Progress in Cardiology

Type 2 diabetes, dyslipidemia, and vascular risk:

Rationale and evidence for correcting the
lipid imbalance
Rafael Carmena, MD, FACP, FRCP Edin Valencia, Spain

Type 2 diabetes is an important cardiovascular risk factor. A significant component of the risk associated with type 2
diabetes is thought to be because of its characteristic lipid btriadQ profile of raised small dense low-density lipoprotein levels,
lowered high-density lipoprotein, and elevated triglycerides (TGs). Trials of statins and fibrates have included substantial
numbers of patients with diabetes and indicate that lipid lowering reduces cardiovascular event rates in these patients.
However, statins alone do not always address all the lipid abnormalities of diabetes. Fibrates, which have low affinity for
peroxisome proliferator–activated receptor a (PPARa), improve most aspects of the atherogenic dyslipidemia of diabetes.
Chronic elevations of free fatty acids (FFA) induce insulin resistance and contribute to the lipid triad of diabetes. Therefore,
reducing their levels is likely to ameliorate insulin resistance and improve the lipid triad of diabetes. PPARs are intimately
involved in the regulation of FFA: PPARa modulation increases FFA catabolism and PPARg agonism (eg, by
thiazolidinediones) increases TG lipolysis, FFA transport, conversion of FFA to TGs, and safe storage of FFA. Integrating
potent PPARa and PPARg activity may deliver greater improvement of the diabetic dyslipidemic profile and its attendant risks
than selective PPAR activation. (Am Heart J 2005;150:859-70.)

Diabetes is a substantial contributor to the global
burden of disease. Current prevalence is estimated at
170 million cases, the majority being type 2 diabetes,
with this figure expected to be more than double by
2030. Excess health-care costs in diabetes are mainly
because of the complications of atherosclerotic cardio-
vascular disease (CVD). The increased risk attributable
to diabetes is such that individuals with diabetes with no
previous history of myocardial infarction (MI) have the
same likelihood of CVD as persons with prior MI but no
diabetes. It is progressively recognized that the
increased CVD morbidity and mortality are because
of the atherogenic dyslipidemia, which characterizes
type 2 diabetes. The causes of this distinct lipid profile
and approaches to reducing the associated CVD risk are
the subject of this review.
Type 2 diabetes and vascular disease
Major traditional cardiovascular risk factors (eg,
hypertension, smoking, and a procoagulant state) only
partly explain the increased risk of CVD in diabetes.
From the University of Valencia and Hospital Clı́nico Universitario, Valencia, Spain.
Submitted October 27, 2004; accepted April 3, 2005.
Supported by a grant from Instituto de Salud Carlos III, RCMN (C03/08), Madrid, Spain.
Reprint requests: Rafael Carmena, Hospital Clı́nico Universitario, Blasco Ibáñez, 17,
46010 Valencia, Spain.
E-mail: carmena@uv.es
0002-8703/$ - see front matter
n 2005, Mosby, Inc. All rights reserved.
doi:10.1016/j.ahj.2005.04.027
There is now abundant evidence of the major impor-
tance of dyslipidemia as a cause of CVD—that lipid
abnormalities are a more important risk factor for CVD
than hyperglycemia. In the UKPDS, intensive treatment
of hyperglycemia prevented or slowed the microvascu-
lar complications of diabetes but only had a small and
nonsignificant effect on CVD risk.1 Decreased high-
density lipoprotein cholesterol (HDL-C) and elevated
low-density lipoprotein cholesterol (LDL-C) levels
predicted coronary heart disease (CHD) in the UKPDS to
a greater extent than hyperglycemia.2
Although high LDL-C predicts increased CVD risk in
patients with diabetes, raised LDL-C levels are not a
characteristic part of the diabetic dyslipidemic profile;
the prevalence of high LDL-C levels in individuals with
diabetes is similar to that in the general population.
However, compared with nondiabetic persons, people
with diabetes often have a different LDL particle size
distribution, which is apparent as an increase in highly
atherogenic, small dense LDL (sdLDL) particles. Diabetes
is further characterized by elevated triglycerides (TGs)
and reduced HDL-C, a pattern that is 2- to 3-fold
more common than in people without diabetes. Thus,
individuals with diabetes have a characteristic
atherogenic dyslipidemia of decreased HDL-C, elevated
TGs, and increased sdLDL.
Pathogenesis of diabetic dyslipidemia
Although diabetes is an established CVD risk
factor, CVD is often already present when diabetes is

860 Carmena
diagnosed. The metabolic syndrome has been identified
as a constellation of metabolic and nonmetabolic
disorders related to defects in insulin sensitivity that
leads to an increased prevalence of CVD and CVD
mortality in some3 but not all epidemiological studies.4
In the metabolic syndrome, as in diabetes, HDL-C levels
are lowered, TG levels raised, and sdLDL increased.
Insulin resistance, defined as the decreased ability of
insulin to act effectively on peripheral target tissues
(especially muscle, adipose tissue, and liver), results
from a combination of genetic susceptibility and
obesity and is a shared characteristic, which almost
certainly contributes to the distinctive lipid triad
associated with both conditions (Table I).
The cause of insulin resistance is under debate, but it
is probably the consequence of chronically elevated
levels of free fatty acids (FFA) that impair insulin-
signaling pathways. Visceral (central) obesity, an energy-
rich (high-saturated-fat) diet, and a sedentary lifestyle are
all strongly correlated with insulin resistance. Increased
plasma levels of FFA accompany all 3 states, but visceral
fat is probably the most important contributor to insulin
resistance because of its high FFA flux. In addition,
insulin resistance can be potentiated by cytokines (eg,
tumor necrosis factor a and interleukin 6) and hormones
that are synthesized by visceral adipose tissue.
Insulin resistance impairs the normal insulin-mediated
suppression of FFA release from visceral adipose tissue.
There is an increased flow of FFA to the liver, which
results in the overproduction of very low-density
lipoprotein (VLDL) and leads to increased plasma TGs.
This situation is exacerbated by the reductions in
lipoprotein lipase (LPL) activity and decreases in TG
metabolism that occur in an insulin-resistant state. In
turn, the increased level of plasma TGs causes lowered
HDL-C levels and increased sdLDL (Figure 1).
Cardiovascular disease risk associated
with the characteristic lipoprotein
changes of type 2 diabetes
The characteristic atherogenic dyslipidemia of low
HDL-C, raised TGs, and high sdLDL seen in diabetes
almost certainly contributes to the CVD risk in
individuals with diabetes. HDL-C is generally considered
to be a cardioprotective lipoprotein, and its importance
is illustrated by epidemiological studies that demon-
strate an inverse relationship between HDL-C levels and
CVD risk for both sexes.5 For example, in the
Framingham study, the CVD risk was increased nearly
6-fold in women with HDL-C levels b1.2 mmol/L
compared with women with HDL-C levels N1.7 mmol/L.5
In individuals with diabetes, the CVD risk that accom-
panies a low HDL-C level is demonstrated by the UKPDS;
the relative risk of CVD increased by 1.15 for each
American Heart Journal
November 2005
Table I. Characteristics of the diabetic dyslipidemic profile
Parameter Consequence
Raised triglyceride levels Enhanced thrombogenicity
Remnant triglyceride-rich lipoproteins
Reduced HDL plasma levels
Increased small dense LDL
Small dense LDL Increased penetration of arterial intima
Enhanced proteoglycan binding
Increased oxidation potential
Reduced plasma HDL levels Reduced antioxidant and
anti-inflammatory activity
0.1 mmol/L decrement in HDL-C.2 VA-HIT demonstrated
that increases in HDL-C can lower the incidence of CHD
events.6
In contrast to the increasing awareness of the
importance of HDL-C, acceptance of the role of raised
TGs in CVD is hampered because they serve as a marker
for other atherogenic factors (eg, low HDL-C concen-
trations and elevated sdLDL levels). However, in a
meta-analysis of prospective studies in the general
population, the contribution of TGs to CVD was
independent of HDL-C.7 After adjusting for HDL-C and
other risk factors, the increased risks associated with a
difference in TG levels of 1 mmol/L was 12% in men and
37% in women. The last component of the diabetic lipid
triad, sdLDL, has been shown to be associated with an
elevated risk of CVD in some8 but not in all studies.9 The
increased risk appears to be independent of HDL-C but
not independent of fasting plasma TGs.
Effects of lipid-modifying therapies on
lipid abnormalities and CVD risk in
type 2 diabetes
Despite a growing appreciation of the significance of
lipid disturbances, management of diabetes often
concentrates on glycemic and blood pressure control.
Most of the commonly used antidiabetic agents have a
neutral effect (eg, sulfonylureas and meglitinides) or
mildly beneficial effect (eg, a-glucosidase inhibitors) on
blood lipids. The exception is metformin, which
appears to reduce total cholesterol (TC) and LDL-C
levels but has no effect on HDL-C or TGs.10 Overall, few
patients with diabetes receive specific therapeutic
interventions to improve their diabetic lipid profile
despite that high sdLDL levels, raised TG concentra-
tions, and low HDL-C levels are all potentially modifi-
able risk factors.
When lipid modification measures are required,
lifestyle changes are generally recommended. Although
such interventions can modify lipid parameters, there
are no data on their long-term effect on CVD outcomes.
Importantly, it is often difficult for patients to maintain
American Heart Journal
Volume 150, Number 5
Figure 1
HL
small, dense HDL
VLDL
LIVER
LPL Chylomicrons
Proposed mechanism for generation of sdLDL and lowering of HDL. Adapted from Syvanne et al. Lancet 1997;350(s1):20-3.
the required lifestyle changes. Therefore, most individ-
uals will require pharmacotherapy, the mainstays being
statins and fibrates. In the general population, lowering
of LDL-C levels by statins reduces CVD morbidity and
mortality, whereas decreasing TGs and raising HDL-C
concentrations with fibrates also improve survival.
However, the proven benefits of lipid-lowering therapy
on mortality in nondiabetic individuals may not be
directly translatable to individuals with diabetes-specific
metabolic abnormalities. Those trials of lipid lowering
that have included patients with diabetes do demon-
strate a reduction in CVD associated with diabetes and
are discussed below. Importantly, many of them inform
recommendations for the treatment of dyslipidemia in
diabetes, including the guidelines formulated by the
American Diabetes Association.11
LDL-C in diabetes: the effect of statins
Statins inhibit hepatic 3-hydroxy-3methylglutaryl
coenzyme A reductase, the enzyme catalyzing the rate-
limiting step in hepatic cholesterol synthesis. The net
effect is to lower plasma concentrations of cholesterol-
carrying lipoproteins, the most prominent being LDL.
Newer members of the class, such as atorvastatin, can
affect LDL subtype composition,12 raise HDL-C, and
lower TG levels,13,14 but these effects tend to be modest
compared with the reductions in LDL-C.
Carmena 861
TG CE TG- rich HDL
CE CETP TG
TG Normal LDL
CE
CE
TG- rich
remnant CETP
TG
TG TG- rich LDL
CE
LPL
HL
FFA
sd LDL
The reduction in the risk of CVD events in general
populations has been demonstrated in 2 primary
prevention trials. However, these studies, the AFCAPS/
TexCAPS and the WOSCOPS, included very few patients
with diabetes (Table II),15,16 and therefore, the evidence
for the impact of statins on primary prevention of CVD
in diabetes is limited. There have been more placebo-
controlled secondary prevention trials of statins that
have included relatively large numbers of individuals
with diabetes (Table III). Together, they indicate that
these agents reduce the risk of CVD events in people
with diabetes. One such investigation was the 4S,17,18
which included 202 individuals with diabetes. The
reduction in risk of total mortality of 43% in the diabetes
group over 5.4 years was not statistically significant, but
there was a significant 55% reduction in the risk of major
CHD events (Table II).17 A subsequent analysis of the 4S
further included 281 patients with diabetes diagnosed
based on a fasting plasma glucose z7.0 mmol/L.18 In
these patients, simvastatin lowered significantly the risk
of major CHD events from 37.5% to 23.5%, which was
similar to the relative reduction in the individuals with
normal glucose status.18 This expanded analysis showed,
for the first time, the benefits of statin treatment in
impaired fasting glucose subjects.
The CARE study and the LIPID study assessed the
effects of pravastatin in individuals with and without
 American Heart Journal
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Table II. Changes in lipid parameters and cardiovascular disease risk with statin therapy in placebo-controlled studies with type 2 diabetes
subgroups
Number of subjects Total population*

Mean Lipid level Mean Change in

duration inclusion Lipid baseline lipid levels
Study Design (y) Total Diabetes criterion parameter lipid levels (%)

WOSCOPS16 Primary prevention 5 6595 76 LDL 4.0-6.0; TG 1.8
12

Pravastatin TC N6.5 HDL 1.1 5
(40 mg/day) LDL 5.0
26
vs placebo sdLDL NR –
ApoA-I NR –
ApoB NR –
AFCAPS/15 Primary 5.2 6605 155 TC 4.65-6.82; TG 1.78
15
TexCAPS prevention LDL 3.36-4.91; HDL 0.96 6
Lovastatin HDL V1.16 for men LDL 3.9
25
(20-40 mg/d) and V1.22 for sdLDL NR –
vs placebo women TG V 4.52 ApoA-I 1.26 7.2T
ApoB 1.2
18.9T
4S17,18,42 Secondary 5.4 4444 202 TC 5.5-8.0 TG 1.5
9
prevention HDL 1.19 8
Simvastatin LDL 4.87
34
(40 mg/d) sdLDL NR –
vs placebo ApoA-I NR –
ApoB NR –
CARE19,43 Secondary 5 4159 586 TC b 6.22; TG 1.7
14
prevention LDL 2.98-4.51; HDL 1 5
Pravastatin TG b3.96 LDL 3.6
28
(40 mg/d) sdLDL NR –
vs placebo ApoA-I NR –
ApoB NR –
LIPID20,21 Secondary 6.1 9014 782 TC 4-7 TG 1.6z
11
prevention HDL 0.9z 5
Pravastatin TG b 5.0 LDL 3.9z 25
(40 mg/d) sdLDL NR –
vs placebo ApoA-I NR –
ApoB NR –
HPS23,44 Primary and 5 20536 5963 TC z3.5 TG 2.1 A
secondary HDL 1.06 z
prevention LDL 3.4 A
Simavastatin sdLDL NR –
(40 mg/d) vs ApoA-I 1.2 A
placebo ApoB 1.16 A
ALLHAT-LLT45 Secondary 4.8 10355 3638 LDL 3.1-4.9 TG 1.7
3.5
prevention (2.6-3.3 if HDL 1.2 3
Pravastatin known CHD LDL 3.8
29
(20 mg/d and TG b3.9) sdLDL NR –
vs usual care) ApoA-I NR –
ApoB NR –
ASCOT-LLA25 Primary 3.3 19342 2532 TC V 6.5 TG 1.7
14
prevention HDL 1.3 0
Atorvastatin LDL 3.4
28
(10 mg) vs sdLDL NR –
placebo ApoA-I NR –
ApoB NR –
CARDS26 Primary 3.9 2838 2838 LDL V 4.14 TG – –
prevention TG V 6.78 HDL – –
Atorvastatin LDL – –
(10 mg) sdLDL – –
vs placebo ApoA-I – –
ApoB – –

TChange at 1 year.
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Table II. continued

Diabetes population* CVD events, total population CVD events, type 2 diabetes

Mean Change in Reduction in Reduction in

baseline lipid levels Active risk of CVD Active risk of CVD
lipid levels (%) Outcome Placebo treatment events (%) Placebo treatment events (%)

NR – Nonfatal 7.9 5.5 31 ( P b .001) – – –

NR – MI plus
NR – fatal CHD
NR –
NR –
NR –
1.9 15 Fatal and 5.5 3.5 37 ( P b .001) 43 ( P = NS)
0.9 6 nonfatal MI,
3.9
5 unstable
NR – angina,
NR – or sudden
NR – cardiac death
1.7
11 All-cause 7.9 5.5 30 ( P b .0003) 43 ( P = .087)
1.1 7 mortality
4.8
36
NR –
NR –
NR –
1.9
13 Nonfatal 13.2 10.2 24 ( P = .003) 20.4 17 13 ( P = NS)
1 4 MI plus
3.5
27 fatal CHD
NR –
NR –
NR –
NR – Nonfatal 15.9 12.3 24 ( P b .001) 23 19 19 ( P = NS)
NR – MI plus
NR – fatal CHD
NR –
NR –
NR –
2.3 A First major 25.2 19.8 24 ( P b .0001) Prior Prior Prior CVD:
1.06 Az vascular event CVD: 36 CVD: 36 18.4
3.2 A ( P = .002)
NR – No CVD: 13.5 No CVD: No CVD: 33
1.2 A 9.3 ( P = .0003)
1.10 A
NR – All-cause 15.3 14.9 1 ( P = NS) – –
3 ( P = NS)
NR – mortality
NR –
NR –
NR –
NR –
NR – Nonfatal 30 1.9
36 ( P = .0005) 3.6 3.0
16 ( P = .43)
NR – MI plus
NR – fatal CHD
NR –
NR –
NR –
1.95
19 Major CV event – – – 9.0 5.8
37 ( P = .001)
1.39 1
3.04
40
NR NR
1.53
0.1
1.17
23
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Table III. Changes in lipid parameters and cardiovascular disease risk with fibrate therapy in placebo-controlled studies with type 2 diabetes
subgroups

Number of subjects Total population*

Mean Lipid level Mean Change in

duration inclusion Lipid baseline lipid levels
Study Design (y) Total Diabetes criterion parameter lipid levels (%)

DAIS27 Secondary 3 418 418 LDL 3.5-4.5 TG – –

prevention and TG V5.2; HDL – –
(coronary or LDL V4.5 LDL – –
atherosclerosis) and TG 1.7-5.2 sdLDL – –
Fenofibrate ApoA-I – –
(200 mg/d) ApoB – –
vs placebo
SENDCAP28 Secondary 5 164 164 TC z5.2; TG – –
prevention trial TG z1.8, HDL – –
Bezafibrate HDL V1.1 LDL – –
(400 mg/d) sdLDL – –
vs placebo ApoA-1 – –
ApoB – –
Non-HDL – –
Helsinki Heart Primary 5 4081 135 Non-HDL z5.2 TG 2
34
Study29,46 prevention HDL 1 10
Gemfibrozil LDL 4.9
8
(1200 mg/d) sdLDL NR –
vs placebo ApoA-I NR –
ApoB NR –
VA-HIT47-50 Secondary 5.1 2531 627 LDL V3.6; TG 1.8
31
prevention HDL V1.0 HDL 0.8 6
Gemfibrozil TG V3.4 LDL 2.8 1
(1200 mg/d) sdLDL NR –
vs placebo ApoA-I NR –
ApoB NR –

TActive treatment; concentrations: mmol/L for TC, LDL, HDL, and TG; g/L for apolipoproteins.

diabetes (Table II).19,20 In the CARE study, the reduction
in the primary end point (death from CHD or nonfatal
MI) was significant in the nondiabetes subset (24%, P =
.003), but the effect in the diabetes group (13%) was not
significant. However, the relative risk of major CHD
events in the latter decreased by 25% ( P = .05), which
was similar to the reduction seen in the overall
population. The relative risk reduction in subjects with
diabetes in the CARE study was substantially lower
than in the 4S, suggesting that the benefit of statin
therapy is less among individuals with diabetes and low
LDL-C levels.
In the LIPID study, the 19% reduction in MI or CHD
death in the subjects with diabetes was not significant,20
a finding that did not change in a 2-year follow-up study.21
In an analysis of the pooled CARE and LIPID results, there
was a nonsignificant reduction of 17% for risk of
combined coronary death and nonfatal MI in people with
diabetes.22 In this pooled analysis, the baseline HDL-C
concentration remained predictive of CHD mortality
during treatment, indicating a statin does not necessarily
correct the risk associated with low HDL-C.22
The HPS assessed the effects of simvastatin on vascular
risk in the largest cohort of individuals with diabetes
recruited so far in a statin trial. The study included 5963
subjects with diabetes, in whom simvastatin reduced
significantly the risk of first major vascular event by 22%.
This reduction was greater in those without prior CVD
(33%) than in those with prior CVD (18%) (Table II).23 In
contrast to the results of the CARE study, the HPS clearly
shows that statin therapy reduces the risk of CVD in
patients with diabetes, irrespective of their baseline
LDL-C concentrations.
The GREACE study also demonstrated the benefit of
statin therapy.24 Although conducted with an open
design, it reported a striking 55% reduction in the risk of
a major CHD event. It was performed in 1600 patients
with established CHD (prior MI or N70% stenosis of at
least 1 coronary artery) who were randomized to receive
atorvastatin (titrated to achieve an LDL-C goal
b2.6 mmol/L) or usual care for 3 years. GREACE
included 313 patients known to have diabetes in whom
there was a 58% risk reduction ( P b .0001). This study,
albeit not conducted to optimum clinical trial design,
American Heart Journal
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Table III. continued

Diabetes population*
CVD events, total population CVD events, type 2 diabetes
Mean Change in Reduction in Reduction in
baseline lipid levels Active risk of CVD Active risk of CVD
lipid levels (%) Outcome Placebo treatment events (%) Placebo treatment events (%)

2.59 ~28 Mixed secondary – – – 23.7 18.4 22 ( P = NS)

1.01 ~7 and primary
3.38 ~6 combined clinical
NR – end points
NR –
NR –

2.24
33 Probable – – – 23 7 67 ( P = .01)

1.02 6 ischemic
3.66
10 change and
NR – documented MI
1.41 –6
1.31 8
4.72
12
– – MI and cardiac death 41.4 27.3 34 ( P = .02) 10.5 3.3 60 ( P = NS)
– –
– –
NR –
NR –
NR –
2.0
20 Combined 21.7 17.3 22 ( P = .006) 36 28 24 ( P = .05)
0.8 5 end point: nonfatal
2.9 No change MI; CHD
NR – death; stroke
NR –
NR –

points to the benefits of more aggressive lipid lowering
in high-risk populations, such as those with diabetes.
Two trials involving persons with diabetes were
stopped early because of an apparent reduction in CVD
risk at interim analysis. The ASCOT-LLA study did not
demonstrate a significant reduction in nonfatal MI or
fatal CHD in the atorvastatin recipients who had
diabetes. However, this may have been because the trial
was stopped early and there was a relatively small
number of diabetes cases (Table II).25 In the CARDS,
there was a significant reduction in the primary end
points of major coronary events, stroke, or coronary
revascularization procedures.26 A total of 2838 patients
with diabetes and without a history of CVD or high
LDL-C received atorvastatin or placebo; the statin led to
a 37% reduction in major cardiovascular events
(Table II). The treatment effect did not vary by LDL-C
pretreatment level. Thus, there does not seem to be a
given LDL-C threshold that determines whether a
patient receives a statin.
The accumulated evidence from these statin trials
among patients with diabetes demonstrates that LDL-C
lowering reduces the incidence of cardiovascular events.
However, substantial cardiovascular risk remains, em-
phasizing the importance of improving other lipid
parameters and optimizing the management of other risk
factors, such as hypertension.
HDL and TGs in diabetes: the effect of fibrates
Fibrates improve many aspects of the atherogenic
dyslipidemia of diabetes. Their main mechanism of
action is to activate peroxisome proliferator–activated
receptor a (PPARa), which is preferentially expressed
in tissues such as the liver, muscle, kidney, and heart
where fatty acids are oxidized. Its activation increases
expression of genes involved in fatty acid and lipopro-
tein oxidation in the liver and muscle, increases the
expression of LPL in the liver, and decreases apolipo-
protein C (apoC)-III concentrations. The hydrolysis of
TGs by LPL is inhibited by apoC-III and, therefore,
lowering of this apolipoprotein results in increased
LPL activity in the liver. Triglyceride levels are further
lowered as PPARa activation enhances their intravas-
cular metabolism. The result is reduced TGs and,

866 Carmena
therefore, VLDL production, which leads to improve-
ments in HDL-C concentrations and reduced sdLDL
formation. Furthermore, PPARa activation modifies the
expression of several key genes that control HDL-C
metabolism (eg, adenosine triphosphate–binding cas-
sette transporter A1), resulting in increased HDL-C
levels. PPARa activation also increases the synthesis of
apoA-I and apoA-II; the former is the main component
of HDL-C.
The effect of fibrate on coronary atherosclerosis in
diabetes was specifically assessed in the DAIS. In
418 individuals with type 2 diabetes (Table III),
fenofibrate (200 mg/d) significantly lowered TC and
LDL-C, lowered TG levels, and raised HDL-C levels.27
Compared with placebo, fenofibrate treatment resulted
in significant but smaller increases in stenosis, a
significantly smaller decrease in minimum lumen diam-
eter, and a nonsignificantly smaller decrease in mean
segment diameter with fenofibrate. The study was
underpowered to examine clinical end points, but
fenofibrate did result in a nonsignificant reduction
(22.3%) in specified cardiovascular events compared
with placebo. In the SENDCAP study, bezafibrate
(400 mg/d) failed to slow the progression of carotid or
femoral arterial disease, but this may have been because
of the very small size of the trial (164 people with
diabetes) (Table III).28 However, there was a 67%
reduction ( P = .01) in the incidence of confirmed and
probable MI. In summary, while giving some insight into
the effects of fibrates on diabetic dyslipidemia, the
relatively small patient numbers in the 2 studies limits
the conclusions that can be reached about CVD risk.
Other studies have evaluated the effects of fibrates in
populations that have included patients with diabetes.
The Helsinki Heart Study investigated the effect of
gemfibrozil (600 mg twice daily) on CHD in 4081 men
aged 40 to 55 years (Table III).29 The relative risk
reduction of major cardiac end points with gemfibrozil
was 34% ( P b .002) in the general population. Both the
increase in concentration of HDL-C and the decrease in
LDL-C levels, but not changes in TG, were predictive of a
reduction in CHD events. Gemfibrozil reduced the
incidence of major CHD events in patients with diabetes
by 60% compared with placebo, although this reduction
was not statistically significant largely because of the
small patient number (135 individuals with diabetes).
VA-HIT was a secondary prevention trial of gemfibrozil
therapy (Table III).6 The incidence of CHD events in the
627 men with diabetes was reduced significantly by
24%, which was similar to the decrease seen in subjects
who did not have diabetes. There was no change in
LDL-C levels, indicating the importance of other lipid
parameters as risk factors.
The reported trials of fibrates have generally included
too few subjects to determine reliably the reduction in
CVD risk in people with diabetes, but they do indicate
American Heart Journal
November 2005
that fibrates are likely to reduce CVD risk in this
population. Two large-scale outcome trials of fibrates
that may further elucidate the contribution of fibrates to
diabetes CVD risk management are the FIELD study and
the LDS; the latter was stopped early because of the
withdrawal of cerivastatin. Their results are awaited
with interest as they are powered to determine the
impact of fibrates on CVD risk in diabetes. Despite the
undoubted benefits of fibrates, as for statins, a substan-
tial degree of cardiovascular risk remains after treatment
with them. This suggests that other options should be
explored to reduce the residual risk.
Combination therapy for diabetic dyslipidemia with
existing lipid-altering agents
Addition of a fibrate to statin therapy can further
increase HDL-C and lower TG levels. However, this
combination is potentially associated with an increased
risk of side effects, particularly myopathy and abnormal
liver function tests. It is becoming clear that of the
fibrates, gemfibrozil has the greatest potential to
interact with statins. It increases statin plasma concen-
tration by affecting glucuronidation pathways in the
liver. In the author’s experience, the combination of
fenofibrate with a statin has proved to be an effective
and well-tolerated drug combination in high-risk indi-
viduals with severe mixed dyslipidemia. Moreover, it
makes sense to monitor safety parameters, and all
patients should be counseled to stop the drugs in case
of severe muscle pain and tenderness suggestive of
myopathy. More formal evidence on the safety of a
statin-fibrate combination should become available from
the ACCORD study, which is investigating the efficacy
of combined fenofibrate and simvastatin therapy. It is
underway in the United States, and results are expected
in 2008 or 2009.
Other combinations have been evaluated in small
populations of diabetic patients and appear to improve
aspects of the lipid profile. The potential of atorvastatin
and extended release nicotinic acid combination was
assessed in 53 patients with diabetes.30 In patients with
low HDL-C, the combination was associated with a
larger increase in LDL-C and LDL particle size and a
greater reduction in TGs than statin monotherapy. In the
HATS, the combination of simvastatin and niacin was
studied in 160 patients with established CHD and low
HDL-C (b0.9 mmol/L in men and b1.03 mmol/L in
women),31 34 of whom had diabetes or impaired fasting
glucose. The combination therapy decreased TGs by
40% and LDL-C by 31% and increased HDL-C by 30%.
The combination therapy was associated with less
progression of average coronary stenosis and a trend
toward fewer clinical events. Glycemic control did not
deteriorate with nicotinic acid therapy.
A new therapy for treating dyslipidemia is the selective
intestinal cholesterol absorption inhibitor ezetimibe. In
American Heart Journal
Volume 150, Number 5
combination with a statin, it results in greater improve-
ments in LDL-C than an increase in the statin dose.
Among patients with diabetes who were taking thiazo-
lideinediones, ezetimibe, in combination with simvasta-
tin 20 mg/d, resulted in a 21% decrease compared with a
0.3% decrease with simvastatin 40 mg/d.32 Thus, this
complementary action is likely to be very useful in
individuals intolerant of higher doses of statins or in
individuals who, despite maximum statin dosage, still do
not achieve their LDL-C goal.
Dual PPARa a/gg agonism as a potential
therapeutic approach to improve
diabetic dyslipidemia
Although the importance of lowering LDL-C with
statins in populations with diabetes is recognized, it is
likely that significant CVD risk will remain because most
agents in this class only have modest effects on HDL-C
and TGs. Elevated FFA levels are a potential therapeutic
target as they are central to the development of insulin
resistance and drive the characteristic lipid abnormali-
ties of diabetes.
Plasma FFA levels can be lowered by nicotinic acid and
nicotinic acid analogues. However, their usefulness is
limited because the initial decrease in plasma FFA levels
is followed by a sharp rebound that temporarily
increases insulin resistance.
PPARa agonism
The benefit of fibrates on CVD risk in diabetes is a
result of their activation of PPARa. Although fibrates
have only relatively low affinity for PPARa, they elevate
HDL-C, lower TG levels, and reduce sdLDL in studies in
nondiabetic and diabetic patients. The lowering of FFA
that accompanies PPARa has the potential to lower
insulin resistance, but whether fibrates do so is
uncertain because clinical studies report either
decreased33 or unaltered34 insulin sensitivity. Specific
high-affinity PPARa agonists decrease insulin resistance
in rats and lower lipid levels.35 Higher-affinity PPARa
agonists may well potentiate the benefits of activation of
this PPAR by increasing FFA catabolism and reducing
insulin resistance, with consequent effects on athero-
genic diabetic dyslipidemia.
PPARg agonism
PPARg is highly expressed in adipose tissue as well as
in other tissues such as the intestine, spleen, and muscle
tissue. Activation of this PPAR isoform (eg, by thiazoli-
dinediones) results in the generation of small adipocytes,
which causes a net flux of fatty acids into subcutaneous
adipose tissue and away from other tissues. This
redistribution has been postulated to improve insulin
sensitivity. Insulin resistance may also be lowered by
PPARg agonism because it increases the synthesis of
Carmena 867
LPL, fatty acid transport protein, and acetyl CoA
synthase, which have important roles in the hydrolysis
of TGs, transport of FFA, and conversion of FFA to
TGs, respectively.
As FFA-induced insulin resistance is linked with
the characteristic lipid disturbances of diabetes, the
insulin-sensitizing effects of PPARg activation may
have clinically relevant effects on the lipid profile.
Both commercially available PPARg agonists, pioglita-
zone and rosiglitazone, improve aspects of the lipid
triad of diabetes, for example, decreasing the propor-
tion of sdLDL.36,37 However, differences between these
thiazolidinediones are emerging.38 For example, al-
though both pioglitazone and rosiglitazone can improve
HDL-C levels, LDL-C and TC levels tend to remain
unchanged or are lowered by pioglitazone,38 whereas
LDL-C and TC levels are slightly raised with rosiglita-
zone.38 Several trials are currently underway or are
being planned to investigate the effects on atheroscle-
rosis of rosiglitazone (eg, STARR) and pioglitazone (eg,
PROACTIVE study).
Dual PPARa/g agonism
Dual PPARa/g agonism has potential advantages over
selective PPAR activation for the improvement of
diabetic dyslipidemia via more effective lowering of
FFA. PPARg exerts its beneficial effect through in-
creased fat storage and improved insulin sensitivity, and
PPARa activation enhances lipid catabolism. Therefore,
dual activation of both receptors may offer improve-
ments in the lipid profile beyond that observed with
activation of the separate PPAR isoforms. Although
theoretically attractive, a combination of selective
PPARa and selective PPARg agonists may not be the
optimal clinical approach. For example, gemfibrozil
considerably increases the plasma concentrations of
rosiglitazone (eg, peak rosiglitazone concentration 24
hours after dosing is increased almost 10-fold and the
half-life prolonged from 3.6 to 7.6 hours), which
increases the risk of concentration-dependent adverse
effects of rosiglitazone and raises the need for careful
monitoring.39 This interaction probably occurs because
of inhibition of CYP450 2C8 enzyme-mediated biotrans-
formation of rosiglitazone by gemfibrozil. It remains to
be determined whether an interaction occurs between
all thiazolidinediones and fibrates.
Dual PPARa/g agonists offer an alternative approach
to combining the activities of selective activation of the
2 PPARs. In animal studies, they have been demonstrat-
ed to lessen insulin resistance and have additional
beneficial effects on FFA and glucose metabolism.40,41
These properties could provide a suitable addition to
existing therapeutic approaches to the treatment of
diabetes, metabolic syndrome, and associated CVD risk.
Therefore, integrating PPARa and PPARg activity may
deliver greater benefits than selective PPAR activation.

868 Carmena
Representatives of the class that are in late clinical
development include muraglitazar and tesaglitazar.
Summary
Diabetes is increasing in prevalence, and it is estimated
that there will be N300 million cases worldwide in 2030.
Diabetes is an accepted cardiovascular risk factor, and its
growing prevalence is likely to be accompanied by
significant increases in cardiovascular morbidity and
mortality. Hyperglycemia associated with diabetes
increases microvascular risk but contributes little to
macrovascular risk; instead, the excess cardiovascular
burden is linked more to the characteristic atherogenic
dyslipidemia of raised sdLDL levels (often with normal
LDL-C levels), lowered HDL-C, and elevated TGs. A cause
of this lipid triad may be insulin resistance, which is
likely to be the consequence of elevations in plasma FFA
production that accompany visceral obesity and a
high-energy diet. Visceral adipose tissue also produces
adipocytokines that can contribute further to insulin
resistance. Insulin resistance impairs suppression of FFA
release from visceral adipose tissue, leading to an
increased flux of FFA to the liver and a consequent rise
in VLDL. The elevations in TGs result in lowered HDL-C
concentrations and elevated LDL-C levels. Epidemiolog-
ical studies demonstrate that elevated sdLDL and TG
levels and a low HDL-C level all independently increase
the risk of CVD.
It is accepted that statins and fibrates reduce the
risk of cardiovascular events in the general population.
Several trials of lipid-lowering therapy with fibrates or
statins have included substantial numbers of diabetes
subjects, reporting significant reductions in cardiovas-
cular event rates. However, substantial cardiovascular
risk remained, emphasizing the importance of impro-
ving other lipid parameters. It is known that neither
type of lipid-altering drug acts to address effectively
the fundamental cause of diabetic dyslipidemia—
elevated plasma FFA level, which consequently leads
insulin resistance.
A promising novel approach to correcting the athero-
genic dyslipidemia of diabetes is dual activation of
PPARa and PPARg, which are intimately involved in the
metabolism and storage of fatty acids. Activation of
PPARa, as occurs with fibrates, lowers FFA levels as it
stimulates the expression of genes involved in fatty
acid and lipoprotein oxidation. PPARg agonism, as
demonstrated by the thiazolidinediones, promotes
redistribution of FFA from visceral stores to more inert
subcutaneous depots. As separate activation of PPARa
and PPARg improves lipid metabolism, integrating
PPARa and PPARg activity may further improve FFA
metabolism by combining the benefits of safer storage of
FFA with increased FFA oxidation. Thus, dual PPARa/g
agonism may lead to improvements in atherogenic
American Heart Journal
November 2005
diabetic dyslipidemia by raising HDL-C levels and
lowering TGs and sdLDL levels.
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