New opportunities for targeting. multiple lipid pathways. Michel FARNIER, DIJON, FRANCE

Transcription

1 New opportunities for targeting multiple lipid pathways Michel FARNIER, DIJN, FRANCE

2 Lipid lowering drug therapy 60s and 70s - nicotinic acid -resins 70s to 90s - fibrates the 90s - statins

3 Coronary heart disease (CHD) event rates in secondary prevention trials are directly proportional to the on-treatment LDL-C levels y = x R² = p < S-P CHD events (%) PRVE-IT-AT HPS-S PRVE-IT-PR HPS-P LIPID-P 4S-S CARE-P LIPID-S CARE-S LDL cholesterol (mg/dl) P S PR AT Placebo Statin Pravastatin Atorvastatin Keefe et al. JACC 2004; 43:

4 Previous lipid intervention strategies for preventing/reversing atherosclerosis Reduce LDL-C - statins Increase HDL-C - fibrates,, niacin

5 Event rates in subjects treated with statins or fibrates are up to 35% lower than in those on placebo. But events are by no means eliminated by the therapy. The challenge now is to devise therapies that can reduce events by much more than can be achieved by the existing medications.

6 Lipid lowering drug therapy 60s and 70s - nicotinic acid -resins 70s to 90s - fibrates the 90s - statins the new millennium - combination with novel agents

7 Future Research in Hyperlipidemia What are the major targets of new LRD? Effect on single risk factor LDL HDL Effect on multiple risk factors Atherogenic Lipid Profile (ALP) Type 2 diabetes, Metabolic Syndrome Effect on atherogenesis

8 Combination therapy in in hyperlipidemia What are the present / near future options in clinical practice? Effect on single risk factor LDL HDL Effect on multiple risk factors TG, HDL, small dense LDL Effect on atherogenesis

9 Combination therapy in in hyperlipidemia What are the present / near future options in clinical practice? Effect on single risk factor LDL Statin + BAS (resin( resin) Statin + Ezetimibe HDL

10 Altmann et al., Science 2004;303:1204 Regulation of intestinal Cholesterol Absorption (NPC1L1 = Niemann-Pick C1 Like 1 Protein) Intestinal Lumen Enterocyte Lymph LXR Fatty Acids TG H TG TG H Cholesterol Micelles ABCG5 ABCG8 Plant Sterols H Cholesterol Fatty Acids ACAT 2 MTP H apo B-48 Chylomicrons H Plant Sterols R NPC1L1 Protein H Plant Sterols Cholesterol CE Blood

11 Regulation of intestinal Cholesterol Absorption Intestinal Lumen Enterocyte Lymph LXR Fatty Acids TG H TG TG H Cholesterol Micelles ABCG5 ABCG8 Ezetemibe Plant Sterols H Cholesterol Fatty Acids ACAT 2 MTP H apo B-48 Chylomicro ns H Plant Sterols R NPC1L1 Protein H Plant Sterols Cholesterol CE

12 Dual Inhibition: Ezetimibe and Statin Statin Synthesis of Cholesterol Bile LDL-C Cholesterol absorption Intestine DARM Ezetimibe Dietary cholesterol Excretion

13 LDL-C Reduction in Usual Doses Mean % changes from end to starting level Eze/Simva 10/20 mg (n=86) - 51%* Simvastatin 20 mg (n=89) -35% Ezetimibe/Simvastatin Simvastatin * p < vs. Simvastatin Goldberg A et al, Mayo Clin Proc. 2004; 79:

14 Percentage of patients reaching target levels of LDL-Cholesterol < 100 mg/dl at a typical dose of Eze/Simva 10/20 EZE/Simva 10/20 mg (n=108) 83%* Simvastatin 20 mg (n=246) 46% % of patients with LDL <100 mg/dl in week 5 (Period 1) * p < vs. Simvastatin 20 mg Data on file MSD and Schering-Plough

15 Combination therapy in in hyperlipidemia What are the present / near future options in clinical practice? Effect on single risk factor LDL HDL

16 Established and emerging HDL raising approaches New PPARα agonists (fibrates) CETP inhibitors LXR agonists Endothelial lipase inhibitors HDL mimetics Niacin receptor agonists

17 Linsel-Nitschke, Tall Nature Reviews/Drug Discovery 2005

18 pportunities for novel HDL-raising therapies Drug target Class of protein Expected biochemical mechanism Niacin receptor agonists GPCR TG lowering, HDL increase (PUMA-G, HM74) LXR agonists Nuclear receptor ABCA1 expression, cholesterol efflux and HDL formation CETP-inhibitors Lipid transfer protein HDL clearance Endothelial lipase inhibitors Enzyme HDL clearance Infusion of peptides related to ApoA1 Increased removal of cholesterol from atheroma

19 Combination therapy in in hyperlipidemia What are the present / near future options in clinical practice? Effect on single risk factor LDL HDL Statin + CETP inhibitor

20 CETP inhibitors Drugs in development : Torcetrapib or CP-529, 414 JTT 705

21 The reverse cholesterol transport route Peripheral tissues (ABC-A1, A1, ABC-G1/G4 transporters) Macrophage ApoA1 interaction HDL VLDL CETP SRB1 interaction LPL HL Small dense LDL Liver LDL receptor

22 CETP inhibition as an anti-atherogenic atherogenic strategy How strong is the evidence base for CETP inhibition and its relationship to atherosclerosis?

23 Effect of CETP on Atherogenicity Transgenic Mice No endogenous CETP expression in wildtype mice High background HDL levels No athero without diet or transgenic induction Introduction of CETP lowers HDL-C Bruce et al. Annu Rev Nutr. 1998;18: Foger et al. Circulation. 1997;96:1. Hayek et al. J Clin Invest. 1995;96: Marotti et al. Nature. 1993;364: Masucci-Magoulas et al. Science. 1997;275:

24 Effect of CETP Inhibition on Atherogenicity Rabbits High endogenous CETP expression Cholesterol diet induces atherosclerosis CETP inhibition elevates HDL-C

25 JTT-705, a CETP inhibitor : inhibits CETP activity by forming a disulphide bond in cholesterol-fed rabbits, increases HDL-C, decreases non-hdl-c and induces a 70% decrease of aortic arch lesions KAMT et al. Nature 2000; 406:

26 Torcetrapib Treatment Inhibits CETP Activity in Rabbits CE Transfer (RFU/sec) 4.5 Control 4.0 CP Treated ~ -75% Weeks of Treatment From: Morehouse et al.aha

27 Effect of Torcetrapib on Lipids and Atherosclerosis in Rabbits Cholesterol (Arbitary Units) Torcetrapib Increases HDL No Change in Non-HDL Week Control Torcetrapib-treated % Aortic Lesion Area Torcetrapib Reduces Aortic Atherosclerosis ~ - 60%* 0 VLDL Retention Time 422 ± ±68 0 Control * p = Torcetrapib LDL 224 ± ± 43 HDL 57 ± 6 Lipoprotein values in mg/dl 208 ± 32 From: Morehouse et al.aha

28 Effects of a CETP inhibitor in normal subjects Clark et al. ATVB 2004; 24 :

29 Torcetrapib: Dose-dependent CETP Inhibition, HDL Raising and LDL Lowering in Healthy Individuals Lipid Profile during Treatment with Torcetrapib versus Placebo for 14 days % Change HDL-C LDL-C TG 0-20 * Torcetrapib (mg) * P< 0.05, P< 0.01, P< Adapted from Clark et al. ATVB 2004, 24:1-9

30 Efficacy of Torcetrapib (with or without Atorvastatin) in subjects with low HDL-C % changes in HDL-C 60% 50% 40% 30% 20% 10% 0% PLB = placebo T = torcetrapib 0% 1% 9% 8% * p = * 28% * 24% 45% 33% 55% PLB T10 T30 T60 T90 * * * * 40% T alone T + Atorva 20 mg Davidson et al. JACC 2005; 45 (Supplt A) : 394A

31 Efficacy of JTT-705 in Humans A randomized phase II Dose-Response Study CETP Activity, % of control * * * Placebo n=50 JTT 300mg n=48 JTT 600mg n=47 JTT 900mg n=52 0,45 0,4 0,35 0,3 0,25 0,2 0,15 0,1 0,05 0 HDL, mmol/l absolute changes ** 0.32 * 0.40 * Placebo n=50 JTT 300mg n=48 JTT 600mg n=47 JTT 900mg n=52 * p < vs placebo ** p < vs placebo de GRTH et al. Circulation 2002; 105:

32 Efficacy of JTT-705 in Humans A randomized phase II Dose-Response Study Treatment with 900 mg JTT-705 for 4 weeks led to a : 37% decrease in CETP activity (p < ) 34% increase in HDL-C (p < ) 7% decrease in LDL-C (p < 0.017) de GRTH et al. Circulation 2002; 105:

33 Combination therapy in in hyperlipidemia What are the present / near future options in clinical practice? Effect on single risk factor LDL HDL Effect on multiple risk factors Statin TG, HDL, + Fenofibrate Statin small dense LDL + Niacin Ezetimibe + Fenofibrate

34 Combination therapy in in hyperlipidemia What are the present / near future options in clinical practice? Effect on single risk factor LDL HDL Effect on multiple risk factors Statin TG, HDL, + Fenofibrate Statin small dense LDL + Niacin Ezetimibe + Fenofibrate

35 Statin-Fibrate combination therapy Rationale Complementary metabolic effects of fibrates and statins Efficacy Combinations with usual doses of statins and fibrates led to : - reductions in LDL-C 40%, TG 50% - increase in HDL-C 20% Farnier. Am J Cardiovasc Drugs 2003; 3: 169 Targeted populations - combined hyperlipidemia - type 2 diabetes or metabolic syndrome

36 Effectiveness and tolerability of Simvastatin plus Fenofibrate for Combined Hyperlipidemia : The SAFARI trial 12-week, double-blind, randomized study in 619 patients with combined hyperlipidemia (TG mg/dl, LDL-C > 130 mg/dl) % change from baseline TG VLDL-C Non-HDL-C LDL-C HDL-C * Baseline * Simva 20 (n=207) * Baseline * Baseline Simva 20 + Feno 160 (n=411) * Baseline * p < Grundy et al. Am J Cardiol 2005; 95:

37 SAFARI Trial : effects on LDL-C C particle subclasses B (Small, Dense) Proportion of total LDL-C AB (Intermediate) A (Larger, Buoyant) N = 618 * * Significantly different pattern between the 2 treatments groups (p < 0.001) Grundy et al. Am J Cardiol 2005; 95:

38 Statin-Fibrate combination therapy Safety use restricted because of severe myopathy and rhabdomyolysis associated with statin-gemfibrozil combination therapy and with cerivastatin-fibrate combination therapy

39 RESULTS : Number of reports of rhabdomyolysis for Fibrate/Statin therapies (1998 to 2002) No. Cases No. Prescriptions No. Cases reported Medications reported 1 dispensed 2 3 per million prescriptions Fenofibrate with Cerivastatin with other statins Fenofibrate total Gemfibrozil with Cerivastatin with other statins Gemfibrozil total Adverse Event Reporting System. U.S. Food and Drug Administration 2 National Prescription Audit Plus report, IMS Health 3 Concomitancy Report, VERISPAN LLC Jones, Davidson. Am J Cardiol 2005; 95:

40 Number of of cases of of rhabdomyolysis in in combination therapy with Statins other than cerivastatin No cases reported per million prescriptions Fenofibrate 15-Fold increase 8.6 Gemfibrozil Jones, Davidson. Am J Cardiol 2005; 95:

41 Alsheikh-Ali Ali et al. Am J Cardiol 2004; 94: Comparative rates of of gemfibrozil- and fenofibrate- associated rhabdomyolysis R (95% CI 8.44 to 13.95) 70 Reports of rhabdomyolysis/one million prescriptions Rhabdomyolysis 5.5 Gemfibrozil Fenofibrate p <

42 VA health care system comparison of Gemfibrozil to Fenofibrate 149 cases of of rhabdomyolysis in in 95,000 patients on statins plus gemfibrozil Rate of of 0.16% No cases of of rhabdomyolysis in in 1500 patients on fenofibrate plus statins Presented by Davidson,, New York, July 2005

43 Statin-Fibrate combination therapy : pharmacokinetic interactions Gemfibrozil Fenofibrate Atorvastatin in C max (expected) No effect Simvastatin in C max by 2 fold No effect Pravastatin in C max by 2-fold No effect Rosuvastatin in C max by 2-fold No effect Fluvastatin No effect No Effect Lovastatin in C max by 2.8-fold Not available Cerivastatin in C max by 2-3-fold No effect

44 Statin-Fibrate interactions Possible explanation = Glucuronidation Glucuronidation is a pathway for the elimination of the active hydroxy acid metabolites of statins Gemfibrozil inhibits simvastatin, atorvastatin, rosuvastatin and more prominently cerivastatin glucuronidation Fenofibrate has less inhibitory effect on statin glucuronidation May explain the lack of significant drug interaction between fenofibrate and statins Prueksaritanont et al. JPET 2002; 301: DMD 2002; 30:

45 ACCRD: NIH/NHLBI Trial Action to Control Cardiovascular Risk in Diabetes Does a therapeutic strategy that targets HbA1c < 6% reduce the rate of CVD versus a target of 7.5% Does a therapeutic strategy of fibrate therapy plus statin therapy reduce CVD greater than statin therapy alone Simvastatin 20mg + Fenofibrate 160mg Simvastatin 20mg Intensive Glycemia Control Standard Glycemia Control

46 Combination therapy in in hyperlipidemia What are the present / near future options in clinical practice? Effect on single risk factor LDL HDL Effect on multiple risk factors Statin TG, HDL, + Fenofibrate Statin small dense LDL + Niacin Ezetimibe + Fenofibrate

47 Lipid-Altering effects of Statin-Niacin regimens Study Study /year /year Statin/dose, Niacin Niacintype/dose, LDL LDL HDL HDL TG TG mg/d mg/d g/d g/d % % % Davignon et et al./1994 Pravastatin,, SR, SR, Jacobson et et al./1994 Fluvastatin,, IR, IR, < Vacek Vacek et et al./1995 Lovastatin,, SR, SR, Keefe et et al./1995 Pravastatin,, IR, IR, Gardner et et al./1996 Lovastatin,, IR, IR, Pasternak et et al./1996 Pravastatin,, SR, SR, Stein Stein et et al./1996 Simvastatin,, SR, SR, Kashyap et et al./2000 Lovastatin,, ER, ER, ER : extended-release; IR : immediate-release; SR : sustained-release Jacobson. Curr Atheroscler Rep 2001; 3:

48 Comparison of Niacin ER/Lovastatin with standard doses of Atorvastatin and Simvastatin : The Advicor Versus ther Cholesterol-modulating Agents Trial Evaluation (ADVCATE) Study Design Week 315 patients with LDL-C 160 mg/dl without CHD or 130 mg/dl with CHD TG < 300 mg/dl HDL-C C < 45 mg/dl (men( men) < 50 mg/dl (women( women) NIACIN ER / LVASTATIN (mg) 500/ /40 NIACIN ER / LVASTATIN (mg) 500/ / / /40 ATRVASTATIN (mg) SIMVAVASTATIN (mg) (n= 79) (n= 78) (n= 82) (n= 76) Bays et al. Am J Cardiol 2003; 91:

49 Comparison of Niacin ER/Lovastatin with standard doses of Atorvastatin and Simvastatin % change from baseline at week 16 % change from baseline LDL-C HDL-C TG Lp(a) - 49 * * * Niacin ER/Lovastatin 2000/40 mg Atorvastatin 40 mg Simvastatin 40 mg - 31 * * -2 * p 0.05 vs simvastatin p 0.05 vs atorvastatin 0 p 0.05 vs niacin ER/lovastatin Bays et al. Am J Cardiol 2003; 91:

50 Combination therapy in in hyperlipidemia What are the present / near future options in clinical practice? Effect on single risk factor LDL HDL Effect on multiple risk factors Statin TG, HDL, + Fenofibrate Statin small dense LDL + Niacin Ezetimibe + Fenofibrate

51 Co-administration of ezetimibe with fenofibrate in patients with mixed hyperlipidemia Study Design Ratio 1 Placebo (n = 64) FEN 160 mg Week 3 FEN 160 mg (n = 189) EZE 10 mg (n = 187) 3 EZE 10 mg +FEN 160 mg EZE 10 mg +FEN 160 mg (n = 185) Placebo run-in wash-out period 12-week double-blind placebo controlled phase 48-week double-blind extension phase Short-term Farnier et al. Eur Heart J 2005; 26: Long-term McKenney, Farnier, JACC, submitted

52 Co-administration of ezetimibe with fenofibrate in patients with mixed hyperlipidemia (baseline : LDL-C 160 mg/dl, TG 275 mg/dl) LDL-C Response with Treatment 5 0.2* Percent Change in LDL-C Placebo EZE 10 mg -13.4* -5.5* -25 FEN 160 mg FEN 160 mg + EZE 10 mg Data are least square mean percent change (standard error); * p < compared to FEN+EZE Farnier et al. Eur Heart J 2005; 26:

53 Farnier et al. Eur Heart J 2005; 26: Co-administration of ezetimibe with fenofibrate in patients with mixed hyperlipidemia LDL-C Response by TG Subgroup TG 3.1 mmol/l TG > 3.1 mmol/l Percent change in LDL-C ,4* -15,3* -9,9* -27,8 Percent change in LDL-C * -11,5-1,1* -12,9 Placebo (n = 61) EZE 10 mg (n = 173) FEN 160 mg (n = 179) FEN 160 mg + EZE 10 mg (n = 175) Data are least square mean percent change (standard error); * p < compared to FEN+EZE within TG strata

54 Farnier et al. Eur Heart J 2005; 26: Co-administration of ezetimibe with fenofibrate in patients with mixed hyperlipidemia HDL-C Percent changes in HDL-C and TG TG Percent change in HDL-C ,2 3,9 18,8 * 19,0 * Percent change in TG ,2 11,1-43,2 * -44,0 * # Placebo EZE 10 mg FEN 160 mg FEN 160 mg + EZE 10 mg * p < vs Placebo and EZE, # p = vs FEN

55 Farnier et al. Eur Heart J 2005; 26: Co-administration of ezetimibe with fenofibrate in patients with mixed hyperlipidemia Percent change in median hs-crp and fibrinogen hs-crp Fibrinogen Percent change in hs CRP ,1-6,1-28,0 * -27,3 * Placebo EZE 10 mg Percent change in fibrinogen FEN 160 mg FEN 160 mg + EZE 10 mg -0,3-0,3-10,1 * -11,5 * * p < vs Placebo and EZE

56 Conclusions (1) The use of combination therapy for the treatment of dyslipidemia is becoming increasingly important in the management of patients with CHD and multiple risk factors High risk patients often require combined drug therapy to achieve LDL-C C and non-hdl HDL-C C goals, and also to normalize HDL-C C and TG Ezetimibe together with a statin is a novel and beneficial approach, providing dual inhibition of two sources of cholesterol.

57 Conclusions (2) Combination therapy with fenofibrate may be of considerable value in combined/mixed hyperlipidemia,, in diabetic patients and in patients with MS The future of the combined therapies with niacin mainly depends of the tolerability of new forms in development Clinical endpoint studies are required to validate the use of these combination therapies

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