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Role of Fenofibrate in Diabetic Dyslipidemia

Role of Fenofibrate in Diabetic Dyslipidemia. 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. TG. HDL-C. Diabetic Dyslipidaemia.

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Role of Fenofibrate in Diabetic Dyslipidemia

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  1. Role of Fenofibrate in Diabetic Dyslipidemia

  2. 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, denseLDL TG HDL-C Diabetic Dyslipidaemia

  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 PPAR Effects on lipidand lipoproteins Other effects 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 Plasma fibrinogenlevels C-reactive protein Uric acidlevels Effects onapolipoproteins Effects oncholesterol transporters Apo AI levels Apo AII levels Apo B levels Up-regulates the synthesis of cholesterol transporters Keating GM, Ormrod D. Drugs 2002;62:1-35

  6. Outcomes in fibrate trials BIP = Bezafibrate Infarction Prevention study; HHS = Helsinki Heart Study; RRR = relative risk reduction; VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial. 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

  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 Diabetic patients have not always been evaluated in the statin trials. When they did, there always remained an important residual risk factor. FIBRATES: appear to be specifically effective in people with Type 2 Diabetes and/or the features of the metabolic syndrome in whomthe excess coronary risk is significantly reduced.

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

  9. FIELDA unique study in type 2 diabetes • 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 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. Fenofibrate 200 mg/day(n = 4,895) Average follow-up: 5 years and 500 CHD events 9,795patients Placebo(n = 4,900) Study design 5-year, double-blind, placebo-controlled study  All patients received usual care, including the option to add other lipid-lowering therapies FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

  12. Outcomes • Primary outcome • First occurrence of nonfatal MI or CHD death • Secondary outcomes • Total CVD events* • (MI, stroke, CVD death, coronary and carotid revascularisation) • Coronary & peripheral revascularisation • Stroke • CHD deaths • CVD deaths • Total mortality * Primary outcome for subgroup analyses • Tertiary outcomes • Progression of renal disease • Laser treatment for diabetic retinopathy • Nonfatal cancers • Vascular & neuropathic amputations • Hospitalisation for angina pectoris • Hospital admissions 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. Baseline characteristics summary Total population: 9,795 Male gender62.7No prior cardiovascular disease (%)78.3Diabetes management with diet plus one oral antidiabetic agent (%) 59.5 Median duration of diabetes (years) 5 Median HbA1c (%) 6.9 Diabetic complications (%) Retinopathy 8.3 Nephropathy 2.8 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 * 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 FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

  16. FIELD Main results

  17. Effects of fenofibrate on lipid levels after 4 months (entire cohort) TC LDL-c HDL-c TG FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

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

  19. 100 80 60 40 20 0 Compliance and use of other lipid-lowering agents Drop-outs HR = 1.01 95% CI = 0.93–1.11 p = 0.76 Placebo Fenofibrate Proportion (%) Drop-ins HR = 0.47 95% CI = 0.44 – 0.51 p < 0.0001 0 1 2 3 4 5 6 years FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

  20. 10 Placebo 8 6 4 2 Fenofibrate 0 0 1 2 3 4 5 6 Placebo Fenofibrate 4,900 4,895 4,835 4,837 4,741 4,745 4,646 4,664 4,547 4,555 2,541 2,553 837 850 Primary endpointCHD events (nonfatal MI, CHD death) HR = 0.89 95% CI = 0.75–1.05 p = 0.16 Cumulative risk (%) Years from randomization Number of patients still followed-up at the given year FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

  21. 100 Nonfatal MI HR = 0.76 95% CI = 0.62–0.94 p = 0.010 80 60 Placebo Fenofibrate Cumulative risk (%) 40 CHD death HR = 1.19 95% CI = 0.90–1.57 p = 0.22 20 0 0 1 2 3 4 5 6 years Primary endpointCHD events (nonfatal MI, CHD death) FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

  22. Secondary endpointTotal CVD events Placebo Fenofibrate 4,900 4,895 4,762 4,771 4,586 4,604 4,419 4,469 4,257 4,307 2,340 2,370 750 775 15 Placebo HR = 0.89 95% CI = 0.80–0.99 p = 0.035 NNT ≈ 70 10 Fenofibrate Cumulative risk (%) 5 0 0 1 2 3 4 5 6 Years after randomization Number of patients still followed-up at the given year FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

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

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

  25. FIELD sub-group analysis

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

  27. FIELD tertiary endpoints

  28. Microvascular disease Retinopathy Need for laser treatment for retinopathy -30% P=0.0003 “This effect cannot be explained by changes in HbA1c or concomitant medications, or by the minor reduction in blood pressure in the fenofibrate group” FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

  29. Progression of microalbuminuria(baseline to study close) 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 HbA1c 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 Hospitalisations for angina pectoris Amputations RR = 0.82 (95% CI = 0.69-1.00) RR = 0.69 (95% CI = 0.48-0.99) p=0.04 p=0.04 300 100 -18% 252 -31% 74 5.1% 75 209 200 1.5% 4.3% 51 50 Number of hospitalisations Number of hospitalisations 1.0% 100 25 0 0 Placebo Fenofibrate Placebo Fenofibrate FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

  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. “Theresultsare 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 complicationsare judged important.” FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61

  38. Clinical implications of the FIELD study

  39. The FIELD study population Overall, 38% dyslipidemic* Relatively early stage of disease Optimal glucose control - same HbA1c at the end of the trial Most patients in primary prevention  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. The FIELD study population RRR = relative risk reduction; * p < 0.001 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

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

  42. Clinical implications of the FIELD study in patients Without previous CV disease 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) No prior CVD 100% Prior CVD 22% No prior CVD 78% Why may fenofibrate be a therapeutic option in diabetics without previous CVD? 1. FIELD Study Investigators. Lancet 2005 Nov 26; 266(9500): 1849-61 2. Heart Protection Study Collaborative Group. Lancet 2003;361:2005-16

  43. Take home messages1 • 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) 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. Take home messages2 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 FIELD Study Investigators. Lancet 2005 Nov 26; 266(9500): 1849-61

  45. FENOFIBRATE BIOAVAILABILITY Fenofibrate Nanotechnology 145 mg

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

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

  48. NEW NanoCrystalTM Technology:increased surface area leads to a more predictable bioavailibility • LIPANTHYL 145 NanoCrystalTM 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 Micronized fenofibrate 9 Source: Elan Corp

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