REVIEW

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Dyslipidemia in type 2 diabetes mellitus

Arshag D Mooradian

INTRODUCTION

S U M M A RY
Dyslipidemia is one of the major risk factors for cardiovascular disease in
diabetes mellitus. The characteristic features of diabetic dyslipidemia are a
high plasma triglyceride concentration, low HDL cholesterol concentration
and increased concentration of small dense LDL-cholesterol particles. The
lipid changes associated with diabetes mellitus are attributed to increased
free fatty acid flux secondary to insulin resistance. The availability of
multiple lipid-lowering drugs and supplements provides new opportunities
for patients to achieve target lipid levels. However, the variety of therapeutic
options poses a challenge in the prioritization of drug therapy. The
prevalence of hypercholesterolemia is not increased in patients with
diabetes mellitus, but mortality from coronary heart disease increases
exponentially as a function of serum cholesterol levels, and lowering of
cholesterol with statins reduces diabetic patients relative cardiovascular
risk. Although drug therapy for dyslipidemia must be individualized, most
people with diabetes mellitus are candidates for statin therapy, and often
need treatment with multiple agents to achieve therapeutic goals.
KEYWORDS cardiovascular disease, diabetes mellitus, dyslipidemia,
insulin resistance

REVIEW CRITERIA
This Review is based on English manuscripts published between July 1998 and
July 2008 that were identified through a MEDLINE search. The literature
search was limited to core clinical journals that have accessible full texts;
the search terms used were lipids and diabetes. A total of 451 manuscripts
were reviewed and the choice of individual references was made at the
discretion of the author. This literature, along with the authors clinical
experience, was used to construct practical suggestions.

AD Mooradian is a Professor and Chair of the Department of Medicine,

University of Florida College of Medicine, Jacksonville, FL, USA.
Correspondence:
Department of Medicine, University of Florida College of Medicine, 6531 West 8th Street,
4th FloorLRC, Jacksonville, FL 32209, USA
arshag.mooradian@jax.ufl.edu
Received 25 July 2008 Accepted 26 November 2008
www.nature.com/clinicalpractice
doi:10.1038/ncpendmet1066

Despite advances made in the prevention and

management of cardiovascular disease, people
with diabetes mellitus continue to have alarmingly high morbidity and mortality secondary
to cardiovascular disease.1 At a time when
cardiovascular-disease mortality is decreasing
in the general population, mortality in women
with diabetes mellitus has increased.2 Epidemiologic studies have demonstrated that diabetes
mellitus is an independent risk factor for cardiovascular disease and that it amplifies the effects
of other common risk factors, such as smoking,
hypertension and hypercholesterolemia.3,4 The
mortality associated with a coronary event in
people with diabetes mellitus is significantly
higher than the mortality in nondiabetic individuals.5 Furthermore, the mortality risk for
people with diabetes mellitus who do not have
known clinical coronary heart disease (CHD)
is similar to that for those without diabetes
mellitus who have already experienced a
myocardial infarction.6 Such observations have
led to the recognition of diabetes mellitus as a
CHD-risk-equivalent condition (i.e. the risk
to patients with diabetes mellitus of dying of a
coronary event is as high as it is in nondiabetic
individuals with a clinical history of CHD).7
The increased risk of atherosclerosis in diabetes mellitus consists of multiple factors.
Diabetes-related changes in plasma lipid levels
are among the key factors that are amenable
to intervention. The spectrum of dyslipidemia
in diabetes mellitus can include all the various
types of dyslipidemia identified in the general
population;8 however, one phenotype is particularly common in diabetes mellitus, which is
attributed mostly to insulin resistance and
insulin deficiency.912 The characteristic features
of this phenotype are a high plasma triglyceride
concentration, low HDL cholesterol concentration and increased concentration of small
dense LDLcholesterol particles. This Review
examines dyslipidemia in type 2 diabetes
mellitus (T2DM) only.

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EPIDEMIOLOGY OF DIABETIC
DYSLIPIDEMIA

In the Framingham Heart Study,13 13% of

men and 24% of women with diabetes mellitus
had increased total plasma cholesterol levels,
compared with 14% of men and 21% of women
without diabetes mellitus. The prevalence of
high LDL cholesterol levels in men and women
with diabetes mellitus (9% and 15%, respectively) did not differ significantly from the
rates in nondiabetic men and women (11% and
16%, respectively). By contrast, the prevalence
of high plasma triglyceride levels in individuals
with diabetes mellitus (19% in men and 17% in
women) was significantly higher than in those
without diabetes mellitus (9% of men and 8%
of women).13 High levels of total cholesterol,
LDL cholesterol and triglyceride were defined as
values above the corresponding 90th percentile
for the US population.
The prevalence of low HDL cholesterol level
(defined as a value below the 10th percentile for the US population) in those with
diabetes mellitus was almost twice as high
as the prevalence in nondiabetic individuals
(21% versus 12% in men and 25% versus 10%
in women, respectively).13 Thus, both men
and women with diabetes had an increased
prevalence of hypertrigyceridemia and low HDL
cholesterol levels, but their total cholesterol and
LDL cholesterol levels did not differ from those
in non-diabetic counterparts.13 A similar pattern
of altered plasma lipid profiles was observed in
the UK Prospective Diabetes Study (UKPDS).14
In this study, total cholesterol levels of those with
diabetes mellitus and control individuals did not
differ. However, women with T2DM had markedly higher LDL cholesterol levels than women
who were not diabetic. The plasma triglyceride
levels of patients with T2DM were substantially
increased, whereas HDL cholesterol levels were
markedly reduced in both men and women with
diabetes mellitus compared with the nondiabetic
controls.14 An important caveat in relation to
observations made in these pivotal epidemiologic studies is that the data were collected before
the cut-off point for fasting plasma glucose that
indicates a diagnosis of diabetes mellitus was
lowered to 6.94 mmol/l.
PATHOPHYSIOLOGY OF DIABETIC
DYSLIPIDEMIA

The precise pathogenesis of diabetic dyslipidemia

is not known; nevertheless, a large body of

MARCH 2009 VOL 5 NO 3 MOORADIAN

evidence suggests that insulin resistance has a

central role in the development of this condition.912 The main cause of the three cardinal
features of diabetic dyslipidemia is the increased
free fatty-acid release from insulin-resistant fat
cells.912 The increased flux of free fatty acids
into the liver in the presence of adequate glycogen
stores promotes triglyceride production, which in
turn stimulates the secretion of apolipoprotein B
(ApoB) and VLDL cholesterol. The impaired
ability of insulin to inhibit free fatty-acid release
leads to enhanced hepatic VLDL cholesterol
production,15 which correlates with the degree
of hepatic fat accumulation.16
Hyperinsulinemia is also associated with
low HDL cholesterol levels.17,18 The increased
number of VLDL cholesterol particles and
increased plasma triglyceride levels decrease
the level of HDL cholesterol and increase the
concentration of small dense LDL-cholesterol
particles via several processes: VLDL-transported
triglyceride is exchanged for HDL-transported
cholesteryl ester through the action of the cholesteryl ester transfer protein (CETP), which
results in increased amounts of both atherogenic cholesterol-rich VLDL remnant particles
and triglyceride-rich, cholesterol-depleted
HDL particles. The triglyceride-enriched HDL
is subsequently hydrolyzed by hepatic lipase or
lipoprotein lipase; ApoA-I dissociates from the
reduced-size HDL, which is filtered by the renal
glomeruli and degraded in renal tubular cells
(Figure 1).18,19 The increased concentration
of small dense LDL-cholesterol particles is
explained by a similar lipid exchange. Increased
levels of VLDL-transported triglyceride enable
CETP to promote the transfer of triglyceride
into LDL in exchange for LDL-transported
cholesteryl ester. The triglyceride-rich LDL
undergoes hydrolysis by hepatic lipase or lipoprotein lipase, which results in lipid-depleted
small dense LDL particles (Figure 1).
The relative importance of the above lipidexchange pathway in individuals with low HDL
cholesterol levels who do not have increased
VLDL cholesterol production or hypertriglyceridemia is not known. In these patients, inability
of insulin to upregulate the ApoA-I production
(owing to insulin resistance) might contribute
to low HDL cholesterol levels.19 Furthermore,
insulin resistance and low HDL levels might have
a common mediator; for example, TNF. TNF is
implicated in obesity-related insulin resistance
and is known to lower serum HDL cholesterol

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Fat cells

Liver
TG
ApoB

FFA

CE
LPL secondary
to insulin resistance

VLDL

CETP

HDL

LPL or HL

TG
CE

CETP

TG

ApoA-I

LDL
LPL or HL

SD
LDL

Kidney

Figure 1 The role of insulin resistance in diabetic dyslipidemia. Insulin

resistance initiates the characteristic triad of high triglyceride level, low HDL
cholesterol level and high small dense LDL level. If the concentration of VLDLtransported triglyceride is high, CETP promotes the transfer of LDL cholesteryl
ester or HDL cholesteryl ester in exchange for triglyceride. Triglyceride-rich
HDL cholesterol or LDL cholesterol can undergo hydrolysis by hepatic lipase or
lipoprotein lipase. Abbreviations: , increased level; ApoA-1, apolipoprotein A-1;
ApoB, apolipoprotein B; CE, cholesteryl ester; CETP, cholesteryl ester transfer
protein; FFA, free fatty acid; HL, hepatic lipase; LPL, lipoprotein lipase; SD LDL,
small dense LDL cholesterol; TG, triglyceride.

levels.19,20 In addition, several key enzymes that

are involved in HDL cholesterol metabolism are
altered in people with insulin resistance.21,22
Insulin resistance is associated with a decreased
ratio of lipoprotein lipase to hepatic lipase in
heparin-treated plasma, which contributes to
the low HDL-cholesterol level seen in such individuals.18 In insulin resistance, the esterification
of cholesterol (mediated by lecithin-cholesterol
acyl transferase) is either modestly increased or
unaltered, whereas CETP activity is increased.
CETP depletes HDL of its cholesteryl ester and
its increased activity contributes to the lowering
of HDL cholesterol levels.18
Plasma CETP mass is a determinant of cholesteryl ester transfer, and has an increased effect
in individuals with high triglyceride levels.23 In
addition, adiponectin might have a direct role
on HDL cholesterol catabolism. Kinetic studies
show a strong negative correlation between
adiponectin level and the ApoA-I fractional
clearance rate, which can explain the positive
correlation between the levels of HDL cholesterol and adiponectin. This positive correlation occurs independently of obesity, insulin
resistance and the triglyceride content of HDLcholesterol particles.24 Another important
determinant of atherosclerosis is the activity of
phospholipid-transfer protein. This protein has
been suggested to have a role in the development

of obesity and diabetes mellitus; thus, it might

become a therapeutic target.25
Of note, high triglyceride and low HDL cholesterol levels might occur in familial and sporadic
syndromes (e.g. familial combined hyperlipidemia
and familial hypertriglyceridemia), but only
combined hyperlipidemia seems to be generally associated with increased cardiovascular
risk. Specialized lipid tests, such as measurement
of plasma ApoB-10026 or ApoB-100 : ApoA-I
ratios,27 might distinguish between these two
phenotypically similar syndromes and identify individuals who have an increased risk of
cardiovascular disease. Overall, insulin resistance
seems to contribute either directly or indirectly
to the triad of plasma lipid abnormalities of
diabetes mellitus, namely hypertriglyceridemia,
low HDL-cholesterol levels and high small dense
LDL-cholesterol levels.
CLINICAL IMPLICATIONS OF DIABETIC
DYSLIPIDEMIA

Linear relationships between LDL cholesterol

levels and the incidence of cardiovascular events
were similar in individuals both with and without
diabetes mellitus in interventional trials on
statins.28 Low HDL cholesterol and increased
triglyceride levels might also contribute to the
increased risk of cardiovascular disease found
in patients with diabetes mellitus. Interventional
trials that used fibrate therapy to achieve target
triglyceride and HDL cholesterol levels have
shown some inconsistency in their clinical
outcomes. In the HDL Intervention Trial (HIT),29
gemfibrozil treatment was associated with a
22% reduction in the risk of CHD and a 25%
reduction in the risk of stroke. The Fenofibrate
Intervention and Event Lowering in Diabetes
(FIELD) study, 30 a randomized trial that assessed
the effects of fenofibrate on coronary morbidity
and mortality in people with diabetes mellitus,
did not show that fenofibrate had a statistically
significant effect on the primary outcome (CHDrelated death or nonfatal myocardial infarction).
Fenofibrate reduced the total prevalence of
cardiovascular disease events, in particular the
prevalence of nonfatal myocardial infarction and
coronary revascularization, but it did not reduce
the risk of fatal events.30 The favorable effect of
gemfibrozil in the primary prevention of CHD
was also demonstrated in previous trials.31
Emerging data suggest that hypertriglyceridemia, in conjunction with increased small
dense LDL cholesterol and low HDL cholesterol

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levels, is an important contributor to accelerated atherosclerosis in diabetes mellitus and

insulin-resistant conditions.7 However, the
association between hypertriglyceridemia and
the increased risk of CHD is not as strong as that
between LDL cholesterol level and CHD risk.
Patients with elevated triglyceride levels might
have accompanying dyslipidemias that increase
the risk for CHD (e.g. familial combined hyperlipidemia or low HDL level). In addition, severe
hypertriglyceridemia (greater than or equal to
5.65 mmol/l) increases the risk of pancreatitis.7
At the present time, we do not know to what
extent the favorable effect of fibrates can be
attributed to their role in fibrinolysis.
MANAGEMENT OF DYSLIPIDEMIA
IN DIABETES MELLITUS

Management of dyslipidemia in people with

diabetes mellitus, just like in any other individual,
starts with a thorough evaluation that aims to
identify secondary causes that might contribute
to the abnormal lipid profile.8 Lifestyle changes,
including increased physical activity and dietary
modifications, are the cornerstones of management.7,32 Many people with T2DM are overweight and benefit from caloric restriction.
The highest priority for diabetic individuals
who have poor glycemic control should be to
achieve near-normal blood-glucose levels, in the
expectation that this approach will also improve
dyslipidemia.33,34 However, many individuals
with T2DM continue to have abnormal plasma
lipid profiles, despite having achieved their
glycemic goals.
Effect of dietary composition

Although the value of caloric restriction and

weight loss for the overweight individual with
diabetes mellitus is indisputable, no consensus
exists on the ideal dietary composition for these
patients. The way that plasma lipid profiles change
in response to dietary modification depend on
genetic factors and the lipid phenotype of the
individual.35 Overall, reducing the dietary intake
of saturated fat is associated with reduced cholesterol content of various plasma lipoproteins,
including LDL cholesterol and HDL cholesterol.3639 The replacement of dietary saturated
fat with carbohydrates might increase a patients
triglyceride level and reduce the levels of HDL
cholesterol and LDL cholesterol;3639 the effect on
HDL cholesterol levels of replacing saturated fat
with monounsaturated or polyunsaturated fat is

MARCH 2009 VOL 5 NO 3 MOORADIAN

less dramatic. Trans-fatty acids or hydrogenatedfat-enriched diets increase LDL cholesterol level,
and either decrease or have no effect on HDL
cholesterol and ApoA-I levels.39 The triglyceridelowering effect of omega-3 fat consumption is
well established.40 However, clinical trials that
used a purified omega-3 fatty-acid formulation
reported no change, or only a modest increase,
in plasma HDL cholesterol levels, and the effect
of this formulation on LDL cholesterol levels
was variable.40
The effect of dietary proteins on plasma lipids
has not been the focus of many studies.41 Some
proteins, such as soy protein, have a specific
effect on HDL cholesterol.39 The replacement
of carbohydrates with proteins led to modest
increases in HDL levels, and a reduction in
triglyceride levels in the Optimal Macronutrient
Intake Heart Trial to Prevent Heart Disease
(OMNI-Heart).42 These changes, however,
could have been the result of limiting glycemic
load, rather than a consequence of increasing
the protein load.37 Commonly used nutritional
supplements might also affect triglyceride and
HDL cholesterol metabolism.43,44 Large doses
of antioxidants in combination therapy with
simvastatin and nicotinic acid, might partially
suppress HDL cholesterol induction,43 and large
concentrations of the antioxidant vitamins C
and E might downregulate ApoA-I production
in hepatocytes.44
Moderate alcohol consumption (12 drinks or
1530 g alcohol in a 24 h period) might decrease
the risk of cardiovascular disease. This favorable
effect might be partly related to the improved
plasmalipid profile associated with increased
concentrations of HDL cholesterol.32 Small to
moderate amounts of alcohol have no acute
effect on glucose and insulin concentrations,
insulin sensitivity, or HDL cholesterol and
triglyceride levels. In some susceptible individuals, however, alcohol will contribute to hyperglycemia and hypertriglyceridemia, especially
when consumed in excessive amounts (3 or more
drinks per day).32
Dietary recommendations should be individualized on the basis of the underlying lipid
abnormality and the patients response and
dietary preferences.32 The dietary recommendation of the Adult Treatment Panel III
(ATP III) 7 for those with a predominantly high
LDL cholesterol level is to limit intake of saturated fat to <7% of total calories, cholesterol
intake to <200 mg per day, polyunsaturated

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Table 1 A list of selected pharmacologic agents available for treating dyslipidemias.

Drug

Efficacy

Adverse effects

Specific agents and doses

Statins

LDL 1855%
HDL 515%
TG 730%

Hepatotoxicity, myopathy,
increased creatine kinase levels

Rosuvastatin, 540 mg orally once daily; fluvastatin,

2080 mg orally nightly; simvastatin, 580 mg orally
every evening; pravastatin, 1080 mg orally once daily;
atorvastatin, 1080 mg orally once daily; lovastatin,
1080 mg orally nightly; extended-release lovastatin,
1060 mg orally nightly

Ezetimibe

LDL 1520%
HDL 1%
TG 8%

No major adverse effects

10 mg orally once daily

Ezetimibe
combined with
simvastatin

LDL 3060%
HDL 9%
TG 20%

Hepatotoxicity, myopathy,
increased serum creatine
kinase levels

10/10 mg to 10/80 mg orally once daily

Nicotinic acid

LDL 525%
HDL 1535%
(ApoA-I )
TG 2050%
Small dense LDL

Hot flashes, hyperglycemia,

hyperuricemia, hepatotoxicity

Nicotinic acid, 12 g orally two or three times daily;

extended-release nicotinic acid, 12 g orally nightly;
sustained-release nicotinic acid, 250750 mg orally once
or twice daily

Nicotinic acid
combined
with statin

LDL 3042%
HDL 2030%
TG 3244%

Hot flashes hyperglycemia,

hyperuricemia, hepatotoxicity,
myopathy, increased serum
creatine kinase levels

Lovastatin and nicotinic acid, 20/500 mg to 20/1,000 mg

orally daily; extended-release nicotinic acid and simvastatin,
500/20 mg, 750/20 mg, or 1,000/20 mg orally daily

Fibrates

LDL 520%
HDL 1015%
TG 2050%
Small dense LDL

Dyspepsia, gallstones,
hepatotoxicity, myopathy

Fenofibrate, micronized, 43130 mg orally once daily;

fenofibrate, micronized, 67200 mg orally once daily;
fenofibrate, 48145 mg orally once daily; gemfibrozil, 600 mg
orally twice daily; bezafibrate, 200 mg orally twice daily;
modified-release bezafibrate, 400 mg once daily

Bile-acid
sequestrants

LDL 1020%
HDL 12%
TG possible

Gastrointestinal distress,
constipation

Colestyramine, 424 g orally daily, two or three times daily,

Colestipol Hydrochloride, 530 g orally once or twice daily;
colesevelam hydrochloride, 1.8753.75 g once or twice daily

Omega-3
fatty acid

LDL 510%
HDL 13%
TG 2530%

Fishy aftertaste,a
gastrointestinal disturbances

Omega-3-acid ethyl esters, 4 g orally daily; over-the-counter

fish oil; dietary supplements containing omega-3 fatty acid,
EPA and DHA, 24 g orally daily

aRefrigeration

will minimize the fishy aftertaste of over-the-counter fish-oil preparations. Abbreviations: , decrease; , increase; DHA, docosahexaenoic acid;
EPA, eicosapentaenoic acid; HDL, HDL cholesterol level; LDL, LDL cholesterol level; TG, triglyceride level. Reproduced from Hachem SB and Mooradian AD8
with permission from Wolters Kluwer Health Adis ( Adis Data Information BV 2006. All rights reserved).

fat intake up to 10% of total calories, monounsaturated fat intake up to 20% and protein
intake up to 20% of total calories. If severe
hypertriglyceridemia is present, patients are
advised to start with a fat-free diet until their
plasma triglyceride level is <11.3 mmol/l,
then start a maintenance diet with total fat
content of <10% of total calories.7
Effect of exercise

Increased physical activity helps to maintain

the weight loss that has been achieved with
caloric restriction.45 Exercise can also improve
insulin sensitivity (independently of weight
loss) and increases HDL cholesterol levels,
especially in people with a high baseline HDL
level (>1.55 mmol/l).46 The magnitude of the
increase in HDL cholesterol level depends on

genetic factors, notably on polymorphisms in

CETP and endothelial lipase.47,48
Either aerobic or resistance training alone
improves glycemic control in T2DM, but the
improvements are greatest with combined
aerobic and resistance training.49 In a study of
postmenopausal women with T2DM, a modest
weight loss that was achieved by either diet alone
or diet plus exercise resulted in similar improvements in the amount of total abdominal fat and
glycemic status. However, the addition of exercise to diet was associated with visceral fat loss.50
In patients with T2DM, a supervised aerobic
exercise program reduced the VLDLApoB pool
size, probably as a result of a decreased rate of
ApoB secretion.51 The potential benefits of exercise are multiple, and extend beyond glycemic
and lipid control.

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Pharmacologic interventions

Several classes of pharmacologic agents are used

to treat dyslipidemias (Table 1).8,52,53 A metaanalysis of clinical trials indicated that statininduced cholesterol reduction in people with
diabetes mellitus is valuable to reduce CHD risk,
as both primary and secondary interventions.28
Even those with normal or low cholesterol levels
(i.e. total cholesterol <5.18 mmol/l or LDL
cholesterol <3.11 mmol/l) benefit from statin
therapy.28 The abundance of clinical experience
with this class of agents has led to statins being the
mainstay of therapy in diabetic dyslipidemia.
In addition to statins, interventional trials
have also shown that fibrates and nicotinic
acid have therapeutic roles in the prevention of
cardiovascular-disease-related events.2931,54 The
choice of which particular agent to administer
depends on the lipid profile that the patient
achieved after 612 weeks of intense lifestyle
changes and possible concomitant use of dietary
supplements, such as stanols, plant sterols and
omega-3 fatty acids.32 The principles of drug
therapy for dyslipidemia in diabetes mellitus
are the same as those for dyslipidemia in individuals who have a high risk of developing cardiovascular disease. Some experts prefer to prioritize
the achievement of target LDL cholesterol levels,
as reduced levels of LDL cholesterol have been
shown most conclusively to be associated with
a reduced risk of cardiovascular disease.33,34
Another approach that some researchers have
suggested is to tailor the choice of pharmacologic agent to the predominant lipid abnormality
(Figure 2).
If the predominant lipid abnormality was
hypertriglyceridemia, with a serum triglyceride
concentration over 5.65 mmol/l, then omega-3
fatty acids would be considered the first-choice
therapy (Figure 2). Omega-3 fatty acids might
be inappropriate in patients who have chylomicronemia associated with a profound lipolytic
defect. An effective alternative for such patients is
fibrate or nicotinic acid. Subsequently, when the
LDL cholesterol level is over 1.8 mmol/l, a statin
can be added in combination with ongoing fibrate
or nicotinic acid therapy. Other drugs that could
be used in combination with fibrates or nicotinic
acid include ezetimibe, a cholesterol-absorption
inhibitor;5557 however, the combination of ezetimibe and these agents has not been well studied.
Other inhibitors of intestinal cholesterol absorption, such as disodium ascorbyl phytostanol
phosphate (FM-VP4) and bile acid transport

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Assess serum lipid levels

Triglyceride >5.65 mmol/l

Triglyceride <5.65 mmol/l

and LDL not at target

Add:
Omega 3 fatty acid and/or
Fibrates and/or
Nicotinic acid

Add statin

LDL not at target

LDL not at target

May add statin

May add:
EZE and/or
Fibrates and/or
Nicotinic acid and/or
Bile acid binding resins
if triglyceride <2.26 mmol/l

Figure 2 A suggested algorithm for drug therapy of dyslipidemia in patients with

diabetes mellitus. One potential approach is to start treatment in all people
with type 2 diabetes mellitus with a highly potent statin, and add other agents
as shown in the algorithm if triglycerides or HDL cholesterol do not reach target
levels. Abbreviations: EZE, ezetimibe; LDL, LDL cholesterol level. Reproduced
from Hachem SB and Mooradian AD8 with permission from Wolters Kluwer
Health Adis ( Adis Data Information BV 2006. All rights reserved).

inhibitors, have shown promising results in early

development trials.58 The new CETP inhibitors
(JTT 705 and anacetrapib) markedly increase the
level of HDL cholesterol and decrease the level
of LDL cholesterol in patients with dyslipidemia,
and do not seem to affect blood pressure. These
agents might be useful in the future treatment of
diabetic dyslipidemia.59
In general, if the patients serum triglyceride
level is less than 5.65 mmol/l and the LDL cholesterol level is above 1.8 mmol/l, a statin would
be the drug of choice. The statin dose should be
titrated up to the maximal approved daily dose to
achieve the therapeutic goal, and a fibrate, nicotinic acid or ezetimibe should only be included if
statin therapy alone is not sufficient. The addition
of bile acid binding resin is an alternative only if
the patients serum triglyceride concentration
does not exceed 2.26 mmol/l (Figure 2), as this
agent might aggravate hypertriglyceridemia.
The results of the Ezetimibe and Simvastatin in
Hypercholesterolemia Enhances Atherosclerosis
Regression (ENHANCE) trial60 cast some doubt
on the clinical utility of ezetimibe; this agent
might be best considered in patients who are

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unable to tolerate alternative regimens. The

outcome of the Reduction of Outcomes: Vytorin
Efficacy International Trial (IMPROVE-IT) trial61
might help to define the role of ezetimibe further
in the management of dyslipidemias.
The efficacy and safety of combination therapies has been the subject of several trials. The
Diabetes and Combined Lipid Therapy Regimen
(DIACOR) study62 found that combination
therapy with simvastatin plus fenofibrate had a
superior ability than monotherapy with either
drug to improve a variety of cardiovascular risk
factors, including reducing levels of small dense
LDL cholesterol (0.88 mmol/l) and VLDL cholesterol (0.259 mmol/l), and increasing HDL type 3
level (+0.06 mmol/l). The HDL-Atherosclerosis
Treatment Study63 showed that combination
therapy with simvastatin plus nicotinic acid
(mean daily doses 13.0 mg and 2.4 g, respectively)
stops angiographically visible progression of
atherosclerosis and reduces major clinical events
by 60% in patients with coronary artery diseases
who have low HDL cholesterol levels. Glycemic
control among patients with diabetes mellitus
declined mildly in the simvastatin plus nicotinic
acid group, but returned to pretreatment levels
after 8 months of treatment.
The efficacy and safety of two regimens that
used a combination of extended-release nicotinic acid (1 g per day and 2 g per day) and
simvastatin (20 mg per day in both regimens)
were compared with simvastatin monotherapy
(20 mg per day) for 24 weeks in 319 patients
who had a high risk of CHD and predominantly
mixed dyslipidemia.64 The combination therapy
resulted in greater improvements in HDL cholesterol, triglycerides, ApoB and lipoprotein(a)
levels, and in the total cholesterol: HDL cholesterol ratio compared with those achieved by
monotherapy. Similar results were observed in
the OCEANS study (Open-Label Evaluation
of the Safety and Efficacy of a Combination of
Niacin ER and Simvastatin in Patients with
Dyslipidemia),65 in which the safety and efficacy
of a combination of extended-release nicotinic
acid and simvastatin was evaluated over 52 weeks
in 520 patients with mixed dyslipidemia. Future
studies with clinical-outcome end points should
be carried out to determine the role of this
combination therapy in the management of
patients with T2DM.
The use of drug combinations as first-line
therapy might become more popular with
the advent of fixed-dose combination pills;

however, clinical experience with this approach

is limited. The combination of a statin and a
fibrate or nicotinic acid increases the risk of
rhabdomyolysis, and, therefore, these agents
should be used at reduced doses and in patients
who are at the least risk of adverse drug interactions. If the dose of nicotinic acid is limited
to less than 2 g per day, its effect on insulin
resistance is modest.54 Nevertheless, in some
patients with impaired glucose tolerance,
initiation of nicotinic-acid treatment might
precipitate overt diabetes mellitus. In addition,
a significant number of patients (up to 30%)
might not tolerate the adverse effects associated with this therapy. Extended-release nicotinic acid administered once daily seems to be
better tolerated than short-acting nicotinic
acid.54 Although some insulin sensitizers, such
as pioglitazone, have substantial favorable effects
on serum triglyceride and HDL cholesterol levels
(independent of their effects on blood-glucose
control), these drugs are not approved for use in
the treatment of dyslipidemia.66
The goals of therapy should be tailored to individual patients; however, a standardized approach
to therapy might have some merits. Notably, the
serum triglyceride value shown in Figure 2 does
not represent the goal of therapy, but is rather a
suggested cut-off value that indicates the need
for initiation of therapy or modification of drug
choices. The ATP III considers diabetes mellitus
to confer a risk equivalent to that of CHD risk
and sets the target LDL cholesterol level of
less than 2.59 mmol/l, with a preferred level
of less than 1.81 mmol/l. In addition, desirable
serum levels are less than 1.95 mmol/l for
triglyceride and more than 1.04 mmol/l for HDL
cholesterol. The non-HDL-cholesterol level (i.e.
total cholesterol level minus HDL cholesterol
level) is a secondary target of therapy in patients
with serum triglyceride greater than or equal to
2.26 mmol/l.7
A study has shown that achieving lower
therapeutic targets can have favorable effects in
adults with T2DM. Participants were randomly
allocated to either treatment targets of LDL
cholesterol less than or equal to1.81 mmol/l
and systolic blood pressure of less than or equal
to 115 mmHg, or to standard targets of LDL
cholesterol (less than or equal to2.59 mmol/l
and systolic blood pressure (less than or equal
to 130 mmHg).67 The achievement of the stringent therapeutic targets resulted in regression
of carotid intimamedia thickening and greater

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decreases in left-ventricular mass, as compared

with values achieved by patients on standard
therapy. The overall number of clinical events
was lower than expected, but did not differ
significantly between treatment groups.67
Unfortunately, a large number of patients fail
to achieve these stringent therapeutic targets.
However, the National Cholesterol Education
Program (NCEP) Evaluation Project Utilizing
Novel E-Technology (NEPTUNE) II survey68
conducted in 2003 reported that of 67% of
4,885 patients with elevated LDL cholesterol
levels achieved their LDL cholesterol treatment
goal. This finding suggests that the management of dyslipidemia has improved in recent
years compared with results from previous
surveys. The improvement might be explained
by increased public awareness of the importance of lowering plasma cholesterol levels, and
increased confidence in the safety of statins. In
the NEPTUNE II survey, the largest gaps between
desirable and actual, post-treatment LDL cholesterol levels were found in patients with CHDrisk-equivalent conditions, and those therapeutic
targets were not based on HDL targets.
Patients will benefit from the development
of powerful agents that can be used safely
in combination with other drugs and have
distinct mechanisms of action. The residual
cardiovascular-disease risk observed in interventional trials with statins supports the rationale
for combination therapy in individuals who are at
high risk of cardiovascular disease, such as those
with T2DM.
CONCLUSIONS

The management of dyslipidemias should be

based on patients predominant phenotypic
feature and include therapeutic agents with a
proven ability to reduce cardiovascular-disease
events. Although the decision to initiate drug
therapy must be individualized, individuals with
diabetes mellitus who are considered to be at high
risk for cardiovascular-disease events are candidates for statin therapy, irrespective of their basal
plasma cholesterol levels. However, given the
complexity of dyslipidemia profiles in patients
with diabetes mellitus, multiple agents are often
required to achieve therapeutic goals. In addition, other risk factors for cardiovascular disease
commonly associated with diabetes mellitus, such
as hypertension, obesity and hyperglycemia, must
be effectively managed to maximize the benefits
of such therapy.

MARCH 2009 VOL 5 NO 3 MOORADIAN

KEY POINTS

Dyslipidemia contributes to the increased risk

of cardiovascular disease in diabetes mellitus

The characteristic features of diabetic

dyslipidemia are high plasma triglyceride
concentration, low HDL cholesterol
concentration and increased concentration
of small dense LDL cholesterol

The most likely cause of diabetic dyslipidemia

is the increased free fatty-acid flux, secondary
to insulin resistance

Although drug therapy for dyslipidemias must

be individualized, most people with diabetes
mellitus are candidates for statin therapy and
often need to be treated with multiple agents
to achieve therapeutic goals

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Competing interests
The author declared no
competing interests.

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