SPECIAL ARTICLE
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 Sep-
tember 1989.
DIABETES CARE, VOL. 13, N O . 2, FEBRUARY 1990
Abhimanyu Garg, MBBS, MD
Scott M. Crundy, MD, PhD
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
P
atients with non-insulin-dependent diabetes mel-
litus (NIDDM) commonly have dyslipidemia that
may contribute to accelerated coronary athero-
sclerosis, the leading cause of death among
NIDDM patients (1). Lipoprotein abnormalities in NIDDM
patients involve all classes of lipoproteins and may con-
sist 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 pa-
tients, improved control of hyperglycemia will mitigate
the dyslipidemia. Unfortunately, complete reversal of
deranged metabolism is rarely possible in NIDDM pa-
tients. Consequently, some degree of dyslipidemia usu-
ally persists despite good glycemic control (3). Some
diabetic patients will have concomitant genetic hyper-
lipidemia; in these patients, diabetes mellitus worsens
the dyslipidemia, but correction of hyperglycemia will
not normalize lipid levels (4). Frequently, in practice, it
153
MANAGEMENT OF DYSLIPIDEMIA IN NIDDM
is not possible to determine with certainty the contri-
butions of diabetes and genetics to elevated serum lip-
ids.
PREVALENCE OF DYSLIPIDEMIA
The prevalence of dyslipidemia in NIDDM patients un-
doubtedly varies among different populations. The World
Health Organization multinational study of vascular dis-
ease 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 re-
duced levels of HDL cholesterol (HDL-chol) were in-
creased twofold in adult diabetic patients compared with
nondiabetic subjects of both sexes (Table 3; 8). The Pro-
spective Cardiovascular Munster Study (9) further con-
firmed a two- to threefold increase in prevalence of hy-
pertriglyceridemia, mixed hyperlipidemia, and low levels
of HDL-chol in middle-aged subjects with NIDDM.
According to the National Cholesterol Education Pro-
gram (NCEP; 10), people should receive medical su-
pervision 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 manage-
ment on the basis of high LDL-chol levels and other risk
factors, whereas only 23.1% of 4666 nondiabetic sub-
jects 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
Men (%) Women (%) Both (%)
Plasma cholesterol (mM)*
>6.72 22 .6 23.5 23 .1
4.65-6.70 58 .2 59.3 58 .8
<4.65 19 .3 17.2 18 .2
Plasma triglycerides (mM)t
S2.82 19 .2
1.13-2.81 56 .2
24 .6
<1.13
*Data on 3189 men and 3295 women.
tData from 5 of 14 centers on 1911 subjects.
154
TABLE 2
Prevalence (%) of dyslipidemia in non-insulin-dependent
diabetes mellitus (NIDDM): Diabetes Intervention Study,
German Democratic Repulic
NIDDM
Dresden (n = 1139)
population
(n = 1216) Men Women
Hypertriglyceridemia
(triglycerides >2.82 mM) 3.4 11.3 11.2
Hypercholesterolemia
(cholesterol >7.76 mM) 3.7 3.8 3.2
Mixed hyperlipoproteinemia 0.5 3.0 2.6
Total 7.6 18.1 17.0
LIPOPROTEIN ABNORMALITIES
The most common lipid abnormality of NIDDM is ele-
vated serum triglycerides (12-16). High levels of serum
triglycerides occur mainly in VLDL and can result from
two abnormalities. First, patients with NIDDM over-
produce triglyceride-rich VLDL, and this response prob-
ably results from increased serum levels of free fatty
acids and glucose (17-19). In many patients, overpro-
duction 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 li-
polysis of VLDL triglycerides, most likely due to reduced
lipoprotein lipase activity (15). If the latter becomes se-
vere due to marked insulin deficiency, patients can de-
velop 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 unes-
terified 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 LDL-
chol concentrations compared with nondiabetic sub-
jects 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 overproduc-
tion 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 par-
ticles frequently are abnormal in NIDDM patients; many
particles are small and dense, but the overall LDL frac-
DIABETES CARE, V O L . 13, N O . 2, FEBRUARY 1990
 A. GARG AND S.M. GRUNDY

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

Men Women

LRC cutoff Normal DM LRC cutoff Normal DM

value* (n = 1074) (n = 130) value* (n = 1449) (n - 135)

Total cholesterol (mM) >6.72 14 13 >7.11 21 24

Triglycerides (mM) >2.65 9 19t >2.26 8 17+
Very-low-density lipoprotein
cholesterol (mM) >1.03 26 34t >0.91 31 38
Low-density lipoprotein
cholesterol (mM) >4.91 11 9 >4.91 16 15
High-density lipoprotein
cholesterol (mM) <0.80 12 21t <1.06 10 25+

* 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 me-
tabolism appear to be partly the result of hypertriglyc-
eridemia. For NIDDM patients with moderately severe
hyperglycemia, a reduced fractional clearance rate for
LDL further raises LDL-apoB concentration (20,27). Be-
cause LDL-apoB levels tend to be increased out of pro-
portion 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 hypergly-
cemia 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 de-
scribed in patients with diabetes mellitus, and if LDL
lipids trapped in the arterial wall become oxidized, up-
take 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
Total cholesterol (mM) LDL-chol (mM)
Desirable <5.2 <3.4
Borderline high risk 5.2-6.2 3.4-4.1
High risk >6.2
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 dis-
ease, or severe obesity.
Low concentrations of HDL-chol and apoAl are yet
another characteristic of NIDDM patients (13-16,25,33-
36). Subfraction analysis of HDL reveals that concentra-
tions of HDL2-chol in particular are reduced. Low levels
of apoAl are due to increased catabolism of HDL be-
cause production rates for apoAl appear to be normal
(37). HDL of diabetic patients is enriched in triglyceride
that may interfere with reverse cholesterol transport; fur-
thermore, preliminary data suggest that in vivo gluco-
sylation 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 di-
rectly accompany diabetes mellitus could accelerate
atherogenesis, i.e., glucosylation of arterial wall pro-
teins and lipoproteins, increased peroxidation of lipids,
microvascular disease, abnormalities in platelet func-
tion, and defective hemostasis (31,32,47-51). Besides
these potential aggravating factors, dyslipidemia of di-
abetes 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 triglycer-
ide 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. How-
ever, when multivariate analysis is used (i.e., when total

DIABETES CARE, VOL. 13, N O . 2, FEBRUARY 1990 155

MANAGEMENT OF DYSUPIDEMIA IN NIDDM
cholesterol and HDL-chol levels are considered), serum
triglycerides lose much of their predictive power. Serum
triglycerides probably are not directly atherogenic, be-
cause triglycerides typically are not found in athero-
sclerotic plaques. On the other hand, elevations of VLDL
triglycerides can induce several lipoprotein abnormali-
ties 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 Pro-
spective Study (59) indicate that hypertriglyceridemia
may be the most potent lipid predictor for CHD mor-
tality. Therefore, although high serum triglycerides may
not directly cause atherosclerosis, concomitant abnor-
malities in lipoprotein metabolism induced by hyper-
triglyceridemia certainly raise the risk for CHD.
Several studies suggest that LDL levels are not in-
creased in patients with NIDDM compared with non-
diabetic individuals. Although by usual criteria LDL-chol
concentrations may not be raised in NIDDM, LDL me-
tabolism cannot be dismissed as benign. Turnover rates
for LDL typically are high in NIDDM patients. Further-
more, LDL particles tend to be abnormally small and
dense, and concentrations of LDL-apoB are often in-
creased (29). All of these abnormalities have been re-
ported to increase coronary risk in nondiabetic subjects
(60,61). Even borderline elevations of LDL-chol may di-
rectly raise CHD risk or signify increased risk in NIDDM
patients. This is illustrated by the finding of a low prev-
alence of CHD among patients with NIDDM in certain
populations, e.g., Pima Indians of Arizona (62), Japa-
nese (5), and Chinese (5); all of these populations have
low concentrations of serum total cholesterol and LDL-
chol (16,63). Thus, if serum LDL-chol could be reduced
to low levels in NIDDM patients belonging to higher-
risk 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 be-
tween HDL levels and CHD risk is well established,
although mechanisms for this connection are poorly
understood. Some investigators believe that HDL is re-
quired 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 con-
centrations 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 coro-
nary risk in NIDDM.
156
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 mel-
litus 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 ab-
sence of other risk factors. This analysis includes total
cholesterol, triglyceride, and HDL-chol, and it must be
done on fasting serum. From these parameters, LDL-
chol 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 indi-
cated 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 li-
poprotein analysis. Because being female does not count
as a risk factor in the guidelines, lipoprotein analysis
theoretically is not required in diabetic women with bor-
derline high cholesterol levels; however, because sev-
eral studies indicate that diabetes wipes out any protec-
tion 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 dyslipi-
demia 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 concen-
trations 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 concentra-
tion <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 popula-
tions 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)
DIABETES CARE, V O L . 13, N O . 2, FEBRUARY 1990

commonly occurs in NIDDM patients (15,16,25,33,34).
Although triglyceride enrichment of VLDL in NIDDM
may increase VLDL triglyceride-to-cholesterol ratios, in-
creased 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 dia-
betic 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 pre-
dominate 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). Die-
tary therapy aims to progressively reduce intakes of sat-
urated fatty acids and cholesterol and to eliminate ex-
cess 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 non-
insulin-dependent diabetes mellitus
Minimum goal Ideal goal
(mM) (mM)
Total cholesterol <5.2 -4.4
Low-density lipoprotein
cholesterol <3.4 -2.6
Non-high-density lipoprotein
cholesterol <4.1 -3.4
DIABETES CARE, VOL. 13, N O . 2, FEBRUARY 1990
A. GARG AND S.M. GRUNDY
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. Satu-
rated 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 ad-
vocates 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 high-
carbohydrate 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 differ-
ences of opinion among investigators regarding the de-
sirable 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 pa-
tients with diabetes mellitus (10).
Encouraged by the Consensus Development Confer-
ence, 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 mono-
unsaturated fatty acids (67). Both diets were low in
saturated fatty acids and cholesterol. Our study revealed
that the diet high in monounsaturates improved gly-
cemic control, reduced triglyceride and VLDL-chol lev-
els, and raised HDL-chol levels compared with the high-
carbohydrate diet. Moreover, preliminary studies from
our laboratory do not support claims that high-carbo-
hydrate diets improve insulin sensitivity in NIDDM pa-
tients (68). Therefore, we suggest that partial replace-
ment 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 dur-
ing 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 unsat-
urated fatty acids, such as eicosapentaenoic acid (EPA;
20:5) and docosahexaenoic acid (DHA; 22:6). The n-
3 polyunsaturates have a potent hypotriglyceridemic ac-
tion that is dose dependent (69,70). Clinically signifi-
cant reductions in plasma triglyceride levels are usually
observed on daily consumption of 5-10 g n-3 polyun-
saturated fatty acids. However, the NCEP panel did not
advocate n-3 polyunsaturates for the treatment of hy-
pertriglyceridemia 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
157
MANAGEMENT OF DYSLIPIDEMIA IN NIDDM
(n-6 plus n-3) should be betwen 7 and 10% of daily
energy intake, and the relative content of n-6 versus n-
3 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 polyun-
saturates 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 recom-
mended, 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 antihy-
pertensive 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 LDL-
chol 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. How-
ever, 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 pa-
tients become discouraged with slow weight reduction
and give up the attempt before they have achieved suc-
cess. 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 pa-
tients, high-carbohydrate high-fiber diets may be more
acceptable, but for others, some fat in the diet may en-
158
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 gly-
cemic control with minimum doses of oral hypoglyce-
mic drugs or insulin, and as the patient responds by
losing weight, the dose can be gradually and progres-
sively reduced. Frequent self-monitoring of blood glu-
cose is essential for some patients to deal with the
changing metabolic and pharmacological environment
during weight reduction. If possible, an exercise pro-
gram 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 help-
ful 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, con-
trolling 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, hypolipi-
demic 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. How-
ever, guidelines of the NCEP panel may not be directly
applicable to NIDDM patients, and advantages and dis-
advantages of each category of drugs for treatment of
diabetic dyslipidemia must be considered.
Nicotinic acid. Because elevated VLDL-chol and re-
duced 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
DIABETES CARE, V O L . 13, N O . 2, FEBRUARY 1990

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 es-
tablished 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 Athero-
sclerosis Study (89) reported a favorable response to ni-
cotinic 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 pa-
tients 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, con-
comitant administration of aspirin or other nonsteroidal
anti-inflammatory agents helps to prevent severe flush-
ing. Other common side effects include exacerbation of
peptic ulcer and reversible abnormalities in liver func-
tion tests. In patients with NIDDM, nicotinic acid ther-
apy 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 tol-
erance 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 con-
verted into bile acids in the liver. The resultant deple-
tion 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-
DIABETES CARE, VOL. 13, N O . 2, FEBRUARY 1990
A. GARG AND S.M. GRUNDY
ommended in patients with significant hypertriglyceri-
demia (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 ther-
apy 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 di-
uretics, and p-adrenergic blockers, and therefore should
be used with caution in patients on multiple medica-
tions. 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 triglyc-
erides (plasma triglycerides <1.69 mM). Serum triglyc-
eride levels should be monitored closely in patients with
NIDDM on sequestrant therapy.
Hydroxymethylglutaryl coenzyme A (HMG CoA) re-
ductase 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-medi-
ated clearance of both LDL and VLDL remnants. Lovas-
tatin was the first drug of this class to be available in the
U.S., and several others, notably pravastatin and sim-
vastatin, 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 lo-
vastatin (20 mg twice daily) is highly effective for low-
ering 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%. Lo-
vastatin therapy also decreased plasma triglyceride and
VLDL-chol levels by 31 and 42%, respectively, and even
more so in patients with borderline (moderate) hyper-
triglyceridemia (Fig. 1). Although lovastatin did not
change the level of HDL-chol, the total cholesterol-to-
HDL-chol ratio fell by 29%, which may reflect an over-
all reduction in coronary risk.
In our view, HMG CoA reductase inhibitors may soon
become the drugs of choice for treatment of dyslipide-
mia 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
159
MANAGEMENT OF DYSLIPIDEMIA IN NIDDM

TOTAL CHOLESTEROL LDL - CHOLESTEROL LDL • APOLIPOPROTEIN - B that could interfere with its disposal or with liver dis-
4.5 140 ease.
6.5
Lovastatin produces cataracts in dogs when given in
120
6.0 4.0 very high doses. Although clinical studies with lova-
100 statin have revealed no increase in formation of lentic-
1 5.5 5
5, 80 ular opacities over a period of 1-2 yr in many nondi-
E
5.0
3.0 60
abetic subjects (109,110), the fact that NIDDM patients
4.5
are at increased risk for developing cataracts justifies
2.5 40
periodic slit-lamp examinations during lovastatin ther-
Placebo Lovastatin
0
Placebo Lovastatin
0
Placebo Lovastatin
apy. Certainly, NIDDM patients with mature cataracts
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
T 2.5 usual doses, lovastatin does not cause marked reduc-
5.0
1.2 T tions in whole-body synthesis of cholesterol nor does it
2.0
4.0 1.1 decrease levels of cholesterol products, e.g., adrenal
i 3.0 5
o
1.5 and gonadal steroids and bile salts. Reduced lithogen-
E
icity of bile with HMG CoA reductase inhibitors may be
2.0 1.0 0.9
potentially advantageous in NIDDM patients who al-
0.8
1.0 0.5 ready appear to be predisposed to formation of choles-
0.7 terol gallstones (111,112). Other minor side effects of
0 0 oi 1 1
Placebo Lovastatin Placebo Lovastatin Placebo Lovastatin lovastatin include headache, sleep disturbances, and skin
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 tri-
triglycerides, 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 stimulat-
triglyceridemic (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,
1988.) LDL-chol concomitantly with triglyceride lowering (114).
Fibric acids can raise HDL-chol levels, possibly through
their action to lower triglyceride concentrations. Treat-
level of ~3.4 mM. Lovastatin, however, is not appro- ment of hypertriglyceridemia by fibric acids could the-
priate 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
erides to a safe range. remnants, may raise HDL-chol, and may reduce the risk
Glycemic control did not deteriorate in our patients of coronary thrombosis. According to some investiga-
on 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 triglyc-
in 10 patients with NIDDM. eride lowering (115,116).
Lovastatin therapy has been reported to cause minor Clofibrate was the first fibric acid to be used exten-
gastrointestinal 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 sug-
of myopathy syndrome (105). Lovastatin-induced my- gesting that clofibrate improves glucose tolerance in ad-
opathy 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 de-
rarely as rhabdomyolysis, myoglobinuria, and acute clined because of the results of the World Health Or-
kidney failure (106-108). Although precise mechanisms ganization study (118). In this study, clofibrate appar-
are 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 dysfunc- Results of the recently published Helsinki Heart Study
tion impairing drug metabolism (108,109). Therefore, (119) showed that long-term gemfibrozil therapy is gen-
lovastatin should be avoided in any patient taking drugs erally safe and effective for reducing risk for CHD in

160 DIABETES CARE, VOL. 13, NO. 2, FEBRUARY 1990


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 gem-
fibrozil for lowering cholesterol to reduce the risk of
CHD in patients with type MB hyperlipoproteinemia,
particularly when accompanied by low HDL-chol lev-
els.
Our experience with gemfibrozil therapy (600 mg
twice daily) suggests that it is highly effective for low-
ering 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 hypertriglyceri-
demia. 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 con-
tention (120). However, as mentioned earlier, the com-
bination of gemfibrozil and lovastatin raises the risk of
severe myopathy (108,109). Because of this, the com-
bination should be used with caution and only in se-
lected patients; it cannot be recommended for routine
use in diabetic patients.
In earlier studies, long-term therapy with gemfibrozil
TOTAL CHOLESTEROL LDL- CHOLESTEROL LDL - APOLIPOPROTEIN - B
140
135
130
120
115
0s
Placebo Gemfibrozil Placebo Gemlibrozil Placebo Gemfibrozil
TRIGLYCERIDES VLDL- CHOLESTEROL 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 li-
poprotein cholesterol (LDL-cholesterol), LDL apolipopro-
tein B, triglycerides, very-low-density lipoprotein choles-
terol (VLDL-cholesterol), and high-density lipoprotein
cholesterol (HDL-cholesterol) in 10 markedly hypertriglyc-
eridemic (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.
DIABETES CARE, VOL. 13, N O . 2, FEBRUARY 1990
A. GARG AND S.M. GRUNDY
was reported to raise fasting and postprandial plasma
glucose levels in patients with NIDDM (121,122). We
observed no deleterious action of gemfibrozil on gly-
cemic 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, oc-
casional changes in hematologic parameters, and ab-
normal 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-me-
diated 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 an-
tioxidant (127). Recently, some investigators have pro-
posed that oxidative modification of LDL may play an
important role in atherogenesis by facilitating accumu-
lation of lipids in arterial wall macrophages (128). If this
mechanism pertains, probucol could retard develop-
ment 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.
SPECIAL CONSIDERATIONS
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 be-
cause the patient's child had homozygous familial hy-
percholesterolemia. Despite controlling hyperglycemia
with insulin therapy, the patient's LDL-chol level re-
mained markedly elevated. However, she responded to
lovastatin therapy with near normalization of her lipo-
protein profile (Fig. 3). Thus, familial hypercholestero-
lemia should be suspected in NIDDM patients who
persist with severe hypercholesterolemia despite nor-
malization of plasma glucose. The preferred drug reg-
imen for heterozygous familial hypercholesterolemia
appears to be the combination of an HMG CoA reduc-
tase 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 pal-
mar creases), accumulation of (3-VLDL, or remnant li-
poproteins rich in cholesterol esters. Patients with type
161
MANAGEMENT OF DYSLIPIDEMIA IN NIDDM
Baseline Insulin + Lovastatln
LDL-C
Insulin Dose (units/day) 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), triglycer-
ides (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 dur-
ing 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 mani-
fest 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 popu-
lation; therefore, the apoE2/E2 phenotype and NIDDM
may be present in an individual as two unrelated dis-
orders (131). The gene frequencies of various apoE al-
leles in patients with NIDDM have been found to be
similar to that in the nondiabetic population, not favor-
ing a genetic linkage between NIDDM and apoE2 hom-
ozygosity (132). On the other hand, there is evidence
of an increased frequency of abnormal glucose toler-
ance and NIDDM in patients with type III hyperlipopro-
teinemia, and this suggests that NIDDM and E2 hom-
ozygosity 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 hyper-
lipidemia (129,133).
Other familial hyperlipidemias. Other familial hyper-
lipidemias, e.g., primary (polygenic) hypercholesterol-
emia, 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 di-
agnose them with certainty in patients with NIDDM.
Some features nonetheless suggest the presence of ac-
companying genetic hyperlipidemias in NIDDM pa-
tients including hyperlipidemia out of proportion to the
degree of hyperglycemia, persistence of marked abnor-
162
malities in lipids and lipoproteins even after long-term
good glycemic control, and the presence of hyperlipi-
demia in nondiabetic first-degree relatives. The finding
of concomitant genetic hyperlipidemia in a diabetic pa-
tient 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
HDL-C
therapy alone for 3-6 mo before turning to hypolipi-
demic 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., hyper-
glycemia, increased energy intake with obesity, mod-
erate-to-heavy alcohol consumption, drugs such as es-
trogen-containing oral contraceptives and (3-adrenergic
blockers, and underlying genetic forms of hypertriglyc-
eridemia) 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 in-
take and should be given parenteral nutrition without
lipid emulsions. Prompt institution of insulin therapy and
control of hyperglycemia are necessary in NIDDM pa-
tients 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 prob-
ably has primary type V hyperlipoproteinemia in addi-
tion 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 tri-
glyceride lowering in NIDDM patients with persistent
severe hypertriglyceridemia and can be recommended
for prevention of acute pancreatitis (120). The n-3 poly-
unsaturated fatty acids have potent hypotriglyceridemic
action, but their potential for treatment of type V hy-
perlipoproteinemia in NIDDM patients needs further in-
vestigation.
Elderly patients with NIDDM. In general, elderly pa-
tients 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). Di-
abetes mellitus seems to impart an unusually high risk
DIABETES CARE, VOL. 13, N O . 2, FEBRUARY 1990

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 el-
derly NIDDM patients are the same as given in Table 5,
although nonpharmacological means of lowering cho-
lesterol 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 ag-
ing, hypolipidemic agents may be more toxic in older
people and should be used with care. In patients 65-
74 yr of age, treatment decisions must be individualized
and based on the presence or absence of other risk fac-
tors 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 choles-
terol reduction with drugs; consequently, dietary mod-
ification 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 chy-
lomicronemia can pose immediate risk for acute pan-
creatitis, especially if serum triglyceride concentrations
exceed 11.3 mM. Therefore, for diabetic women with
severe hypertriglyceridemia, intake of fat should be re-
stricted, and hyperglycemia should be controlled with
insulin in the attempt to reduce serum triglyceride lev-
els. If marked hypertriglyceridemia persists, fish oil
polyunsaturates may be tried in moderate amounts (5-
10 g n-3 polyunsaturates/day), closely monitoring gly-
cemic control because fish oils may cause hypergly-
cemia.
Diabetic nephropathy. The presentation of diabetic ne-
phropathy may range from microalbuminuria to chronic
renal insufficiency and/or nephrotic syndrome (135).
Several studies in IDDM patients have shown that dia-
betic nephropathy in its early stages presenting with mi-
croalbuminuria 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
DIABETES CARE, VOL. 13, N O . 2, FEBRUARY 1990
A. GARG AND S.M. GRUNDY
chronic renal insufficiency (140). Although this ap-
proach 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. Fur-
thermore, hyperlipidemic patients with diabetic ne-
phropathy, especially those with nephrotic syndrome,
may not be responsive to usual dietary modifications,
i.e., reduction in dietary saturated fatty acids and cho-
lesterol.
There is a paucity of information on the safety and
effectiveness of lipid-lowering drugs for patients with
renal insufficiency. Recently, however, HMG CoA re-
ductase inhibitors have been shown to be effective for
lowering cholesterol in nondiabetic patients with ne-
phrotic 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 lovas-
tatin, 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 di-
abetic 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, se-
vere rhabdomyolysis and myoglobinuria occurred that
resulted in acute renal failure (124,144). Myotoxicity is
attributed to the presence of toxic concentrations of clo-
fibrate and its metabolites occurring with renal insuffi-
ciency, because the drug is excreted predominantly by
the kidneys. Even reduction in the dose of clofibrate, as
suggested by some investigators (145), has not com-
pletely eliminated the risk of myopathy in uremic pa-
tients (146). Renal excretion is the major route of elim-
ination 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 fail-
ure, 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 hypertri-
glyceridemia with chylomicronemia can occur in insu-
lin-deficient patients who are in poor glycemic control
163
MANAGEMENT OF DYSLIPIDEMIA IN NIDDM
and have ketoacidosis (149). Such patients can have
eruptive xanthomas and lipemia retinalis and may de-
velop acute pancreatitis. The severe hypertriglyceride-
mia in most of these patients will disappear with appro-
priate 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, VLDL-
chol, LDL-chol, and LDL-apoB and lower HDL-chol
levels than those without microalbuminuria (136,137).
Worsening of dyslipidemia often occurs with progres-
sion of diabetic nephropathy. Therefore, IDDM patients
who develop nephropathy may deserve special attention
for lowering lipids and lipoproteins. Unfortunately, ex-
perience with hypolipidemic drugs is virtually non-
existent 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 se-
questrants 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 multivar-
iate 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 hypertrig-
lyceridemia manifest impaired glucose tolerance,
hyperinsulinemia, or other abnormalities in glucose me-
tabolism, and this association further complicates the
issue; most patients with primary hypertriglyceridemia
never develop frank diabetes mellitus (155-157). Ad-
ditional 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 low-
ering in NIDDM include both VLDL and LDL (non-
HDL-chol) rather than LDL-chol alone. Furthermore,
maximum reduction in cholesterol levels may be indi-
cated to minimize risk for CHD in NIDDM. Thus, we
propose that a minimum goal of therapy for non-HDL-
chol 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 empha-
sized in NIDDM patients, and for the therapeutic diet,
we suggest an alternative approach to use monounsa-
turated fatty acids rather than carbohydrates as a re-
placement 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, hypolipi-
demic therapy may be started without a prolonged trial
of dietary therapy. The following recommendations re-
flect 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 hypertriglyceri-
demia, 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, in-
duces hyperuricemia and, in our view, cannot be con-
sidered a first-line drug for NIDDM patients.
ACKNOWLEDGMENTS
This work was supported in part by the Veterans Admin-
istration, National Institutes of Health Grants HL-29252
and M01-RR-00633, the Southwestern Medical Foun-
dation, and the Moss Heart Foundation of Dallas, Texas.
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