detection and management of lipid disorders in diabetes · nent. decreases in triglyceride levels...

C O N S E N S U S S T A T E M E N T

Detection and Management ofLipid Disorders in DiabetesAMERICAN DIABETES ASSOCIATION

A ltered concentrations of bloodplasma lipoproteins are powerfulpredictors of coronary heart disease

(CHD) and of other manifestations of ath-erosclerosis. Reduction of elevated low-density lipoprotein cholesterol (LDL choles-teroD and concomitant increases in high-density lipoprotein cholesterol (HDLcholesterol) have been shown to reducemyocardial infarction and death from CHDin people with no previous history of vas-cular events. Other studies using angiogra-phy have demonstrated that the atheroscle-rotic lesions can be stabilized or caused toregress in the coronary vessels of patientswho have clinically evident disease.

Diabetes mellitus markedly in-creases the risk of death and disability fromthe various complications of atherosclerosis.Seventy-five to 80% of adult diabetic pa-tients die from CHD, cerebrovascular dis-ease, and/or peripheral vascular disease.The lipoprotein risk factors defined in thegeneral population also occur in diabeticpatients. Elevated LDL cholesterol, reducedHDL cholesterol, and hypeitriglyceridemiaare frequently found in insulin-dependentdiabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM).There is considerable evidence that higherblood triglycerides and lower HDL choles-terol may be intrinsically related to the ab-normal physiology produced by insulin re-sistance or inadequate insulin action, withthe concomitant metabolic disturbances.

The significant advances in theunderstanding of lipoprotein structureand metabolism, as well as the large bodyof data illustrating the efficacy of treatinglipoprotein disorders, stimulated the

APPROVED IN JANUARY 1993.

American Diabetes Association to exam-ine the possibility of better defining andaltering vascular disease risk associatedwith diabetes mellitus. Studies of diabe-tes in special ethnic groups, physiologi-cal characteristics of glucose/insulin andlipoprotein interrelationships, and the ef-fect of various interventions using diet,exercise, and drug therapy of lipoproteindisorders are now available for the plan-ning of new clinical strategies in vasculardisease prevention. These developmentsled to the consensus development con-ference on the Detection and Managementof Lipid Disorders in Diabetes held in Dal-las, Texas, on 11-13 January 1993. Pre-sentations by 24 experts in a variety ofrelevant subjects were given over a 2-dayperiod. An eight-member panel withclinical and research experience in nutri-tion, epidemiology, physiology, and thecare of patients with diabetes and lipiddisorders considered a broad spectrumof issues. An audience of health profes-sionals joined the panel in the discussionof the material presented. The report ofthis panel is provided in the form ofanswers to the following questions:

1. What is the epidemiology of lipidlevels in diabetes?

2. What is the relationship betweenlipid levels and cardiovascular dis-ease (CVD) in diabetes?

3. Are lipid disorders different in peoplewith diabetes, and, if so, what is thepathophysiology of this difference?

4. What can be accomplished by thevarious treatments of lipid disor-ders in diabetes?

5. What are the goals of therapy forlipid disorders in diabetes?

6. What further research is needed onthis subject?

QUESTION 1: WHAT IS THEEPIDEMIOLOGY OF LIPID LEVELSIN DIABETES?— NIDDM is primar-ily a disease of middle-aged or olderadults. The mean age of incident cases inCaucasians is —60 yr; in minority popu-lations, such as African Americans, His-panics, and Native Americans, the dis-ease appears 10-15 yr earlier. Theincidence of NIDDM increases with age.Most (-80%) NIDDM patients in theU.S. are overweight, at least during theearly stages of their disease. Early studiesshowed a considerable and strong rela-tionship between a simple measure ofobesity, such as body mass index, and riskof diabetes. Subsequently, it was shownthat body fat distribution, as measured bya high waist-to-hip ratio, was an impor-tant risk factor for the development ofNIDDM. The most recent studies havesuggested that deep abdominal or mesen-teric fat is a more specific risk factor forNIDDM. The increase in mesenteric fatmay be related to a higher fat intake in thediet. Some studies have also suggested thatdecreased physical activity may be a riskfactor for diabetes. There is also a verystrong familial and genetic component tothe etiology of NIDDM.

The most common lipid abnor-malities in NIDDM relate to triglycerideand HDL metabolism. NIDDM subjectshave higher triglyceride levels than thegeneral population. These levels areprobably higher than in individuals withthe same degree of obesity who do nothave diabetes. However, there are fewstudies that have measured both abdom-inal fat and fat intake among diabetic andnondiabetic subjects to measure the spe-cific effect of diabetes on triglyceride lev-els independent of obesity and diet. Theelevated triglyceride levels are not an im-mutable part of the pathophysiology ofNIDDM. Weight loss will substantiallydecrease the triglyceride levels among di-abetic and nondiabetic patients. Therealso appear to be relatively little datacomparing triglyceride levels among di-

828 DIABETES CARE, VOLUME 16, NUMBER 5, MAY 1993

Consensus Statement

abetic patients in different ethnic groupsand populations.

The levels of HDL cholesterol arelower among NIDDM patients than in non-diabetic subjects. The level of the HDL2

cholesterol subtraction is especially lower inNIDDM patients. The lower HDL choles-terol levels are related to the higher triglyc-eride levels, degree of central or intra-abdominal obesity, and glucose and insulinlevels. The epidemiology of HDL choles-terol among diabetic patients appears to besimilar to that in nondiabetic subjects.Women with NIDDM tend to have higherHDL cholesterol levels and higher subtrac-tions of HDL2 cholesterol than men. Thelimited data suggest that African Americanswith NIDDM have higher HDL cholesterollevels than Caucasians.

An association among glucose andinsulin levels, obesity, high triglyceride lev-els, and lower HDL cholesterol levels hasbeen found in practically all diabetic pop-ulations in the U.S. including Caucasians,Hispanics, African Americans, NativeAmericans, Asians, and Indians.

The total cholesterol and LDL cho-lesterol levels are similar among NIDDMpatients and age- and obesity-matchednondiabetic subjects. However, there ap-pears to be a higher prevalence of smalldense LDL particles among NIDDM pa-tients. The small dense LDL particles are,in part, determined by the higher triglyc-eride levels among diabetic patients andmay also have a familial genetic compo-nent. Decreases in triglyceride levelsthrough weight loss lead to a reduction inthe prevalence of dense LDL particles.

LDL cholesterol levels increase withage, at least up to about age 50-55 yr inmen and 65 yr among women. The LDLcholesterol levels will also be higher in pop-ulations that consume more saturated fatand cholesterol in their diet. NIDDM pop-ulations in the U.S. have higher LDL cho-lesterol levels than similar diabetic popula-tions in Japan. The higher LDL cholesterollevels are the likely reason for substantialworldwide geographic variation in risk ofCHD among NIDDM patients. Higher trig-lyceride levels are also found in NIDDM

patients with the apolipoprotein (apo) E-IIphenotype and elevated LDL cholesterollevels among those with the ApoE-IV phe-notype.

In the U.S., the Pima Indians, andperhaps other Native American popula-tions, have lower LDL cholesterol levelsthan U.S. Caucasian populations, despiteapparent central obesity, a relativelyhigh-fat diet, and a very high prevalenceof NIDDM. This may account for theirlow prevalence of CHD.

The abnormal lipoprotein levelscharacteristic of NIDDM have also been ob-served among "prediabetic" individuals, es-pecially lower HDL cholesterol and highertriglyceride levels. In most populations,central obesity and higher insulin levels aredirectly related to triglyceride levels and tolower HDL cholesterol, especially HDL2

cholesterol. Increased blood glucose val-ues, even within the "nondiabetic range"(fasting and after a glucose load), are alsorelated to higher triglyceride and lowerHDL cholesterol levels.

There does not appear to be asubstantial difference in lipoprotein(a)[Lp(a)] levels between NIDDM patientsand control subjects. The data, however,are sparse. There are few data describingdifferences in the distribution of types offatty acids in triglycerides, phospholipid,or cholesterol esters in diabetic individ-uals compared with control subjects.

There is little overall difference inlipoprotein levels in IDDM subjects ingood glycemic control compared withnormal control subjects. Poor control ofIDDM may be associated with high trig-lyceride and LDL cholesterol levels.

QUESTION 2 : WHAT IS THERELATIONSHIP BETWEEN LIPIDLEVELS AND CVD INDIABETES? — The risk of CVD amongdiabetic patients is directly related to thelevels of blood pressure, cigarette smok-ing, and total cholesterol. The combina-tion of these risk factors substantially in-creases the rate of CVD. At any level ofthese risk factors, diabetic patients prob-

ably have four to five times the risk of CVDcompared with nondiabetic individuals.

There is a paucity of evidenceshowing an increased risk of cardiovas-cular complications in relation to theHDL cholesterol or triglyceride levelsamong diabetic subjects. However, thelimited data that are available would sug-gest that low HDL cholesterol levels andprobably high triglyceride levels are inde-pendent risk factors for cardiovascular dis-ease among NIDDM patients. There is alsoan inconsistent relationship between bloodglucose and/or insulin levels, and the riskof CHD or CVD among NIDDM patients.

In diabetic populations that con-sume a diet low in saturated fat and cho-lesterol and have a low LDL cholesterol,the incidence of and mortality due to CHDis relatively low. Most diabetic patients areobese. Abdominal obesity appears to be anindependent CHD risk factor and is di-rectly related to insulin and triglyceridelevels and inversely related to HDL choles-terol levels. It has not been conclusivelydetermined whether any of the followingparameters are independent determinantsof the risk of CVD among diabetic sub-jects: lower HDL cholesterol or higher trig-lyceride levels, insulin resistance, elevatedglucose levels, abnormal composition oflipoproteins, the effects of lipoproteins onclotting or fibrolysis, or urinary albuminexcretion rates.

Metabolic studies have proposedinsulin resistance as a possible mechanismaccounting for the excess cardiovascularrisk. However, there are neither long-termobservational studies nor intervention trialsto substantiate this important hypothesis.Also, to date, there is little evidence thatLp(a) levels are associated with increasedrisk of CVD among diabetic patients.

QUESTION 3 : ARE LIPIDDISORDERS DIFFERENT INPEOPLE WITH DIABETES AND,IF S O , WHAT IS THEPATHOPHYSIOLOGY OF THISDIFFERENCE?— The pathophysiol-ogy of lipid metabolism in diabetes mel-

DIABETES CARE, VOLUME 16, NUMBER 5, MAY 1993 829

Consensus Statement

litus depends on the nature of the under-lyingmetabolic defect. Disturbances inlipid metabolism may induce alterationsin the various lipids and lipoproteins inthe plasma, due to either changes in syn-thetic or fractional clearance rates, alter-ations in the composition of the lipopro-tein particles, or differences in thedistribution of subspecies of particles.The specific lipid pattern observed willbe influenced by genetic factors, as mod-ified by environmental influences on themetabolic milieu of the individual.

Numerous observations in 1DDMsubjects indicate that patients who aremaintained near normoglycemia havenormal levels of very-low-density li-poprotein (VLDL) triglyceride and cho-lesterol and LDL-C but slightly elevatedlevels of HDL cholesterol. When insulindeficiency occurs, hyperglycemia is ac-companied by extremely elevated VLDLtriglyceride and sometimes small in-creases in LDL cholesterol can be ob-served (particularly noted in adolescentwomen). Hyperglycemic IDDM patientshave a qualitative change in LDL parti-cles. The small dense LDL (Sf 3-6) andintermediate-density lipoprotein parti-cles are increased, whereas more bouyantLDL particles (Sf 6-12) are decreased.Because lipoprotein lipase is insulin de-pendent, adipose tissue enzyme activityis reduced. Lp(a) levels may be increasedonly in a subset of IDDM patients whohave microalbuminuria. Cholesterol es-ter transport is increased presumably be-cause the VLDL particle is abnormal andnot because cholesterol ester transportprotein activity is altered. Intensive insu-lin treatment of IDDM patients will nor-malize most of the VLDL and LDL ab-normalities and enzyme activities if nearnormoglycemia is maintained for 3-6mo. However, composition of VLDL andHDL particles in IDDM patients showabnormal free cholesterol enrichment,which is quite resistant to correction byeven normoglycemic regulation.

Other factors can adversely influ-ence lipid and lipoprotein metabolism indiabetic patients. These include 1) an

increase in urinary albumin excretionrate, 2) development of uremia, 3) typeof diet, 4) certain antihypertensive drugs,5) hypothyroidism, and 6 underlying ge-netic lipid disturbances.

Lipid and lipoprotein abnormali-ties appear to be an integral part of theinsulin-resistance syndrome with orwithout NIDDM. Individuals with thesyndrome of increased intra-abdominalobesity have increased levels of VLDLparticles and total triglycerides and de-creased HDL cholesterol levels whencompared with normal control subjectsor individuals with lower body obesity.Individuals with increased intra-abdom-inal obesity show marked peripheral andhepatic resistance to insulin action. Insu-lin secretion is increased and hepatic in-sulin extraction is decreased leading toincreased insulin levels. The increasedVLDL particles are due to an increasedsecretory rate from the liver. An in-creased free fatty acid flux, and perhapsincreased glucose, play a significant rolein the increased triglyceride synthesis.Lipoprotein lipase and hepatic triglycer-ide lipase activities may also be dimin-ished. The decreased HDL cholesterol iscaused by an increased transfer of cho-lesterol ester to triglyceride-rich lipopro-teins and an increase in HDL clearance.An increase in small dense LDL particlesis also present. The major factors causingthese metabolic changes are insulin resis-tance and the degree of abdominal obe-sity. NIDDM occurs in these patientswith abdominal obesity when the (3- cellscannot maintain compensatory hyperin-sulinemia. As the insulin levels decrease,VLDL fractional clearance may furtherdecrease, LDL receptor activity de-creases, and hepatic glucose productionrises. More severe hyperglycemia is asso-ciated with greater abnormalities inVLDL triglyceride and HDL cholesterollevels. The VLDL overproduction reflectsincreases in ApoB and triglyceride syn-thesis but the relative increments in trig-lyceride and ApoB content of the parti-cles may vary.

The composition of lipoprotein

particles in NIDDM is also altered. VLDLparticles contain relatively greater num-bers of larger particles (Sf > 60) that areenriched in other lipids and may havelower triglyceride content. The smallerVLDL particles (Sf 20-60) are enrichedin cholesterol and non-ApoB proteins.The HDL cholesterol compartmentshows a reduction in HDL subspeciesand a reduced ApoAx cholesterol ratio.LDL cholesterol particles have an in-crease in triglycerides. Several observa-tions show that patients with diabetesdevelop more atherogenic disease thannondiabetic subjects with the samequantitative lipid and lipoprotein pro-files, suggesting that LDL particles inpeople with diabetes may differ fromthose in normal subjects.

Studies in normal subjects andNIDDM individuals indicate that LDL par-ticles are found in two major distributionpatterns. The A pattern consists of a majorpeak of LDLX or LDL2 particles (Sf 6-12class). The B pattern consists of a majorpeak of LDL3, which is the smaller, moredense particle (Sf 3-6 class). The B patternis associated with higher levels of triglyc-erides, LDL cholesterol and ApoB, andlower levels of HDL cholesterol and ApoA,than the A pattern. The frequency of the Bpattern is increased in NIDDM and insu-lin-resistant states.

Both clinical and laboratory in-vestigations show that lipoprotein parti-cles are modified in NIDDM by glyca-tion, the formation of advancedglycosylation products, aggregation, andoxidation. All of these processes occurwith greater frequency in patients withhyperglycemia. Glycated LDL particlesare cleared through an LDL-receptor—independent mechanism. The clearanceof these particles with altered constitu-ents is prolonged by 10-25% comparedwith normal particles. Oxidized and gly-cated LDL particles have an increaseduptake by macrophages and are thoughtto increase the production of foam cellsand stimulate the atherogenic process.Some studies indicate that glycation andoxidation may facilitate each other.


Consensus Statement

QUESTION 4 : WHAT CAN BEACCOMPLISHED BY THEVARIOUS TREATMENTS OF LIPIDDISORDERS IN DIABETES?

Diet and exerciseNutrition and physical activity changesare cornerstones in the management oflipid disorders in people with diabetes.The goals of dietary therapy should be toaffect the underlying metabolic distur-bances related to lipid disorders. Treat-ment of lipid disorders in diabetic sub-jects should focus on three majorstrategies: an aggressive approach toweight loss as indicated, increased phys-ical activity, and a low-fat (<30% Kcalfat) low-saturated fat dietary pattern.

Weight reduction in overweightpatients should be recommended for in-dividuals considered "prediabetic" and forthose with diagnosed diabetes. Weight lossis associated with improvements in triglyc-erides, insulin sensitivity, glucose control,and reduction in total cholesterol and LDLcholesterol, and increases in HDL choles-terol levels. Generally, the greater theweight loss, the greater the improvementin these parameters, but even with aweight loss of <10 lb, improvement inlipid patterns has been observed. Weightloss should be achieved by reducing totalcalorie intake and total fat intake and byincreasing physical activity.

Physical activity should be rec-ommended as part of the management oflipid disorders in diabetic subjects. In-creased caloric expenditure throughphysical activity should be used as partof weight-loss treatment. This increasedphysical activity has been shown to en-hance total weight loss and to facilitateweight maintenance. The resultingchanges in body weight and body com-position lower triglyceride, total choles-terol, and LDL cholesterol levels, andincrease HDL cholesterol levels.

Recommendations for increasedphysical activity should be individual-ized, with the recognition that many di-abetic patients have low levels of fitness.Undertaking a program of increased ex-

ercise will be difficult and require moti-vation, support, and follow-up. Gradualincreases in low-intensity physical activityshould be recommended and can provideimportant benefits.

Recommendations for increasedphysical activity need to be made in thecontext of the patient's history and medicalstatus. Medical evaluation for diabeticcomplications and cardiovascular diseaseare needed before a patient begins an ex-ercise program. Physical activity may in-crease risks associated with severe cardio-vascular and microvascular disease.

The dietary pattern recom-mended for the treatment of lipid disor-ders in diabetes includes:

Calorie restriction for individualsneeding weight loss.

Total fat intake <30% of Kcal.Saturated fat intake <10% of total

Kcal. Reduction to <7% of totalKcal may also provide greater re-duction in total cholesterol and LDLcholesterol.

Total cholesterol intake of <300 mg/day; further reduction to <200 mg/day may also provide greater reduc-tion in total cholesterol and LDLcholesterol levels.

Carbohydrate intake of 50-60% of to-tal calories. The diet pattern shouldemphasize complex carbohydratesand include at least 5 portions/day offruits and vegetables. Sources of sol-uble fiber Qegumes, oats, and somefruits and vegetables) may have addi-tional beneficial effects on total cho-lesterol and LDL cholesterol levels aswell as on the glycemic index. Thechoice of appropriate carbohydratesources to maintain glycemic controlis a critical component of dietarytreatment.

The American Diabetes Associa-tion exchange diet provides the founda-tion for dietary changes for both weightloss and fat reduction. This diet providesthe framework for choosing foods, basedon carbohydrate and fat content, withthe specific intent of glycemic control. It

provides patients with the structureneeded for meal planning, portion con-trol, and dietary self-monitoring; tech-niques that have been shown to improveweight loss and dietary fat reduction inmany settings. Additional educationshould be provided on the saturated fatand cholesterol content of foods. Opti-mal dietary therapy should include refer-ral to a registered dietitian for individu-alization of the diet treatment plan andappropriate nutrition education.

For diabetic patients who havehypertension, in addition to lipid abnor-malities, the dietary treatment approachwould be the same as described abovewith the addition of sodium reduction to<2400 mg/day. Weight loss of >10 lbcan have a significant effect on loweringblood pressure. As with lipids, thegreater the weight loss, the greater theblood pressure lowering.

Glucose controlLipid abnormalities often characterizepoorly controlled diabetic patients. Hy-pertriglyceridemia, hypercholesterol-emia, and low HDL cholesterol levelsmay greatly improve with aggressivetreatment of hyperglycemia. Therefore,the first approach to hyperlipidemia in thediabetic patient should be optimization ofdiabetes control with diet, exercise, and,when indicated, oral antihyperglycemicagents and/or insulin.

In IDDM, the occurrence of dia-betic ketoacidosis results in a profounddisorder of lipid metabolism. Severe hy-pertriglyceridemia, elevated nonesteri-fied fatty acids, and low lipoproteinlipase activity in association with re-duced LDL cholesterol and HDL choles-terol levels are improved within hours ofadequate insulin therapy. The beneficialeffects on lipids of correcting less severemetabolic derangements in IDDM areless dramatic but still important. The re-cent results of the Diabetes Control andComplications Trial have demonstratedthat intensified insulin therapy canachieve greatly improved average glyce-mic levels in motivated IDDM patients.


Consensus Statement

Intensified insulin therapy involves thecombination of education, diet planning,scheduled exercise, and multiple insulininjections in combination with self-monitoring of blood glucose. Whetherthis approach or a less-intensive treat-ment regimen is used is not crucial aslong as the goal of therapy is to bring theaverage blood glucose value as close aspossible to the upper limit of normal,usually assessed by the glycosylated he-moglobin concentration.

The normal-weight patient withIDDM who has acceptable blood glucosecontrol is usually characterized by lipidlevels in the normal range. However, thecomposition of lipoprotein particles maybe abnormal. These abnormalities may berelated to the abnormal daily glucose pat-tern achieved with existing therapies, thehyperinsulinemia that accompanies subcu-taneous administration of insulin, or othermetabolic/genetic abnormalities that coex-ist with the diabetic state. Correction ofthese abnormalities is not yet possible.

In NIDDM patients, hypertriglyc-eridemia, a tendency for reduced HDLcholesterol levels, and an abnormal com-position of lipoproteins are characteris-tic. Although treatment of the hypergly-cemia in these patients is necessary, itusually does not completely correct thelipid abnormalities to normal. Treatmentof the insulin resistance in NIDDM isbest approached with emphasis on diet-induced weight loss and a physical exer-cise program. Because the insulin resis-tance may be the underlying cause of thehyperlipidemia in NIDDM, a major effortby the patient and health-care teamshould be devoted to improving the pa-tient's life-style. Unfortunately, pharma-cological interventions aimed at increas-ing insulin sensitivity in NIDDM are notavailable for clinical use.

Pharmacological therapyIf there is an unacceptable response to anadequate therapeutic trial of diet, exer-cise, and improved glucose control, lip-id-lowering pharmacological agents arethe next therapeutic tool. Currently,

there have been no primary or secondaryprevention trials of lipid-lowering agents indiabetic patients. To the contrary, mosttrials have systematically excluded diabeticsubjects. Thus, a complete characterizationof pharmacological agents with respect totheir effects in diabetes is necessarily lim-ited to the existing literature, which con-sists primarily of short-term studies in rel-atively small populations. The followingclasses of lipid-lowering agents may beused, as indicated, for the treatment of oneor more of the lipid disorders seen in dia-betes.

Bile acid binding resins. These agents(colestipol and cholestyramine) are in-soluble ion-exchange resins that selec-tively, but not exclusively, bind bile acidsand sequester them within the gastroin-testinal tract, thereby preventing theirenterohepatic recirculation. As a conse-quence, hepatic sterol biosynthesis is ac-celerated toward bile aicd production andcell surface LDL receptors (Apo-B/E recep-tors) are increased in number. Because ofthese actions, bile acid binding resins lowerprimarily total and LDL cholesterol andhave little effect on HDL cholesterol. Bileacid binding resins have been effective inreducing CHD in both primary and second-ary prevention trials, whether used alone orin combination with other agents.

These agents can elevate VLDLtriglyceride levels, particularly if they arealready elevated above 250 mg/dl. Thus,bile acid resins may be problematic asprimary therapy in patients with NIDDMbecause mild to moderate triglyceride el-evation is the most frequent lipid abnor-mality. Also, isolated hypercholesterol-emia is relatively uncommon in eitherIDDM or NIDDM, and accounts for<10% of all dyslipidemias. However,mixed or so-called "combined" dyslipi-demias in diabetes, consisting of bothcholesterol and triglyceride elevations,are much more common in, and muchless amenable to, monotherapy in dia-betic patients. Thus, small dosages of bileacid binding resins may be used as adju-vant therapy for patients with both VLDLand LDL elevations, particularly if a

fibric acid derivative is used as primarytherapy. Similarily, for patients with fa-milial hypercholesterolemia, combina-tion reductase inhibitor—bile acid bind-ing resin therapy—is generally moreefficacious and less toxic than monother-apy with reductase inhibitors alone.

Bile acid binding resins should beused with great care in the elderly or indiabetic patients with gastrointestinal auto-nomic neuropathy because these resins mayproduce constipation or even fecal impac-tion. These agents do not have an adverseeffect on glucose control.Fibric acid derivatives. Gemfibrozil andclofibrate are the only fibric acid derivativesavailable in the U.S. These drugs activatelipoprotein lipase, reduce VLDL triglycer-ide, increase HDL cholesterol, and havesome variable but generally small time-dependent effects on LDL cholesterol lev-els. One of these agents, gemfibrozil, hasbeen used effectively in a CHD primaryprevention trial (Helsinki Heart Study) inwhich nondiabetic and diabetic patientswere enrolled. The direction and magni-tude of change in lipid levels in the dia-betic patients paralleled the changes seenin the nondiabetic population.

The greatest benefit in CHD re-duction in the Helsinki Trial was notedin patients with mixed dyslipidemias, in-cluding high triglyceride, high LDL cho-lesterol, and low HDL cholesterol levels.In these patients, coronary events werereduced -70%.

Fibric acid derivatives do not ap-pear to alter carbohydrate tolerance in dia-betic patients. However, the fibrates as aclass may increase the incidence of choleli-thiasis, a condition already more prevalentin diabetic populations. In patients with ex-tremely high triglyceride levels, treatmentwith gemfibrozil may cause an elevation ofLDL cholesterol levels as triglyceride levelsfall. Persistent diet and continuing phara-macological therapy appear to overcomethis effect. Unlike bile acid binding resinsand HMG-CoA reductase inhibitors, whichrequire 4-8 wk for full efficiency, fibratesrequire a minimum of 3 mo and probably 6mo to achieve a full effect.


Consensus Statement

For diabetic patients with mixeddyslipidemias having persistent LDL choles-terol elevations after an adequate trial ofgemfibrozil, small dosages of bile acid bind-ing resins may produce satisfactory reduc-tions of LDL cholesterol.HMG-CoA reductase inhibitors. Theseagents specifically inhibit the key regula-tory enzyme for cholesterol biosynthesis:HMG-CoA reductase, which producesmevalonic acid, the first compound com-mitted to sterol biosynthesis. As a conse-quence, hepatic cholesterol synthesis de-clines and surface LDL particle receptors(Apo-B/E receptors) are induced approx-imately twofold. LDL cholesterol clear-ance is therefore increased, and LDL lev-els decline 20-35% after 4 -8 wk oftherapy with these agents. Reductase in-hibitors have no effect on glucose con-trol, although effects on insulin resis-tance have not been investigated. Theseagents should be used to reduce LDLcholesterol levels in diabetic patients. Inthe treatment of familial forms of hyper-cholesterolemia they can be used asmonotherapy or in combination withbile acid binding resins. Beneficial effectson triglyceride and HDL cholesterol lev-els have been reported. However, theseeffects are only marginal in the lowHDL-high triglyceride patient.Nicotinic Acid. Niacin and its deriva-tives have long been used as lipid-lowering agents in both diabetic andnondiabetic patients. These agents in-crease fatty acid reesterification to tri-glycerides, lower free fatty acid levels,reduce VLDL secretion, and increaseHDL cholesterol levels while decreasingLDL cholesterol levels. Nicotinic acid hasbeen used successfully in primary andsecondary prevention trials, both aloneor in combination with other lipid-lowering agents, and has, in a singlestudy, appeared to improve mortality innondiabetic hyperlipidemic subjects. Ni-acin also increases insulin resistance, andincreases both fasting and postprandialhyperglycemia and hyperinsulinemia.Although highly regarded as a therapeu-tic agent for patients with mixed dyslip-

idemias, the use of nicotinic acid in anyform as first-line therapy in dyslipidemicdiabetic patients is not recommended.These agents should be reserved for pa-tients with refractory dyslipidemias andonly after careful consideration and withconsiderable follow-up evaluation. An in-ability to maintain acceptable control of hy-perglycemia mandates a discontinuation ofthese agents. Nicotinic acid is also relativelycontraindicated in insulin-resistant "predia-betic" patients, because it may accelerate theappearance of clinical diabetes. In one re-cent study 6% of established nondiabeticpatients converted to clinical diabetes dur-ing 2.5 yr of niacin therapy (1).

Antioxidant therapiesA number of agents (probucol, vitamins Eand C, and p-carotene) possess antioxidantproperties that may prevent LDL oxidationand its subsequent uptake by macrophages,thereby potentially slowing atherogenesis.Probucol also reduces total and LDL cho-lesterol levels by unknown mechanisms.However, this agent also reduces HDL cho-lesterol levels to an even greater extent. Vi-tamins E and C and P-carotene are eachtheoretically active as antioxidants with dif-fering loci of action; e.g., vitamin E beinglipid soluble, whereas vitamin C is watersoluble. There are several primary and sec-ondary prevention trials in progress evalu-ating these agents. Thus, no firm recom-mendation for their use can be made indiabetic patients.

EstrogenPremenopausal women have a much re-duced risk of CHD when compared withmen of the same age. Diabetes mellituslargely, if not completely, obliterates thiscardioprotective effect. Postmenopausalwomen have a gradual increase in coro-nary risk, and postmenopausal womenwith NIDDM are at increased risk forCHD. Recent recommendations from theU.S. Public Health Service on cardiovas-cular risk include estrogen replacementtherapy in postmenopausal women to re-duce CHD risk. Estrogen administrationto postmenopausal women raises HDL

cholesteral levels and reduces cardiovas-cular risk. In diabetic patients with anincreased risk for endometrial cancer,unopposed estrogen should not be used.A progestational agent should be in-cluded in hormonal replacement ther-apy. In marked hypertriglyceridemia, es-trogen should be used in minimal doseand with careful followup evaluation.

QUESTION 5: WHAT ARE THEGOALS OF THERAPY FOR LIPIDDISORDERS IN DIABETES? Theabsence of intervention trials demonstratingthat correcting lipid abnormalities in pa-tients with diabetes will reduce the in-creased risk for CHD and other macrovas-cular disorders greatly complicates the taskfor recommending goals for therapy. How-ever, the following information can be usedin formulating an approach to treating dia-betic patients with lipid disorders:

1. Diabetes is a major risk factor formorbidity and mortality due to CHD,cerebrovascular disease, and periph-eral vascular disease. There is a two-to fourfold increase in the prevalenceof these macrovascular diseases in di-abetic populations.

2. A significant number of patientswith diabetes have lipid disorders.For example, the Early TreatmentDiabetes Retinopathy Study foundthat 36% of subjects had choles-terol levels >240 mg/dl and 26%had LDL cholesterol values >160mg/dl (2).

3. Available data from the Framing-ham Study and the Multiple RiskFactor Intervention Trial suggestthat lipid abnormalities adverselyimpact the development of mac-rovascular disease.

4. Primary and secondary interven-tion trials in nondiabetic subjectshave demonstrated that diet, exercise,and pharmacological therapy de-signed to correct lipid abnormalitiescan decrease progression and even in-crease regression of angiographicallyproven CHD. These interventions canalso decrease the incidence of CHDevents.


Consensus Statement

Table 1—Lipid

RISK FOR ADULT

DIABETIC PATIENTS

ACCEPTABLE

BORDERLINE

HIGH

levels for adults

CHOLESTEROL

(MG/DL)

<200200-239

>240

HDL CHOLESTEROL

(MG/DL)

<35

L D L CHOLESTEROL

(MG/DL)

<130130-159

>160

TRIGLYCERIDES

(MG/DL)

<200200-399

>400

5. Intervention trials have included fewsubjects with known diabetes, and notrials were devoted to a populationpredominantly composed of patientswith either IDDM or NIDDM. How-ever, there are no studies that suggestthat subjects with diabetes will notbenefit from correction of lipid disor-ders.

6. Given the increased prevalence ofmacrovascular disease in patientswith diabetes, it is reasonable tosuggest that such patients mighthave a greater benefit from risk fac-tor amelioration.

Laboratory evaluation for lipiddisorders in diabetesAdult patients with diabetes should betested for lipid disorders annually with afasting serum cholesterol, triglyceride, HDLcholesterol and calculated LDL cholesterol.If all values are within acceptable limits, theclinician may consider obtaining this lipidprofile less frequently. If the cholesterol andLDL cholesterol values are elevated, a serumTSH should be measured to rule out hypo-thyroidism, a not uncommon disorder inpatients with diabetes. Pediarric patientswith diabetes should be tested soon afterdiagnosis and, if any values are abnormal,annual testing should be performed. Ac-ceptable, borderline, and high-risk lipid lev-els for adults are shown in Table 1.

Adult patients without evidence ofmacrovascular disease in the borderline orhigh-risk category, should be treated vigor-ously with diet, exercise, and glucose con-trol. If high-risk LDL cholesterol (>160mg/dl) or triglyceride (>400 mg/dl) valuespersist after 6 mo of the above control mea-sures, pharmacological therapy should beconsidered with the goal of achieving ac-ceptable LDL cholesterol and triglyceride

levels. In addition, adult patients with dia-betes and any one of the following majorcardiovascular risk factors should be con-sidered for pharmacological therapy if theydo not achieve acceptable LDL cholesteroland triglyceride levels: an HDL cholesterol<35 mg/dl, cigarette smoking, hyperten-sion, or a family history of premature CHD.

Treatment recommendations forlipid disorders in adult diabetic patientsmust also account for the degree of mac-rovascular risk. Patients with evidence ofmacrovascular disease are at greatest risk forcardiovascular morbidity and mortality.Based on the results of intervention trials inpatients without diabetes, one should striveto achieve the following lipid values in thesehigh-risk patients: LDL cholesterol <100mg/dl and triglycerides <150 mg/dl.

People with diabetes who havetriglyceride levels >1000 mg/dl are atrisk of pancreatitis and other manifesta-tions of the hyperchylomicronemic syn-drome. These individuals need special,immediate attention.

QUESTION 6 : WHAT FURTHERRESEARCH IS NEEDED ON THISSUBJECTS?— The following studiesare urgently needed to resolve major is-sues in the control of lipid levels in peo-ple with diabetes:

1. Unfortunately, many of the key re-search questions proposed in the1989 American Diabetes Associationconsensus statement on Role of Car-diovascular Disease in Diabetes haveyet to be answered and should beaddressed with high priority (3).

2. The efficacy of interventions that cansignificantly raise low levels of HDL

cholesterol in patients with NIDDMshould be investigated. These studiesshould examine end points involvingthe anatomical and clinical manifesta-tions of atherosclerosis. The specificinterventions should include life-stylechanges that can alter excess body fat(particularly central or intra-abdomi-nal obesity) as well as an assessmentof appropriate lipid-altering drugs.

3. Studies to determine the cardiovas-cular benefits of aggressive reduc-tion of LDL cholesterol in patientswith NIDDM below the goals de-fined by the National CholesterolEducation Program.

4. The value of estrogen replacementtherapy in preventing coronary ar-tery disease and/or peripheral vas-cular disease should be tested inpostmenopausal diabetic women.

5. The relationship between intra-ab-dominal fat mass and insulin re-sistance needs to be better defined.Intra-abdominal fat should be quan-ritated and related to other aspects ofthe insulin-resistant syndrome atbaseline and after interventions thatreduce the intra-abdominal fat mass.

Acknowledgments—This conference wassupported by an educational grant providedby Parke-Davis, a Division of Warner-Lam-bert Company.

References

1. Brown G, Albers J, Fisher L, Schaefer S,Lin J-T, Kaplan C, Zhao X-Q, Bisson B,Fitzpatrick V, Dodge H: Regression of cor-onary artery disease as a result of intensivelipid-lowering therapy in men with highlevels of apolypoprotein B. N Engl J Med323:1289-98, 1990

2. The Diabetic Retinopathy Study ResearchGroup: Early Treatment Diabetic Retino-pathy Study design and baseline patientcharacteristics. Ophthalmology 98 (Suppl.):741-56,1991

3. American Diabetes Association: Role ofcardiovascular risk factors in preventionand treatment of macrovascular disease indiabetes. Diabetes Care 12:573-79, 1989


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