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Clinical evaluation of CB 1 receptor blockade

Clinical evaluation of CB 1 receptor blockade. Rimonabant clinical trial program. Rimonabant In Obesity (RIO) program. Randomized, double-blind, placebo-controlled trials.

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Clinical evaluation of CB 1 receptor blockade

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  1. Clinical evaluation of CB1 receptor blockade Rimonabant clinical trial program

  2. Rimonabant In Obesity (RIO) program Randomized, double-blind, placebo-controlled trials 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

  3. 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 < 0.001, †P < 0.0001, ‡P < 0.05 vs placebo

  4. RIO program: Decreased metabolic syndrome incidence 39% 51% 54% 15% 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

  5. RIO program: Safety and tolerability Rimonabant 20 mg • CNS adverse effects* • Dizziness (5.6%–10.4%) • Insomnia (5.8%–6.4%) • Anxiety (5%–8.7%) • Depressed mood (5.2%) • GI adverse effects* • Nausea (11.2%–12.9%) • Diarrhea (5.3%–7.2%) • Adverse effect-related discontinuation rates • Rimonabant (12.8%–15%) • Placebo (5%–9.2%) • Overall discontinuation rates • Rimonabant (32%–44.9%) • Placebo (33.6%–49.1%) 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

  6. RIO program: No significant effect on mood Hospital Anxiety and Depression (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. Scheen AJ et al. Lancet. 2006. Zigmond AS, Snaith RP. Acta Psychiatr Scand. 1983. HAD scale: 0–7 = normal;8–10 = borderline symptoms; ≥11 = significant symptoms

  7. RIO program: Mood at 1 year n = 1545 in rimonabant 20 mg group 0-7 8-10 ≥11 Baseline HAD depression score No impairment Improved Impairment HAD scores: 0-7 = normal, 8-10 = borderline symptoms, ≥11 = significant symptoms Pi-Sunyer FX. JAMA. 2006;296:650-651.

  8. RIO clinical trial program efficacy summary Rimonabant 20 mg combined with diet over 1 year • Significant decreases in weight and waist circumference • 11.7–16.4 lbs absolute loss • 8.7–12.0 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.

  9. 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: Δ weight and waist circumference, FG, insulin, C-peptide, HOMA-IR, HDL-C, TG, BP Follow-up: 6 months Iranmanesh A et al. Diabet Med. 2006;23(suppl 4):230.NIH. www.clinicaltrials.gov.

  10. SERENADE: Change in A1C at 6 months Placebo Rimonabant 20 mg P = 0.0002 Baseline A1C = 7.9% Iranmanesh A et al. Diabet Med. 2006;23(suppl 4):230.

  11. 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. 2006;47:1919-26.

  12. Ongoing trials with rimonabant in abdominal adiposity NIH. www.clinicaltrials.gov.

  13. Current and emerging pharmacologic combinations for treating cardiometabolic risk Adiposity Dyslipidemia Dysglycemia Hypertension Fat absorption inhibitorsNE and serotonin reuptake inhibitors ACEIsARBsAlpha-blockersBeta-blockersCCBsDiureticsVasodilators Cholesterol absorption inhibitorsFibratesNicotinic acidStatins DPP-IV inhibitorsGLP-1 agonistsInsulinInsulin secretagoguesInsulin sensitizers + CB1 receptor blockers? Adapted from Gerich JE. Met Syn Rel Dis. 2006;4:315-27.Krentz AJ. Met Syn Rel Dis. 2006;4:328-41. Added to lifestyle modification

  14. Managing cardiometabolic risk A AdiposityA1C B Blood pressure C Cholesterol D DietDon’t smoke E Exercise Adapted from Cohen JD. Lancet. 2001;357:972-3.

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