Keech AC et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial Lancet 2007, published online 6th November DOI:10.1016/S0140-6736(07)61607-9
What is the background to this? – Retinopathy, which can lead to blindness, is an important complication of type 2 diabetes. It is the leading cause of vision loss and blindness in working age adults in developed and developing countries. Laser treatment has been shown to slow or prevent further vision loss, but is frequently associated with visual field reduction and other ocular side effects.
What does this study claim? – In people with type 2 diabetes aged between 50-75 years and compared with placebo, fenofibrate 200mg once a day for five years resulted in a 31% relative reduction in the number of people having one or more laser treatments for any retinopathy (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.56 to 0.84); NNT Number needed to treat (NNT) = 67, 95%CI 43 to 143), P=0.0002. There was no effect on worsening of visual acuity (two-line worsening on a Snellen chart) P=0.67
How does this relate to other studies? – This study was actually a subset (1012 patients) of the FIELD study which was published in 2005. In brief, this was a randomised controlled trial (RCT) of fenofibrate 200mg/day versus placebo in 9,795 participants aged 50–75 years, with type 2 diabetes mellitus, and not taking statin therapy at study entry. There was no significant reduction in the primary outcome of coronary events (death from coronary heart disease or non-fatal MI): HR 0·89, 95% CI 0·75–1·05; p=0·16. Total mortality was also not reduced by fenofibrate treatment (6·6% in the placebo group and 7·3% in the fenofibrate group (P=0·18). Similar proportions in each group discontinued study medication (10% placebo vs 11% fenofibrate) but more than twice as many patients allocated placebo (17%) than fenofibrate (8%; P = 0·0001) commenced other lipid treatments, predominantly statins. The need for laser eye treatment was a tertiary outcome of the FIELD study (see later). In the original publication, the effects on the need for laser eye treatment were also reported, albeit with very slightly different figures.
So what? – Much of these data are not new – the headline figures of rates of laser treatment were published in the main FIELD report almost exactly two years ago. They also relate to a tertiary outcome in a small (albeit prespecified) subgroup in a study which failed to detect a statistically significant difference in its primary outcome – the effect on coronary events. As Prof Nick Freemantle has written, we should be very cautious about accepting secondary (and tertiary outcomes) in these situations. He quotes another writer: “The primary end point, chosen from many possible end points and afforded particular and unique attention during the trial, becomes unceremoniously unseated when it is discovered to be negative at the trial’s conclusion. Like the `crazy aunt in the attic,’ the negative primary end point receives little attention in the end, is referred to only obliquely or in passing, and is left to languish in scientific backwaters”.
Even if we accept the reported effect on need for laser eye treatment as scientifically valid – how clinically important is it? Although avoiding this would no-doubt be a good thing, fenofibrate had no effect on the eye outcome of most direct importance to patients: prevention of a comparatively large reduction in visual acuity. As we have blogged previously, the MHRA and CHM have recently advised that fibrates should not be used as first choice lipid-lowering drugs for primary or secondary prevention of cardiovascular disease. Only two trials, both with gemfibrozil, out of the five fibrate RCTs assessed by the MHRA/CHM showed a statistically significant reduction in non-fatal cardiovascular events in patients given fibrates. Most trials showed an overall negative effect on mortality, with slightly more deaths in patients given fibrates compared with control group.
Action – Health care professionals should not change their choice of lipid-lowering drug for most people with type 2 diabetes on the basis of this study: statins are first choice. They should also bear in mind the recent MHRA/CHM advice: in patients with mixed hyperlipidaemia, fibrates should be considered only when a statin or other effective treatments are contraindicated or not tolerated. In patients with primary hypercholesterolaemia, gemfibrozil may be considered but again only when a statin or other effective treatments are contraindicated or not tolerated.
You can find more information on management of hyperlipidaemia, including an analysis of the FIELD study and the rest of the evidence base for fibrates, on the lipids section of NPC. You can further explore NPC to learn more about management of type 2 diabetes.