1. Role of Fenofibrate in Diabetic Dyslipidemia

2. Diabetic Dyslipidaemia Occurs in type 2 diabetes mellitus High levels of triglycerides Low levels of HDL-C LDL-C not significantly increased Small, dense LDL particles increased  Atherogenic dyslipidaemia Small, dense LDL HDL-C TG

3. DM macrovascular complications Statins reduce CHD risk by 25% CV risk differs in DM, CHD and CHD and DM combined. Do statins reduce CV risk similarly in all groups? Is there a role for fibrates? DM microvascular complications: statins have no impact on retinopathy (HPS) treatment of DM nephropathy includes lipid control

4. Main trials of statins in diabetics CV risk remains high when HDL is low despite normal LDL ASCOT-LLA study showed less effective Atorvastatin among DM subjects CARDS: CV event reduction by 37% stroke by 48% but risk for major CV event at 10 years remained at 25% ASPEN study did not show significant CHD benefit in low risk DM subjects.

5. Fenofibrate activates PPAR Keating GM, Ormrod D. Drugs 2002;62:1-35  Lipolysis of TG-rich particles  Plasma clearance of TG-rich particles  Oxidation of fatty acids  TG synthesis  Levels of dense LDL subfractions  HDL-c  Lp (a) level Effects on lipid and lipoproteins  Plasma fibrinogen levels  C-reactive protein  Uric acid levels Other effects  Apo AI levels  Apo AII levels  Apo B levels Effects on apolipoproteins Up-regulates the synthesis of cholesterol transporters Effects on cholesterol transporters PPAR

6. Trialn Major CVD event rate (%) RRR (%) p-Value controldrug Primary prevention HHS 1 Overall:4,08141.427.334<0.02 Diabetes:29213.03.971<0.005 Secondary prevention BIP 2 Overall:3,09015.013.69.40.26 Diabetes:1,47018.414.1250.03 VA-HIT 3 Overall:2,53121.717.3220.006 Diabetes:76929.421.2320.004 1. Frick MH et al. N Engl J Med 1987;317:1237–45 2. The BIP Study Group. Circulation 2000;102:21–7 3. Rubins HB et al. N Engl J Med 1999;341:410–8 BIP = Bezafibrate Infarction Prevention study; HHS = Helsinki Heart Study; RRR = relative risk reduction; VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial. Outcomes in fibrate trials

7. Conclusions STATINS: patients with cardiovascular disease receive significant (greater?) cardiovascular benefits from statin therapy But STATINS do not remove the risk associated with a low HDL-C or other features of the metabolic syndrome FIBRATES: appear to be specifically effective in people with Type 2 Diabetes and/or the features of the metabolic syndrome in whom the excess coronary risk is significantly reduced. Diabetic patients have not always been evaluated in the statin trials. When they did, there always remained an important residual risk factor.

8. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Trial FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

9. With 9,795 patients, FIELD is the largest clinical outcomes study ever conducted in patients with type 2 diabetes With 7,664 patients without prior cardiovascular disease, FIELD includes the largest group of primary prevention patients with type 2 diabetes FIELD was designed to assess whether intervention with fenofibrate could prevent cardiovascular events in patients with type 2 diabetes, with or without dyslipidemia FIELD A unique study in type 2 diabetes FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

10. FIELD: the largest clinical outcomes study ever conducted in patients with type 2 diabetes (1) 1.FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849- 61 2.Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7-22. 3.Colhoun HM, Betteridge DJ, Durrington PN et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS) multicentre randomised placebo-controlled trial. Lancet 2004; 364 (9435): 685-96. 4.Sever PS, Dahlof B, Poulter NR et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361 (9364): 1149- 58. 5.Rubins BH, Robins ST, Collins D et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999; 341: 410-8. 6.Sacks FM, Pfeffer MA, Moye LA et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001-9. 7.The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383-9.

11. Study design 5-year, double-blind, placebo-controlled study All patients received usual care, including the option to add other lipid-lowering therapies 9,795 patients Fenofibrate 200 mg/day (n = 4,895) Placebo (n = 4,900) Average follow-up: 5 years and 500 CHD events FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

12. First occurrence of nonfatal MI or CHD death Outcomes Primary outcome Total CVD events* (MI, stroke, CVD death, coronary and carotid revascularisation) Coronary & peripheral revascularisation Secondary outcomes Tertiary outcomes Progression of renal disease Laser treatment for diabetic retinopathy Nonfatal cancers Vascular & neuropathic amputations Hospitalisation for angina pectoris Hospital admissions Stroke CHD deaths CVD deaths Total mortality * Primary outcome for subgroup analyses FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

13. Inclusion criteria Type 2 diabetes Age 50–75 years Total cholesterol 115–250 mg/dl (3.0–6.5 mmol/L), plus either: Total cholesterol : HDL-cholesterol ratio ≥ 4, or Triglycerides > 89 mg/dl (1 mmol/L) No clear indication for lipid-lowering therapy FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

14. Exclusion criteria Triglycerides > 443 mg/dl (5 mmol/L) Concurrent lipid-lowering therapy at baseline lipid-lowering agents could be added after randomization FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

15. * TG > 150 mg/dl (1.7 mmol/L) and HDL-c < 40 mg/dl (1 mmol/L) for men or < 50 mg/dl (1.3 mmol/L) for women Baseline characteristics summary Total population: 9,795 Male gender62.7 No prior cardiovascular disease (%)78.3 Diabetes management with diet plus one oral antidiabetic agent (%)59.5 Median duration of diabetes (years)5 Median HbA 1c (%)6.9 Diabetic complications (%) Retinopathy8.3 Nephropathy2.8 Lipid parameters (mg/dl [mmol/L]) Total cholesterol (mean)194 [5.0] LDL-cholesterol (mean)119 [3.1] HDL-cholesterol (mean)42 [1.1] Triglycerides (median)153 [1.7] Dyslipidemia (%)*38 FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

16. FIELD Main results

17. TCLDL-cHDL-cTG Effects of fenofibrate on lipid levels after 4 months (entire cohort) FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

18. Effects of fenofibrate on lipid levels at study close (entire cohort) FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61 TCLDL-cHDL-cTG Percentage change from baseline after close-out (corrected for placebo effect)

19. Drop-outs HR = 1.01 95% CI = 0.93–1.11 p = 0.76 Drop-ins HR = 0.47 95% CI = 0.44 – 0.51 p < 0.0001 Placebo Fenofibrate 100 80 60 40 20 0 0123456 years Proportion (%) Compliance and use of other lipid- lowering agents FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

20. Cumulative risk (%) Years from randomization 4,900 4,895 4,835 4,837 4,741 4,745 4,646 4,664 4,547 4,555 2,541 2,553 Placebo Fenofibrate 837 850 10 8 6 4 2 0 012345 Fenofibrate Placebo 6 Primary endpoint CHD events (nonfatal MI, CHD death) HR = 0.89 95% CI = 0.75–1.05 p = 0.16 Number of patients still followed-up at the given year FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

21. Nonfatal MI HR = 0.76 95% CI = 0.62–0.94 p = 0.010 CHD death HR = 1.19 95% CI = 0.90–1.57 p = 0.22 Placebo Fenofibrate 100 80 60 40 20 0 0123456 years Cumulative risk (%) Primary endpoint CHD events (nonfatal MI, CHD death) FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

22. Cumulative risk (%) HR = 0.89 95% CI = 0.80–0.99 p = 0.035 NNT ≈ 70 15 10 5 0 012345 Fenofibrate Placebo 6 Secondary endpoint Total CVD events Years after randomization 4,900 4,895 4,762 4,771 4,586 4,604 4,419 4,469 4,257 4,307 2,340 2,370 Placebo Fenofibrate 750 775 Number of patients still followed-up at the given year FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

23. p = 0.16 Primary endpoint Primary endpoint, adjusted for new lipid-lowering therapy p = 0.01 Primary endpoint adjusted for new lipid lowering therapy CHD events (nonfatal MI, CHD death) FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

24. Secondary endpoint adjusted for new lipid lowering therapy Total CVD events p = 0.035 Secondary endpoint Secondary endpoint, adjusted for new lipid-lowering therapy p = 0.004 FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

25. FIELD sub-group analysis

26. p = 0.85 p = 0.004 p = 0.035 Subgroup analysis: Secondary endpoint Primary vs secondary prevention (n = 9,795)(n = 7,664)(n = 2,131) p = 0.05* OverallPrimary prevention Secondary prevention * P value for interaction FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

27. FIELD tertiary endpoints

28. Need for laser treatment for retinopathy “This effect cannot be explained by changes in HbA 1c or concomitant medications, or by the minor reduction in blood pressure in the fenofibrate group” P=0.0003 -30 % Microvascular disease Retinopathy FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

29. Progression of microalbuminuria (baseline to study close) RegressionNo changeProgression Placebo (n=4900) 400 (8.2%) 3654 (74.6%) 539 (11.0%) Fenofibrate (n=4895) 462 (9.4%) 3583 (73.2%) 466 (9.5%) Mann-Whitney test:P=0.002 Albuminuria status categories: Normal: <3.5 mg/mmol; microalbuminuria:3.5-<35 mg/mmol; macroalbuminuria: > 35 mg/mol “This effect cannot be explained by changes in HbA 1c or concomitant medications, or by the minor reduction in blood pressure in the fenofibrate group” FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

30. Other tertiary outcomes 300 0 Number of hospitalisations 200 100 PlaceboFenofibrate Hospitalisations for angina pectoris RR = 0.82 (95% CI = 0.69-1.00) p=0.04 100 0 Number of hospitalisations 50 PlaceboFenofibrate Amputations RR = 0.69 (95% CI = 0.48-0.99) p=0.04 252 75 25 5.1 % 209 4.3 % 74 1.5 % 51 1.0 % FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61 -18 % -31 %

31. FIELD Conclusions

32. This landmark trial was the largest ever conducted in patients with type 2 diabetes. It contains the largest group of patients without a prior cardiovascular event ever studied in type 2 diabetes FIELD enrolled a patient population with good overall glycemic control, with and without dyslipidemia Results must be interpreted while taking into account the substantially higher level of statin use in the placebo group FIELD study: Conclusions (1) FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

33. Fenofibrate was associated with a non significant 11 % reduction in the primary endpoint (first nonfatal MI or CHD death; p = 0.16) After adjusting for statin use, fenofibrate was associated with a significant 19 % reduction in the primary endpoint (p = 0.01) FIELD study: Conclusions (2) FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

34. Fenofibrate was associated with a significant 11 % reduction in total CVD events (p = 0.035) When adjusted for statin use, fenofibrate was associated with a 15 % reduction in total CVD events (p = 0.004) In the subset of patients without a prior cardiovascular event, fenofibrate significantly reduced the primary endpoint (total CHD events) by 25 % (p = 0.014) and total CVD events by 19% (p = 0.004) FIELD study: Conclusions (3) FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

35. Treatment with fenofibrate also significantly reduced microvascular events in all tertiary end points progression to albuminuria need for laser treatment for retinopathy amputations* Fenofibrate was well tolerated alone and in combination with statins FIELD study: Conclusions (4) * An endpoint possibly related to micro and/or macrovascular disease FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

36. This is the first time a lipid-lowering agent has reduced rates of both macrovascular and microvascular events in an endpoint study FIELD study: Conclusions (5) FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

37. “The results are likely to be of particular importance among patients without previous cardiovascular disease and in settings where both the prevention of non-fatal macrovascular events and microvascular complications are judged important.” FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

38. Clinical implications of the FIELD study

39. Parameter Value Diabetes duration (y) Age (y) HbA1c (%) LDL-c (mg/dl) HDL-c (mg/dl) Triglycerides (mg/dl) No prior CV disease (%) Coronary event rate (5y) ** 5 (210) 62.2 (6.2) 6.9 (6.17.8) 119 42 153 78 6% Relatively early stage of disease Optimal glucose control - same HbA1c at the end of the trial Overall, 38% dyslipidemic* Most patients in primary prevention The FIELD study population  Moderate 10-year risk  12% * Triglycerides > 150 mg/dl and HDL-c < 40 mg/dl (men) or < 50 mg/dl (women). ** First nonfatal MI or CHD death FIELD Study Investigators. Lancet 2005 Nov 26; 266(9500): 1849-61

40. 1. FIELD Study Investigators. Lancet 2005 Nov 26; 266(9500): 1849-61 2. Colhoun HM et al. Lancet 2004;364:685–96; 3. Heart Protection Study Collaborative Group. Lancet 2003;361:2005-16 The FIELD study population RRR = relative risk reduction; * p < 0.001 Parameter FIELD 1 (n = 9,795) Diabetes duration (y) Age (y) HbA1c (%) LDL-c (mg/dl) HDL-c (mg/dl) Triglycerides (mg/dl) No prior CV disease (%) Coronary event rate (10y, %) 5 62.2 6.9 (6.17.8) 119 42 153 78 12 CARDS 2 (n = 2,838) HPS 3 (n = 5,963) 8 61.2 7.8 118 54 150 100 15 9 62.1 7.1 124 41 204 50 25 Major CV events (RRR, %) -11-37*-22*

41. Primary endpoints – FIELD No significant benefit on major coronary events (first nonfatal MI or CHD death)  11%, p = 0.16 Secondary endpoints – FIELD Significant benefits on total cardiovascular events  - 11%, p = 0.035 FIELD Study Investigators. Lancet 2005 Nov 26; 266(9500): 1849-61

42. 22 % Prior CVD Why may fenofibrate be a therapeutic option in diabetics without previous CVD? Clinical implications of the FIELD study in patients Without previous CV disease No prior CVD100 % No prior CVD78 % 1. FIELD Study Investigators. Lancet 2005 Nov 26; 266(9500): 1849-61 2. Heart Protection Study Collaborative Group. Lancet 2003;361:2005-16 FIELD: 1 significant benefit on total cardiovascular events (NNT= 50 pts for 5 years to prevent one or more CVD events in 1 patient) CARDS: 2 significant benefit on major cardiovascular events (NNT= 27 pts for 4 years to prevent one CVD event in 1 patient)

43. This is the first time a lipid-modifying agent has reduced rates of both macrovascular and microvascular events In early-stage type 2 diabetics: without previous CVD with optimal glycemic control with or without atherogenic dyslipidemia (and no elevation of LDL-c) Take home messages 1 Fenofibrate may represent a therapeutic option (alone or with a statin) to reduce both total cardiovascular events and the progression of microangiopathy (retinopathy and microalbuminuria) FIELD Study Investigators. Lancet 2005 Nov 26; 266(9500): 1849-61

44. In patients with type 2 diabetes, the use of statins remains the strategy of choice for reducing cardiovascular (CV) events, particularly in those with previous CV disease Fenofibrate may provide additional benefits in reducing total cardiovascular events in type 2 diabetes when used with statin therapy Both fenofibrate monotherapy and combination fenofibrate/statin therapy are safe and well tolerated Take home messages 2 FIELD Study Investigators. Lancet 2005 Nov 26; 266(9500): 1849-61

45. FENOFIBRATE BIOAVAILABILITY Fenofibrate Nanotechnology 145 mg

46. NANOTECHNOLOGY: a question of scale… 0.1 nm 1 nm 10 nm 100 nm 1 μm 10 μm 100 μm 1 mm 1 cm 10 cm 1 m Nanoworld molecule protein DNA Cell Hair Flea Butterfly Human being Lipanthyl 300mg / 100mg Lipanthyl 200M / 160mg SUPRA Lipanthyl 145 NT

47. LIPANTHYL 145 NT entering into the Nanoworld STANDARD MICRONIZED NanoCrystal TM Technology 200M SUPRA Median Ø = 150µm Median Ø < 15µm Median Ø < 400 nm 145 NT

48. NEW NanoCrystal TM Technology: increased surface area leads to a more predictable bioavailibility LIPANTHYL 145 NanoCrystal TM Technology means no difference in bioavailability when Lipanthyl 145 is taken with or without food Previous Lipanthyl formulation resulted in 35% difference in absorption when the previous formulation was taken without a meal 9 Source: Elan Corp Micronized fenofibrate