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
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{at}columbia.edu
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Introduction
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More cardiovascular disease occurs in patients
with either type 1 or 2 diabetes. The link between diabetes and
atherosclerosis 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.
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Causes of lipoprotein abnormalities in diabetes
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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 abnormalities
exclusive of hyperglycemia.
Type 1 diabetes, previously termed insulin-dependent diabetes mellitus,
provides a much clearer understanding of the relationship among
diabetes, insulin deficiency, and lipid/lipoprotein metabolism. In
poorly controlled type 1 diabetes and even ketoacidosis,
hypertriglyceridemia and reduced HDL commonly occur (1).
Replacement of insulin in these patients may correct these
abnormalities, and well controlled diabetics may have increased HDL and
lower than average triglyceride levels.
The lipoprotein abnormalities commonly present in type 2 diabetes,
previously termed noninsulin-dependent diabetes 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
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 peripheral tissues and
lead to a greater improvement in lipid profiles 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 insulin on adipose and muscle.
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Insulin regulation of liver apoproteins and lipid-metabolizing
proteins
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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 degradation 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 apobetalipoproteinemia). 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 involved in degradation of
circulating lipoproteins. In some studies insulin directly increased
degradation of newly synthesized 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 uptake
via the LDL receptor-related protein (LRP). Hepatic lipase is an enzyme
synthesized by hepatocytes that hydrolyzes 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 primarily 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 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 production (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
patients 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 monoglycerides that can be
transferred across the plasma membrane 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).
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Specific lipoprotein abnormalities
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Postprandial lipemia. Compared with normal subjects, patients
with type 2 diabetes have a slower clearance of chylomicrons from the
blood after dietary fat (14, 22, 23); in 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 remnant, is created. Chylomicrons contain a truncated form
of 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.

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Figure 1. Effects of diabetes on postprandial lipemia.
A defect in removal of lipids from the bloodstream after a meal is
common in patients with diabetes. Chylomicron 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 capillaries. LpL
activity is regulated by insulin, and its actions are decreased in
diabetes. Triglyceride-depleted remnant lipoproteins are primarily
degraded in the liver. This requires them to be trapped by liver
heparan sulfate proteoglycans (HSPG) and then internalized 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.
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Remnant lipoproteins can be removed from the bloodstream 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 percolate 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 proteoglycan production
(29) may be reduced in diabetes. The second step in
remnant clearance is via cellular internalization and degradation of
the particles. Some of the remnants may be directly internalized along
with cell surface proteoglycans. Most remnant uptake is via receptors.
ApoE is a ligand for both the LDL receptor and LRP. Lipase enzymes (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 macrophages (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 retinalis, and pancreatitis. Most of these
patients have an underlying lipid disorder, such as heterozygous LpL
deficiency, that is then exacerbated by diabetes (31).
The relationship between severe hypertriglyceridemia and diabetes is
sometimes obscured because primary LpL deficiency can lead to recurrent
pancreatitis and insulin deficiency. 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
infusion 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
).

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Figure 2. Effects of diabetes on VLDL production.
Poorly controlled type 1 diabetes and type 2 diabetes are associated
with increased plasma levels of VLDL. Two factors may increase VLDL
production in the liver: the return of more fatty acids due to
increased actions of hormone-sensitive lipase (HSL) in adipose tissue
and insulin actions directly 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 production
of LDL or the return of partially degraded lipoprotein to the liver.
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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 competition between liver
uptake of partially catabolized lipoproteins and intracapillary
lipolysis, a process that may require several steps to complete VLDL
conversion to LDL.
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 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 buoyancy 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 triglyceride will be converted to small, denser forms. This
is true for both HDL and LDL.

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Figure 3. Plasma lipid exchange. In the presence of
increased concentrations of VLDL in the circulation, CETP will exchange
VLDL triglyceride 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.
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A decrease in the size and an increase in density of LDL are
characteristic of most hypertriglyceridemic states, including diabetes.
Because of this, small dense LDL is considered by many to be one of the
hallmarks of diabetic dyslipidemia rather than the expected companion
of reduced HDL and increased triglyceride levels (2). The
special designation given to LDL size, rather than HDL and VLDL size,
is based on a large amount of clinical and experimental data implying
that these particles confer additional atherosclerotic 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 surface 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 observation may be restricted to patients with increased levels of
apoB and decreased HDL (35). In other studies the
concomitant association of hypertriglyceridemia and low HDL appears to
obscure any additional risk profiling attributable to LDL size
(36). In dietary studies using primates, larger, not
smaller, LDL size correlates with atherosclerosis, presumably because
each of these LDL carries more cholesterol (37).
Although one could question the need to search for additional risk
factors in diabetic patients who are clearly at increased risk of
disease, many clinicians and research centers 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. Another method of determining the likelihood of a patient
having 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 concentrations of
plasma VLDL drive the exchange of triglyceride 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 in the presence of hypertriglyceridemia
(40). Clinical measurements of HDL are of HDL cholesterol;
therefore, substitution 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 substrate for
plasma lipases, especially hepatic lipase that converts 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 transferred to HDL during VLDL and
chylomicron lipolysis. This increases HDL lipid content. Defective
lipolysis leads to reduced HDL production.

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Figure 4. Effects of diabetes on HDL metabolism. HDL
production requires the addition of lipid to small nascent particles.
This lipid arrives via hydrolysis of VLDL and chylomicrons with
transfer of surface lipids [phospholipid (PL) and free cholesterol
(FC)] via the actions of phospholipid transfer protein (PLTP). A
second pathway is via efflux of cellular free cholesterol (FC), a
process 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 scavenger 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 molecules. In contrast, the
kidney degrades HDL protein (apoAI) without lipid, perhaps by filtering
nonlipid-containing protein.
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Within the last 2 yr a number of additional enzymes and 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 amphipathic 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 lipoproteins, HDL
protein and lipid metabolism are sometimes disparate. Cholesterol is
the substrate for steroid hormones and bile. Liver, adrenal, and gonads
can obtain HDL lipid without 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 several 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 different 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 patients
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 macrovascular 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 abnormalities and not
the glucose per se that are atherogenic?
A variety of animal models have been used to try to reproduce the
relationship between diabetes and macrovascular 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 lipoproteins and were unable
to penetrate the vessel and lead to lipid deposition (53).
This pathophysiological situation is not reproduced in human diabetes,
except for the rare situation in which patients are also LpL
deficient.
Other animal studies have more closely imitated the situation in man.
Limited studies have been performed in monkeys 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 progression. Except for a small increase in lesions
in BALB/c mice, most nontransgenic strains of mice do not have
diabetes-induced atherogenesis (57); most importantly,
atherosclerosis was not increased in C57BL6 mice fed an atherogenic
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 knockout 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 crossing with brown adipose
tissue-deficient mice did not increase atherosclerosis in these mice
(61). If one were convinced that hyperglycemia alone is
responsible for accelerated atherosclerosis, it would appear that the
mouse, despite its production of AGEs, is resistant to diabetic
macrovascular disease. 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 cardiac 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 available 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. Although 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 modest 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, approximately 25% triglyceride reduction, and fewer
recurrent events. Therefore, it is this authors 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 increased risk for pancreatitis, proof
that reduction of triglycerides is of benefit is lacking. Several
investigators quote the VA-HIT trial and several subgroup analyses of
fibric acid studies as evidence that treatment of elevated
triglycerides is beneficial. Triglycerides can be reduced with
niacin, fibric acids, 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 abnormalities 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.
Received August 17, 2000.
Revised October 9, 2000.
Accepted October 10, 2000.
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