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The British Journal of Diabetes & Vascular
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DOI: 10.1177/1474651410397245
2011 11: 4 British Journal of Diabetes & Vascular Disease
Robert Elkeles
Fibrates: old drugs with a new role in type 2 diabetes prevention?

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REVIEW
Abstract
T
he incidence of type 2 diabetes is increasing
throughout the world resulting in a huge growth
in demands on health services. Despite advances in
treatment, complications still occur. Prevention of type 2
diabetes or delaying its onset is therefore a desirable
goal. In trials, lifestyle measures have been partially suc-
cessful but continuing adherence is difficult. A number
of drugs have been tried with varying success. Those
people who develop type 2 diabetes have been found to
have a more atherogenic lipid profile and to be more
insulin resistant, than those who do not, and at increased
cardiovascular risk. Fibrates, which are safe and cheap,
could help to correct these abnormalities at an early
stage and reduce cardiovascular risk. They would seem
a suitable option for prevention of type 2 diabetes.
Evidence is presented to suggest that the fibrates, in
particular bezafibrate, could have a role in prevention
of type 2 diabetes in those at high risk and that a
randomised trial would seem justified.
Br J Diabetes Vasc Dis 2011;11:4-9.
Key words: bezafibrate, diabetes prevention, fibrates, type 2
diabetes
Introduction
Type 2 diabetes now affects 2.8 million people in the UK and
its incidence both here and worldwide is increasing with IDF
predicting a 54% increase by 2030 to give a global prevalence
of 438.4 million.
1,2
People with type 2 diabetes are at greatly
increased risk from CVD as well chronic renal failure, retino pathy
and neuropathy. People with IFG and IGT are at high risk of devel-
oping type 2 diabetes
3
but also are at increased risk of CVD.
4
Current methods of treating type 2 diabetes are still inad-
equate and it has not been possible to eliminate the risk of
Fibrates: old drugs with a new role in
type 2 diabetes prevention?
ROBERT ELKELES
The Author(s), 2011. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/1474651410397245 4
Department of Metabolic Medicine, Imperial College Healthcare,
St Marys Hospital, London, UK.
Correspondence to: Professor Robert Elkeles
Department of Metabolic Medicine, Imperial College Healthcare,
St Marys Hospital, Praed Street, London, W2 1NY, UK.
Tel: +44 (0)20 3312 6037; Fax: +44 (0)020 3312 1563
E-mail: robert.elkeles@imperial.nhs.uk
Abbreviations and acronyms
ACCORD Action to Control Cardiovascular Risk in Diabetes
Apo apoprotein
BIP Bezafibrate Infarction Prevention Study
CHD coronary heart disease
CVD cardiovascular disease
DAIS Diabetes Atherosclerosis Intervention Study
DECODE Diabetes Epidemiology Collaborative Criteria in Europe
DREAM Diabetes Reduction Assessment with Ramipril and
Rosiglitazone Medication
ECG electrocardiogram
FIELD Effects of Long-term Fenofibrate Therapy on
Cardiovascular Events in People with Type 2
Diabetes Mellitus
HOMA-IR homeostasis model assessment insulin resistance
HDL high-density lipoprotein
IDF International Diabetes Federation
IFG impaired fasting glucose
IGT impaired glucose tolerance
IRAS Insulin Resistance Atherosclerosis Study
LDL low-density lipoprotein
LPL lipoprotein lipase
MI myocardial infarction
OGTT oral glucose tolerance test
PPAR- peroxisome proliferator activated receptor
SENDCAP St Marys Ealing Northwick Park Diabetes
Cardiovascular Prevention Study
STOP-NIDDM Study to Prevent NIDDM
VAHIT Veterans Affairs High-Density Lipoprotein
Cholesterol Intervention Study
VLDL very low-density lipoprotein
Robert Elkeles
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THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 5
REVIEW
complications. It would therefore be highly desirable to prevent
its occurrence or at least delay its onset. Type 2 diabetes is
associated with both peripheral insulin resistance and impaired
beta cell function. Insulin resistance is present for many years
before the onset of type 2 diabetes
5
and it is possible that
intervention at an early stage could delay onset or reduce the
incidence of type 2 diabetes.
Could fibrate drugs have a role in the prevention of type 2
diabetes? They have been widely used to modify plasma
lipids. Their mode of action is to activate the nuclear receptor
PPAR (figure 1). PPAR modulates the transcription of genes
involved in the synthesis of apo-CIII and fatty acids while
increasing the expression of genes involved in the synthesis of
apoA-V and LPL and those involved in fatty acid oxidation
(table 1). The results of these actions are to decrease the pro-
duction and to increase the removal of triglyceride rich lipopro-
teins thereby reducing circulating triglyceride concentration.
The increased apoA-I and apoA-II gene expression and LPL
activity also result in increased HDL formation. These and the
other effects of fibrates on inflammation, coagulation and
haemostasis have been well described.
6
Less well known are
their effects on blood glucose and insulin resistance.
Effects of fibrates on blood glucose and insulin
resistance
In small, randomised placebo controlled studies both bezafi-
brate and gemfibrozil have been shown to reduce both fasting
and postprandial blood glucose in type 2 diabetic patients.
7-9
The SENDCAP study was set up to find out whether bezaf-
ibrate had any effect on cardiovascular outcomes in type 2
diabetes.
10
In this study, 117 male and 47 female type 2 dia-
betic patients were randomised to receive either bezafibrate or
placebo. After a median of 3.5 years, there was a small rise in
fasting blood glucose in the placebo group but no change in
the bezafibrate treated group. The bezafibrate group also
showed a small fall in insulin resistance as measured by
HOMA-IR.
11.
In non-obese Japanese type 2 diabetic patients treatment
with bezafibrate 400 mg daily for 3 months was associated
with a reduction in fasting blood glucose, serum insulin and in
insulin resistance measured by HOMA-IR.
12
The BIP study was
set up to study the effect of bezafibrate on the combined inci-
dence of non-fatal MI or death from CHD in people who had
sustained a previous MI. They received either bezafibrate
400 mg daily or placebo. Over a two-year period there were
significant rises in serum insulin and HOMAR-IR in the placebo
group but no significant changes in the bezafibrate group.
Thus, bezafibrate was able to attenuate the rise in insulin resis-
tance over time found in the placebo group.
13.

Effects on serum lipids and lipoprotein metabolism
In general most studies have shown that fibrates reduced
plasma triglyceride concentration by 3050% and increase HDL
Figure 1. Mechanism of action of fibrates
Mechanism of action of fibrates
Fibrate
PPAR
PPRE/target genes Inflammation
Haemostasis
Activated
PPAR/RXR
Cellular cholesterol
homeostasis
Lipoprotein
metabolism
Fatty acid
metabolism
Reproduced with from Chapman MJ. Fibrates: therapeutic review.
Br J Diabetes Vasc Dis 2006;6:11-21.
Table 1. PPAR-mediated gene regulation by fibrates
Target gene Function of
gene product
Gene
expression
Apolipoprotein CIII Inhibitor of VLDL
clearance

Lipoprotein lipase Lipolysis, TGRL


Apolipoprotein AI HDL formation, reverse
cholesterol transport

Apolipoprotein AII HDL formation, reverse


cholesterol transport

ABCA1 Cellular cholesterol


efflux/HDL formation

Fatty acid binding


protein
Cellular fatty acid uptake
Acyl CoA synthetase Fatty acid activation,
acyl CoA esters

b-oxidation pathway Fatty acid oxidation


Acetyl CoA carboxyrase Fatty acid synthesis
Fibrinogen Blood clotting
C-reactive protein,
interleukin6
Acute prase reactant
Cyclooxygenase 2 Fatty acid metabolism
VCAM-1 Adhesion molecule
Key: HDL = high-density lipoprotein; TGRL = triglyceride-rich
lipoproteins; VLDL = very low-density lipoprotein; PPAR = peroxisome
proliferator activated receptor.
Adapted from Chapman (2003)
3
Reproduced with permission.
6
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6 VOLUME 11 ISSUE 1
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cholesterol by 1015% although there is considerable variation
in the size of these effects.
14
The effects of the fibrates on LDL
cholesterol are variable. LDL-cholesterol may be decreased by
up to 10%. However, in those with significantly elevated tri-
glycerides an increase in LDL-cholesterol may be found. This is
presumably due to increased LPL activity which increases the
conversion of VLDL to LDL. However, in these subjects the par-
ticle size of LDL is increased to the larger more buoyant variety,
which is thought to be less atherogenic.
Effects on cardiovascular outcomes
The effects of fibrates on cardiovascular outcomes have been
somewhat overshadowed by the striking results found with
statins. However, before the advent of statins, the Helsinki
Heart Study, which was a primary prevention study in middle-
aged dyslipidaemic men, showed that in comparison with a
placebo group those treated with gemfibrozil had significantly
fewer coronary events.
15
This beneficial effect on risk reduction
was most marked in those with obesity, those with the highest
serum triglycerides and those with the lowest HDL cholesterol.
Gemfibrozil-induced serum lipid changes in the diabetic
patients in this study were similar to those in non-diabetic sub-
jects and also reduced CHD incidence.
16
The BIP study was a
secondary intervention study designed to determine the effects
of bezafibrate on CHD. Although overall the study was nega-
tive, in those with hypertriglyceridaemia (plasma triglycerides
> 2.25 mmol/L) there was a significant (39%) reduction in
coronary events.
17
In contrast the VAHIT was a secondary inter-
vention study using gemfibrozil in men selected for low HDL
cholesterol and normal LDL cholesterol. Those treated with
gemfibrozil had significantly fewer events and a reduction in
coronary mortality.
18
Similar results were found for those who
had type 2 diabetes.
The SENDCAP study was probably the first, though small,
prospective study to investigate the effects of lipid modification
on cardiovascular outcomes specifically in type 2 diabetes.
10

Type 2 diabetic patients were randomised to bezafibrate
400 mg or placebo daily and followed for a mean period of
3 years. The primary outcome was change in carotid intima
media thickness. Although there was no significant difference
in the progress of ultrasonically measured arterial disease, in
those treated with bezafibrate there was a significant reduction
in the combined incidence of Minnesota-coded probable isch-
aemic changes on the resting ECG and of documented MI.
DAIS was a double-blind placebo-controlled study using feno-
fibrate in the actively treated participants to find out whether
correcting lipid abnormalities typically seen in type 2 diabetes
would alter the progression of angiographically measured coro-
nary artery disease.
19
The fenofibrate-treated group had signifi-
cantly less angiographic progression than the placebo group.
There was also a 23% reduction in clinical events in the feno-
fibrate treated group but the study was not powered to be a
clinical event study. The FIELD study was a large prospective
study of the effects of fenofibrate on cardiovascular events
in type 2 diabetes. Overall, fenofibrate failed to reduce the
number of coronary events or total mortality.
20
However, there
was a 24% reduction in non-fatal MIs, a significant reduction
in total CVD events and reduced progression of albuminuria
and retinopathy. The lack of effect on mortality may have been
due to the large numbers given statins in the placebo group. In
a pre-specified analysis it was also associated with reduction in
lower limb amputation rate.
21
The much awaited ACCORD
study investigated whether combination therapy with a statin
plus fibrate as compared with statin alone would reduce risk of
CVD in patients with type 2 diabetes who were at high risk
from CVD.
22
This showed that fenofibrate given in addition to
statin did not lead to any reduction in mortality. However, in
the subgroup with high triglycerides and low HDL cholesterol
the primary outcome rate was 12.4% in the fenofibrate group
compared with 17.3% in in the placebo group; this failed to
reach statistical significance. The main fibrate cardiovascular
outcome studies in type 2 diabetes are listed in table 2.
A recent large meta-analysis identified 18 trials with data
from 45,058 subjects including 2,870 major cardiovascular
events.
23
Fibrate therapy produced a 10% reduction for major
cardiovascular events and a 13% reduction in coronary events
There was no benefit for stroke or cardiovascular or all-cause
mortality.
Thus, overall, fibrates do seem to have a modest effect in
reducing cardiovascular outcomes especially in those with the
metabolic syndrome or type 2 diabetes.
The rationale for early intervention to prevent type 2
diabetes
A significant problem in prevention of cardiovascular complica-
tions of type 2 diabetes is that at diagnosis people with type 2
diabetes are already at greatly increased risk of CHD and
stroke.
24
Even people with IGT or IFG have about a two-fold
increased risk for developing CVD events compared with those
with normal blood glucose levels.
25
The DECODE study anal-
ysed 10 prospective European cohort studies including 15,388
Table 2. Fibrate trials of cardiovascular outcomes involving type 2
diabetic patients
Study References
Helsinki Heart Study 15,16
SENDCAP (St Marys Ealing Northwick Park
Diabetes Cardiovascular Prevention Study)
10
VA-HIT (Veterans Affairs High-Density Lipoprotein
Cholesterol Intervention Study)
18
DAIS (Diabetes Atherosclerosis Intervention Study) 19
FIELD (Effects of Long-term Fenofibrate Therapy
on Cardiovascular Events in People with Type 2
Diabetes Mellitus)
20
ACCORD (Action to Control Cardiovascular Risk
in Diabetes)
22
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THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 7
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men and 7,126 women.
4
There appeared to be a linear rela-
tionship between blood glucose concentration and CVD
mortality even within the normal glucose range.
Both IGT and IFG are associated with insulin resistance.
26

Insulin resistant subjects tend to have higher total and VLDL tri-
glyceride and lower HDL cholesterol than more insulin sensitive
subjects,
27
a pattern thought to be atherogenic and common in
type 2 diabetes.
There is evidence to implicate insulin resistance in the
genesis of atherosclerosis. Insulin-mediated glucose disposal
was measured in healthy individuals using euglycaemic
hyperinsulinaemic clamps and ultrasound of the carotid and
femoral arteries to detect asymptomatic atherosclerosis.
Those with asymptomatic atherosclerosis showed a 20%
decrease in insulin sensitivity compared with those without.
28

Furthermore, in IRAS a significant negative association was
found between insulin sensitivity as measured by the fre-
quently sampled glucose tolerance test and carotid intima
media thickness.
29
There is also considerable evidence that insulin resistance is
associated with cardiovascular disease. In the San Antonio Heart
Study, Mexican and non-Hispanic white residents underwent
baseline examination with HOMA-IR measurements. During the
follow-up period a significant association was found between
HOMA-IR and risk of cardiovascular events after adjustment for
multiple covariates.
30
In the Bruneck population study in Italy,
HOMA-IR estimated insulin resistance was associated with sub-
sequent symptomatic cardiovascular disease independently of all
classical and several non-traditional risk factors.
31
There is evidence that insulin resistance and associated
cardiovascular risk factors are present many years before the
onset of type 2 diabetes. In the San Antonio cohort,
32
those
who converted to type 2 diabetes had higher total and LDL
cholesterol, triglyceride and serum triglyceride, lower HDL
cholesterol and fasting glucose, insulin, 2-h glucose, body
mass index and blood pressure than those who did not
develop type 2 diabetes. When those with IGT at baseline
were excluded those who converted to type 2 diabetes still
had a more atherogenic pattern of risk factors including lower
HDL cholesterol at baseline.
In a group of Pima Indians studied prospectively with OGTT
and hyperinsulinaemic clamp studies at baseline, insulin resis-
tance was the strongest predictor of conversion to type 2 diabe-
tes.
33
In the 7-year follow up of the San Antonio Heart Study,
those who converted to type 2 diabetes had significantly higher
body mass index, waist circumference triglyceride blood pres-
sure and lower HDL cholesterol than non-converters.
34
Thus, it
would appear that the seeds of increased cardiovascular risk
characteristic of type 2 diabetes are sewn long before the onset
of the level of hyperglycaemia at which type 2 diabetes is diag-
nosed. This led Haffner to postulate that, unlike microvascular
complications, for which the clock starts ticking with the onset
of clinical diabetes, for macrovascular disease precipitating
events may begin decades earlier. Haffner has called this the
ticking clock hypothesis.
32
It therefore seems reasonable to
suggest that intervention at this early so-called pre-diabetic
stage to reduce insulin resistance and modify the atherogenic
lipid profile could have a role in prevention not only of type 2
diabetes but also its associated cardiovascular complications.
The fibrate group of drugs could provide just such a mechanism.
Previous interventions to prevent type 2 diabetes
Intervention with lifestyle measures of diet and exercise was
shown by Tuomilehto et al. to reduce the incidence of type 2
diabetes in people with IGT by 58% over a period of 3.2 years
35

and by 43% in the Da Qing study in a Chinese population.
36
In
the Diabetes Prevention Program, in people with either IFG or
IGT, lifestyle advice or metformin reduced the incidence of type
2 diabetes by 58%, and 31% respectively compared to placebo
over 2.8 years follow-up.
37
The STOP-NIDDM study
38
the alpha-
glucosidase inhibitor acarbose, reduced incidence of new dia-
betes in those with IFG by 25% over 3.3 years. It is noteworthy
that 25% of subjects given acarbose withdrew from the study,
mainly due to gastrointestinal side effects.
Another approach to prevention has been to reduce insulin
resistance pharmacologically in those with IFG or IGT. In the
DREAM
39
study 5,269 people with IFG or IGT were randomised
to receive either rosiglitazone or placebo. The composite end-
point was incident diabetes or death. Rosiglitazone substantially
reduced the incident type 2 diabetes. Cardiovascular event rates
were similar in the two groups but there was an increase in
those developing heart failure in the rosiglitazone group.
Could fibrates have a role in prevention of type 2
diabetes?
As mentioned above, those who develop type 2 diabetes have
been found to be more insulin resistant, have higher triglycer-
ides and lower HDL-cholesterol those who do not. Furthermore,
at diagnosis of type 2 diabetes cardiovascular disease is already
present. Therefore intervention at an early stage in those with
IFG or IGT with an agent which could correct these metabolic
abnormalities and in addition reduce blood glucose and risk
of cardiovascular events could make sense where lifestyle
measures are not effective. The fibrates seem to fit these
requirements better than other classes of drugs. The effect of
bezafibrate on the progression of IFG to type 2 diabetes was
studied in 303 participants aged 4274 years with coronary
artery disease over 6.2 years. New onset diabetes was recorded
in 54% of subjects given placebo and 42% given bezafibrate,
a significant reduction in incidence.
40
In a retrospective cohort
study from the General Practice Research Database in the UK,
individuals chronically exposed to bezafibrate were compared
with those exposed to other fibrates for incident type 2 diabe-
tes.
41
Those on bezafibrate had a lower incidence of type 2
diabetes than those on other fibrates. In a post-hoc analysis
those on bezafibrate also showed a lower incidence of progres-
sion to oral antidiabetic agents or progression to use of insulin.
Gemfibrozil has not been widely used in the UK and there
may be interactions between it and the statins. For a trial of
prevention of type 2 diabetes, the choice would seem to lie
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between bezafibrate or fenofibrate. Bezafibrate is inexpen-
sive, has a good safety record, and has been shown to have
beneficial effects on blood glucose and insulin resistance in
addition to its well described effects on improving the ath-
erogenic lipid profile. These effects taken together might be
able to prevent or delay the onset of type 2 diabetes and to
reduce cardiovascular risk in those at high risk for developing
type 2 diabetes.
Conclusion
There seems to be a reasonable case for a randomised control
trial of bezafibrate to delay the onset of, or to prevent, type 2
diabetes in those at high risk.
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Key messages
Delaying onset or prevention of type 2 diabetes is an
important aim
The fibrate drugs, in particular bezafibrate:
reduce blood glucose and insulin resistance
improve the atherogenic lipid profile
A trial of bezafibrate to prevent type 2 diabetes is
justified
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THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE 9
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