FIELD study

The effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus was examined in the FIELD study (1,2,3):

• study design (1):
  • a multinational, randomised controlled trial with 9795 participants aged 50-75 years, with type 2 diabetes mellitus, and not taking statin therapy at study entry
  • a placebo and a fenofibrate run-in phase, then randomly assigned patients (2131 with previous cardiovascular disease and 7664 without) with a total-cholesterol concentration of 3.0-6.5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4.0 or more or plasma triglyceride of 1.0-5.0 mmol/L to micronised fenofibrate 200 mg daily (n=4895) or matching placebo (n=4900)
  • primary outcome was coronary events (coronary heart disease death or non-fatal myocardial infarction); the outcome for prespecified subgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke, and coronary and carotid revascularisation).
    • patients with triglyceride levels of > 5mml/l excluded because likely to need fibrate treatment anyway (2)
    • of those recruited into the trial, over 50% had low HDL or high TGs, over 33% had both abnormalities (2)
    • 4900 were in the placebo group and 4895 in the fenofibrate group
  • exclusion criteria included renal impairment (blood creatinine >130 µmol/L), known chronic liver disease or symptomatic gallbladder disease, and a cardiovascular event within the 3 months before recruitment
  • more patients allocated placebo (17%) than fenofibrate (8%; p<0.0001) commenced other lipid treatments, predominantly statins
• study results:
  • 5 years duration
    • showed that fenofibrate reduced the risk of the primary outcome (coronary events) by 11% (hazard ratio 0.89, 95% CI 0.75 to 1.05), which was not statistically significant (3)
      • corresponds to a significant 24% relative risk reduction in non-fatal myocardial infarction (0.76, 0.62-0.94; p=0.010) and a non-significant increase in coronary heart disease mortality (1.19, 0.90-1.57; p=0.22)
    • total cardiovascular disease events were significantly reduced from 13.9% to 12.5% (relative risk reduction of 11%)
      • this finding included a 21% reduction in coronary revascularisation (0.79, 0.68-0.93; p=0.003
    • other effects:
      • fenofibrate was associated with less albuminuria progression (p=0.002), and less retinopathy needing laser treatment (5.2%vs 3.6%, p=0.0003)
      • increase in plasma creatinine (see notes below)
      • slight increase in pancreatitis (0.5%vs 0.8%, p=0.031) and pulmonary embolism (0.7%vs 1.1%, p=0.022), but no other significant adverse effects
    • no difference in total mortality
• conclusions:
  • the study authors concluded that fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. However the use of fenofibrate did reduce total cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularisations
  • higher rate of starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit

The place of fibrates in people with type 2 diabetes has not been firmly established by this trial (3).

Notes:

• similar proportions in each group discontinued study medication (10% placebo vs 11% fenofibrate)
• during the study, plasma creatinine remained an average of 10–12 µmol/L higher in the fenofibrate group, which had a median concentration of 91 µmol/L at study close compared with 80 µmol/L in placebo-allocated patients (p<0·001)
  • in the subset of 661 patients restudied 8 weeks after ceasing study medications at the end of the trial, the plasma creatinine fell from a median of 92 µmol/L to 77 µmol/L in those previously allocated to fenofibrate, and from 82 µmol/L to 79 µmol/L in those allocated placebo
• use of statins during the FIELD study (2):
  • if adjust for statin use then relative risk reduction of coronary events is significant at 19% (without adjustment 11% non-significant); also total cardiovascular events were reduced 15% (without adjustment 11%)

Reference:

1. Keech A et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005 Nov 26;366(9500):1849-61
2. Keech A, Simpson R. Lecture during 14th International Workshop in Cardiovascular Disease (27/1/2006).
3. JBS2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91 (Supp 5).