FIELD New results

Aims of the FIELD eye study A.“FIELD sub-analysis”; To analyse the reasons for reduction in laser therapy in FIELD B.“Ophthalmology sub-study”; To assess the effect of fenofibrate on the progression of diabetic retinopathy in a sub-group of FIELD patients FIELD Study Investigators. The Lancet. 2007

First course of laser therapy FIELD Study Investigators. The Lancet % Rapid benefits of fenofibrate were seen from eight months onward and increased throughout the study period These benefits were additive to tight blood pressure and glycaemic control

The risk reduction was essentially due to macular oedema A significant 31% reduction due to macular oedema related laser treatment A significant 30% (p=0.015) reduction for proliferative retinopathy FIELD Study Investigators. The Lancet. 2007

Multiple courses of laser therapy EventPlaceboFenofibrateHazard Ratio 95% CIP-value 1 laser only , , % reduction 2-12 laser courses 11770

Fenofibrate benefits patients from cumulative use of laser therapy The relative reduction seen with fenofibrate was significant in patients without prior retinopathy (49%, p=0.0002) FIELD Study Investigators. The Lancet Fenofibrate Favours fenofibrate

Summary Main study findings: -31%first laser overallp= %for maculopathyp= %for proliferative retinopathyp= %total laser therapiesp= %all laser - primaryp=0.0002

1012 patients entered the ophthalmology sub-study 512 assigned to fenofibrate 24 retinopathy history 488 no retinopathy history 500 assigned to placebo 22 retinopathy history 478 no retinopathy history 421 assessed at end of study 19 deaths 57 sub-study follow- up not available 3 withdrew consent 16 deaths 67 sub-study follow- up not available 0 withdrew consent 429 assessed at end of study FIELD Eye Sub-study

Sub-study main endpoint Development of retinopathy defined as at least a 2-step increase in the ETDRS grade after 2 or more years of follow-up for all patients. Also sub classified as:  Primary prevention: 2-step progression to retinopathy in those with a baseline grade of 15 or less.  Secondary prevention: 2-step progression of existing retinopathy in those with a baseline grade of 20 or greater

Sub-study composite endpoint Exploratory combined outcome characterizing significant retinal pathology, composed of:  2-step progression of retinopathy grade  development of macular oedema  or laser therapy

2-step progression of retinopathy grade (ETDRS) and macular oedema GroupPlaceboFenofibratep value All patients57 (12.3%) 46 (9.6%) 0.19 No prior retinopathy 43 (11.7%) 43 (11.4%) 0.87 Prior retinopathy* 14 (14.6%) 3 (3.1%) Macular oedema 10 (2.2%) 4 (0.8%) 0.09 *79% reduction

Exploratory composite endpoint: EventPlaceboFenofibrateHazard Ratio 95% CIp-value Composite Endpoint* *34% reduction  laser therapy  2-step progression of retinopathy grade  macular oedema

Summary Sub-study findings: -79%first laser therapyp= %2-step progression,p=0.004 (existing retinopathy) -64%macular oedemap= %combined end-pointp=0.022 (laser, macular oedema, 2-step progression)

Clinical Application - 5 years treatment with fenofibrate With pre-existing retinopathy Avoid first laser: NNT = fewer multiple laser events per 100 Rx Without known prior eye disease Avoid first laser: NNT = fewer multiple laser events per 100 Rx

Conclusions In all subjects with diabetes, the use of fenofibrate could be considered for both its macro- and microvascular benefits Even for subjects on statin therapy at target LDL-C, fenofibrate could be considered as add- on therapy to further attenuate residual diabetes-mediated risk and its microvascular complications (ACCORD study will provide further evidence for combination statin-fenofibrate therapy)

Other tertiary outcomes Number of hospitalisations PlaceboFenofibrate Hospitalisations for angina pectoris 1 RR = 0.82 (95% CI = ) p= Number of amputations 50 PlaceboFenofibrate Amputations 2 RR = 0.62 (95% CI = ) p= % % % % -18 % -38 % 1.FIELD study investigators. Atherosclerosis, Abstract We-S15: 2 Atherosclerosis in Supplement 2006; 7(3): FIELD study investigators. Oral communication-AHA, 2007.

Silent MI

On-study myocardial infarction (9795 subjects with T2DM) Total MI = 640 = 6.5% Clinical MI = 395 = 4.0% Silent MI = 245 = 2.5% Silent MI = 40% of all MIs NoneSilentClinical 9155

Results

Conclusions Silent MI is common in individuals with type 2 diabetes - almost 40% of all MI There were 16% fewer first silent MI events on fenofibrate (p = 0.154) Fenofibrate significantly reduced the occurrence all MI events by 20% (95% CI 6- 31%, p=0.006) After silent MI, fenofibrate reduced the risk of further clinical CVD events (p=0.008)

Dyslipidaemia

TG  2.3 mmol/L Low HDL-C* Triglyceride  2.3 mmol/L plus low HDL-C *M<1.03 mmol/L; F<1.29 mmol/L Placebo Fenofibrate HR (95% CI) HR P (%) (%) CVD Event Rate Reductions for Dyslipidemia (HDL-C criteria for Metabolic Syndrome)

Dyslipidaemic criteria Hazard Ratio (NNT) Event rate Placebo Event Rate Placebo Triglyceride criteria ( 2.3 mmol/L) 0.76 (26.3)(17.2)(13.4) Low HDL-C*0.85 (47.6)(15.1)(13.0) TG  2.3 mmol/L plus low HDL-C *M<1.03 mmol/L; F<1.29 mmol/L 0.74 (23.3)(17.8)(13.5)

CVD Event Rate Reductions for Dyslipidemia (High TG and/or low HDL-C as defined by NCEP-ATP III) Triglyceride criteria ( 2.3 mmol/L) HDL-C < 1 mmol/L both genders Triglyceride  2.3 mmol/L plus HDL-C < 1 mmol/L Placebo FenofibrateHR (95% CI) HR P (%) (%)

CVD Event Rate Reductions for Dyslipidemia (High TG and/or low HDL-C as defined by NCEP-ATP III) Dyslipidaemic criteria Hazard Ratio (NNT) Event rate Placebo Event Rate Placebo Triglyceride criteria ( 2.3 mmol/L) 0.76 (26.3)(17.2)(13.4) HDL-C < 1 mmol/L both genders 0.84 (37.0)(18.1)(15.3) Triglyceride  2.3 mmol/L plus HDLc < 1 mmol/L 0.74 (20.8)(19.8)(15.0)

LIPANTHYL Lipanthyl snížil výskyt kardiovaskulárních příhod o 26 % u pacientů s dyslipidémii typickou pro DM typu 2 Lipanthyl snížil výskyt kardiovaskulárních příhod o 26 % u pacientů s dyslipidémii typickou pro DM typu 2 Právě pacienti s diabetem mellitem 2. typu nebo metabolickým syndromem profi tují nejvíce z léčby Lipanthylem Právě pacienti s diabetem mellitem 2. typu nebo metabolickým syndromem profi tují nejvíce z léčby Lipanthylem A.. Keech: Features of Metabolic Syndrome Identify Individuals with Type 2 Diabetes Mellitus at high risk for CV events and greater benefits of fenofibrate. AHA 2007, Orlando, Abstract

Redukce rizika (%) Albuminurie Retinopatie Mikrovaskulární efekty a úloha fenofibrátu 14%14% p=0,002 31%31% p= Amputace 38%38% p=0,001 Lancet 2007, AHA 2007 abstract Lipanthyl je jediné hypolipidemikum s prokázanou účinnost na makro a zároveň mikrovaskulární komplikace DM LIPANTHYL