The cholesterol challenge(s) in cardiovascular risk in 2014

Transcription

1 The cholesterol challenge(s) in cardiovascular risk in 2014 Alberto Zambon University of Padova - Italy

2 Italy

3 University of Padova The Oldest Medical School in the World (established in a.d. 1222)

4 The Cholesterol Challenges in 2014: Evidence Applied to Everyday Practice Global (mis)perceptions The priority of dyslipidemia treatment is LDL-C management It is time to forget LDL targets? (US vs EU, SA,NZ,AU) In Europe we (GPs, Specialists) also believe that: Elevated TG and/or low HDL-C have no clinical value when LDL-C is on target Non HDL-C: clinically useless, LDL-C it s enough! Fibrates in combination with statin therapy have not demonstrated CV event reduction and safety is a concern! Is there any perception that: Fibrates can do more that other lipid modifying agents

5 The Cholesterol Challenges in 2014: Evidence Applied to Everyday Practice Global (mis)perceptions PERCEPTION The priority of dyslipidemia treatment is LDL-C management 1. True 2. False

6 Reduction in Event Rate (%) Reduction in Event rate (%) Lancet 2005; 366: Reduction in incidence of major coronary and cardiovascular events and mean absolute LDL-C reduction (Meta-analysis of 14 trials, n=90.056, ) 50 Major Coronary Events 50 Major Cardiovascular Events Lp(a ) Reduction in LDL-C (mmol/l) -10 Reduction in LDL-C (mg/dl) -23% every 1 mmol/l LDL-C -21% every 1 mmol/l LDL-C

7 CORRIERE DELLA SERA Thursday November 14 th Cholesterol: Not a problem! - Pills only for very high levels!

8 Effect of Treatment in Patients with HoFH Cardiovascular morbidity and mortality characteristics of patients with Homozygous FH before and after the advent of statins (1990) yrs yrs yrs *P< P<0.001 P<0.01 MACE indicates major adverse cardiac event; MIs, myocardial infarctions; CABG, coronary artery bypass surgery; AVR, aortic valve replacement; PTCA, percutaneous coronary angioplasty; and TIA, transient ischemic attack. Raal et al Circulation 2011;124:

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10 The Cholesterol Challenges in 2014: Evidence Applied to Everyday Practice Global (mis)perceptions LDL-C #1 priority to reduce risk of CVD events: TRUE

11 The Cholesterol Challenges in 2014: Evidence Applied to Everyday Practice PERCEPTION It is time to forget LDL targets? (US vs EU, SA, AU,NZ) 1. True 2. False

12 SIMILARITIES AND DIFFERENCES 2011 ESC-EAS Management of Dyslipidaemias Guidelines vs 2013 ACC/AHA Guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk EAS/ESC 1 AHA/ACC 2 SECONDARY PREVENTION PRIMARY PREVENTION LDL > 4.9 mmol/l PRIMARY PREVENTION IN DIABETES PRIMARY PREVENTION HIGH RISK Target LDL-C < 1.8 mmol/l, or at least 50% reduction. If target cannot be reached with statin, drug combination may be considered. Target LDL-C < 2.5 mmol/l. If target cannot be reached maximal reduction of LDL-C, using appropriate drug combinations in tolerated doses. Diabetes with other risk factors or organ damage: Target LDL-C = 1.8 mmol/l, or at least 50% reduction. Uncomplicated diabetes: Target LDL < 2.5 mmol/l. SCORE = 5% risk of fatal CVD: Target <2.5 mmol/l. High-intensity statin. If 50% reduction is not reached drug combination may be considered. High-intensity statin therapy, aimed at achieving at least 50% reduction of LDL-C. If 50% reduction cannot be achieved, consider additional therapy. Diabetes with high risk: High-intensity statin therapy. Diabetes with low risk: Moderate-intensity statin therapy. Total risk for CVD event >7.5%: Moderate- to high-intensity statin therapy. Risk 5-7.5% risk of CVD event: moderate-intensity statin therapy. Shared emphasis on the importance of LDL-C lowering in cardiovascular prevention Very similar view on which high risk groups should be the targets for drug treatment No LDL-C Targets (AHA/ACC) Intensity of Statin therapy as goal of treatment (AHA/ACC) 1 EAS/ESC Guidelines European Heart Journal (2011) 32, Stone NJ et al Circulation. 2013, doi: /01.cir a

13 Major CV Events in 5 Large Trials Comparing Intensive-Dose to Moderate-Dose Statin Therapy Meta-Analysis Cases Total No (%) Intensive Dose Moderate Dose Incident CVD PROVE-IT TIMI /1707(18.4) 355/1688 (21) 0.85 A to Z 212/1768 (12) 234/1736 (13.5) 0.87 TNT 647/3798 (17) 830/3797 (24.6) 0.73 IDEAL 776/3737 (20.8) 917/3724 (24.6) 0.80 SEARCH 1184/5398 (21.9) 1214/5399 (22.5) 0.97 Pooled odd ratio 3134/16408 (19.1) 3550/16344 (21.7) 0.84 Intensive vs Moderate LDL-C mmol/l Intensive vs Moderate= Odds Ratio (95% CI) 16% CV Events Preiss D. et al. JAMA. 2011;305(24):

14 LDL-C mmol/l LDL-C mmol/l Adherence to statin last three months Intervention to Improve Adherence to Lipid-Lowering Medication and Lipid-Levels in Patients With High CVD Risk C Adherence to lipid-lowering medication Patients n=2500, from Amsterdam, The Netherlands, age 49,2 yrs, 52% primary prevention, BMI 28,1 RC: routine care (blue circles), Nurse counselling once/year, lipid profile at 3, 9, 18 month, no LDL-C targets EC: extended care (red triangles) Nurse counselling four times year, lipid profile at 3, 9, 18 month, yes LDL-C targets Months from start intervention 5 Primary CVD Prevention 5 Secondary CVD Prevention * p<0.01 * * Months from start intervention Months from start intervention Nieuwkerk PT et al. Am J Cardiol 2012;110:

15 The Importance of Monitoring Measures to improve adherence are inseparably bound to achievement of the clinical goals for which the drugs are prescribed. For cardiovascular disease, perhaps the most clinically relevant of these are the regular measurement of serum lipids. Haynes RB et al. The Cochrane Database of Systematic Reviews 2002, Issue 2. Art. No.: CD DOI: / CD000011

16 SIMILARITIES AND DIFFERENCES 2011 ESC-EAS Management of Dyslipidaemias Guidelines vs 2013 ACC/AHA Guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk EAS/ESC 1 AHA/ACC 2 SECONDARY PREVENTION PRIMARY PREVENTION LDL > 4.9 mmol/l PRIMARY PREVENTION IN DIABETES PRIMARY PREVENTION HIGH RISK Target LDL-C < 1.8 mmol/l, or at least 50% reduction. If target cannot be reached with statin, drug combination may be considered. Target LDL-C < 2.5 mmol/l. If target cannot be reached maximal reduction of LDL-C, using appropriate drug combinations in tolerated doses. Diabetes with other risk factors or organ damage: Target LDL-C = 1.8 mmol/l, or at least 50% reduction. Uncomplicated diabetes: Target LDL < 2.5 mmol/l. SCORE 5% risk of fatal CVD: Target <2.5 mmol/l. High-intensity statin. If 50% reduction is not reached drug combination may be considered. High-intensity statin therapy, aimed at achieving at least 50% reduction of LDL-C. If 50% reduction cannot be achieved, consider additional therapy. Diabetes with high risk: High-intensity statin therapy. Diabetes with low risk: Moderate-intensity statin therapy. Total risk for CVD event >7.5%: Moderate- to high-intensity statin therapy. Risk 5-7.5% risk of CVD event: moderate-intensity statin therapy. Impact on Population in Primary Prevention (AHA/ACC vs EAS/ESC) 1 EAS/ESC Guidelines European Heart Journal (2011) 32, Stone NJ et al Circulation. 2013, doi: /01.cir a

17 JAMA 2014;311(14): subjects from the Rotterdam Study age >65 yrs, primary prevention ON STATIN THERAPY Females Males Males ACC/AHA vs ATP III and ESC: ACC/AHA recommend statin therapy for more adults who would be expected to have future cardiovascular events (higher sensitivity) but would also include many adults who would not have future events (lower specificity).

18 online publish-ahead-of-print 17 March 2014

19 online publish-ahead-of-print 17 March 2014 The ACC/AHA 2013 guidelines Vs The ESC/EAS 2011 guidelines Abolition of LDL-C targets: - confusing for many physicians - detrimental for medication adherence and patient engagement in self-management Reduction in the threshold for treatment in primary prevention: - greater number of patients being prescribed statin - good in young patients with high life time risk - very large number of older patients offered therapy! Current Recommendation by ESC-EAS The ESC/EAS guidelines from 2011 seem to be the most wide ranging, pragmatic, and appropriate option for European countries In clinical practice maintain the use of LDL-C targets

20 The Cholesterol Challenges in 2014: Evidence Applied to Everyday Practice Global (mis)perceptions LDL-C #1 priority to reduce risk of CVD events: TRUE It is time to forget LDL targets (US vs EU, AU, SA): QUESTIONABLE

21 (Mis) Perceptions in Dyslipidaemia: Evidence Applied to Everyday Practice In Europe we (GPs and Specialists) also believe that: PERCEPTION Elevated TG and/or low HDL-C have NO clinical value when LDL-C is on target 1. True 2. False

22 Relative cardiovascular risk reduction* (%) 30-day risk of death, MI or recurrent ACS (%) PROVE IT-TIMI 22: Reaching target LDL alone with statin therapy does not achieve maximal CV risk reduction if TGs are raised For people at target LDL, those with low TGs have an additional 12% reduction in cardiovascular risk versus those with raised TGs LDL 1.8 TG 1.7 0% LDL <1.8 TG % LDL <1.8 TG <1.7 LDL and TG in mmol/l PROVE IT-TIMI 22 study TG +56% p= % -28% p=0.017 vs reference group (LDL 1.8, TG 1.7) <2.2 (n=603) (n=2,796) On-treatment TG mmol/l in patients with LDL-C <1.8 mmol/l LDL-C <70 mg/dl= 1.8 mmol/l TG <150 mg/dl= 1.7 mmol/l, TG 200 mg/dl= 2.2 mmol/l *Based on combined endpoint of overall mortality, myocardial infarction or hospitalisation due to recurring ACS ACS, acute coronary syndrome; CV, cardiovascular; LDL, low-density lipoprotein; TG, triglyceride Miller M, Cannon CP, Murphy SA, et al. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2008; 51:

23 5 y risk of MCVEs (%) MCVE Frequency by HDL-C level in group with LDL-C < 70 mg/dl (1.8 mmol/l) HR (95% CI) vs Q1 Q ( ) Q ( ) Q ( ) Q ( ) + 39 % Q1 Q2 Q3 Q4 Q5 0 (<37) [0.96] (37-42) [ ] * HDL-C at month 3 of the double-blind treatment phase (42-47) [ ] (47-55) [ ] Quintile of HDL-C* (mg/dl) [mmol/l] (>55) [1.42] Barter et al. N Engl J Med 2007; 357:

24 % of events ACCORD-Lipid Study Residual Risk on Statin* (Placebo Group) Previous CVD Lipid Sub-groups Overall Yes No TG 2.3 and HDL 0.9 HDL 0.9 % events = non fatal MI, non fatal stroke, CV death (follow-up : 4.7 years) * LDL-C 2.0 mmol/l on Simvastatin (mean dose 22 mg) ACCORD Study Group. NEJM 2010; 362: TG 2.3 TG<2.3 and HDL>0.9

25 The Cholesterol Challenges in 2014: Evidence Applied to Everyday Practice Global (mis)perceptions LDL-C #1 priority to reduce risk of CVD events: TRUTH It is time to forget LDL targets (US vs AU,NZ,EU): QUESTIONABLE In Europe we (GPs) also believe that: Elevated TG and/or low HDL-Chave HAVE no CLINICAL clinical value VALUE when when LDL-C LDL-C is on target is on target : FALSE : HIGH CV RESIDUAL RISK

26 The Cholesterol Challenges in 2014: Evidence Applied to Everyday Practice PERCEPTION Non HDL-C: clinically useless LDL-C it s enough! 1. True 2. False

27 Non-HDL Cholesterol HDL LDL IDL VLDL Anti Atherogenic Lipoproteins Atherogenic Lipoproteins Non HDL-C= total Cholesterol-HDL-C

28 Non-HDL-C and Apo B in Diabetes- Guidelines APO B NON-HDL Cholesterol HDL LDL IDL VLDL Lp(a) NON-HDL C Secondary goal: NZ/AU, ADA EAS/ESC Inexpensive, easy to calculate: Total cholesterol HDL-C Target levels easy to remember: Non HDL-C goals: LDL-C goal mmol/l European Heart Journal (2011) 32, Better CV predictor than LDL-C in diabetics since it takes into account all the atherogenic lipids!!!

29 Association of LDL-C, Non HDL Cholesterol, and Apo B With Risk of Cardiovascular Events Among Patients Treated With Statins A Meta-analysis patients enrolled in 8 trials published between 1994 and 2008 Risk of Major Cardiovascular Events by LDL and non-hdl Cholesterol Categories +32% Data markers indicate hazard ratios (HRs) and 95% CIs for risk of major cardiovascular events. Results are shown for 4 categories of statin-treated patients based on whether or not they reached the LDL-C target of 100 mg/dl (2.6 mmol)l) and the non HDL-C target of 130 mg/dl (3.4 mmol/l). HRs were adjusted for sex, age, smoking, diabetes, systolic blood pressure, and trial. Boekholdt M et al. JAMA. 2012;307(12):

30 Non-HDL Cholesterol HDL LDL IDL VLDL At Target <2.6 mmol/l Triglycerices Anti Atherogenic Lipoproteins Non HDL-C= >3.4 mmol/l NOT AT TARGET Atherogenic Lipoproteins Non-HDL cholesterol: emerging as #1 TARGET for treatment of Residual Cardiovascular Risk

31 The Cholesterol Challenges in 2014: Evidence Applied to Everyday Practice Global (mis)perceptions LDL-C #1 priority to reduce risk of CVD events: TRUE It is time to forget LDL targets (US vs EU): QUESTIONABLE In Europe we also believe that: Elevated TG and/or low HDL-C HAVE CLINICAL VALUE when LDL-C is on target : HIGH CV RESIDUAL RISK Non HDL-C: clinically emerging useless #1 TARGET, LDL-C for it s CV enough! (Residual) FALSERisk

32 The Cholesterol Challenges in 2014: Evidence Applied to Everyday Practice PERCEPTION Fibrates in combination with statin therapy have not demonstrated CV event reduction and safety is a concern! 1. True 2. False

33 Mean % change from baseline to 12 weeks (mg/dl) Mean % change from baseline to 12 weeks (mg/dl) Adding Fenofibric Acid* to a moderate-dose statin improved the three key lipids vs. monotherapy Randomisation 2,715 patients with mixed dyslipidaemia : LDL-C 3.4 mmol/l, TG 1.7 mmol/l and HDL-C <1.0 for men and <1.3 mmol/l for women Feno + low-dose statin*: pooled results through 12 weeks HDL-C TG LDL-C p< % +9% -5% Moderate-dose statin Feno + Moderate-dose statin Fenofibric acid -24% p< % p< % *Moderate-dose statins included in study: simvastatin 40 mg, atorvastatin 40 mg and rosuvastatin 20 mg *Bioequivalent to 145 mg of fenofibrate Jones PH et al. J Clin Lipidol. 2010;3(2):

34 Major Cardiovascular Events (%) ACCORD Pre-specified subgroup analysis Patients with Elevated TG and Low HDL-C - Similar selection criteria -Same lipid-lowering therapy: simvastatin mg -Same LDL-C on therapy: 2.0 mmol/l Simvastatin Simvastatin + Fenofibrate High TG/Low HDL-C subgroup had 70% higher event rate +70% Small, dense LDL % RRR 4.95% ARR p= NNT=20 Triglycerides VLDL-TG 5 HDL-C 0 All Others in ACCORD 82.4% (n=4548) of the entire cohort High TG ( 2,3 mmol/l) and Low HDL-C ( 0,88 mmol/l) 17.6% (n=941) of the entire cohort **Major CV events defined as CV death, nonfatal MI and nonfatal stroke ACCORD Study Group. N Engl J Med March 14, Epub. Elam M, Lovato L, Ginsberg H. Clinical Lipidology 2011;6:9-20

35 Bruckert E et al J Cardiovasc PharmacolT 57:267, 2011 Sacks FM et al. N Engl J Med 2010 Effect of fibrates in subgroups without (A) and with (B) dyslipidemia A total of 2428 fibrate-treated subjects (302 events) and 2298 placebo-treated subjects (408 events) with dyslipidemia were included in the analysis B Subgroups with Dyslipidemia Study ACCORD FIELD BIP HHS VA-HIT Odds Ratio (95% CI) 31% 27% 39% 78% 28% A Complementary Subgroups Study Odds Ratio (95% CI) ACCORD FIELD BIP HHS VA-HIT Summary 0.65 ( ) % Summary 0.94 ( ) % ACCORD lipid criteria TG 2.30 mmol/l, HDL-C 0.88 mmol/l Fibrate treatment reduce CVD among patients with atherogenic dyslipidemia

36 CV Risk Reduction by Baseline non-hdl-c in ACCORD Lipid Patients Receiving a Statin at Baseline Baseline Non-HDL-C and LDL-C Hazard ratio (95% CI) Fenofibratesimvastatin monotherapy Simvastatin % with events (N) Withingroup p value Non-HDL-C 3.4 mmol/l LDL-C < 2.6 mmol/l 8.8 (217) 16.3 (196) Non-HDL-C 130 mg/dl LDL-C < 100 mg/dl Fenofibrate better Control better Source: Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm htm

37 Concerns regarding statin-fibrate use Adverse pharmacokinetic interactions Idiosyncratic drug interactions Major potential adverse drug effects: Myopathy and rhabdomyolysis Hepatic dysfunction Renal impairment and renal failure Pancreatitis

38 Statin-fibrate pharmacokinetic interactions Gemfibrozil Fenofibrate Atorvastatin C max increase expected No effect Simvastatin C max increase 2-fold No effect Pravastatin C max increase 2-fold No effect Rosuvastatin C max increase 2-fold No effect Fluvastatin No effect No effect Lovastatin C max increase 2.8-fold Not available

39 Mean plasma concentration-time profiles of simvastatin following multiple oral doses of 80 mg SIMVASTATIN with or without multiple oral doses of FENOFIBRATE (n = 22) and GEMFIBROZIL (n=21) Plasma Concentration (ng/ml) Simvastatin without fenofibrate Simvastatin with fenofibrate Simvastatin with gemfibrozil Time (hr) A.J. Bergman et al., Journal of Clinical Pharmacology 2004;44:

40 ACCORD Lipid: adverse event profile Adverse event Fenofibrate + simvastatin (20-40mg) (n=2,765) Placebo + simvastatin (20-40mg) (n=2,753) p-value Any gall bladder-related event 0.3% 0.2% 0.57 DVT/PE ALT ever >3xULN 1.9% 1.5% 0.21 ALT ever >5xULN 0.6% 0.2% 0.03 CPK ever >5xULN 1.9% 2.2% 0.43 CPK ever >10xULN 0.4% 0.3% 0.83 Any myopathy / myositis / rhabdomyolysis serious AE 0.1% 0.1% 1.00 Serum creatinine elevation Women ever >1.3 mg/dl 235 (28%) 157 (19%) <0.001 Men ever >1.5 mg/dl 698 (37%) 350 (19%) <0.001 Adapted from Ginsberg et al, DVT = deep venous thrombosis; PE = pulmonary embolism; ALT = alanine aminotransferase; CPK = creatinine phosphokinase; ULN = upper limit of normal. To convert values for serum creatinine from mg/dl to micromol/l, multiply by Randomised controlled trial (ACCORD-Lipid) comparing simvastatin + placebo versus simvastatin + fenofibrate (145mg bioequivalent 2 ) on major CV events in patients with type 2 diabetes over 4.7 years (mean). 1 Ginsberg HN, et al. NEJM 2010;362: :supplementary appendix 1

41 Mean (95% CI) Plasma Creatinine (umol/l) Mean egfr (ml/min m -2 ) Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study Davis TME, Ting R, Keech AC et al. Diabetologia 2011;54: On average umol/l Higher than (p<0.01) Fenofibrate -1.9 ml min Placebo -6.9 ml min Time from randomization (months) of renal function Values are mean (95% CI); p=0.0003; p=0.065; p< Fenofibrate Placebo 5.0 ml min egrf better on Fenofibrate Acute reversible changes in plasma creatinine Longer term egfr preservation in type 2 diabetes (mostly evident after treatment withdrawal) No evidence to date of permanent renal injury Fenofibrate reduces albuminuria progression and may reduce loss

42 The Cholesterol Challenges in 2014: Evidence Applied to Everyday Practice Global (mis)perceptions LDL-C #1 priority to reduce risk of CVD events: TRUE It is time to forget LDL targets (US vs EU): QUESTIONABLE In Europe we also believe that: Elevated TG and/or low HDL-C HAVE CLINICAL VALUE when LDL-C is on target : HIGH CV RESIDUAL RISK Non HDL-C: emerging #1 TARGET for CV (Residual) Risk Fenofibrate Fibrates in combination with with statin simvastatin have not has demonstrated CV further event reduction, CV event safety reduction is a concern! in patients BOTH with FALSE diabetes and high TG/low HDL-C Safety of fenofibrate-statin combination is NOT A BARRIER

43 The Cholesterol Challenges in 2014: Evidence Applied to Everyday Practice PERCEPTION We (GPs) also believe that: Fibrates can do more than other lipid modifying agents 1. True 2. False

44 Diabetic Retinopathy (DR) is the most common microvascular complication of diabetes 1 Diabetic Retinopathy Almost everyone with type 1 diabetes and over 60% of people with type 2 diabetes will be affected 2,3 Diabetic Nephropathy About half of patients develop microalbuminuria at some point 4 Diabetic Neuropathy Patients with diabetes have a 30-50% lifetime risk of developing chronic peripheral neuropathy 4 1. Negi A, Vernon SA. J R Soc Med. 2003;96(6): Klein R et al. Ophthalmology. 2008;115: Klein R et al. Arch Ophthalmol. 1994;112(9): Marshall SM, Flyvbjerg A. BMJ. 2006;333(7566):

45 Development or progression of diabetic microvascular complications STENO 2 study: 13.3 yrs follow-up Intensive treatment: oral anti-diabetic therapy, antihypertensive, lipidlowering agents + diet and lifestyle program, after a mean follow-up of 13.3 years HbA1c= 7.7% Sys BP=140 mmhg Dias BP=74 mmhg LDL-C= 71 mg/dl (1.8) HDL-C=51 mg/dl (1.3) TG= 99 mg/dl (1.12) Gaede P et al. N Eng J Med 2008;358: NEUROPATHY NEPHROPATHY RETINOPATHY 25%: development of nephropathy 55%: progression of neuropathy 51%: progression of retinopathy

46 Effect of Fenofibrate on Diabetic Retinopathy Adjudicated data from FIELD Parameter Placebo Fenofibrate P NNT Total N of Patients First Laser for DR a No retinopathy Prior retinopathy % Reduction first laser treatment (P.0002) DR: diabetic retinopathy defined as laser treatment for proliferative retinopathy or macular edema or increase by >2 steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale; NNT number needed to treat. a Data are given as absolute event rates (%) Effect of Fenofibrate on Diabetic Retinopathy Data from ACCORD-Eye Parameter Placebo Fenofibrate P NNT Simva. Simvastatin Total N of Patients Progression of DR a No retinopathy Prior retinopathy % Reduction in the progression of DR (P.006) Similar to benefits seen on intensive glucose lowering approach DR diabetic retinopathy defined as 3-step progression of ETDRS grade or development of diabetic retinopathy requiring laser photocoagulation or vitrectomy NNT number needed to treat. a Data are given as absolute event rates (%) Am J Ophthalmol 2012;154:6 12.

47 Direct Effects of Fibrates on Retinal Inflammation and Angiogenesis Diabetic Rodent Model Fenofibrate PPAR alpha activation Diabetes Oxygen-induced Retinopathy Model Fenofibrate PPAR alpha activation INFLAMMATION NF-kB MCP-1 ICAM-1 Leukostasis VASCULAR PERMEABILITY ISCHEMIA HIF-1alpha VEGF MCP-1 ICAM-1 Vascular Permeability, Endothelial Cell migration & gross ANGIOGENESIS Adapted from Abcouver SF. Diabetes. 2013;62:36-38

48 PPARa Ligands Inhibit VEGF-Induced Corneal Neoangiogenesis in mice Fenofibrate at 200 mg/kg/day (d), WY14643 at 50 mg/kg/day (e), ETYA at 50 mg/kg/day (f), Bezafibrate at 400 mg/kg/day (g), or Gemfibrozil at 400 mg/kg/day (Panigrahy D, Folkman J et al. PNAS, Jan 22, 2008, 105:985-90)

49 Fenofibrate provides a systemic treatment option to reduce DR progression at early stages Fenofibrate is approved in Australia for use in patients with type 2 diabetes and existing retonopathy to reduce progression of DR The benefit of fenofibrate in patients with existing DR is achieve on top of glycemic, blood pressure and LDL-C control The benefit is independent of baseline lipid levels (LDL-C, HDL-C,TG) Unlike current standard therapy, laser treatment, fenofibrate is noninvasive and there is no risk of ocular side effects

50 TAKE HOME MESSAGE The Cholesterol Challenges Applied to Everyday Practice in 2014 LDL-C #1 priority to reduce risk of CVD events LDL-C targets help therapeutic adherence to achieve clinical goals Elevated TG and/or low HDL-C have clinical value when LDL-C is on target : HIGH CV RESIDUAL RISK Non HDL-C: emerging as #1 TARGET for CV Risk Reduction Fenofibrate in combination with simvastatin has demonstrated further CV event reduction in diabetes and high TG/low HDL-C Safety of fenofibrate-statin combination is NOT A BARRIER Fenofibrate is the only lipid modifying agent that reduces the progression of DR in type 2 diabetes patients with existing DR