CLINICAL REVIEW 124

Diabetic Dyslipidemia: Causes and Consequences

IRA J. GOLDBERG

Division of Preventive Medicine and Nutrition, Columbia University College of Physicians andSurgeons, New York, New York 10032

More cardiovascular disease occurs in patients with eithertype 1 or 2 diabetes. The link between diabetes and athero-sclerosis is, however, not completely understood. Among themetabolic abnormalities that commonly accompany diabetesare disturbances in the production and clearance of plasmalipoproteins. Moreover, development of dyslipidemia may bea harbinger of future diabetes. A characteristic pattern, termeddiabetic dyslipidemia, consists of low high density lipoprotein(HDL), increased triglycerides, and postprandial lipemia. Thispattern is most frequently seen in type 2 diabetes and may bea treatable risk factor for subsequent cardiovascular disease.The pathophysiological alterations in diabetes that lead to thisdyslipidemia will be reviewed in this article.

Causes of lipoprotein abnormalities in diabetes

Defects in insulin action and hyperglycemia could lead tochanges in plasma lipoproteins in patients with diabetes.Alternatively, especially in the case of type 2 diabetes, theobesity/insulin-resistant metabolic disarray that is at theroot 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 ofthe 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 inthese patients may correct these abnormalities, and well con-trolled diabetics may have increased HDL and lower thanaverage triglyceride levels.

The lipoprotein abnormalities commonly present in type2 diabetes, previously termed noninsulin-dependent diabe-tes mellitus, include hypertriglyceridemia and reducedplasma HDL cholesterol. In addition, low density lipoprotein(LDL) are converted to smaller, perhaps more atherogenic,lipoproteins termed small dense LDL (2). In contrast to type1 diabetes, this phenotype is not usually fully corrected withglycemic control. Moreover, this dyslipidemia often is foundin prediabetics, patients with insulin resistance but normal

indexes of plasma glucose (3). Therefore, abnormalities ininsulin action and not hyperglycemia per se are associatedwith 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 diabeticdyslipidemia: insulin effects on liver apoprotein production,regulation of lipoprotein lipase (LpL), actions of cholesterylester 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 havedemonstrated that liver production of apolipoprotein B(apoB), the major protein component of very low densitylipoprotein (VLDL) and LDL, is increased in type 2 diabetes.ApoB is a large (.500-kDa) protein whose production is notmodulated at the level of protein synthesis. In animals andcultured liver cells, transcription of the apoB gene is notremarkably altered by dietary changes and diabetes. Rather,a large amount of newly synthesized protein is degradedeither during or immediately after translation. This degra-dation is prevented when lipid is added to the protein; thisoccurs via the actions of microsomal triglyceride transferprotein (the protein that is defective in patients with apo-betalipoproteinemia). Thus, lipid regulates apoB production.Increased lipolysis in adipocytes due to poor insulinizationresults in increased fatty acid release from fat cells. Theensuing increase in fatty acid transport to the liver, which isa 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 thatfatty acids modulate liver apoB secretion.

A second regulatory process may be a direct effect ofinsulin on liver production of apoB and other proteins in-volved in degradation of circulating lipoproteins. In somestudies insulin directly increased degradation of newly syn-thesized apoB (8). Therefore, insulin deficiency or hepaticinsulin resistance may increase the secretion of apoB. Insulinmay modulate the production of a number of other proteinsthat affect circulating levels of lipoproteins. These includeapoCIII (9), a small apoprotein that may increase VLDL bypreventing the actions of LpL and inhibiting lipoprotein

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, ColumbiaUniversity College of Physicians and Surgeons, 630 West 168th Street,New York, New York 10032. E-mail: ijg3@columbia.edu.

0021-972X/01/$03.00/0 Vol. 86, No. 3The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A.Copyright 2001 by The Endocrine Society

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uptake via the LDL receptor-related protein (LRP). Hepaticlipase is an enzyme synthesized by hepatocytes that hydro-lyzes phospholipids and triglycerides on HDL and remnantlipoproteins. Some (10, 11), but not all (12), studies suggestthat this enzyme is reduced by insulin deficiency. One effectof hepatic lipase deficiency is to decrease the clearance ofpostprandial remnant lipoproteins (see below).

LpL is the major enzyme responsible for conversion oflipoprotein triglyceride into free fatty acids. This protein hasan unusual intercellular transport; LpL is synthesized pri-marily by adipocytes and myocytes, but must be transferredto the luminal side of capillary endothelial cells, where it caninteract with circulating triglyceride-rich lipoproteins suchas VLDL and chylomicrons (13). Humans with both type 1and type 2 diabetes have been reported to have reduced LpLactivity measured in postheparin blood (14); the enzyme isreleased from the capillary walls and into the circulation byheparin. Several steps in the production of biologically activeLpL may be altered in diabetes, including its cellular pro-duction (15, 16) and possibly its transport to and associationwith 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 requiresconversion 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 forthis is hormone-sensitive lipase (HSSL). HSSL is inhibited byinsulin, which decreases phosphorylation of HSSL and itsassociation 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

treated type 1 patients, abnormalities in the postprandialperiod may not be found (24). This increased postprandiallipemia is especially marked in women, who generally haveless postprandial lipemia than men. Chylomicron clearancerequires several steps (Fig. 1). After chylomicrons enter thebloodstream via the thoracic duct, apoCII, the activator ofLpL, is transferred to these particles primarily from HDL.The particle then interacts with LpL on capillary lumenalendothelial cells of cardiac and skeletal muscle and adiposetissue. Released fatty acids are taken up by those tissues,perhaps via the fatty acid transporter, CD36 (25), and asmaller triglyceride-depleted particle, a chylomicron rem-nant, is created. Chylomicrons contain a truncated form ofapoB termed apoB48. This protein is 48% of full-length apoBand lacks the portion of apoB that interacts with the LDLreceptor. A correlation between postprandial lipemia andatherosclerosis has been found in a number of clinical studies(26). In addition, apoB48 remnants are found in a number ofatherogenic animal models made with diets and geneticmodifications (27, 28). It is generally accepted that remnantlipoproteins, in addition to LDL, are atherogenic.

Remnant lipoproteins can be removed from the blood-stream via several pathways, some of which appear to bemodulated by diabetes. Liver is the major, although notexclusive, site of remnant clearance. As these particles per-colate through the liver, they are trapped by association withthe negatively charged proteoglycans within the space ofDisse. This process may be aided by the presence of apoE andhepatic lipase, proteins that bind to both lipid particles andproteoglycans. Both hepatic lipase and heparan sulfate pro-teoglycan production (29) may be reduced in diabetes. Thesecond step in remnant clearance is via cellular internaliza-tion and degradation of the particles. Some of the remnantsmay be directly internalized along with cell surface proteo-glycans. Most remnant uptake is via receptors. ApoE is aligand 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 iscommon in patients with diabetes. Chy-lomicron metabolism requires thatthese lipoproteins obtain apoCII afterthey enter the bloodstream from thethoracic duct. Triglyceride within theparticles can then be hydrolyzed byLpL, which is found on the wall of cap-illaries. LpL activity is regulated by in-sulin, and its actions are decreased indiabetes. Triglyceride-depleted rem-nant lipoproteins are primarily de-graded in the liver. This requires themto be trapped by liver heparan sulfateproteoglycans (HSPG) and then inter-nalized by lipoprotein receptors, LDLreceptor and LRP. Because remnantscontain a truncated form of apoB,apoB48, that does not interact withthese receptors, this uptake is mediatedby apoE.

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(LpL and hepatic lipase) also interact with the LRP. In verypoorly 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 diabetesdevelop hypertriglyceridemia, occasional patients developsevere hyperchylomicronemia. Triglyceride levels exceeding1000 mg/dL lead to visibly lipemic serum. At higher levelsthe 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 anddiabetes is sometimes obscured because primary LpL defi-ciency can lead to recurrent pancreatitis and insulin defi-ciency. In contrast to this, recent experimental data haveshown that the LpL is expressed in the islet cells, and it hasbeen postulated that this enzyme may promote fat-inducedtoxicity leading to defective insulin secretion (32).

Increased plasma VLDL. Patients with diabetes, especially type2 diabetes, have increased VLDL production (1). Insulin in-fusion will correct this abnormality (7) either because of theconcomitant reduction in plasma fatty acids or because ofdirect effects of insulin on the liver (Fig. 2).

Both the composition and the size of VLDL determine itsmetabolic fate. In diabetes greater amounts of fatty acidsreturning to the liver are reassembled into triglycerides andsecreted in VLDL. A greater content of triglyceride leads tothe production of larger particles. Not all VLDL are equallylikely to be converted to LDL. A greater proportion of largelighter VLDL return to the liver without complete conversionto LDL (33); this pathway is akin to that of chylomicrons. Likechylomicrons, apoE may be the ligand that mediates liveruptake of these particles. Thus, VLDL metabolism is a com-petition between liver uptake of partially catabolized li-poproteins and intracapillary lipolysis, a process that mayrequire several steps to complete VLDL conversion to LDL.

LDL are not usually increased in diabetes. In part this mayrepresent a balance of factors that affect LDL production andcatabolism. A necessary step in LDL production is hydrolysisof its precursor VLDL by LpL. A reduction in this step dueto LpL deficiency or excess surface apoproteins (C1, C3, orpossibly E) decreases LDL synthesis. Conversely, increases inthis lipolytic step that accompany weight loss, fibric aciddrug therapy, and treatment of diabetes may increase LDLlevels. In diabetes a reduction in LDL production may becounterbalanced by decreases in LDL receptors and/or theaffinity of LDL for those receptors. Both glycosylated LDLand small, dense LDL bind to LDL receptors less avidly thandoes normal LDL. Occasionally diabetic patients, especiallythose with very poor glycemic control, may have increasedLDL that is reduced by treatment of their diabetes. This is dueto effects on either the LDL or the receptor.

Increased small dense LDL. Heterogeneity exists in the size andcomposition of all classes of lipoproteins. The ratio of lipidto denser protein varies, and this determines both the buoy-ancy and the size of the particle, as the lipids are primarilycontained in the core. In the case of VLDL and HDL, theparticles also differ in their content of apoproteins, especiallyin the amounts of apoCs and apoE on the particle. The coreof all lipoproteins contains hydrophobic cholesteryl ester andtriglyceride. The proportions of these lipids are determinedby CETP-mediated exchange of lipids (Fig. 3) and the actionsof lipases that remove triglyceride by converting it intomonoglycerides, glycerol, and free fatty acids. In the absenceof a defect in these enzymes, lipoproteins enriched in tri-glyceride will be converted to small, denser forms. This istrue for both HDL and LDL.

A decrease in the size and an increase in density of LDLare 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 reducedHDL and increased triglyceride levels (2). The special des-ignation given to LDL size, rather than HDL and VLDL size,

FIG. 2. Effects of diabetes on VLDLproduction. Poorly controlled type 1 di-abetes and type 2 diabetes are associ-ated with increased plasma levels ofVLDL. Two factors may increase VLDLproduction in the liver: the return ofmore 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 theseprocesses will prevent the degradationof newly synthesized apoB and lead toincreased lipoprotein production. VLDL,like chylomicrons, requires LpL to beginits plasma catabolism, leading to the pro-duction of LDL or the return of partiallydegraded lipoprotein to the liver.

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is based on a large amount of clinical and experimental dataimplying that these particles confer additional atheroscle-rotic risk. In vitro, small dense LDL can be oxidized moreeasily, the particles do not interact with LDL receptors aswell, and they may associate with proteoglycans on the sur-face of cells or in matrix more readily. Although severalhuman studies imply that small dense LDL are an additionalmarker for atherosclerosis development (34), this observa-tion may be restricted to patients with increased levels ofapoB 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 toLDL size (36). In dietary studies using primates, larger, notsmaller, 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 atincreased risk of disease, many clinicians and research cen-ters do measure LDL density and/or size. This can be doneby measuring LDL density using an ultracentrifuge or bymeasuring 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 andeasier test (38, 39). Obesity and insulin resistance are highlycorrelated with small dense LDL.

Reduced HDL. There are several reasons for the decrease inHDL 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 reducedHDL can be accounted for; CETP-mediated exchange ofVLDL triglyceride for HDL cholesteryl esters is accelerated

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 theparticle 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 clearedfrom the plasma (41). Another contributor to HDL is thesurface lipid from triglyceride-rich particles that are trans-ferred to HDL during VLDL and chylomicron lipolysis. Thisincreases HDL lipid content. Defective lipolysis leads to re-duced HDL production.

Within the last 2 yr a number of additional enzymes andreceptors have been discovered that are integral regulators ofHDL metabolism and presumably the effects of HDL onatherosclerosis. It is not yet clear whether hyperglycemia orinsulin is an important regulator of these molecules. One ofthe first steps in HDL production is the addition of lipid tothe small, newly formed HDL particles manufactured in theliver and intestine. Phospholipid transfer protein may berequired for lipid transfer from triglyceride-rich lipoproteins(42). In addition, newly formed HDL receive cholesterol fromnonhepatic tissues. Theoretically, the most important ofthese tissues for atherosclerosis development should be thearterial wall and lipid-rich vessel macrophages. Severalgroups have recently identified the gene responsible forTangier disease, a rare defect associated with very low levelsof HDL and deposits of cholesterol in the tonsils and otherlymphoid 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 excesscholesterol out of cells and into HDL. Cholesterol is an am-phipathic molecule that would be expected to remain on thesurface of a lipoprotein. Lecithin acyl transferase convertscholesterol into its hydrophobic ester form, allowing it toenter 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 andbile. Liver, adrenal, and gonads can obtain HDL lipid with-out uptake and degradation of the entire lipoprotein. Thisprocess involves scavenger receptor-BI. By controlling thereturn of cholesterol to the liver, this receptor appears to playan antiatherogenic role in models of mouse atherosclerosis(44, 45). Kidneys are a major site of degradation of apoAI, themajor protein component of HDL. This appears to occur dueto filtration of this 22-kDa protein when it is freed from HDLlipid. Fatty acids may be important for this effect; these fattyacids may be derived from hepatic lipase hydrolysis of HDLtriglyceride (46).

Relationship of diabetic dyslipidemia to atherosclerotic risk. Trialsof glucose reduction have confirmed that glucose control isthe key to preventing microvascular diabetic complications.These trials have, however, failed to show a marked benefitof glucose control on macrovascular disease. There are sev-eral reasons why this could have occurred. The time courseof the effects of diabetes on diseases of large arteries andsmall vessels differs (47), and longer trials may be needed.Reversal of underlying vascular disease may require a dif-

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. Thistriglyceride can then be converted to free fatty acids by the actions ofplasma lipases, primarily hepatic lipase. The net effect is a decreasein size and an increase in density of both LDL and HDL.

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ferent degree of control or may follow a different time coursethan that for small vessels. Finally, the pathological processesare probably different. Small vessel disease of diabetic pa-tients occurs in both type 1 and type 2 diabetes and does notoccur in nondiabetics. It is clearly related to the defectiveglucose 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 mostimportant. For this reason it may not be surprising thattreatment of these other processes, such as hypertension (48,49) and hyperlipidemia (50), appears to impact macrovas-cular disease more than does glucose control. Similarly, theincidence of coronary heart disease in a diabetic populationwith low plasma cholesterol levels is much less than thatfound in western, atherosclerosis-prone populations (51). Incontrast, the metabolic abnormalities associated with theinsulin-resistant syndrome and increased coronary arterydisease are found in the U.S. population even before thedevelopment 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) usedalloxan to produce diabetes in cholesterol-fed rabbits. In aseemingly paradoxical result the diabetic rabbits had less, notmore, atherosclerosis. This atherosclerosis was increasedwith insulin treatment. The reasons for this result are nowapparent. These rabbits developed hyperlipidemia that wasdue in part to a marked defect in LpL. Large chylomicronswere not converted to more atherogenic remnant lipopro-teins and were unable to penetrate the vessel and lead to lipiddeposition (53). This pathophysiological situation is not re-produced in human diabetes, except for the rare situation inwhich patients are also LpL deficient.

Other animal studies have more closely imitated the sit-

uation in man. Limited studies have been performed in mon-keys made diabetic using streptozotocin; in some studies themonkeys have increased LDL retention and reduced HDL(54, 55). Alloxan-treated pigs develop diabetes and increasedatherosclerosis (56); however, plasma LDL was more thandoubled by the diabetes. Thus, the effects of diabetes cannotbe discerned, because increased lipoprotein levels aloneshould increase atherosclerosis.

Within the past decade, genetic manipulation has mademice the most widely used animal for the study of humandisease. For this reason, several investigative groups havestudied the effects of hyperglycemia on atherosclerosis pro-gression. Except for a small increase in lesions in BALB/cmice, 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 ofatherosclerosis, and all have been studied under diabeticconditions. Park et al. (58) found that diabetes increasedlesion size in diabetic mice deficient in apoE0, an effect thatwas inhibited by the infusion of soluble fragments of thereceptor for advanced glycosylation end products. In thesemice the diabetes markedly increased circulating cholesterollevels, perhaps due to a decrease in liver uptake of remnantlipoproteins via the proteoglycan-mediated pathway (29).Therefore, the secondary hyperlipidemia, rather than effectsof the diabetes itself, might have been the primary reason forthe 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 humanapoB are more hyperlipidemic than wild-type animals anddevelop atherosclerotic lesions when fed a diet similar to thateaten 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

FIG. 4. Effects of diabetes on HDL me-tabolism. HDL production requires theaddition of lipid to small nascent par-ticles. This lipid arrives via hydrolysisof 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 effluxof cellular free cholesterol (FC), a pro-cess that involves the newly describedABC1 transporter and esterification ofthis cholesterol by the enzyme lecithincholesterol acyl transferase (LCAT).HDL catabolism may occur throughseveral steps. Hepatic lipase and scav-enger receptor-BI are found in the liverand in steroid-producing cells. HDLlipid can be obtained by these tissueswithout degradation of entire HDL mol-ecules. In contrast, the kidney degradesHDL protein (apoAI) without lipid, per-haps by filtering nonlipid-containingprotein.

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atherosclerosis in these mice (61). If one were convinced thathyperglycemia 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 theknown human data and is consistent with the mouse andother animal models is that diabetes-mediated accelerationof vascular disease requires some additional factors missingin the mouse model. One such factor is diabetic dyslipidemia.

Treatment of dyslipidemia in patients with diabetes. There are tworeasons to specifically correct lipoprotein abnormalities inpatients with diabetes. These are to prevent pancreatitis dueto severe hypertriglyceridemia and to reduce the risk ofmacrovascular complications. A number of recent reviewshave focused on the use of lipid-lowering medications indiabetic patients (62). The objectives of that therapy will bediscussed here.

The American Diabetes Association has published clinicalgoals for lipoprotein levels in adults with diabetes (63). Theyare as follows: optimal LDL cholesterol levels less than 100mg/dL (2.60 mmol/L), optimal HDL cholesterol levels morethan 45 mg/dL (1.15 mmol/L), and desirable triglyceridelevels less than 200 mg/dL (2.3 mmol/L). The rationale forthe LDL recommendation is based on the observations thatadult patients with diabetes and no overt macrovasculardisease appear to have the same risk of development ofcardiac events as nondiabetics who already have had a car-diac event (64). The current National Cholesterol EducationProgram goal for patients with coronary heart disease is LDLlevels below 100 mg/dL. Most importantly, there are avail-able medications that should allow practitioners to reach thisgoal in most patients. Moreover, data exist showing thatstatin drugs are efficacious for LDL-lowering and diseaseprevention 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 theirphysicians it is not a practical one. This is acknowledged inthe American Diabetes Association report (63). Unlike forLDL, there are limited options to achieve this goal, especiallyin patients with diabetic dyslipidemia who begin with HDLcholesterol levels below 35 mg/dL. Exercise, weight loss, andsmoking cessation all increase HDL. Diets low in cholesteroland saturated fat tend to decrease HDL. The most effectivesingle medication to raise HDL is niacin (65). A good responseto this medication is an increase in HDL of 25%, which is stillnot enough to raise many low HDL levels to the goal. Althoughniacin can be given to diabetic patients, it is generally avoidedbecause it causes worsening hyperglycemia. Fibric acids andstatins also increase HDL; however, their effects are more mod-est that those found with niacin. Two recent intervention trialsshowed effective methods to reduce cardiac disease in subjectswith low HDL. Neither method raised HDL to the ADA goal,nor did the studies use medications that are likely to achieve thisgoal in most patients. In one study subjects with HDL below 50were treated with statins; lower LDL was associated with fewercardiac events (66). In the second, termed VA-HIT (67), patientswith cardiac disease and average HDL of 31 mg/dL weretreated with gemfibrozil, leading to a 7% HDL increase, ap-proximately 25% triglyceride reduction, and fewer recurrent

events. Therefore, it is this authors opinion that to set a goal forHDL at 45 mg/dL is impractical, and the benefits of such a goalare unproven.

Triglyceride levels below 200 mg/dL are termed desirable;this appears to differentiate this from a goal. The primary andin many cases essential approach to triglyceride reduction isglycemic control. In type 2 patients this also means weightreduction. Although severe hypertriglyceridemia leads to in-creased risk for pancreatitis, proof that reduction of triglycer-ides is of benefit is lacking. Several investigators quote theVA-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,high dose statins, and fish oil. It should be noted that the useof fibric acids to reduce triglyceride along with statins increasesthe risk of myositis and should be used with caution.

Summary. Much of the pathophysiology linking diabetes anddyslipidemia has been elucidated. Although undoubtedly ofimportance, diabetic dyslipidemia is likely to be but one ofmany reasons for the accelerated macrovascular disease indiabetic patients. Nonetheless, treatment of lipid abnormal-ities has the potential to reduce cardiovascular events morethan 50%, to rates that are seen in countries with lowercholesterol and less atherosclerotic burden. This leads to theexpectation that treatment of elevated lipid levels will allowpatients with diabetes to lead longer healthier lives.

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