management plan
• CB1 receptor blockade provides a novel approach
  to treat cardiometabolic risk factors
• Indirectly (via weight loss)
• Directly (via actions in peripheral tissues)

Gelfand EV, Cannon CP. J Am Coll Cardiol.
2006471919-26.
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Ongoing trials with rimonabant in abdominal
adiposity
Study Concomitant conditions Primary endpoints
ADAGIO-Lipids Dyslipidemia Change in HDL-C and TG
ARPEGGIO T2DM Change in A1C
AUDITOR MetSCarotid atherosclerosis Progression of carotid atherosclerosis
CRESCENDO High CV risk MI, stroke, CV death
RAPSODI IFG and/or IGT Progression to T2DM
RIO-Asia Change in weight
STRADIVARIUS Smoking and/or MetS Progression of coronary atherosclerosis (IVUS)
VICTORIA MetS Change in visceral fat
NIH. www.clinicaltrials.gov.
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Current and emerging pharmacologic combinations
for treating cardiometabolic risk
Adiposity
Dysglycemia
Hypertension
Dyslipidemia
Fat absorption inhibitorsNE and serotonin
reuptake inhibitors
DPP-IV inhibitorsGLP-1 agonistsInsulinInsulin
secretagoguesInsulin sensitizers
ACEIsARBsAlpha-blockersBeta-blockersCCBsDiure
ticsVasodilators
Cholesterol absorption inhibitorsFibratesNico
tinic acidStatins
CB1 receptor blockers?
Adapted from Gerich JE. Met Syn Rel Dis.
20064315-27.Krentz AJ. Met Syn Rel Dis.
20064328-41.
Added to lifestyle modification
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Managing cardiometabolic risk
AdiposityA1C
A
B
Blood pressure
C
Cholesterol
D
DietDont smoke
E
Exercise
Adapted from Cohen JD. Lancet. 2001357972-3.