Rimonabant: New therapeutic option for managing cardiometabolic risk

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RimonabantNew therapeutic option for managing
cardiometabolic risk
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Unmet needs in obesity and the metabolic syndrome

• Obesity, implicated in metabolic syndrome and
  diabetes, has reached epidemic proportions
• Increased prevalence of these conditions is
  projected to have a major impact on CV disease
  and associated costs of care
• Even modest weight loss (510) can reduce
  cardiometabolic risk factors
• Current behavioral and dietary approaches to
  weight loss have limited success
• New approaches to weight loss are urgently needed

Gelfand EV, Cannon CP. J Am Coll Cardiol.
2006471919-26.NIH Expert Panel. Obes Res.
19986(suppl 2)51S-209S.
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Endocannabinoid system (ECS) Overview
Endocannabinoid ligands

• Produced on demand
• Act locally
• Inactivated rapidly
• Bind to transmembrane G-protein
  receptors,principally inhibiting
  neurotransmitter release

Cannabinoid receptor type 1 (CB1)
Cannabinoid receptor type 2 (CB2)
Cannabinoid receptor type 1 (CB1)
Immune cells
Most widespread CB receptor (brain, spinal cord
peripheral nervous system, organs, tissues)
Gelfand EV, Cannon CP. J Am Coll Cardiol.
2006471919-26.Pagotto U et al. Ann Med.
200537270-5.
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Implications of CB1 receptor activation
Central nervous system
Peripheral tissue
Liver
GI tract
Adipose tissue
Skeletal muscle
Hypothalamus
Limbic system
?Appetite
?Motivation to eat/smoke
?Lipogenesis Altered glucose metabolism
Gelfand EV, Cannon CP. J Am Coll Cardiol.
2006471919-26.Pagotto U et al. Ann Med.
200537270-5.

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Overview of rimonabant clinical trial programs
for the treatment of multiple cardiometabolic
risk factors

• Rimonabant In Obesity (RIO)
• RIO-Europe
• RIO-Lipids
• RIO-North America (NA)
• RIO-Diabetes
• Studies with Rimonabant and Tobacco Use (STRATUS)
• STRATUS-United States
• STRATUS-Europe
• STRATUS-Worldwide
• Strategy to Reduce Atherosclerosis Development
  Involving Administration of RimonabantThe
  Intravascular Ultrasound Study (STRADIVARIUS)

Gelfand EV, Cannon CP. J Am Coll Cardiol.
2006471919-26.
6
Rimonabant In Obesity (RIO) program
Després J-P et al. N Engl J Med. 2005.Pi-Sunyer
FX et al. JAMA. 2006. Gelfand EV et al. J Am Coll
Cardiol. 2006.
Hypertension and/or dyslipidemia RIO-NA
Rimonabant patients re-randomized at 1 year to
placebo or continued rimonabant
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RIO clinical trial program Efficacy overview
RIO-Europe, RIO-Lipids, RIO-NA Placebo-corrected
change from baseline at 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.
P 0.002 vs placebo P 0.02 vs placebo
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Significant decrease in metabolic syndrome
Rimonabant 20 mg
?51
?39
?54
(n 599)
(n 346)
(n 1222)
Van Gaal LF et al. Lancet. 2005.Després J-P et
al. N Engl J Med. 2005.Pi-Sunyer FX et al. JAMA.
2006.
ATP III criteria P lt 0.001 vs placebo
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RIO clinical trial program Safety and
tolerability overview

• Most common drug-related adverse event was mild
  nausea
• Rimonabant 5 mg (5.17.2) 20 mg (11.212.9)
• Adverse event-related discontinuation rate was
  similar or slightly higher vs placebo
• Rimonabant 5 mg (8.39.4) 20 mg (12.815.0)
  placebo (7.09.2)
• Changes in anxiety and depression scores (HAD
  scale) were similar across treatment and placebo
  groups

Van Gaal LF et al. Lancet. 2005.Després J-P et
al. N Engl J Med. 2005.Pi-Sunyer FX et al. JAMA.
2006.
HAD Hospital Anxiety and Depression
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Rimonabant No significant effect on mood
HAD scale Scores at 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.
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Rimonabant RIO program summary

• Over 1 year, rimonabant 20 mg combined with diet
  demonstrated
• Significant decreases in weight and waist
  circumference
• Weight loss 14.015.3 lbs absolute change,
  10.412.0 lbs placebo-corrected change
• Favorable changes in cardiometabolic risk factor
  profile

Van Gaal LF et al. Lancet. 20053651389-97.
Després J-P et al. N Engl J Med.
20053532121-34.Pi-Sunyer FX et al. JAMA.
2006295761-75.
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Rimonabant Emerging therapeutic potential

• Cannabinoid receptor blockade is a novel approach
  to treatment of cardiometabolic risk factors
• Any degree of weight loss can impact metabolic
  syndrome and diabetes, ultimately reducing CV
  risk
• Moderate weight loss encourages continued
  health-promoting behaviors and adherence to
  medical therapy

Gelfand EV, Cannon CP. J Am Coll Cardiol.
2006471919-26.