0021-972X/01/$03.00/0 Vol. 86, No.

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The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A.
Copyright © 2001 by The Endocrine Society

CLINICAL REVIEW 124

Diabetic Dyslipidemia: Causes and Consequences
IRA J. GOLDBERG
Division of Preventive Medicine and Nutrition, Columbia University College of Physicians and
Surgeons, New York, New York 10032

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More cardiovascular disease occurs in patients with either
type 1 or 2 diabetes. The link between diabetes and athero-
sclerosis is, however, not completely understood. Among the
metabolic abnormalities that commonly accompany diabetes
are disturbances in the production and clearance of plasma
lipoproteins. Moreover, development of dyslipidemia may be
a harbinger of future diabetes. A characteristic pattern, termed
diabetic dyslipidemia, consists of low high density lipoprotein
(HDL), increased triglycerides, and postprandial lipemia. This
pattern is most frequently seen in type 2 diabetes and may be
a treatable risk factor for subsequent cardiovascular disease.
The pathophysiological alterations in diabetes that lead to this
dyslipidemia will be reviewed in this article.
Causes of lipoprotein abnormalities in diabetes
Defects in insulin action and hyperglycemia could lead to
changes in plasma lipoproteins in patients with diabetes.
Alternatively, especially in the case of type 2 diabetes, the
obesity/insulin-resistant metabolic disarray that is at the
root of this form of diabetes could, itself, lead to lipid ab-
normalities exclusive of hyperglycemia.
Type 1 diabetes, previously termed insulin-dependent di-
abetes mellitus, provides a much clearer understanding of
the relationship among diabetes, insulin deficiency, and lip-
id/lipoprotein metabolism. In poorly controlled type 1 di-
abetes and even ketoacidosis, hypertriglyceridemia and re-
duced HDL commonly occur (1). Replacement of insulin in
these patients may correct these abnormalities, and well con-
trolled diabetics may have increased HDL and lower than
average triglyceride levels.
The lipoprotein abnormalities commonly present in type
2 diabetes, previously termed noninsulin-dependent diabe-
tes mellitus, include hypertriglyceridemia and reduced
plasma HDL cholesterol. In addition, low density lipoprotein
(LDL) are converted to smaller, perhaps more atherogenic,
lipoproteins termed small dense LDL (2). In contrast to type
1 diabetes, this phenotype is not usually fully corrected with
glycemic control. Moreover, this dyslipidemia often is found
in prediabetics, patients with insulin resistance but normal
Received August 17, 2000. Revision received October 9, 2000. Ac-
cepted October 10, 2000.
Address all correspondence and requests for reprints to: Dr. Ira J.
Goldberg, Division of Preventive Medicine and Nutrition, Columbia
University College of Physicians and Surgeons, 630 West 168th Street,
New York, New York 10032. E-mail: ijg3@columbia.edu.
indexes of plasma glucose (3). Therefore, abnormalities in
insulin action and not hyperglycemia per se are associated
with this lipid abnormality. In support of this hypothesis,
some thiazoladinediones improve insulin actions on periph-
eral tissues and lead to a greater improvement in lipid pro-
files than seen with other glucose-reducing agents (4).
Several factors are likely to be responsible for diabetic
dyslipidemia: insulin effects on liver apoprotein production,
regulation of lipoprotein lipase (LpL), actions of cholesteryl
ester transfer protein (CETP), and peripheral actions of in-
sulin on adipose and muscle.
Insulin regulation of liver apoproteins and lipid-
metabolizing proteins
A number of studies using tracer kinetics in humans have
demonstrated that liver production of apolipoprotein B
(apoB), the major protein component of very low density
lipoprotein (VLDL) and LDL, is increased in type 2 diabetes.
ApoB is a large (⬎500-kDa) protein whose production is not
modulated at the level of protein synthesis. In animals and
cultured liver cells, transcription of the apoB gene is not
remarkably altered by dietary changes and diabetes. Rather,
a large amount of newly synthesized protein is degraded
either during or immediately after translation. This degra-
dation is prevented when lipid is added to the protein; this
occurs via the actions of microsomal triglyceride transfer
protein (the protein that is defective in patients with apo-
betalipoproteinemia). Thus, lipid regulates apoB production.
Increased lipolysis in adipocytes due to poor insulinization
results in increased fatty acid release from fat cells. The
ensuing increase in fatty acid transport to the liver, which is
a common abnormality seen in insulin-resistant diabetes,
may cause an increase in VLDL secretion. Tissue culture (5),
animal experiments (6), and human studies (7) suggest that
fatty acids modulate liver apoB secretion.
A second regulatory process may be a direct effect of
insulin on liver production of apoB and other proteins in-
volved in degradation of circulating lipoproteins. In some
studies insulin directly increased degradation of newly syn-
thesized apoB (8). Therefore, insulin deficiency or hepatic
insulin resistance may increase the secretion of apoB. Insulin
may modulate the production of a number of other proteins
that affect circulating levels of lipoproteins. These include
apoCIII (9), a small apoprotein that may increase VLDL by
preventing the actions of LpL and inhibiting lipoprotein

965
966 GOLDBERG JCE & M • 2001
Vol. 86 • No. 3

uptake via the LDL receptor-related protein (LRP). Hepatic
lipase is an enzyme synthesized by hepatocytes that hydro-
lyzes phospholipids and triglycerides on HDL and remnant
lipoproteins. Some (10, 11), but not all (12), studies suggest
that this enzyme is reduced by insulin deficiency. One effect
of hepatic lipase deficiency is to decrease the clearance of
postprandial remnant lipoproteins (see below).
LpL is the major enzyme responsible for conversion of
lipoprotein triglyceride into free fatty acids. This protein has
an unusual intercellular transport; LpL is synthesized pri-
marily by adipocytes and myocytes, but must be transferred
to the luminal side of capillary endothelial cells, where it can
interact with circulating triglyceride-rich lipoproteins such
treated type 1 patients, abnormalities in the postprandial
period may not be found (24). This increased postprandial
lipemia is especially marked in women, who generally have
less postprandial lipemia than men. Chylomicron clearance
requires several steps (Fig. 1). After chylomicrons enter the
bloodstream via the thoracic duct, apoCII, the activator of
LpL, is transferred to these particles primarily from HDL.
The particle then interacts with LpL on capillary lumenal
endothelial cells of cardiac and skeletal muscle and adipose
tissue. Released fatty acids are taken up by those tissues,
perhaps via the fatty acid transporter, CD36 (25), and a
smaller triglyceride-depleted particle, a chylomicron rem-
nant, is created. Chylomicrons contain a truncated form of

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as VLDL and chylomicrons (13). Humans with both type 1
and type 2 diabetes have been reported to have reduced LpL
activity measured in postheparin blood (14); the enzyme is
released from the capillary walls and into the circulation by
heparin. Several steps in the production of biologically active
LpL may be altered in diabetes, including its cellular pro-
duction (15, 16) and possibly its transport to and association
with endothelial cells (17). LpL is stimulated by acute (18)
and chronic insulin therapy (19). LpL activity is low in pa-
tients with diabetes and is increased with insulin therapy
(20).
The release of stored fatty acids from adipocytes requires
conversion of stored triglyceride into fatty acids and mono-
glycerides that can be transferred across the plasma mem-
brane of the cell. The primary enzyme that is responsible for
this is hormone-sensitive lipase (HSSL). HSSL is inhibited by
insulin, which decreases phosphorylation of HSSL and its
association with the stored lipid droplet (21).
Specific lipoprotein abnormalities
Postprandial lipemia. Compared with normal subjects, pa-
tients with type 2 diabetes have a slower clearance of chy-
lomicrons from the blood after dietary fat (14, 22, 23); in
apoB termed apoB48. This protein is 48% of full-length apoB
and lacks the portion of apoB that interacts with the LDL
receptor. A correlation between postprandial lipemia and
atherosclerosis has been found in a number of clinical studies
(26). In addition, apoB48 remnants are found in a number of
atherogenic animal models made with diets and genetic
modifications (27, 28). It is generally accepted that remnant
lipoproteins, in addition to LDL, are atherogenic.
Remnant lipoproteins can be removed from the blood-
stream via several pathways, some of which appear to be
modulated by diabetes. Liver is the major, although not
exclusive, site of remnant clearance. As these particles per-
colate through the liver, they are trapped by association with
the negatively charged proteoglycans within the space of
Disse. This process may be aided by the presence of apoE and
hepatic lipase, proteins that bind to both lipid particles and
proteoglycans. Both hepatic lipase and heparan sulfate pro-
teoglycan production (29) may be reduced in diabetes. The
second step in remnant clearance is via cellular internaliza-
tion and degradation of the particles. Some of the remnants
may be directly internalized along with cell surface proteo-
glycans. Most remnant uptake is via receptors. ApoE is a
ligand for both the LDL receptor and LRP. Lipase enzymes

FIG. 1. Effects of diabetes on postpran-

dial lipemia. A defect in removal of lip-
ids from the bloodstream after a meal is
common in patients with diabetes. Chy-
lomicron metabolism requires that
these lipoproteins obtain apoCII after
they enter the bloodstream from the
thoracic duct. Triglyceride within the
particles can then be hydrolyzed by
LpL, which is found on the wall of cap-
illaries. LpL activity is regulated by in-
sulin, and its actions are decreased in
diabetes. Triglyceride-depleted rem-
nant lipoproteins are primarily de-
graded in the liver. This requires them
to be trapped by liver heparan sulfate
proteoglycans (HSPG) and then inter-
nalized by lipoprotein receptors, LDL
receptor and LRP. Because remnants
contain a truncated form of apoB,
apoB48, that does not interact with
these receptors, this uptake is mediated
by apoE.
 CLINICAL REVIEW
(LpL and hepatic lipase) also interact with the LRP. In very
poorly controlled diabetes LDL receptors may be decreased.
Although LRP may be regulated by insulin in cultured mac-
rophages (30), liver LRP is not decreased in diabetic mice
(29).
Although most patients with poorly controlled diabetes
develop hypertriglyceridemia, occasional patients develop
severe hyperchylomicronemia. Triglyceride levels exceeding
1000 mg/dL lead to visibly lipemic serum. At higher levels
the patients can develop eruptive xanthomas, lipemia reti-
nalis, and pancreatitis. Most of these patients have an un-
derlying lipid disorder, such as heterozygous LpL defi-
ciency, that is then exacerbated by diabetes (31).
The relationship between severe hypertriglyceridemia and
diabetes is sometimes obscured because primary LpL defi-
ciency can lead to recurrent pancreatitis and insulin defi-
ciency. In contrast to this, recent experimental data have
shown that the LpL is expressed in the islet cells, and it has
been postulated that this enzyme may promote fat-induced
toxicity leading to defective insulin secretion (32).
Increased plasma VLDL. Patients with diabetes, especially type
2 diabetes, have increased VLDL production (1). Insulin in-
fusion will correct this abnormality (7) either because of the
concomitant reduction in plasma fatty acids or because of
direct effects of insulin on the liver (Fig. 2).
Both the composition and the size of VLDL determine its
metabolic fate. In diabetes greater amounts of fatty acids
returning to the liver are reassembled into triglycerides and
secreted in VLDL. A greater content of triglyceride leads to
the production of larger particles. Not all VLDL are equally
likely to be converted to LDL. A greater proportion of large
lighter VLDL return to the liver without complete conversion
to LDL (33); this pathway is akin to that of chylomicrons. Like
chylomicrons, apoE may be the ligand that mediates liver
uptake of these particles. Thus, VLDL metabolism is a com-
petition between liver uptake of partially catabolized li-
poproteins and intracapillary lipolysis, a process that may
require several steps to complete VLDL conversion to LDL.
FIG. 2. Effects of diabetes on VLDL
production. Poorly controlled type 1 di-
abetes and type 2 diabetes are associ-
ated with increased plasma levels of
VLDL. Two factors may increase VLDL
production in the liver: the return of
more fatty acids due to increased ac-
tions of hormone-sensitive lipase (HSL)
in adipose tissue and insulin actions di-
rectly on apoB synthesis. Both of these
processes will prevent the degradation
of newly synthesized apoB and lead to
increased lipoprotein production. VLDL,
like chylomicrons, requires LpL to begin
its plasma catabolism, leading to the pro-
duction of LDL or the return of partially
degraded lipoprotein to the liver.
967
LDL are not usually increased in diabetes. In part this may
represent a balance of factors that affect LDL production and
catabolism. A necessary step in LDL production is hydrolysis
of its precursor VLDL by LpL. A reduction in this step due
to LpL deficiency or excess surface apoproteins (C1, C3, or
possibly E) decreases LDL synthesis. Conversely, increases in
this lipolytic step that accompany weight loss, fibric acid
drug therapy, and treatment of diabetes may increase LDL
levels. In diabetes a reduction in LDL production may be
counterbalanced by decreases in LDL receptors and/or the
affinity of LDL for those receptors. Both glycosylated LDL
and small, dense LDL bind to LDL receptors less avidly than
does normal LDL. Occasionally diabetic patients, especially
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those with very poor glycemic control, may have increased
LDL that is reduced by treatment of their diabetes. This is due
to effects on either the LDL or the receptor.
Increased small dense LDL. Heterogeneity exists in the size and
composition of all classes of lipoproteins. The ratio of lipid
to denser protein varies, and this determines both the buoy-
ancy and the size of the particle, as the lipids are primarily
contained in the core. In the case of VLDL and HDL, the
particles also differ in their content of apoproteins, especially
in the amounts of apoCs and apoE on the particle. The core
of all lipoproteins contains hydrophobic cholesteryl ester and
triglyceride. The proportions of these lipids are determined
by CETP-mediated exchange of lipids (Fig. 3) and the actions
of lipases that remove triglyceride by converting it into
monoglycerides, glycerol, and free fatty acids. In the absence
of a defect in these enzymes, lipoproteins enriched in tri-
glyceride will be converted to small, denser forms. This is
true for both HDL and LDL.
A decrease in the size and an increase in density of LDL
are characteristic of most hypertriglyceridemic states, in-
cluding diabetes. Because of this, small dense LDL is con-
sidered by many to be one of the hallmarks of diabetic dys-
lipidemia rather than the expected companion of reduced
HDL and increased triglyceride levels (2). The special des-
ignation given to LDL size, rather than HDL and VLDL size,
968 GOLDBERG
FIG. 3. Plasma lipid exchange. In the presence of increased concen-
trations of VLDL in the circulation, CETP will exchange VLDL tri-
glyceride for cholesteryl ester in the core of LDL and HDL. This
triglyceride can then be converted to free fatty acids by the actions of
plasma lipases, primarily hepatic lipase. The net effect is a decrease
in size and an increase in density of both LDL and HDL.
is based on a large amount of clinical and experimental data
implying that these particles confer additional atheroscle-
rotic risk. In vitro, small dense LDL can be oxidized more
easily, the particles do not interact with LDL receptors as
well, and they may associate with proteoglycans on the sur-
face of cells or in matrix more readily. Although several
human studies imply that small dense LDL are an additional
marker for atherosclerosis development (34), this observa-
tion may be restricted to patients with increased levels of
apoB and decreased HDL (35). In other studies the concom-
itant association of hypertriglyceridemia and low HDL ap-
pears to obscure any additional risk profiling attributable to
LDL size (36). In dietary studies using primates, larger, not
smaller, LDL size correlates with atherosclerosis, presum-
ably because each of these LDL carries more cholesterol (37).
Although one could question the need to search for ad-
ditional risk factors in diabetic patients who are clearly at
increased risk of disease, many clinicians and research cen-
ters do measure LDL density and/or size. This can be done
by measuring LDL density using an ultracentrifuge or by
measuring size using gradient gels or light scattering. An-
other method of determining the likelihood of a patient hav-
ing small dense LDL is by waist measurement, a cheaper and
easier test (38, 39). Obesity and insulin resistance are highly
correlated with small dense LDL.
Reduced HDL. There are several reasons for the decrease in
HDL found in patients with diabetes (Fig. 4). Increased con-
centrations of plasma VLDL drive the exchange of triglyc-
eride from VLDL for the cholesteryl esters found in HDL.
Thus, the etiology of the hypertriglyceridemia and reduced
HDL can be accounted for; CETP-mediated exchange of
VLDL triglyceride for HDL cholesteryl esters is accelerated
JCE & M • 2001
Vol. 86 • No. 3
in the presence of hypertriglyceridemia (40). Clinical mea-
surements of HDL are of HDL cholesterol; therefore, sub-
stitution of triglyceride for cholesteryl ester in the core of the
particle leads to a decrease in this measurement. Moreover,
the triglyceride, but not cholesteryl ester, in HDL is a sub-
strate for plasma lipases, especially hepatic lipase that con-
verts HDL to a smaller particle that is more rapidly cleared
from the plasma (41). Another contributor to HDL is the
surface lipid from triglyceride-rich particles that are trans-
ferred to HDL during VLDL and chylomicron lipolysis. This
increases HDL lipid content. Defective lipolysis leads to re-
duced HDL production.
Within the last 2 yr a number of additional enzymes and
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receptors have been discovered that are integral regulators of
HDL metabolism and presumably the effects of HDL on
atherosclerosis. It is not yet clear whether hyperglycemia or
insulin is an important regulator of these molecules. One of
the first steps in HDL production is the addition of lipid to
the small, newly formed HDL particles manufactured in the
liver and intestine. Phospholipid transfer protein may be
required for lipid transfer from triglyceride-rich lipoproteins
(42). In addition, newly formed HDL receive cholesterol from
nonhepatic tissues. Theoretically, the most important of
these tissues for atherosclerosis development should be the
arterial wall and lipid-rich vessel macrophages. Several
groups have recently identified the gene responsible for
Tangier disease, a rare defect associated with very low levels
of HDL and deposits of cholesterol in the tonsils and other
lymphoid tissues. ABC1, a member of a family of ATP-
binding cassette transporters, is defective in this disease (43).
This protein appears to be necessary for transfer of excess
cholesterol out of cells and into HDL. Cholesterol is an am-
phipathic molecule that would be expected to remain on the
surface of a lipoprotein. Lecithin acyl transferase converts
cholesterol into its hydrophobic ester form, allowing it to
enter the core of the lipoprotein particle.
Unlike LDL, but more akin to triglyceride-rich lipopro-
teins, HDL protein and lipid metabolism are sometimes dis-
parate. Cholesterol is the substrate for steroid hormones and
bile. Liver, adrenal, and gonads can obtain HDL lipid with-
out uptake and degradation of the entire lipoprotein. This
process involves scavenger receptor-BI. By controlling the
return of cholesterol to the liver, this receptor appears to play
an antiatherogenic role in models of mouse atherosclerosis
(44, 45). Kidneys are a major site of degradation of apoAI, the
major protein component of HDL. This appears to occur due
to filtration of this 22-kDa protein when it is freed from HDL
lipid. Fatty acids may be important for this effect; these fatty
acids may be derived from hepatic lipase hydrolysis of HDL
triglyceride (46).
Relationship of diabetic dyslipidemia to atherosclerotic risk. Trials
of glucose reduction have confirmed that glucose control is
the key to preventing microvascular diabetic complications.
These trials have, however, failed to show a marked benefit
of glucose control on macrovascular disease. There are sev-
eral reasons why this could have occurred. The time course
of the effects of diabetes on diseases of large arteries and
small vessels differs (47), and longer trials may be needed.
Reversal of underlying vascular disease may require a dif-
 CLINICAL REVIEW
FIG. 4. Effects of diabetes on HDL me-
tabolism. HDL production requires the
addition of lipid to small nascent par-
ticles. This lipid arrives via hydrolysis
of VLDL and chylomicrons with trans-
fer of surface lipids [phospholipid (PL)
and free cholesterol (FC)] via the ac-
tions of phospholipid transfer protein
(PLTP). A second pathway is via efflux
of cellular free cholesterol (FC), a pro-
cess that involves the newly described
ABC1 transporter and esterification of
this cholesterol by the enzyme lecithin
cholesterol acyl transferase (LCAT).
HDL catabolism may occur through
several steps. Hepatic lipase and scav-
enger receptor-BI are found in the liver
and in steroid-producing cells. HDL
lipid can be obtained by these tissues
without degradation of entire HDL mol-
ecules. In contrast, the kidney degrades
HDL protein (apoAI) without lipid, per-
haps by filtering nonlipid-containing
protein.
ferent degree of control or may follow a different time course
than that for small vessels. Finally, the pathological processes
are probably different. Small vessel disease of diabetic pa-
tients occurs in both type 1 and type 2 diabetes and does not
occur in nondiabetics. It is clearly related to the defective
glucose control. Large vessel atherosclerosis is not a diabetes-
specific disorder, yet it is worse in patients with diabetes;
however, processes unrelated to diabetes must be the most
important. For this reason it may not be surprising that
treatment of these other processes, such as hypertension (48,
49) and hyperlipidemia (50), appears to impact macrovas-
cular disease more than does glucose control. Similarly, the
incidence of coronary heart disease in a diabetic population
with low plasma cholesterol levels is much less than that
found in western, atherosclerosis-prone populations (51). In
contrast, the metabolic abnormalities associated with the
insulin-resistant syndrome and increased coronary artery
disease are found in the U.S. population even before the
development of overt hyperglycemia (3). Is it these abnor-
malities and not the glucose per se that are atherogenic?
A variety of animal models have been used to try to re-
produce the relationship between diabetes and macrovas-
cular disease. In a classic experiment, Duff et al. (52) used
alloxan to produce diabetes in cholesterol-fed rabbits. In a
seemingly paradoxical result the diabetic rabbits had less, not
more, atherosclerosis. This atherosclerosis was increased
with insulin treatment. The reasons for this result are now
apparent. These rabbits developed hyperlipidemia that was
due in part to a marked defect in LpL. Large chylomicrons
were not converted to more atherogenic remnant lipopro-
teins and were unable to penetrate the vessel and lead to lipid
deposition (53). This pathophysiological situation is not re-
produced in human diabetes, except for the rare situation in
which patients are also LpL deficient.
Other animal studies have more closely imitated the sit-
969
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uation in man. Limited studies have been performed in mon-
keys made diabetic using streptozotocin; in some studies the
monkeys have increased LDL retention and reduced HDL
(54, 55). Alloxan-treated pigs develop diabetes and increased
atherosclerosis (56); however, plasma LDL was more than
doubled by the diabetes. Thus, the effects of diabetes cannot
be discerned, because increased lipoprotein levels alone
should increase atherosclerosis.
Within the past decade, genetic manipulation has made
mice the most widely used animal for the study of human
disease. For this reason, several investigative groups have
studied the effects of hyperglycemia on atherosclerosis pro-
gression. Except for a small increase in lesions in BALB/c
mice, most nontransgenic strains of mice do not have dia-
betes-induced atherogenesis (57); most importantly, athero-
sclerosis was not increased in C57BL6 mice fed an athero-
genic diet. There are three well defined mouse models of
atherosclerosis, and all have been studied under diabetic
conditions. Park et al. (58) found that diabetes increased
lesion size in diabetic mice deficient in apoE0, an effect that
was inhibited by the infusion of soluble fragments of the
receptor for advanced glycosylation end products. In these
mice the diabetes markedly increased circulating cholesterol
levels, perhaps due to a decrease in liver uptake of remnant
lipoproteins via the proteoglycan-mediated pathway (29).
Therefore, the secondary hyperlipidemia, rather than effects
of the diabetes itself, might have been the primary reason for
the increased atherosclerosis. Diabetic LDL receptor knock-
out mice do not have more atherosclerosis than control mice
(59). Mice that contain a transgene for expression of human
apoB are more hyperlipidemic than wild-type animals and
develop atherosclerotic lesions when fed a diet similar to that
eaten by inhabitants of northern Europe and North America.
Addition of diabetes using streptozotocin (60) and by cross-
ing with brown adipose tissue-deficient mice did not increase
970 GOLDBERG
atherosclerosis in these mice (61). If one were convinced that
hyperglycemia alone is responsible for accelerated athero-
sclerosis, it would appear that the mouse, despite its pro-
duction of AGEs, is resistant to diabetic macrovascular dis-
ease. An alternative hypothesis that is compatible with the
known human data and is consistent with the mouse and
other animal models is that diabetes-mediated acceleration
of vascular disease requires some additional factors missing
in the mouse model. One such factor is diabetic dyslipidemia.
Treatment of dyslipidemia in patients with diabetes. There are two
reasons to specifically correct lipoprotein abnormalities in
patients with diabetes. These are to prevent pancreatitis due
to severe hypertriglyceridemia and to reduce the risk of
macrovascular complications. A number of recent reviews
have focused on the use of lipid-lowering medications in
diabetic patients (62). The objectives of that therapy will be
discussed here.
The American Diabetes Association has published clinical
goals for lipoprotein levels in adults with diabetes (63). They
are as follows: optimal LDL cholesterol levels less than 100
mg/dL (2.60 mmol/L), optimal HDL cholesterol levels more
than 45 mg/dL (1.15 mmol/L), and desirable triglyceride
levels less than 200 mg/dL (2.3 mmol/L). The rationale for
the LDL recommendation is based on the observations that
adult patients with diabetes and no overt macrovascular
disease appear to have the same risk of development of
cardiac events as nondiabetics who already have had a car-
diac event (64). The current National Cholesterol Education
Program goal for patients with coronary heart disease is LDL
levels below 100 mg/dL. Most importantly, there are avail-
able medications that should allow practitioners to reach this
goal in most patients. Moreover, data exist showing that
statin drugs are efficacious for LDL-lowering and disease
prevention in diabetic patients.
The second goal is to increase HDL to 45 or greater. Al-
though this may be an ideal goal, for many patients and their
physicians it is not a practical one. This is acknowledged in
the American Diabetes Association report (63). Unlike for
LDL, there are limited options to achieve this goal, especially
in patients with diabetic dyslipidemia who begin with HDL
cholesterol levels below 35 mg/dL. Exercise, weight loss, and
smoking cessation all increase HDL. Diets low in cholesterol
and saturated fat tend to decrease HDL. The most effective
single medication to raise HDL is niacin (65). A good response
to this medication is an increase in HDL of 25%, which is still
not enough to raise many low HDL levels to the goal. Although
niacin can be given to diabetic patients, it is generally avoided
because it causes worsening hyperglycemia. Fibric acids and
statins also increase HDL; however, their effects are more mod-
est that those found with niacin. Two recent intervention trials
showed effective methods to reduce cardiac disease in subjects
with low HDL. Neither method raised HDL to the ADA goal,
nor did the studies use medications that are likely to achieve this
goal in most patients. In one study subjects with HDL below 50
were treated with statins; lower LDL was associated with fewer
cardiac events (66). In the second, termed VA-HIT (67), patients
with cardiac disease and average HDL of 31 mg/dL were
treated with gemfibrozil, leading to a 7% HDL increase, ap-
proximately 25% triglyceride reduction, and fewer recurrent
JCE & M • 2001
Vol. 86 • No. 3
events. Therefore, it is this author’s opinion that to set a goal for
HDL at 45 mg/dL is impractical, and the benefits of such a goal
are unproven.
Triglyceride levels below 200 mg/dL are termed desirable;
this appears to differentiate this from a goal. The primary and
in many cases essential approach to triglyceride reduction is
glycemic control. In type 2 patients this also means weight
reduction. Although severe hypertriglyceridemia leads to in-
creased risk for pancreatitis, proof that reduction of triglycer-
ides is of benefit is lacking. Several investigators quote the
VA-HIT trial and several subgroup analyses of fibric acid stud-
ies as evidence that treatment of elevated triglycerides is ben-
eficial. Triglycerides can be reduced with niacin, fibric acids,
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high dose statins, and fish oil. It should be noted that the use
of fibric acids to reduce triglyceride along with statins increases
the risk of myositis and should be used with caution.
Summary. Much of the pathophysiology linking diabetes and
dyslipidemia has been elucidated. Although undoubtedly of
importance, diabetic dyslipidemia is likely to be but one of
many reasons for the accelerated macrovascular disease in
diabetic patients. Nonetheless, treatment of lipid abnormal-
ities has the potential to reduce cardiovascular events more
than 50%, to rates that are seen in countries with lower
cholesterol and less atherosclerotic burden. This leads to the
expectation that treatment of elevated lipid levels will allow
patients with diabetes to lead longer healthier lives.
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