Bezafibrate in men with lower extremity arterial disease: randomised controlled trial

Dear Dr Smith,

Re: Bezafibrate in men with lower extremity arterial disease:
randomised control trial
BMJ 2002: 325: 1139-

The 40% reduction in non-fatal myocardial infarction over 4.6 years
with bezafibrate therapy reported in the recent ‘Bezafibrate in men with
lower extremity arterial disease: randomised control trial’ (LEADER
study)1 is an important finding for the management of patients with
diffuse atherosclerotic disease. A similar clinical benefit of bezafibrate
has also been reported in the SENDCAP, a primary prevention lipid lowering
trial in type 2 diabetes. This compared treatment with a fibrate
(bezafibrate) to placebo in 164 type 2 diabetic patients followed
prospectively for at least three years. In those treated with
bezafibrate, there was a 68% reduction (p = 0.01, log-rank test) in the
prespecified secondary trial endpoint of clinical CHD (as determined by
the combined incidence of Minnesota-coded probable ischaemic change on the
resting ECG and of documented myocardial infarction)2 . Both these fibrate
studies have shown that despite modest reductions in total cholesterol (-
8% and -7% respectively) clinical CHD can be reduced.

The LEADER study is also an important addition to the list of fibrate
outcome trials which have shown that with relatively small cholesterol
lowering, CHD end-point reductions were similar to that of the statin
trials which reported greater cholesterol lowering treatment effects. As
fibrates have been shown to have greater triglyceride reduction compared
to statins, the potential improvement in LDL composition with the
triglyceride lowering -by a shift from the atherogenic small dense LDL to
a less atherogenic large LDL- combined with an increase in HDL cholesterol
may be key lipid factors modified by these drugs. The enhanced reduction
in new CHD events in relation to percentage fall in LDL cholesterol in the
triglyceride lowering drug trials compared to the LDL lowering drug trials
has been recognised 4 .

The lack of treatment benefit in the LEADER study in the primary endpoint
of stroke was also observed in SENDCAP where bezafibrate therapy did not
significantly alter the primary endpoint of change in carotid intima-media
-thickness. One possible explanation for the lack stroke benefit may be
the addition of specific antihypertensive therapies in particular
angiotensin converting enzyme inhibitors in the placebo and treatment
groups acting to offset any lipid lowering drug effect for this
cardiovascular end-point.

Another important feature of both the LEADER and other fibrate studies is
the good tolerability and lack of significant side-effects in long term
therapy.

Dr MD Feher
Consultant Physician in Diabetes and Clinical
Pharmacology
Beta Cell Diabetes Centre, Chelsea & Westminster
Hospital, London SW10

Dr RS Elkeles
Consultant Physician
Unit for Metabolic Medicine
St
Mary’s Hospital, London W2 1 NY

1. Tom Meade, Riaz Zuhrie, Claire Cook, Jackie Cooper, statistician,
on behalf of MRC General Practice Research Framework. Bezafibrate in men
with lower extremity arterial disease: randomised controlled trial. BMJ
2002;325:1139-48

2. Elkeles RS, Diamond JR, Poulter C, et al. Cardiovascular outcomes in
type 2 diabetes. A double-blind placebo-controlled study of bezafibrate:
the St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease
Prevention (SENDCAP) Study. Diabetes Care 1998; 21: 641-8.

3. Feher MD, Caslake M, Foxton J, Cox A, Packard CJ. Atherogenic
lipoprotein phenotype in type 2 diabetes: reversal with micronised
fenofibrate. Diabetes Metab Res Rev 1999; 15: 395-9.

4. Durrington PN, Illingworth DR. Lipid-lowering drug therapy: more
knowledge leads to more problems for composers of guidelines. Curr Opin
Lipidol 2000; 11: 345–9.

Competing interests:  
None declared