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SPECIAL ARTICLE

Abhimanyu Garg, MBBS, MD Scott M. Crundy, MD, PhD

Management of Dyslipidemia in NIDDM

Coronary heart disease is the leading cause of death among patients with non-insulin-dependent diabetes mellitus (NIDDM). NIDDM patients have a high frequency of dyslipidemia, which along with obesity, hypertension, and hyperglycemia may contribute significantly to accelerated coronary atherosclerosis. Because risk factors for coronary heart disease are additive and perhaps multiplicative, even mild degrees of dyslipidemia may enhance coronary heart disease risk. Therefore, therapeutic strategies for management of NIDDM should give equal emphasis to controlling hyperglycemia and dyslipidemia. The National Cholesterol Education Program recently issued guidelines for treatment of hyperlipidemia in adults including diabetic patients. Because of the unique features of diabetic dyslipidemia, however, we suggest that certain modifications in these guidelines be made to meet specific needs of diabetic patients. For example, therapeutic goals for serum cholesterol reduction should be lower in diabetic patients than in nondiabetic subjects. Particular emphasis should be given to weight reduction in NIDDM patients. In some diabetic patients, monounsaturated fatty acids may be a better replacement for saturated fatty acids than carbohydrates. The target for cholesterol lowering should include both very-low-density lipoprotein and low-density lipoprotein (LDL) (non-high-density lipoprotein) rather than LDL alone. To obtain a substantial reduction of cholesterol levels, drug therapy From the Center for Human Nutrition and the Departments of Clinical Nutrition, Internal Medicine, and Biochemistry, University of Texas Southwestern Medical Center at Dallas; and the Veterans Administration Medical Center, Dallas, Texas. Address correspondence and reprint requests to Scott M. Grundy, MD, PhD, Director, Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75235-9052. Received for publication 29 June 1989 and accepted in revised form 20 September 1989.

DIABETES CARE, VOL. 13, N O . 2, FEBRUARY 1990

may be required in many patients. However, first-line drugs for nondiabetic patients (nicotinic acid and bile acid sequestrants) may be less desirable in NIDDM patients than hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors and even fibric acids. In fact, HMG CoA reductase inhibitors may be the drugs of choice for NIDDM patients with elevated LDL cholesterol and borderline hypertriglyceridemia, whereas gemfibrozil appears preferable for NIDDM patients with severe hypertriglyceridemia. Diabetes Care 13:153-69, 1990

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atients with non-insulin-dependent diabetes mellitus (NIDDM) commonly have dyslipidemia that may contribute to accelerated coronary atherosclerosis, the leading cause of death among NIDDM patients (1). Lipoprotein abnormalities in NIDDM patients involve all classes of lipoproteins and may consist of chylomicronemia, high levels of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), and low levels of high-density lipoprotein (HDL) (2). In some patients with NIDDM, dyslipidemia is secondary to derangement in intermediary metabolism caused by insulin deficiency and insulin resistance; in these patients, improved control of hyperglycemia will mitigate the dyslipidemia. Unfortunately, complete reversal of deranged metabolism is rarely possible in NIDDM patients. Consequently, some degree of dyslipidemia usually persists despite good glycemic control (3). Some diabetic patients will have concomitant genetic hyperlipidemia; in these patients, diabetes mellitus worsens the dyslipidemia, but correction of hyperglycemia will not normalize lipid levels (4). Frequently, in practice, it

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is not possible to determine with certainty the contributions of diabetes and genetics to elevated serum lipids.

TABLE 2 Prevalence (%) of dyslipidemia in non-insulin-dependent diabetes mellitus (NIDDM): Diabetes Intervention Study, German Democratic Repulic

PREVALENCE OF DYSLIPIDEMIA The prevalence of dyslipidemia in NIDDM patients undoubtedly varies among different populations. The World Health Organization multinational study of vascular disease in diabetic subjects revealed a high frequency of both hypercholesterolemia and hypertriglyceridemia among adult diabetic individuals from many countries (5,6; Table 1). The Diabetes Intervention Study found a twofold increase in hyperlipidemia in men and women with NIDDM compared with the general population of Dresden, GDR (Table 2; 7). Likewise, the Framingham Heart Study noted that hypertriglyceridemia and reduced levels of HDL cholesterol (HDL-chol) were increased twofold in adult diabetic patients compared with nondiabetic subjects of both sexes (Table 3; 8). The Prospective Cardiovascular Munster Study (9) further confirmed a two- to threefold increase in prevalence of hypertriglyceridemia, mixed hyperlipidemia, and low levels of HDL-chol in middle-aged subjects with NIDDM. According to the National Cholesterol Education Program (NCEP; 10), people should receive medical supervision to lower serum cholesterol if they have an LDL-chol level constantly >4.1 mM or a level ranging from 3.4 to 4.1 mM in the presence of coronary heart disease (CHD) or two other CHD risk factors (Table 4). Stern et al. (11) recently assessed the frequency at which NIDDM patients and nondiabetic individuals fall into one of these two risk categories. Among 460 NIDDM patients, 43.5% qualified for active medical management on the basis of high LDL-chol levels and other risk factors, whereas only 23.1% of 4666 nondiabetic subjects were so qualified. An additional 22.8% of patients with NIDDM had serum triglyceride levels >2.8 mM and/or HDL-chol <0.9 mM, both of which may raise CHD risk.

TABLE 1 Prevalence of dyslipidemia in adult patients with diabetes mellitus: World Health Organization multinational study

Plasma cholesterol (mM)* >6.72 4.65-6.70 <4.65 Plasma triglycerides (mM)t S2.82 1.13-2.81 <1.13

Men (%)

Women (%)

Both (%)

22 .6 58 .2 19 .3

23.5 59.3 17.2

23 .1 58 .8 18 .2

*Data on 3189 men and 3295 women. tData from 5 of 14 centers on 1911 subjects.

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19 .2 56 .2 24 .6

NIDDM (n = 1139)

Dresden population (n = 1216)

Men

Women

3.4

11.3

11.2

3.7 0.5 7.6

3.8 3.0 18.1

3.2 2.6 17.0

Hypertriglyceridemia (triglycerides >2.82 mM) Hypercholesterolemia (cholesterol >7.76 mM) Mixed hyperlipoproteinemia Total

LIPOPROTEIN ABNORMALITIES The most common lipid abnormality of NIDDM is elevated serum triglycerides (12-16). High levels of serum triglycerides occur mainly in VLDL and can result from two abnormalities. First, patients with NIDDM overproduce triglyceride-rich VLDL, and this response probably results from increased serum levels of free fatty acids and glucose (17-19). In many patients, overproduction of VLDL results partly from obesity and insulin resistance, but a decrease in insulin secretion in NIDDM may further enhance synthesis of VLDL triglycerides (20). A second cause of hypertriglyceridemia is retarded lipolysis of VLDL triglycerides, most likely due to reduced lipoprotein lipase activity (15). If the latter becomes severe due to marked insulin deficiency, patients can develop chylomicronemia in addition to elevated VLDL (type V hyperlipoproteinemia), and such patients are at high risk for acute pancreatitis (21,22). Beyond high concentrations of VLDL, which include VLDL remnants or Svedberg flotation constant Sf 20-100 lipoproteins, VLDL particles of diabetic patients contain excess unesterified cholesterol; the latter may interfere with reverse cholesterol transport and perhaps even make VLDL more prone to uptake by arterial wall macrophages (23,24). In some diabetic patients, the presence of homozygosity for apolipoprotein E2 (apoE2) may predispose them to development of dysbetalipoproteinemia. Patients with NIDDM often do not manifest high LDLchol concentrations compared with nondiabetic subjects of the same population, but many will have an increase in LDL-apoB levels, similar to that of other hypertriglyceridemic states (25,26). Kissebah et al. (27) reported that patients with NIDDM frequently have high turnover rates for LDL-apoB, due to either overproduction of apoB-containing lipoproteins or to increased conversion of VLDL to LDL. This increased input of LDL may raise LDL-chol levels, but even when they are not elevated, LDL-apoB concentrations can be increased (hyperapobetalipoproteinemia). Furthermore, LDL particles frequently are abnormal in NIDDM patients; many particles are small and dense, but the overall LDL frac-

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TABLE 3 Prevalence (%) of dyslipidemia in adult patients with diabetes mellitus (DM): Framingham heart study Women

Men

Total cholesterol (mM) Triglycerides (mM) Very-low-density lipoprotein cholesterol (mM) Low-density lipoprotein cholesterol (mM) High-density lipoprotein cholesterol (mM)

LRC cutoff value*

Normal (n = 1074)

DM (n = 130)

LRC cutoff value*

Normal (n = 1449)

DM (n - 135)

>6.72 >2.65

14 9

13 19t

>7.11 >2.26

21 8

24

>1.03

26

34t

>0.91

31

38

>4.91

11

9

>4.91

16

15

<0.80

12

21t

<1.06

10

25+

17+

* Approximate 90th or 10th percentile age- and sex-matched values from Lipid Research Clinic (LRC) tables are given for comparison with other studies (see ref. 158). +P <0.05.

tion tends to be unusually heterogeneous (polydisperse) (28,29). The abnormalities in LDL composition and metabolism appear to be partly the result of hypertriglyceridemia. For NIDDM patients with moderately severe hyperglycemia, a reduced fractional clearance rate for LDL further raises LDL-apoB concentration (20,27). Because LDL-apoB levels tend to be increased out of proportion to LDL-chol concentrations in NIDDM patients, the levels of LDL-chol fail to reflect true concentrations of LDL particles. Some investigators have speculated that hyperglycemia can cause glucosylation of LDL-apoB and thereby promote uptake of LDL by arterial wall macrophages (30). Glucosylated LDL has been identified in plasma but is present in low concentrations, whereas heavier glucosylation may occur in LDL trapped in the arterial wall and helps to facilitate LDL uptake by macrophages. Likewise, increased peroxidation of lipids has been described in patients with diabetes mellitus, and if LDL lipids trapped in the arterial wall become oxidized, uptake of LDL by macrophages may be enhanced (31,32).

TABLE 4 Classification based on total and low-density lipoprotein cholesterol (LDL-chol): National Cholesterol Education Program

Desirable Borderline high risk High risk

Total cholesterol (mM)

LDL-chol (mM)

<5.2 5.2-6.2 >6.2

<3.4 3.4-4.1

Treatment decisions with either diet or drug therapy are based on risk status of patients, whether they already have definite coronary heart disease, or if they have any two of the following risk factors: male sex, family history of premature coronary heart disease, cigarette smoking, hypertension, LDL- or high-density lipoprotein cholesterol, diabetes mellitus, definite cerebrovascular or peripheral vascular disease, or severe obesity.

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Low concentrations of HDL-chol and apoAl are yet another characteristic of NIDDM patients (13-16,25,3336). Subfraction analysis of HDL reveals that concentrations of HDL2-chol in particular are reduced. Low levels of apoAl are due to increased catabolism of HDL because production rates for apoAl appear to be normal (37). HDL of diabetic patients is enriched in triglyceride that may interfere with reverse cholesterol transport; furthermore, preliminary data suggest that in vivo glucosylation of HDL apolipoproteins can slow down reverse cholesterol transport (38).

RELATIONSHIP OF DYSLIPIDEMIA IN NIDDM TO CHD RISK

Risk for CHD in NIDDM patients is at least twice that of comparable nondiabetic populations (8,39-46). This increased risk may be related to dyslipidemia, although coexisting coronary risk factors, e.g., obesity (>30% above ideal body weight) and hypertension, may also contribute. In addition, various phenomenon that directly accompany diabetes mellitus could accelerate atherogenesis, i.e., glucosylation of arterial wall proteins and lipoproteins, increased peroxidation of lipids, microvascular disease, abnormalities in platelet function, and defective hemostasis (31,32,47-51). Besides these potential aggravating factors, dyslipidemia of diabetes may play an important role in increasing CHD risk; thus, the role of serum lipids and lipoproteins in causation of CHD can be considered briefly. The possible connection between elevated triglyceride concentrations and CHD risk has been a subject of long debate. Some investigators contend that increased triglycerides are an independent risk factor for CHD (52,53); in most epidemiological studies, triglyceride levels are positively correlated with CHD rates. However, when multivariate analysis is used (i.e., when total

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cholesterol and HDL-chol levels are considered), serum triglycerides lose much of their predictive power. Serum triglycerides probably are not directly atherogenic, because triglycerides typically are not found in atherosclerotic plaques. On the other hand, elevations of VLDL triglycerides can induce several lipoprotein abnormalities that have been implicated in atherogenesis, which include high concentrations of chylomicron remnants, VLDL remnants, intermediate density lipoproteins, small dense LDL, and reduced concentrations of HDL-chol (54-57). Moreover, VLDL from NIDDM patients exhibit altered metabolic behavior, i.e., they are taken up more readily by macrophages than normal VLDL (58). Recent reports of the 11-yr follow-up of patients with NIDDM or with impaired glucose tolerance from the Paris Prospective Study (59) indicate that hypertriglyceridemia may be the most potent lipid predictor for CHD mortality. Therefore, although high serum triglycerides may not directly cause atherosclerosis, concomitant abnormalities in lipoprotein metabolism induced by hypertriglyceridemia certainly raise the risk for CHD. Several studies suggest that LDL levels are not increased in patients with NIDDM compared with nondiabetic individuals. Although by usual criteria LDL-chol concentrations may not be raised in NIDDM, LDL metabolism cannot be dismissed as benign. Turnover rates for LDL typically are high in NIDDM patients. Furthermore, LDL particles tend to be abnormally small and dense, and concentrations of LDL-apoB are often increased (29). All of these abnormalities have been reported to increase coronary risk in nondiabetic subjects (60,61). Even borderline elevations of LDL-chol may directly raise CHD risk or signify increased risk in NIDDM patients. This is illustrated by the finding of a low prevalence of CHD among patients with NIDDM in certain populations, e.g., Pima Indians of Arizona (62), Japanese (5), and Chinese (5); all of these populations have low concentrations of serum total cholesterol and LDLchol (16,63). Thus, if serum LDL-chol could be reduced to low levels in NIDDM patients belonging to higherrisk populations, this change should appreciably reduce their risk for CHD. Another common abnormality in NIDDM is a low concentration of HDL-chol. An inverse correlation between HDL levels and CHD risk is well established, although mechanisms for this connection are poorly understood. Some investigators believe that HDL is required for reverse cholesterol transport and that low HDL levels interfere with removal of excess cholesterol from the walls of coronary arteries. Others suggest that low HDL concentrations signify the presence of high concentrations of other atherogenic lipoproteins, e.g., VLDL remnants and small dense LDL particles. Whatever the mechanism, there is no reason to doubt that low HDL levels in NIDDM patients are indicative of increased risk for CHD. Thus, abnormalities in all lipoprotein fractions (VLDL, LDL, and HDL) contribute to heightened coronary risk in NIDDM.

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CLASSIFICATION, DETECTION, AND EVALUATION OF DYSUPIDEMIA: TARGETS FOR THERAPY A guide to management of dyslipidemia in patients with NIDDM is outlined in the adult treatment panel report of the NCEP (10). This report designates diabetes mellitus as a major risk factor for CHD, and its presence modifies goals for cholesterol lowering. According to the guidelines, the initial measurement for all patients is serum total cholesterol. If total cholesterol exceeds 6.2 mM in any individual, diabetic or not, a lipoprotein analysis is indicated regardless of the presence or absence of other risk factors. This analysis includes total cholesterol, triglyceride, and HDL-chol, and it must be done on fasting serum. From these parameters, LDLchol is estimated by the following equation: LDL-chol (mM) = total cholesterol - HDL-chol - triglycerides/ 2.18. Furthermore, if the total cholesterol level is in the range of 5.2-6.2 mM, a lipoprotein analysis is indicated if CHD or two other risk factors are present (Table 4). Because male sex counts as a risk factor, all NIDDM men with a borderline high cholesterol level need lipoprotein analysis. Because being female does not count as a risk factor in the guidelines, lipoprotein analysis theoretically is not required in diabetic women with borderline high cholesterol levels; however, because several studies indicate that diabetes wipes out any protection afforded by the female sex against CHD, it seems prudent to measure lipoproteins in NIDDM women with borderline high cholesterol levels as well as in NIDDM men (8,39-41,43,44,46). In fact, considering the high prevalence of CHD and complex dyslipidemias in NIDDM patients, a lipoprotein analysis in patients of both sexes probably is justified regardless of the total cholesterol concentration. The NCEP panel based targets for therapy of dyslipidemia primarily on estimated LDL-chol levels. In the absence of CHD or other risk factors, the minimum goal of lipid-lowering therapy is to lower LDL-chol concentrations to <4.1 mM. In patients with two other risk factors, which we propose should include all NIDDM patients, the minimum goal is an LDL-chol concentration <3.4 mM. Indeed, the NCEP panel indicated that an optimal goal for LDL lowering in high-risk patients is a level in the range of 2.6 mM (10). This goal appears appropriate for NIDDM patients who already carry such high risk for CHD and in whom the LDL-chol level may underestimate the true concentration of LDL particles. Because prevalence of CHD is low in diabetic populations that typically have LDL-chol levels in the range of 2.6-3.4 mM, it seems reasonable that this level is a desirable goal for all NIDDM patients (16,63). However, whether lipid-lowering therapy of NIDDM patients should be directed solely toward LDL-chol can be questioned. An abnormal distribution of cholesterol in various lipoprotein fractions (VLDL, LDL, and HDL)

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commonly occurs in NIDDM patients (15,16,25,33,34). Although triglyceride enrichment of VLDL in NIDDM may increase VLDL triglyceride-to-cholesterol ratios, increased triglyceride levels typically are accompanied by an elevated VLDL-chol level. Indeed, a high VLDL-chol level, in addition to a high LDL-chol level, appears to be a risk factor in NIDDM patients (6,59,64). For this reason, we propose that cholesterol in both VLDL and LDL be included in risk assessment and therapeutic goals. This combined fraction may be called non-HDL-chol and can be the target for cholesterol lowering (Table 5). Because of the high prevalence of hypertriglyceridemia and triglyceride enrichment of VLDL particles in NIDDM patients, calculated values of LDL-chol may be falsely low. The use of non-HDL-chol for NIDDM patients as the therapeutic target is simple, accurate, and practical. It is independent of triglyceride levels and gives weight to both VLDL-chol and LDL-chol in risk assessment. If this approach is accepted, the minimum goal of therapy in patients with NIDDM is a non-HDL-chol level <4.1 mM, with the ideal goal being 3.4 mM. Our proposed use of non-HDL-chol as a target of therapy does not extend to the choice of hypolipidemic therapy in diabetic patients. It is necessary to distinguish between VLDL and LDL in the selection of specific therapy in individual patients. One or the other lipoprotein species may predominate in a given individual and require a particular mode of therapy. DIETARY THERAPY OF DIABETIC DYSLIPIDEMIA The NCEP panel advises that dietary therapy for elevated cholesterol levels should occur in two steps (10). Dietary therapy aims to progressively reduce intakes of saturated fatty acids and cholesterol and to eliminate excess energy intake. The Step-One Diet calls for reduction of saturated fatty acids to <10% of total energy intake and daily cholesterol to <300 mg. The Step-Two Diet recommends curtailing saturated fatty acids to <7% of total energy intake and cholesterol consumption to <200 mg/day. In both diets, saturated fatty acids are replaced by carbohydrates, and both diets have a high content of carbohydrates (50-60% of total energy). The diet for NIDDM patients recommended by the American Diabetes Association (ADA) is similar to the TABLE 5 Proposed therapeutic goals for men and women with noninsulin-dependent diabetes mellitus

Total cholesterol Low-density lipoprotein cholesterol Non-high-density lipoprotein cholesterol

Minimum goal (mM)

Ideal goal (mM)

<5.2

-4.4

<3.4

-2.6

<4.1

-3.4

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Step-One Diet of the NCEP (65). ADA advises liberal intakes of carbohydrates up to 55-60% of total energy and restriction of total fat to 30% of total energy. Saturated fatty acids are limited to <10% of total energy and cholesterol to <300 mg/day. In addition, high-fiber foods are recommended to increase fiber intake to ~40 g/day. For NIDDM patients with hyperlipidemia, the ADA advocates further restriction of dietary fats to 20% of total energy intake and cholesterol to 100-150 mg/day. Despite these recommendations, a recent Consensus Development Conference on Diet and Exercise in NIDDM, sponsored by the National Institutes of Health (66), questioned the wisdom of recommending highcarbohydrate diets to all diabetic patients because of their potentially harmful effects on lipoprotein levels. Concern was expressed about raised triglyceride and VLDL-chol levels and lowered HDL-chol levels resulting from high-carbohydrate diets. In recognition of differences of opinion among investigators regarding the desirable proportion of carbohydrates and fats for diabetic patients, the NCEP panel indicated that an alternative diet with lower intakes of carbohydrates (i.e., 40-45% of energy) may be appropriate for hyperlipidemic patients with diabetes mellitus (10). Encouraged by the Consensus Development Conference, we recently compared two approaches to dietary treatment of dyslipidemia in patients with NIDDM, i.e., a diet high in carbohydrates versus one high in monounsaturated fatty acids (67). Both diets were low in saturated fatty acids and cholesterol. Our study revealed that the diet high in monounsaturates improved glycemic control, reduced triglyceride and VLDL-chol levels, and raised HDL-chol levels compared with the highcarbohydrate diet. Moreover, preliminary studies from our laboratory do not support claims that high-carbohydrate diets improve insulin sensitivity in NIDDM patients (68). Therefore, we suggest that partial replacement of dietary carbohydrates with monounsaturated fatty acids may be beneficial for certain groups of NIDDM patients (e.g., hypertriglyceridemic patients, those with HDL-chol levels <0.9 mM, and elderly patients with poor compliance with high-carbohydrate diets) and during pregnancy when energy requirements are high. Another issue for the diabetic patient pertains to the appropriate dietary content of n-3 polyunsaturated fatty acids. Fish oils are a rich source of these highly unsaturated fatty acids, such as eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6). The n3 polyunsaturates have a potent hypotriglyceridemic action that is dose dependent (69,70). Clinically significant reductions in plasma triglyceride levels are usually observed on daily consumption of 5-10 g n-3 polyunsaturated fatty acids. However, the NCEP panel did not advocate n-3 polyunsaturates for the treatment of hypertriglyceridemia and advised against the use of fish oil capsules as a supplement in a therapeutic diet for high-risk LDL-chol levels (10). According to the NCEP panel, the total amount of polyunsaturated fatty acids

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(n-6 plus n-3) should be betwen 7 and 10% of daily energy intake, and the relative content of n-6 versus n3 polyunsaturated fatty acids was not further elaborated. According to ADA (65), EPA is acceptable in the diet of patients with diabetes mellitus, but ADA did not make specific recommendations as to desirable EPA intakes. Preliminary evidence indicates that fish oil polyunsaturates can reduce serum triglyceride levels in NIDDM patients, but they may have adverse effects on glycemic control (71-73). Of further concern is the increase in LDL-chol and LDL-apoB concentrations that can occur in hypertriglyceridemic subjects given fish oil (74,75). Side effects of n-3 polyunsaturates are rare and limited to gastric upset and a bleeding tendency. Furthermore, if studies prove that n-3 polyunsaturates directly prevent atherosclerosis, they could have an important role in the treatment of patients with NIDDM. However, until that time, their use as a supplement cannot be recommended, although their ingestion with fish need not be curtailed. Whatever approach to dietary treatment of NIDDM is selected, emphasis should be on reducing excess body weight by restricting total energy intake and increasing energy expenditure by appropriate exercise. Weight loss has been shown to improve both glycemic control and lipoprotein pattern in NIDDM patients (76-78). Weight reduction may further reduce requirements for antihypertensive agents in hypertensive patients with NIDDM. Weight loss is perhaps the only effective measure to reduce resistance to the peripheral action of insulin (79, 80). High levels of serum triglycerides often respond markedly to weight loss, and a modest decrease in LDLchol levels may occur after only a small reduction in body weight. HDL-chol levels also have been reported to rise after weight reduction, but normalization is not a consistent finding in NIDDM patients (76-78). The best approach to weight reduction in NIDDM patients is a matter of dispute. Very-low-energy diets are widely used and have the advantage of promoting rapid weight reduction that is desired by many patients. However, there are disadvantages to this approach. Rapid weight loss can result in undesirable loss of lean body mass or skeletal muscle volume, which is potentially detrimental (81). It also induces cholesterol gallstones in many patients (82). A gradual sustained weight loss is theoretically better because it allows for behavior modification, maintenance of muscle mass, and a lower risk for gallstone formation. Unfortunately, many patients become discouraged with slow weight reduction and give up the attempt before they have achieved success. Disagreement about the best weight-reducing diet for diabetic patients also extends to diet composition. Although some believe that high-carbohydrate diets will promote weight loss, this remains to be proved (83). At this time, long-term studies are lacking to determine which nutrient, carbohydrates, or monounsaturated fatty acids are better for inducing weight loss. For some patients, high-carbohydrate high-fiber diets may be more acceptable, but for others, some fat in the diet may en-

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hance satiety and allow for a decrease in total energy intake (84). Diabetic patients should consume at least three meals every day. In some patients with mild hyperglycemia, oral hypoglycemic drugs or insulin may be discontinued before initiation of a weight-loss program. In others, weight reduction can be started after stabilizing glycemic control with minimum doses of oral hypoglycemic drugs or insulin, and as the patient responds by losing weight, the dose can be gradually and progressively reduced. Frequent self-monitoring of blood glucose is essential for some patients to deal with the changing metabolic and pharmacological environment during weight reduction. If possible, an exercise program should be initiated, although amounts and types of exercise will depend on the patient's cardiovascular status. If patients have peripheral vascular disease or diabetic foot disease, they may be unable to increase walking, although they can be encouraged to conduct upper-body exercises. Appetite suppressants are to be avoided completely in NIDDM patients. For most patients, use of dietary therapy to control both glucose and lipid levels should be continued for a period of 3-6 mo before resorting to lipid-lowering drugs. Dietary therapy may be supervised by a physician, but assistance of a registered dietitian can be especially helpful in diabetic patients. Any smoker must be urged to drop the habit. An effort should be made to reduce the dose of or if possible avoid drugs having adverse effects on lipids and lipoproteins (e.g., p-adrenergic blocking agents and thiazide and loop diuretics). During dietary therapy, depending on the severity of hyperglycemia, a decision can be made about use of oral hypoglycemic agents or insulin for glycemic control. Without fail, controlling hyperglycemia often mitigates abnormalities in lipoproteins and will reduce the need for lipid-lowering drugs.

DRUG THERAPY Although the severity of dyslipidemia can be improved by glycemic control and weight reduction, hypolipidemic drugs may be appropriate for selected patients after other therapeutic measures have failed to achieve the proposed goals for cholesterol lowering. According to the NCEP panel report (10), nicotinic acid and bile acid sequestrants are drugs of first choice for treatment of hyperlipidemia; other drugs worthy of consideration include lovastatin, gemfibrozil, and probucol. However, guidelines of the NCEP panel may not be directly applicable to NIDDM patients, and advantages and disadvantages of each category of drugs for treatment of diabetic dyslipidemia must be considered. Nicotinic acid. Because elevated VLDL-chol and reduced HDL-chol levels are the characteristic lipoprotein pattern in most patients with NIDDM, nicotinic acid theoretically should be the drug of choice for diabetic dyslipidemia. Nicotinic acid therapy reduces hepatic

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production of VLDL and thereby lowers both VLDL and LDL levels (85). Furthermore, the drug usually increases HDL-chol levels (86). The Coronary Drug Project (87) evaluated long-term nicotinic acid therapy and observed a decrease in recurrence rates of myocardial infarction compared with placebo in nondiabetic patients with established CHD. In a 15-yr follow-up of the Coronary Drug Project, a reduction in total mortality rate was noted for patients who had received nicotinic acid during the trial (88). Likewise, the Cholesterol Lowering Atherosclerosis Study (89) reported a favorable response to nicotinic acid therapy. In this study, the combination of diet, bile acid sequestrants, and nicotinic acid was shown to retard formation of new atheromas and to cause regression of coronary plaque in some nondiabetic patients with preexisting coronary artery disease. However, nicotinic acid therapy is accompanied by many side effects. Flushing of skin occurs immediately after starting the drug, but its intensity usually decreases after a period of several weeks. In some patients, concomitant administration of aspirin or other nonsteroidal anti-inflammatory agents helps to prevent severe flushing. Other common side effects include exacerbation of peptic ulcer and reversible abnormalities in liver function tests. In patients with NIDDM, nicotinic acid therapy unfortunately worsens glycemic control and raises plasma uric acid levels (90-93). We observed definite increases in plasma glucose values and glycosylated hemoglobin concentrations and increased glycosuria during nicotinic acid therapy in NIDDM patients (93). Although precise mechanisms whereby nicotinic acid therapy worsens hyperglycemia in NIDDM patients are not known, this response may be due to accentuation of insulin resistance (91,94). Moreover, hyperuricemia induced by nicotinic acid therapy can precipitate gout, because patients with NIDDM and impaired glucose tolerance are already at increased risk for gout (95,96). Hyperuricemia may also worsen renal function due to uric acid nephropathy. Consequently, despite its action to improve lipid and lipoprotein levels, nicotinic acid therapy must be used with considerable caution or avoided altogether in patients with NIDDM. For this reason, nicotinic acid cannot be considered first-line therapy for the dyslipidemia of NIDDM, although it may be useful in primary forms of dyslipidemia. Bile acid sequestrants. These drugs bind to bile acids in the intestinal tract and interrupt their enterohepatic circulation. Consequently, more cholesterol is converted into bile acids in the liver. The resultant depletion of hepatic cholesterol content stimulates hepatic LDL-receptor synthesis and thereby promotes removal of LDL from the circulation (97). In the Lipid Research Clinic Primary Prevention Trial, hypercholesterolemic middle-aged men without diabetes had a reduction in CHD risk with cholestyramine therapy (98). As shown in this trial, bile acid sequestrants in doses of 16-20 g/day usually induce a 15-30% lowering of LDL-chol levels. Unfortunately, sequestrants tend to increase serum triglycerides; therefore, their use cannot be rec-

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ommended in patients with significant hypertriglyceridemia (99). To date, there is a paucity of data on the effectiveness of bile acid sequestrants in patients with NIDDM (100, 101). A few comments nonetheless may be in order. Worsening of hypertriglyceridemia by sequestrant therapy cannot be considered desirable in NIDDM patients who already have a tendency for high levels of plasma triglycerides. Another common side effect of bile acid sequestrants is constipation that may be worsened by autonomic neuropathy in diabetic patients. Sequestrants can interfere with intestinal absorption of various drugs, e.g., digoxin, digitoxin, warfarin, thyroxine, thiazide diuretics, and p-adrenergic blockers, and therefore should be used with caution in patients on multiple medications. Because of these considerations, use of bile acid sequestrants probably should be limited to a select group of patients with NIDDM, i.e., those having an isolated increase in LDL-chol levels and normal serum triglycerides (plasma triglycerides <1.69 mM). Serum triglyceride levels should be monitored closely in patients with NIDDM on sequestrant therapy. Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors. This new class of drugs reduces cholesterol synthesis by competitive inhibition of the rate-limiting enzyme hydroxymethylglutaryl coenzyme A (HMG CoA) reductase (102). These drugs reduce the cholesterol content of cells and stimulate synthesis of LDL receptors, particularly in the liver (97). Increased hepatic LDL-receptor activity promotes receptor-mediated clearance of both LDL and VLDL remnants. Lovastatin was the first drug of this class to be available in the U.S., and several others, notably pravastatin and simvastatin, are under evaluation. Lovastatin has now been used in patients for >7 yr and, based on results thus far, holds considerable promise as a cholesterol-lowering drug. Recent studies from our laboratory revealed that lovastatin (20 mg twice daily) is highly effective for lowering plasma lipids in NIDDM patients who have mild to moderate increases in total cholesterol levels (103). In our patients, lovastatin reduced total cholesterol by 26%, LDL-chol by 28%, and LDL-apoB by 26%. Lovastatin therapy also decreased plasma triglyceride and VLDL-chol levels by 31 and 42%, respectively, and even more so in patients with borderline (moderate) hypertriglyceridemia (Fig. 1). Although lovastatin did not change the level of HDL-chol, the total cholesterol-toHDL-chol ratio fell by 29%, which may reflect an overall reduction in coronary risk. In our view, HMG CoA reductase inhibitors may soon become the drugs of choice for treatment of dyslipidemia in NIDDM. In our study (103), LDL-chol levels were reduced close to the ideal level for NIDDM patients, i.e., 2.6 mM. Lovastatin therapy effectively lowered not only LDL-chol levels but also decreased concentrations of remnant lipoproteins, as evidenced by a decrease in VLDL-chol. This action on both VLDL and LDL should reduce non-HDL-chol concentrations to near the ideal

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that could interfere with its disposal or with liver disease. 140 4.5 6.5 Lovastatin produces cataracts in dogs when given in 120 6.0 4.0 very high doses. Although clinical studies with lova100 statin have revealed no increase in formation of lentic1 5.5 5 ular opacities over a period of 1-2 yr in many nondi5, 80 5.0 abetic subjects (109,110), the fact that NIDDM patients 3.0 60 are at increased risk for developing cataracts justifies 4.5 40 2.5 periodic slit-lamp examinations during lovastatin therapy. Certainly, NIDDM patients with mature cataracts 0 0 Placebo Lovastatin Placebo Lovastatin Placebo Lovastatin or who have already undergone lens extraction do not TRIGLYCERDES VLDL - CHOLESTEROL HDL - CHOLESTEROL need slit-lamp examinations if on lovastatin therapy. In 1.3 2.5 usual doses, lovastatin does not cause marked reducT 5.0 1.2 tions in whole-body synthesis of cholesterol nor does it 2.0 4.0 1.1 decrease levels of cholesterol products, e.g., adrenal 5 1.5 and gonadal steroids and bile salts. Reduced lithogen3.0 i o icity of bile with HMG CoA reductase inhibitors may be 0.9 1.0 2.0 potentially advantageous in NIDDM patients who al0.8 ready appear to be predisposed to formation of choles0.5 1.0 0.7 terol gallstones (111,112). Other minor side effects of 0 oi 1 1 0 Placebo Lovastatin Placebo Lovastatin lovastatin include headache, sleep disturbances, and skin Placebo Lovastatin rash. FIG. 1. Patients with non-insulin-dependent diabetes mellitus during treatment with placebo and lovastatin. Fibric acid derivatives. Drugs of this class (gemfibrozil, Plasma levels of total cholesterol, low-density lipopro- clofibrate, and fenofibrate) are potent lipid-lowering tein cholesterol (LDL-cholesterol), LDL apolipoprotein B, drugs. They may reduce hepatic formation of VLDL tritriglycerides, very-low-density lipoprotein cholesterol glycerides, but they promote lipolysis of serum triglyc(VLDL-cholesterol), and high-density lipoprotein choles- erides by enhancing the activity of lipoprotein lipase terol (HDL-cholesterol) in normotriglyceridemic (•, n = (113). In patients with normal triglyceride levels, fibric 7, plasma triglycerides <2.82 mM) and borderline hyper- acids also reduce LDL-chol concentrations by stimulattriglyceridemic (A, n = 9, plasma triglycerides 2.82-5.65 ing clearance of LDL from the circulation. On the other mM) patients. Values are means ± SE. (Figure modified hand, in hypertriglyceridemic patients, fibric acids raise from Garg A, Grundy SM: Cardiovasc Rev Rep 9:30-39, LDL-chol concomitantly with triglyceride lowering (114). 1988.) Fibric acids can raise HDL-chol levels, possibly through their action to lower triglyceride concentrations. Treatlevel of ~3.4 mM. Lovastatin, however, is not appro- ment of hypertriglyceridemia by fibric acids could thepriate for patients having severe hypertriglyceridemia with oretically reduce the risk for CHD in several ways. Fibric excess chylomicrons because it will not reduce triglyc- acid therapy will decrease levels of atherogenic VLDL remnants, may raise HDL-chol, and may reduce the risk erides to a safe range. Glycemic control did not deteriorate in our patients of coronary thrombosis. According to some investigaon lovastatin therapy, and the drug was well tolerated. tors, hypertriglyceridemia predisposes to coronary Our finding that this class of drugs does not adversely thrombosis possibly by raising levels of activated factor affect glycemic control has been confirmed recently by X and enhancing platelet responsiveness; therefore, these Yoshinoetal. (104) in a 1-yr study of pravastatin therapy abnormalities presumably will be reversed by triglyceride lowering (115,116). in 10 patients with NIDDM. Lovastatin therapy has been reported to cause minor Clofibrate was the first fibric acid to be used extengastrointestinal upsets, mild and reversible abnormali- sively, and experience with this drug extends to patients ties in liver function tests, and occasional development with diabetes mellitus. Indeed, there are studies sugof myopathy syndrome (105). Lovastatin-induced my- gesting that clofibrate improves glucose tolerance in adopathy can manifest as muscle weakness, soreness and dition to its action to lower triglycerides (117). Despite tenderness, elevated serum creatine kinase levels and these potential advantages, clofibrate usage has derarely as rhabdomyolysis, myoglobinuria, and acute clined because of the results of the World Health Orkidney failure (106-108). Although precise mechanisms ganization study (118). In this study, clofibrate apparare not known, myopathy probably results from high ently had side effects that offset its beneficial effect to serum levels of lovastatin and its metabolites. Severe reduce risk for CHD. Furthermore, more patients in the myopathy is most likely to occur during concomitant clofibrate group developed diabetes mellitus than in the use of other medications, e.g., cyclosporin, gemfibrozil, placebo group. and nicotinic acid, or in patients with hepatic dysfuncResults of the recently published Helsinki Heart Study tion impairing drug metabolism (108,109). Therefore, (119) showed that long-term gemfibrozil therapy is genlovastatin should be avoided in any patient taking drugs erally safe and effective for reducing risk for CHD in TOTAL CHOLESTEROL

LDL • APOLIPOPROTEIN - B

LDL - CHOLESTEROL

E

T

E

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nondiabetic patients with hypercholesterolemia. Part of the reduction in CHD risk was attributed to an increase in HDL-chol levels. This study has rekindled interest in fibric acid derivatives as lipid-lowering drugs. The Food and Drug Administration recently approved use of gemfibrozil for lowering cholesterol to reduce the risk of CHD in patients with type MB hyperlipoproteinemia, particularly when accompanied by low HDL-chol levels. Our experience with gemfibrozil therapy (600 mg twice daily) suggests that it is highly effective for lowering plasma triglyceride levels in NIDDM patients with severe hypertriglyceridemia, and thus it should reduce risk for acute pancreatitis in these patients (120). Modest elevations in HDL-chol concentrations also occurred in our study, but in most patients, HDL-chol remained <0.9 mM despite treatment. Furthermore, LDL-chol levels frequently rose, and LDL-apoB concentrations were not reduced (Fig. 2). Therefore, only limited reduction in coronary risk can be expected with gemfibrozil used alone in NIDDM patients with marked hypertriglyceridemia. In fact, to reduce risk of CHD, lovastatin might be added to gemfibrozil therapy for lowering LDL-chol and LDL-apoB levels, and our results support this contention (120). However, as mentioned earlier, the combination of gemfibrozil and lovastatin raises the risk of severe myopathy (108,109). Because of this, the combination should be used with caution and only in selected patients; it cannot be recommended for routine use in diabetic patients. In earlier studies, long-term therapy with gemfibrozil TOTAL CHOLESTEROL

LDL- CHOLESTEROL

was reported to raise fasting and postprandial plasma glucose levels in patients with NIDDM (121,122). We observed no deleterious action of gemfibrozil on glycemic control. Gemfibrozil, like clofibrate, can cause lithogenic bile, and therefore could increase the risk for gallstones during long-term use in patients with NIDDM (123). Fibric acid derivatives can induce myopathy when used alone, particularly in patients with impaired renal function (124). Other side effects of gemfibrozil of lesser concern include various gastrointestinal symptoms, occasional changes in hematologic parameters, and abnormal liver function tests. There is no evidence that gemfibrozil increases risk for malignancy. Probucol. Probucol is an LDL-loweringdrug. It reduces LDL-chol levels by increasing the clearance of LDL (125). Whether or not enhanced removal of LDL by probucol occurs through receptor-mediated or non-receptor-mediated mechanisms has not been determined. Probucol also lowers HDL-chol concentrations but does not affect plasma triglyceride levels. Although probucol reduces HDL-chol levels, it apparently can cause regression of xanthomas in some hypercholesterolemic patients (126). Probucol is carried in LDL particles and is a potent antioxidant (127). Recently, some investigators have proposed that oxidative modification of LDL may play an important role in atherogenesis by facilitating accumulation of lipids in arterial wall macrophages (128). If this mechanism pertains, probucol could retard development of atherosclerosis because it resists oxidation of LDL. However, this possibility does not justify routine use of probucol in NIDDM patients, because it currently remains a theory.

LDL - APOLIPOPROTEIN - B 140

SPECIAL CONSIDERATIONS

135 130

120 115 0s Placebo Gemfibrozil

Placebo Gemlibrozil

TRIGLYCERIDES

VLDL- CHOLESTEROL

Placebo Gemfibrozil HDL - CHOLESTEROL 0.80 0.75 0.70 0.65 0.60 0.55

Placebo Gemfibrozil

Placebo Gemfibrozil

Placebo Gemfibrozil

FIG. 2. Plasma levels of total cholesterol, low-density lipoprotein cholesterol (LDL-cholesterol), LDL apolipoprotein B, triglycerides, very-low-density lipoprotein cholesterol (VLDL-cholesterol), and high-density lipoprotein cholesterol (HDL-cholesterol) in 10 markedly hypertriglyceridemic (plasma triglycerides >5.65 mM) patients with non-insulin-dependent diabetes mellitus during treatment with placebo and gemfibrozil. Values are means ± SE. * P < 0.002; * * P < 0.001.

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Familial hypercholesterolemia. Some patients with NIDDM have concomitant hyperlipidemias of genetic origin. For example, we recently studied a woman with NIDDM who was an obligate heterozygote for familial hypercholesterolemia; the diagnosis was known because the patient's child had homozygous familial hypercholesterolemia. Despite controlling hyperglycemia with insulin therapy, the patient's LDL-chol level remained markedly elevated. However, she responded to lovastatin therapy with near normalization of her lipoprotein profile (Fig. 3). Thus, familial hypercholesterolemia should be suspected in NIDDM patients who persist with severe hypercholesterolemia despite normalization of plasma glucose. The preferred drug regimen for heterozygous familial hypercholesterolemia appears to be the combination of an HMG CoA reductase inhibitor with bile acid sequestrants (97). Familial dysbetalipoproteinemia. A few patients with NIDDM will have concomitant dysbetalipoproteinemia or type III hyperlipoproteinemia. Such patients usually have tuberous xanthomas or planar xanthomas (in palmar creases), accumulation of (3-VLDL, or remnant lipoproteins rich in cholesterol esters. Patients with type

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Baseline

Insulin + Lovastatln

LDL-C

Insulin Dose (units/day)

HDL-C

0

Mean Plasma Glucoso (mmol/l)

17.7

Mean Body Weight (kg)

65.0

66.5

Glucosylalod Hemoglobin (%)

17.3

12.3

FIG. 3. Plasma levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in 37-yr-old woman with non-insulin-dependent diabetes mellitus and obligate heterozygous familial hypercholesterolemia during baseline period (mean of 4 daily determinations), after 18 days of intensive insulin therapy (insulin; mean of 5 daily determinations), and 4 wk after treatment with insulin and lovastatin (mean of 6 daily determinations). Results are means ± SE.

Ill hyperlipoproteinemia are usually homozygous for apoE2/E2 (129). VLDL remnants containing only apoE2 have a poor affinity for hepatic LDL receptors, which explains why VLDL remnants accumulate in plasma. Even so, most individuals with apoE2/E2 do not manifest type III hyperlipoproteinemia; apparently, another form of hyperlipidemia must be present concomitantly. Other mutations in apoE, which do not manifest as apoE2, also may impair affinity for LDL receptors and thus may contribute to type III hyperlipoproteinemia (130). ApoE2 homozygosity is present in — 1 % of the general population; therefore, the apoE2/E2 phenotype and NIDDM may be present in an individual as two unrelated disorders (131). The gene frequencies of various apoE alleles in patients with NIDDM have been found to be similar to that in the nondiabetic population, not favoring a genetic linkage between NIDDM and apoE2 homozygosity (132). On the other hand, there is evidence of an increased frequency of abnormal glucose tolerance and NIDDM in patients with type III hyperlipoproteinemia, and this suggests that NIDDM and E2 homozygosity interact strongly to produce the type III pattern (129). Fibric acids are efficacious in most patients with type III hyperlipoproteinemia, although lovastatin also has been reported to be effective in this form of hyperlipidemia (129,133). Other familial hyperlipidemias. Other familial hyperlipidemias, e.g., primary (polygenic) hypercholesterolemia, familial combined hyperlipidemia, and familial hypertriglyceridemia may coexist in patients with NIDDM. Unfortunately, a lack of unique markers for these familial hyperlipidemias makes it difficult to diagnose them with certainty in patients with NIDDM. Some features nonetheless suggest the presence of accompanying genetic hyperlipidemias in NIDDM patients including hyperlipidemia out of proportion to the degree of hyperglycemia, persistence of marked abnor-

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malities in lipids and lipoproteins even after long-term good glycemic control, and the presence of hyperlipidemia in nondiabetic first-degree relatives. The finding of concomitant genetic hyperlipidemia in a diabetic patient should further enhance risk for CHD that will add to the justification for the use of lipid-lowering drugs. In such patients, it may not be necessary to try dietary therapy alone for 3-6 mo before turning to hypolipidemic drugs. Type V hyperlipoproteinemia. Occasionally, NIDDM patients present with severe hypertriglyceridemia and marked elevations in both VLDL and chylomicrons (type V hyperlipoproteinemia). Multiple factors (i.e., hyperglycemia, increased energy intake with obesity, moderate-to-heavy alcohol consumption, drugs such as estrogen-containing oral contraceptives and (3-adrenergic blockers, and underlying genetic forms of hypertriglyceridemia) may contribute to marked elevations in serum triglycerides in diabetic patients. Such patients are at increased risk of acute pancreatitis. Miller et al. (22) reported that severe abdominal pain of pancreatitis is likely to occur in patients with serum triglycerides >68 mM, whereas less severe attacks are common when serum triglycerides are between 23 and 56 mM. Reduction of serum triglycerides in patients with type V hyperlipoproteinemia is mandatory to decrease the risk for acute pancreatitis. Serum triglycerides preferably should be lowered to <5.6 mM. Patients presenting with acute pancreatitis may need discontinuation of oral intake and should be given parenteral nutrition without lipid emulsions. Prompt institution of insulin therapy and control of hyperglycemia are necessary in NIDDM patients with type V hyperlipoproteinemia. In most cases, chylomicronemia can be eliminated by good control of hyperglycemia. If severe hypertriglyceridemia persists despite appropriate glycemic control, the patient probably has primary type V hyperlipoproteinemia in addition to NIDDM. For such patients, very-low-fat diets are helpful for minimizing chylomicron production. Weight reduction and restriction of alcohol intake will promote reduction of triglyceride levels. (3-Adrenergic blocking agents can cause marked hypertriglyceridemia in some NIDDM patients and should be withdrawn if possible. Fibric acids, e.g., gemfibrozil, are useful for serum triglyceride lowering in NIDDM patients with persistent severe hypertriglyceridemia and can be recommended for prevention of acute pancreatitis (120). The n-3 polyunsaturated fatty acids have potent hypotriglyceridemic action, but their potential for treatment of type V hyperlipoproteinemia in NIDDM patients needs further investigation. Elderly patients with NIDDM. In general, elderly patients have not been included in trials for prevention of CHD, but trial results obtained in younger individuals are frequently extrapolated to the elderly. Recent data from the Framingham Heart Study reveal that lipid risk profiles, including total serum cholesterol, predict CHD nearly as well in older as in younger people (134). Diabetes mellitus seems to impart an unusually high risk

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for CHD in the elderly (134). Therefore, reduction of cholesterol levels should be appropriate for older NIDDM patients with dyslipidemia. The goals of therapy in elderly NIDDM patients are the same as given in Table 5, although nonpharmacological means of lowering cholesterol may be more appropriate for them. Increased prevalence of hypothyroidism in the elderly, particularly in women, justifies excluding the diagnosis of secondary hyperlipidemias due to this condition. Because pharmacokinetics of drugs change with aging, hypolipidemic agents may be more toxic in older people and should be used with care. In patients 6574 yr of age, treatment decisions must be individualized and based on the presence or absence of other risk factors and overall health, especially hepatic and renal function. For those >75 yr of age, the risk-benefit ratio for drug therapy will often be too high to use drugs. Moreover, life expectancy of patients >75 yr of age may be too short to expect a long-term benefit from cholesterol reduction with drugs; consequently, dietary modification should be stressed. Pregnancy. For pregnant women with NIDDM, dietary therapy is definitely the first choice for lipid lowering. Because the teratogenic effects of hypolipidemic drugs are not known, it is best to avoid drug therapy unless absolutely necessary. Hypertriglyceridemia with chylomicronemia can pose immediate risk for acute pancreatitis, especially if serum triglyceride concentrations exceed 11.3 mM. Therefore, for diabetic women with severe hypertriglyceridemia, intake of fat should be restricted, and hyperglycemia should be controlled with insulin in the attempt to reduce serum triglyceride levels. If marked hypertriglyceridemia persists, fish oil polyunsaturates may be tried in moderate amounts (510 g n-3 polyunsaturates/day), closely monitoring glycemic control because fish oils may cause hyperglycemia. Diabetic nephropathy. The presentation of diabetic nephropathy may range from microalbuminuria to chronic renal insufficiency and/or nephrotic syndrome (135). Several studies in IDDM patients have shown that diabetic nephropathy in its early stages presenting with microalbuminuria can raise levels of serum triglycerides, VLDL-chol, LDL-chol, and LDL-apoB and reduce levels of HDL-chol, in particular HDL2-chol (136,137). This association also may extend to NIDDM patients but has yet to be documented. In patients with chronic renal insufficiency, reduced functional activity of lipoprotein lipase appears to be the predominant mechanism for hypertriglyceridemia and low levels of HDL-chol (138). In patients with nephrotic syndrome, two mechanisms (i.e., overproduction of apoB-containing lipoproteins, VLDL and LDL, and reduced lipoprotein lipase activity) probably account for high levels of both VLDL and LDL (139). Often patients with diabetic nephropathy have both chronic renal failure and nephrotic syndrome, and their presence may accentuate diabetic dyslipidemia. Restriction in protein intake to —40 g/day or 0.8 g/kg body wt/day is often advised for NIDDM patients with

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chronic renal insufficiency (140). Although this approach has both experimental and theoretical rationales, there is limited experience with low-protein diets in clinical practice. General acceptance of such diets by most diabetic patients remains to be documented. Furthermore, hyperlipidemic patients with diabetic nephropathy, especially those with nephrotic syndrome, may not be responsive to usual dietary modifications, i.e., reduction in dietary saturated fatty acids and cholesterol. There is a paucity of information on the safety and effectiveness of lipid-lowering drugs for patients with renal insufficiency. Recently, however, HMG CoA reductase inhibitors have been shown to be effective for lowering cholesterol in nondiabetic patients with nephrotic syndrome; therefore, these drugs could be of use in diabetic nephrotic syndrome (139,141,142). The liver appears to be the primary route of excretion of lovastatin, and ~10% of the orally administered drug and its metabolites are excreted in urine. Therefore, lovastatin should be safe for patients with nephrotic syndrome who have only mild renal insufficiency; whether it is equally safe for patients with moderately severe renal failure is unclear. Experience with lovastatin in patients with diabetic nephropathy is not available, and the drug must be used with great caution if at all. Bile acid-binding resins and probucol also have been observed to be safe in patients with nephrotic syndrome, but they are not as effective in lowering LDL-chol levels as HMG CoA reductase inhibitors (141,143). For treatment of hypertriglyceridemia in patients with chronic renal failure or nephrotic syndrome, clofibrate has been used in the past, but an unacceptably high incidence of myopathy is reported; in some cases, severe rhabdomyolysis and myoglobinuria occurred that resulted in acute renal failure (124,144). Myotoxicity is attributed to the presence of toxic concentrations of clofibrate and its metabolites occurring with renal insufficiency, because the drug is excreted predominantly by the kidneys. Even reduction in the dose of clofibrate, as suggested by some investigators (145), has not completely eliminated the risk of myopathy in uremic patients (146). Renal excretion is the major route of elimination of other fibric acid derivatives, e.g., bezafibrate, fenofibrate, and gemfibrozil, and the increased risk of myopathy with fibrates in patients with chronic renal failure warrants careful monitoring (147). Theoretically, n-3 polyunsaturated fatty acids should be safe for serum triglyceride reduction in patients with chronic renal failure, but their effectiveness for lowering lipids in such patients remains to be studied. Implications for insulin-dependent diabetes mellitus (IDDM). Most patients with IDDM who are maintained under good glycemic control have normal levels of lipids and lipoproteins, and some patients may even have subnormal levels of VLDL and LDL and increased HDL-chol levels (148). Nonetheless, marked hypertriglyceridemia with chylomicronemia can occur in insulin-deficient patients who are in poor glycemic control

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and have ketoacidosis (149). Such patients can have eruptive xanthomas and lipemia retinalis and may develop acute pancreatitis. The severe hypertriglyceridemia in most of these patients will disappear with appropriate insulin therapy, and hypolipidemic drugs are rarely required (149). However, it has been noted that IDDM patients with microalbuminuria or early incipient nephropathy may have higher concentrations of serum triglycerides, VLDLchol, LDL-chol, and LDL-apoB and lower HDL-chol levels than those without microalbuminuria (136,137). Worsening of dyslipidemia often occurs with progression of diabetic nephropathy. Therefore, IDDM patients who develop nephropathy may deserve special attention for lowering lipids and lipoproteins. Unfortunately, experience with hypolipidemic drugs is virtually nonexistent in IDDM patients, and it seems premature to use them in routine practice. Modification of the diet should be stressed instead. If hypolipidemic therapy is deemed necessary for IDDM patients with hypercholesterolemia, bile acid sequestrants may be preferable to lovastatin because no information is available on lovastatin therapy for IDDM. Gemfibrozil may be used in IDDM patients with marked hypertriglyceridemia not responding to diet and insulin therapy; most of these patients will have concomitant genetic hyperlipidemia. Nicotinic acid probably should be avoided in IDDM patients because of its numerous side effects. Impaired glucose tolerance. Several studies claim that impaired glucose tolerance is associated with increased CHD risk (41,150,151). Similar claims have been made for hyperinsulinemia in the absence of frank diabetes mellitus (152-154). However, documentation of a link between these factors and CHD risk is not nearly as strong as for clinical diabetes mellitus. When multivariate analysis is used considering other CHD risk factors, e.g., hypertension, smoking, and lipoproteins, impaired glucose tolerance or hyperinsulinemia lose much of their predictive value. Most patients with primary hypertriglyceridemia manifest impaired glucose tolerance, hyperinsulinemia, or other abnormalities in glucose metabolism, and this association further complicates the issue; most patients with primary hypertriglyceridemia never develop frank diabetes mellitus (155-157). Additional research will be required to determine whether impaired glucose tolerance and hyperinsulinemia are truly linked independently to CHD, the mechanisms for such a connection, and whether their presence requires modification of lipid-lowering regimens.

CONCLUSIONS

N

IDDM is a major risk factor for CHD, and the lipoprotein abnormalities that occur with NIDDM probably contribute to increased CHD risk. Because of the unique features of diabetic dyslipidemia, special consideration must be given to its

164

management. We propose several modifications of the guidelines of the NCEPs adult treatment panel to meet specific needs of NIDDM patients. For example, we suggest that the therapeutic target for cholesterol lowering in NIDDM include both VLDL and LDL (nonHDL-chol) rather than LDL-chol alone. Furthermore, maximum reduction in cholesterol levels may be indicated to minimize risk for CHD in NIDDM. Thus, we propose that a minimum goal of therapy for non-HDLchol be <4.1 mM and the ideal goal be 3.4 mM. This suggestion is made because diabetes appears to enhance risk for CHD even more than other risk factors. At the very least, the panel's guidelines should be followed. Reduction in adiposity should be particularly emphasized in NIDDM patients, and for the therapeutic diet, we suggest an alternative approach to use monounsaturated fatty acids rather than carbohydrates as a replacement for saturated fatty acids. For most NIDDM patients, lipid-lowering drugs should be considered only if a combination of diet, exercise, and hypoglycemic therapy tried for 3-6 mo fails to achieve desirable levels of cholesterol. For those with concomitant genetic hyperlipoproteinemias, hypolipidemic therapy may be started without a prolonged trial of dietary therapy. The following recommendations reflect our clinical approach to use of lipid-lowering drugs, although consideration can be given to using drugs in the sequence outlined by the NCEP panel. We suggest that for patients with isolated elevations of LDL-chol or with elevated LDL-chol and borderline hypertriglyceridemia, lovastatin is preferred over bile acid sequestrants because the latter may exacerbate hypertriglyceridemia. Gemfibrozil, however, is a better choice than lovastatin for NIDDM patients with marked hypertriglyceridemia. Finally, nicotinic acid deteriorates glycemic control, induces hyperuricemia and, in our view, cannot be considered a first-line drug for NIDDM patients.

ACKNOWLEDGMENTS This work was supported in part by the Veterans Administration, National Institutes of Health Grants HL-29252 and M01-RR-00633, the Southwestern Medical Foundation, and the Moss Heart Foundation of Dallas, Texas.

REFERENCES 1. Barrett-Connor E, Orchard T: Diabetes and heart disease. In Diabetes in America. Diabetes Data Compiled 1984. National Diabetes Data Group. Washington, DC, Dept. of Health and Human Services, 1985, p. XVI-141 (NIH publ. no. 85-1468) 2. Howard BV: Lipoprotein metabolism in diabetes mellitus. J Lipid Res 28:613-28, 1987 3. Reaven GM: Non-insulin-dependent diabetes mellitus, abnormal lipoprotein metabolism, and atherosclerosis. Metabolism 36 (Suppl. 1):1-8, 1987

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