F enofibrate I ntervention and E vent L owering in D iabetes

1. Fenofibrate Intervention and Event Lowering in Diabetes The FIELD Study Investigators A randomised trial of the effects of fenofibrate on coronary morbidityand mortality in people with diabetes

2. Contributors Management Committee A Keech (study chairman), P Barter, J Best, R Scott, RJ Simes, M-R Taskinen (Executive Committee); P Colman, M d’Emden, T Davis, P Drury, C Ehnholm, P Glasziou, D Hunt, YA Kesäniemi, M Laakso, D Sullivan, M Whiting; J-C Ansquer, B Fraitag (non-voting sponsor attendees); P Forder, A Pillai (study statisticians) Outcomes Assessment Committee D Hunt (chairman), N Anderson, G Hankey, S Lehto, S Mann, M Romo; LP Li (outcomes officer, in attendance) Safety and Data Monitoring Committee S MacMahon (chairman), C Hennekens, S Pocock, A Tonkin, L Wilhelmsen Coordinating centres and laboratory staff 300 medical and nurse investigators and ~10 000 patients Sponsor: Laboratoires Fournier SA

3. Objective To provide the first randomised evidence of the effects of fenofibrate on the risk of major coronary disease events (nonfatal myocardial infarction or CHD death) in patients with diabetes: • with and without pre-existing vascular disease • men and women • younger (<65 years) and older (≥65 years) • with and without other lipid abnormalities

4. 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 • Vascular & neuropathic amputations • Hospitalisation for angina pectoris • Hospital admissions • Tertiary outcomes • Progression of renal disease • Laser treatment for diabetic retinopathy • Nonfatal cancers

5. Flow of patients 9795 randomised 6051 Australia, 2351 New Zealand,1393 Finland 4900 Placebo 4895 Fenofibrate 200 mg 4 withdrew consent 12 lost to follow-up 5 withdrew consent 10 lost to follow-up 4856 (99%) primary outcome confirmed 4852 (99%) primary outcome confirmed

6. Placebo Fenofibrate Results: primary outcome CHD events (CHD death + nonfatal MI) HR = 0.89 95% CI = 0.75–1.05 P=0.16

7. Placebo Fenofibrate Total CVD events HR = 0.89 95% CI = 0.80–0.99 P=0.035 NNT ≈ 70

8. Placebo Fenofibrate Coronary revascularisations HR = 0.79 95% CI = 0.68–0.93 P=0.003

9. Results: secondary outcomes Placebo Fenofibrate HR (95% CI) P (%) (%) 0.035 0.41 0.18 0.36 0.43 0.003 0.001 Total CVD events 13.9 12.5 CVD mortality 2.6 2.9 Total mortality 6.6 7.3 Total stroke 3.6 3.2 Nonhaemorrhagic stroke 3.2 2.9 Coronary revascularisation 7.4 5.9 All revascularisation 9.6 7.8 favours fenofibrate favours placebo

10. Placebo Fenofibrate Total CVD in subgroups Prior CVD HR = 1.02 95% CI = 0.86–1.20 P=0.85 No prior CVD HR = 0.81 95% CI = 0.70–0.94 P=0.004

11. Placebo Fenofibrate Results: retinal laser therapy HR = 0.70 95% CI = 0.58–0.85 P=0.0003

12. Safety: non-CVD causes of death Cancer 148 (3.0) 168 (3.4) Respiratory disease 16 (0.3) 19 (0.4) Trauma 12 (0.2) 11 (0.2) Other 20 (0.4) 18 (0.3) Any death 196 (4.0) 216 (4.4) Placebo Fenofibraten (%) n (%)

13. Conclusions • Observed effects of fenofibrate appear to have been modestly attenuated by differential statin use. • Use of fenofibrate should now be considered in the context of well-established statin therapy • its main use is likely to be in combination • fenofibrate was well tolerated alone and in combination with statins.

14. Conclusions • The effect of fenofibrate on the primary outcome (CHD death or nonfatal MI) was not statistically significant. • However, fenofibrate significantly reduced total CVD events, particularly due to reductions in nonfatal MI and coronary revascularisation, without reducing fatal events. • Fenofibrate also conferred beneficial microvascular-associated effects on renal and eye disease.