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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 . (>6600 patients enrolled). RIO - North America: 2-year treatment RIO - Europe: 2-year treatment RIO - Lipids: 1-year treatment

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Rimonabant: A new approach to multiple cardiometabolic risk factors

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  1. Rimonabant: A new approach to multiple cardiometabolic risk factors Version 1.1 29 April 2005

  2. RIOprogramme RIO: Rimonabant In Overweight/Obesity (>6600 patients enrolled) • RIO-NorthAmerica: 2-year treatment • RIO-Europe: 2-year treatment • RIO-Lipids: 1-year treatment • RIO-Diabetes: 1-year treatment

  3. Rimonabant In Overweight/Obesity N=6627 Pi-Sunyer. Obes Res 2004, 12(Suppl)108-OR, A27

  4. Placebo run-in Single-blind Treatment period: 1 or 2 years double-blind Screening Re-randomization: RIO-NA Mild hypocaloric diet, reduced by 600 kcal/day Placebo Placebo Rimonabant 5 mg Placebo Placebo Rimonabant 5 mg Rimonabant 20 mg Placebo Rimonabant 20 mg Week - 6 Week - 4 Week 0 Inclusion Randomization Week 52 Inclusion Randomization Week 104 RIO programme study design Pi-Sunyer. Obes Res 2004, 12(Suppl)108-OR, A27

  5. 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

  6. Associated medical conditionsindicated at baseline or screening *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, 2831 October

  7. Rimonabant induces consistent changes in: Waist circumference Weight change

  8. 0 -2 -4 -6 -8 -10 0 4 8 12 16 20 24 28 32 36 40 44 48 52 LOCF Consistent Changes in Waist Circumference Completers Placebo R 20 mg -4.5cm* Waist circumference change (cm) Placebo R 20 mg -8.5cm* Placebo R 20 mg 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

  9. 0 Placebo -2 Rimonabant 20 mg -4 Weight change (kg) Placebo -6 Rimonabant 20 mg -8 -10 0 16 32 48 Weeks Placebo Rimonabant 20 mg Consistent weight change at 1 year Completers 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

  10. Placebo Rimonabant 5 mg Rimonabant 20 mg Changes in weight & waist circumference at 1-year: RIO-Europe Completers Waist (cm) Weight (kg) Waist circumference change (cm) Weight change (kg) - 3.6 - 4.5 - 4.8 p=0.042 - 5.3 - 8.5 p<0.001 - 8.6 p<0.001 Weeks 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) ITT 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) L.Van Gaal, Lancet 2005; 365: 1389-97

  11. 44.3% 50 p<0.001 38.2% 39.0% 45 p<0.001 p<0.001 40 35 Percent (%) 30 25 12.4% 20 13.6% 10.3% 15 10 5 RIO~Europe RIO~Lipids 0 Placebo Rimonabant 20 mg Weight loss ≥ 10% at 1-year Completers L.Van Gaal, Lancet 2005; 365: 1389-97, X. Pi-Sunyer, Circulation 2005:111(13);1727, N. Finer , Poster presented at IASO congress 2004

  12. Rimonabant produces consistent change in metabolic parameters: 1 year results • Lipids (triglycerides, HDL) • Insulin resistance (HOMA)

  13. Change in HDL-cholesterol and triglycerides: RIO-Europe 30 27.0% p<0.001 25 6.6% 4.9% 20 19.0% % change 17.3% 15 10 5 -10.6% p<0.001 0 0 4 8 12 14 20 24 28 32 36 40 44 48 52 Placebo Rimonabant 5 mg Rimonabant 20 mg Completers HDL-cholesterol Triglycerides % change Weeks Weeks 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) L.Van Gaal, Lancet 2005; 365: 1389-97

  14. Improvements in lipids adjusted forweight loss: RIO-North America 10 44% Weight-dependent effect Overall effect: + 7.2% 5 56% Weight-independent effect TG 0 Weight-independent effect 47% % change HDL-C -5 Overall effect: - 13.2% -10 Weight-dependent effect 53% -15 20 mg vs placebo p=0.008 20 mg vs placebo p<0.001 X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

  15. Improvement in fasting insulin and insulin resistance adjusted for weight loss:RIO-North America 1 Year Analysis 0.0 0.0 50% Weight- dependent effect 51% Weight- independent effect 50% Weight- independent effect 2 - 0.5 - 0.2 - 1.0 - 0.4 Change in HOMA (%) Overall effect - 0.80* Change in fasting insulin (µU/mL) 49%Weight-dependent effect - 1.5 Overall effect - 2.8* - 2.0 - 0.6 - 2.5 - 0.8 HOMA-IR 20 mg vs Placebo *p<0.001 FASTING INSULIN 20 mg vs Placebo *p<0.001 - 3.0 X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

  16. AUC ulU/mL*min AUC ulU/mL*min Rimonabant 20mg 110 Placebo With MS Without MS With MS Without MS 100 110 90 100 80 90 70 80 60 ulU/mL 70 50 60 ulU/mL 40 50 30 40 20 30 10 10 20 0 0 0 mn 30 mn 60 mn 90 mn 120 mn Time 0 mn 30 mn 60 mn 90 mn 120 mn Baseline with MS Baseline without MS Time Year 1 without MS Year 1 with MS Insulin during OGTT among patients with/without metabolic syndrome (MS) at baseline: RIO-Lipids ITT-LOCF R, Després J-P. Presented at the ACC congress, March 2004, Abstr. 409-1

  17. 3.2 3.1 3.1 3.1 3.0 3.0 2.8 HOMA (%) 2.8 2.6 2.6 2.4 Placebo Rimonabant 20 mg Rimonabant 5 mg Effect on HOMA-derived insulin resistance: RIO-Europe  - 0.7  0.3 p=0.005 Completers 1 year Baseline ITT LOCF 5 mg vs placebo: ns 20 mg vs placebo: p=0.003 L.Van Gaal, Lancet 2005; 365: 1389-97

  18. Changes in leptin and adiponectin: RIO-Lipids ITT-LOCF Leptin Adiponectin  - 3.8 ng/mL p<0.001  1.6 g/mL p=0.001 10 22 8.2 6.7 20 18 18 18 8 41% 5.9 5.8 18 6 Adiponectin levels (g/mL) Leptin levels (ng/mL) 16 14 4 14 2 12 0 10 Placebo Rimonabant 20 mg Placebo Rimonabant 20 mg Baseline 1 Year JP. Després, presented as a poster in ENDO congress 2004, Abst P1-345

  19. Metabolic syndrome NCEP-ATP IIICriteria To fulfill the diagnostic criteria for the metabolic syndrome patients must meet three of the following criteria: • 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 NCEP-ATP-III, JAMA 2001, 285: 2486-2497

  20. 0 - 8% - 10 - 21% - 21% - 20 - 39% p<0.001 Reduction in metabolic syndrome (%) - 30 - 40 - 51% p<0.001 - 53% p<0.001 - 50 - 60 Rimonabant 20 mg Placebo Reduction in metabolic syndrome 1 year ITT 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

  21. Rimonabant induces improvement in atherogenic parameters

  22. 262 259.4 259.3 259.1 258.4 260 258 LDL peak particle size (Å) 256 254 252 250 Placebo Rimonabant 20 mg LDL peak particle size: RIO-Lipids ITT-LOCF  1.2 Å p<0.001 Baseline 1 Year Data on file

  23.  6.3% p<0.001  - 4.7% p=0.002 41.2 45 40.2 40.0 34 40 32 29.5 35.1 30 35 26.2 % large LDL particles % small LDL particles 25.8 28 24.4 30 26 24 25 22 20 20 Placebo Rimonabant 20 mg Placebo Rimonabant 20 mg Baseline 1 Year Change in proportion of small and large LDL particles: RIO-Lipids ITT-LOCF Proportion of large LDL particles Proportion of small LDL particles R, Després J-P. Presented at the ACC congress, March 2004, Abstr. 409-1

  24.  - 0.6 mg/L p=0.007 5 3.7 3.6 3.2 4 2.7 3 CRP levels (mg/L)*  27% 2 1 0 Placebo Rimonabant 20 mg Baseline 1 Year C-reactive protein : RIO-Lipids ITT-LOCF * Excluding values>10mg/L R, Després J-P. Presented at the ACC congress, March 2004, Abstr. 409-1

  25. Rimonabant maintains metabolic benefits over 2 years

  26. Waist circumference (cm) change from baseline at 2 years (Mean + SEM) 0 - 2 - 3.4 ± 0.5 cm - 4 - 3.8 ± 0.4 cm Waist circumference (cm) - 6 - 7.6 ± 0.4 cm - 8 - 10 52 68 84 100 LOCF Placebo Rimonabant 20 mg/Placebo Rimonabant 20 mg/20 mg Waist circumference maintenance over 2 years in re-randomized patients:RIO-North America ITT-LOCF Weeks X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

  27. 0 - 2.3 ± 0.5 kg - 3 - 3.2 ± 0.4 kg - 6 Weight change (kg) - 7.4 ± 0.4 kg - 9 - 12 LOCF 52 60 68 76 84 92 100 Weeks Placebo Rimonabant 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) X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

  28. ITT (LOCF) Placebo Placebo 0 Rimonabant 20 mg Rimonabant 20 mg -2 -4 Waist(cm) -6 -8 -10 -12 0 4 12 20 28 36 44 52 60 68 76 84 92 104 LOCF Weeks RIO~EU COMPLETERS COMPLETERS 20 mg vs. placebo: -4.1cm (p<0.001) Consistent Waist Circumference Changes in RIO Studies RIO~NA 20 mg vs. placebo: -4.2cm (p<0.001) Van Gaal L., . Presented at the ACC congress, March 2005, presentation 410-13

  29. 80 80 *p<0.001 *p<0.001 62.5%* 60 60 % of patients % of patients 36.7% 33.2% 40 40 32.8%* 20.0% 16.4% 20 20 0 0 Rimonabant 20 mg Rimonabant5 mg Placebo Rimonabant 20mg Rimonabant5 mg Placebo Weight loss in completers on the same treatment for 2 years: RIO-North America >5% weight loss >10% weight loss ITT LOCF Placebo: 8.3% 5 mg: 8.5% (ns vs placebo) 20 mg: 16.5% (p<0.001 vs placebo) ITT LOCF Placebo: 19.3% 5 mg: 19.0% (ns vs placebo) 20 mg: 39.7% (p<0.001 vs placebo) X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

  30. 34.8% 34.7% 40 31.7% Baseline 30 29.9% 29.2% 22.5% p<0.001 20 2 years of treatment 10 0 Placebo Rimonabant 5 mg Rimonabant 20 mg Change in metabolic syndrome status at 2 years: RIO-North America ITT, LOCF Patients (%) X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

  31. Consistent Reduction in Metabolic Syndrome at 2Years COMPLETERS Placebo Rimonabant20 mg Placebo Rimonabant20 mg 0 -10 -20 -28 % -34 % -30 -40 -54 % -54% -50 -57% -57 % OR= 0.599 (p<0.05) -60 OR= 0.483 (p<0.05) Reductionin Metabolic Syndrome (%) Van Gaal L., . Presented at the ACC congress, March 2005, presentation 410-1 X. Pi-Sunyer, presented at a late breaking session at the AHA congress 2004

  32. Completers Placebo Rimonabant 5 mg Rimonabant 20 mg 30 24.5% 25 20 15.6% 15 HDL-C (% change) 13.8% 10 5 0 0 12 24 36 52 64 76 88 104 Weeks HDL-cholesterol over 2 years: RIO-North America ITT-LOCF 5 mg vs placebo: ns 20 mg vs placebo: p<0.001 Data on file

  33. Placebo Rimonabant 5 mg Rimonabant 20 mg 15 15.3 15.0 13 Fasting insulin (µIU/ml) 13.1 11 9 0 12 24 36 52 64 76 88 104 LOCF Weeks D 20 mg vs Placebo: - 1.8 ± 0.7 µIU/ml;p=0.014 Fasting insulin over 2 years by visit: RIO-North America ITT-LOCF Data on file

  34. Rimonabant improves quality of life

  35. Improvement Placebo Rimonabant 20 mg Improvement in quality-of-life scale Mean IW-quality of life score change from baseline to year 1 16 14 12 10 8 Mean 6 4 2 0 Physical Total Self- Sexual Public Work score esteem comfort function life - 2 - 4 JP. Després, Obes Res 2004, 12 (suppl) 231-P, A 61

  36. Safety and tolerability of rimonabant

  37. RIOprogramme pooled 1-year overall safety Rimonabant Rimonabant Placebo N=1254 5 mg N=2162 20 mg N=2164 Subjects with any adverse event 82.5% 83.0% 86.1% Subjects with any serious adverse event 4.1% 5.0% 5.6% Deaths n=1 n=2 n=1 Subjects discontinued due to adverse event 7.7% 8.9% 13.6% Pooled year 1 data: RIO-LIPIDS, RIO-EUROPE, RIO-NORTH AMERICA Data on file

  38. RIO programme pooled 1-year overall safety: AEs leading to discontinuation According to MedDRA code, 0.5% in any rimonabant group: in the 3 main system organ class. Data on file

  39. RIOprogramme pooled 1-year cardiovascular safety Rimonabant 20 mg Placebo Mean (SD) N subjects N subjects Mean (SD) Blood pressure (mmHg) (ITT) - 0.8 (12.3) - 0.1 (11.6) Supine SBP change 1225 2130 Supine DBP change - 0.2 (8.1) - 0.7 (8.4) 0.6 (8.2) - 0.1 (7.9) 1850 1052 Heart rate change (bpm) Mean QTcB changes 1052 - 2.0 (19.7) - 0.6 (19.5) 1850 Data on file

  40. RIO~Europe Overall Safety Placebo Rimonabant 5mg Rimonabant 20mg n=305 n=603 n=599 Subjects discontinued due to adverse event Yr 1 and Yr 2 13.1 % 10.9 % 18.9 % Year 1 9.2 % 8.3 % 14.5 % 2.6 % 3.9 % 4.4 % Year 2 Van Gaal L., . Presented at the ACC congress, March 2005, presentation 410-13

  41. 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

  42. 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

  43. DISCLAIMERRimonabant is not yet licensedThis information is provided for medical information purpose

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