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Dyslipidemia in The Metabolic Syndrome: M H A F S
Dyslipidemia in The Metabolic Syndrome: M H A F S
Dyslipidemia
in the Metabolic Syndrome
MARKOLF HANEFELD AND FRANK SCHAPER
CENTER OF CLINICAL STUDIES, TECHNICAL UNIVERSITY, DRESDEN, GERMANY
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
Resumen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
The lipid triad . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Dyslipidemia profile in the Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
Pathophysiology of metabolism of triglyceride rich lipoproteins (TRLs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
Dyslipidemia in the Metabolic Syndrome primarily a postprandial phenomenon? . . . . . . . . . . . . . . . . . . . . . . . 352
Dyslipidemia and insulin resistance in the Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
Dyslipidemia and vascular disease in the Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
348 • Related Diseases in the Metabolic Syndrome
Summary
Dyslipidemia is a central component of the Metabolic Syndrome. In the WHO and in the NCEP-ATPIII definitions low HDL and hyper-
triglyceridemia are considered as one and two separated traits respectively. Hypertriglyceridemia, low HDL-chloesterol and small,
dense LDL -called the lipid triad- are present in 40-50% of the patients with the Metabolic Syndrome. However the dyslipidemia of the
Metabolic Syndrome is more complex, comprising anomalies in fatty acids regulation and changes in the pattern and composition of
triglyceride-rich proteins as well as in HDL-cholesterol and LDL subfractions. The increase in the triglyceride content of LDL increases
the length of their exposure to oxidation and glycation, increasing their atherogenicity. Anomalies in visceral fat cell metabolism and in-
sulin resistance are mayor players in the underlying pathophysiology. Disturbances in VLDL synthesis and in the removal of triglyc-
eride-rich lipoproteins are first observed in the postprandial phase, before type 2 diabetes is diagnosed. Type 2 diabetes amplifies the
functional and structural changes in lipoprotein metabolism. Dyslipidemia is a prominent risk factor for both diabetes and atheroscle-
rosis. However the full cluster of the Metabolic Syndrome confers higher risk. This speaks in favor of the hypothesis that dyslipidemia
acts together with the other risk factors (diseases of the Metabolic Syndrome) in a vicious cycle. Early signals from prospective studies
indicate that the strict correction of dyslipidemia may be an option for primary and secondary prevention of cardiovascular diseases
and type 2 diabetes.
Resumen
La dislipidemia es un componente central del síndrome metabólico. Tanto en la definición de la OMS (WHO) como en la que el
NCEP-ATPIII hacen del síndrome metabólico, niveles bajos de colesterol-HDL y elevados de triglicéridos son considerados como
uno solo o dos rasgos independientes. Hipertrigliceridemia, colesterol-HDL bajo y la presencia de particulas de LDL densas y pe-
queñas –la llamada tríada lipídica– se encuentran en el 40 a 50% de los pacientes con síndrome metabólico. Sin embargo, la dis-
lipidemia del síndrome metabólico es más compleja e incluye alteraciones en la regulación de los ácidos grasos libres y cambios
en el patrón y composición de las proteínas enriquecidas con triglicéridos, así como también en las subfracciones de colesterol-
HDL y de LDL. El incremento en el contenido de triglicéridos de las LDL aumenta su exposición a los procesos de oxidación y
glicación, aumentando así su aterogencidad. Anomalías metabólicas en las células de la grasa visceral junto con la insulino-re-
sistencia juegan un papel sumamente importante en la fisiopatología subyacente. En el estado postprandial, aun antes de que se
haya diagnosticado una diabetes tipo 2, se observan alteraciones en la síntesis de VLDL y en la eliminación de la circulacion de
proteínas ricas en triglicéridos. La presencia de diabetes tipo 2 amplifica los cambios estructurales y funcionales en el metabo-
lismo de las lipoproteínas. La dislipidemia es un importante factor de riesgo tanto para el desarrollo de la diabetes como para el
de enfermedades cardiovasculares. Sin embargo, el síndrome metabólico, como un todo, se asocia con un riesgo mayor. Este he-
cho favorece la hipotésis de que los varios componentes (factores de riesgo) del síndrome metabólico actúan conjuntamente con
la dislipidemia, en un círculo vicioso. Datos recientes, provenientes de estudios clínicos prospectivos, señalan que la corrección
estricta de la dislipidemia podría ser una opción para la prevención primaria y secundaria de las enfermedades cardiovasculares
y de la diabetes tipo 2.
Atheros-
Metabolic Syndrome is primarily based on the measure-
erin
clerosis
yp
ro
Table 21-3. Prevalence of the Metabolic Syndrome and its different components in male
and female subjects with NGT, abnormal IFG/IGT and diabetic glucose
tolerance13
NG IFG/IGT TYPE 2 DM
All 35-70 Male Female Male Female Male Female
years
Metabolic 15 10 64 42 84 78
syndrome
Obesity 76 36 86 51 92 78
Dyslipidemia 29 16 45 31 54 56
Hypertension 23 24 31 35 55 59
Micro 4 3 7 6 22 12
albuminuria
Insulin 25 25 58 59 87 89
Resistance
Data are %
countries. The aim of the study was to identify metabolic in the parameters of the lipid triad starts far before dia-
abnormalities in families with type 2 diabetes. Glucose betes is diagnosed (Fig. 21-2). Both studies showed a
tolerance was assessed according to WHO criteria using stepwise increase in dyslipidemia from normal glucose
75 g OGTT. The prevalence of the Metabolic Syndrome tolerance to newly detected type 2 diabetes with a sig-
(WHO definition) and of its single traits by sex and cate- nificantly higher prevalence in the female sex with nor-
gory of glucose tolerance is given in Table 21-3. The most mal glucose tolerance and impaired fasting glucose/im-
frequent combinations were obesity and dyslipidemia, paired glucose tolerance.
followed by hypertension and dyslipidemia. In the Bothnia study 10% of the patients with normal
In the Risk Factors in IGT of Atherosclerosis and glucose tolerance, about 50% of the subjects with predi-
Diabetes (RIAD) study using NCEPIII criteria hyper- abetes (IFG/IGT) and about 80% of the patients with
triglyceridemia and low HDL were found as single traits type 2 diabetes suffered from the Metabolic Syndrome
in 20-40% of the population (Table 21-4)14. The increment according to the WHO definition.
Dyslipidemia profile in
7 the Metabolic Syndrome
6
Lipid abnormalities in these high risk
mean values (mmol/l)
Forty years ago Randle et al.17 demonstrated that in- ment of type 2 diabetes and diseases of the Metabolic
creased availability of fatty acids decreased glucose Syndrome21 (Fig. 21-3).
oxidation and glucose uptake in the perfused rat´s
heart. Based on these findings they proposed a glucose- Pathophysiology of metabolism
fatty acid cycle presumed to be of fundamental impor- of triglyceride rich lipoproteins (TRLs)
tance for the control of blood glucose and insulin sen-
sitivity in subjects with and without diabetes. As Increases in triglyceride rich lipoproteins and changes in
shown by Reaven et al.18 FFA and insulin levels are in- their composition are typical of the Metabolic Syndrome
creased in obese patients with type 2 diabetes. In vivo with and without diabetes. Postprandial hyperlipidemia
elevated FFA have been shown to enhance hepatic glu- is frequently found in subjects with IGT and type 2 dia-
cose and triglyceride production19. Long-term increase betes22-24. This strongly depends on fasting triglyceride
of FFA may also inhibit insulin secretion (lipotoxici- levels25. The postprandial excursion of chylomicrons is
ty)20. In an elegant review of the evidence supporting elevated and lasts longer in subjects with dyslipidemia
a central role for the anomalies in lipid metabolism in and other traits of the Metabolic Syndrome.
the development of type 2 diabetes entitled “What if Very low density lipoproteins (VLDL) are produced
Minkowski had been ageusic? An alternative angle on by the liver depending on the flow of free fatty acids
diabetes” McGarry came to the conclusion that anom- from visceral fat depots, insulin sensitivity to hepatic
alies in fatty acid regulation and triglyceride-rich glucose and triglyceride synthesis26 (Fig. 21-4). VLDL
lipoproteins may play a central role in the develop- particles can be separated into two major subclasses:
large buoyant VLDL1 and smaller,
denser VLDL2. It is a consistent find-
Pancreas ing that the fasting hypertriglyc-
? + + eridemia in type 2 diabetes and in
Hyperinsulinemia
(Hyperamylinemia?)
the Metabolic Syndrome is mainly
due to an increase in VLDL126. The
Liver elevation of VLDL1 has serious con-
VLDL triglycerides
sequences for TRL catabolism: the
production of slowly metabolised
LDL leads to the generation of small
Adipose tissue Muscle
dense LDL with a prolonged half-life
Fat deposition (early) Triglyceride and fatty acids
FFA reesterfication (later) Glycogen synthesis time. This is presumed to promote
Glucose oxidation oxidation and glycosylation of apo B
+
Plasma FFA Insulin resistance
in lipoprotein remnants and LDL.
140
pertriglyceridemia is triglyceride enrichment of HDL 120
particles, particularly of HDL2. This chemical modifica-
100
tion enhances the catabolism of HDL in people with28 DM
type 2 diabetes. 80
This is even the case in subjects with normal glucose 60 IGT
0
Dyslipidemia in the Metabolic Syndrome 0 10 20 30 40 50
primarily a postprandial phenomenon? AUC-TG mmol/l/6h
The Metabolic Syndrome may be considered to develop as Figure 21-5. Relationship between postprandial triglycerides,
an initial postprandial disease since alterations in hor- glucose excursions and insulin resistance25.
Dyslipidemia in the Metabolic Syndrome • 353
Dyslipidemia and insulin resistance compared to diabetic controls, type 2 diabetes was an in-
in the Metabolic Syndrome dependent predictor of LDL phenotype B and of slowed
clearance of triglyceride rich lipoproteins, which was
In 1988 G. Reaven44 introduced insulin resistance as the linked to insulin resistance.
unifying pathophysiology of a cluster of diseases that Insulin resistance is also a determinant of postprandi-
had been previously described as plurimetabolic syn- al hypertriglyceridemia, regardless of the stage of glu-
drome45 and Metabolic Syndrome1. It is of interest that a cose tolerance25. At the moment there is only very limit-
primary role for dyslipidemia, fatty acid-glucose cycle ed data available from studies with drugs that specifi-
and non-alcoholic fatty liver in the pathogenesis of the cally act on dyslipidemia, with prevention of insulin
Metabolic Syndrome had been already described in the resistance syndrome as a secondary objective.
early description of the plurimetabolic syndrome by Fibrates can reduce triglycerides by 30-50% and, at the
G. Crepaldi45 and in the first comprehensive elaboration same time, alter the quality of lipoprotein particles. They
of a definition and the pathophysiology by M. Hanefeld lower small dense LDL levels and moderately decrease
and W. Leonhardt1. The introduction of the CLAMP tech- FFA levels. This is particularly useful in patients with dys-
nique46 and of the homeostasis model assessment of in- lipidemia and the Metabolic Syndrome65. So far there is
sulin resistance (HOMAIR)47 revealed that insulin resist- little information on their effect in prediabetic subjects to
ance is a common finding in diseases of the Metabolic reduce the progression to diabetes. In the Bezafibrate
Syndrome and closely related to all components of dys- Coronary Atherosclerosis Intervention Trial (BECAIT) in
lipidemia. Thus, the term “insulin resistance syndrome” young male survivors of myocardial infarction a reduc-
had been widely used to indicate insulin resistance as tion in newly diagnosed diabetes as well as a significant
common soil48,49. In the Strong Heart Study in nondia- decrease in clinical coronary events were observed66.
betic American Indians the levels of HDL-cholesterol de- Recently the DAIS investigators reported a reduction in
creased and triglyceride levels increased across tertiles of albuminuria in a prospective study with fenofibrate67.
HOMAIR50. Triglycerides were increased and HDL-cho- Primary prevention trials are needed to evaluate the po-
lesterol lowered in people with high fasting insulin com- tential role of fibrates as drugs for the treatment of the
pared to participants with low insulin level in the San Metabolic Syndrome. Thiazolidindiones (TZD) are a fam-
Antonio Heart Study51. Consistent data from cross-sec- ily of PPARγ agonists which act primarily on insulin re-
tional52,53 and a few prospective studies13,58,59 confirm the sistance68. PPARγ is highly expressed in adipose tissue,
close relationship between dyslipidemia and insulin re- particularly of visceral fat cells, where it plays a crucial
sistance. Insulin resistance however was not related to to- role in the regulation of fatty acid metabolism and glu-
tal and LDL-cholesterol57. Nevertheless hyperinsuline- cose homeostasis. TZDs lower FFA and triglycerides and
mia and insulin resistance are inversely correlated to increase HDL-cholesterol69,70. This is associated with a
LDL particle size58,59 in type 2 diabetes. This also applies substantial improvement in the insulin sensitivity of
to non-diabetic subjects with insulin resistance. Insulin muscle, liver and endothelial cells. Further pleiotropic ef-
resistance is associated with a preponderance of small fects in the Metabolic Syndrome are the reduction of
dense LDL in diabetic and non-diabetic subjects. blood pressure in hypertensive patients71, the down-reg-
Furthermore, insulin resistance is associated with an ulation of low grade inflammation72 – a new component
increase in ApoB and a decrease in apoA160. The IRIS II of Metabolic Syndrome – and the improvement in en-
study was performed in 4265 patients with type 2 dia- dothelial function73 irrespective of the level of glycemic
betes in order to find a practical clinical algorithm for es- control. TZD have also been effective in preventing dia-
timation of insulin resistance. Multiple regression analy- betes in gestational women.
sis revealed triglycerides and HDLl-cholesterol along Thus, the actions of TZD support the hypothesis that
with fasting blood glucose and BMI as the most power- anomalies in adipocyte metabolism with increased FFA
ful predictors of insulin resistance61. The cross-sectional may play a primary role in promoting insulin resistance
design of the study does not allow us to infer whether and dyslipidemia.
dyslipidemia is a consequence, a bystander or con-
tributes to insulin resistance. In prospective studies in- Dyslipidemia and vascular disease
creased fasting insulin or HOMAIR predicted develop- in the Metabolic Syndrome
ment of hypertriglyceridemia/low HDL as well as an in-
crease in ApoB and a decrease in ApoA162-64. In a study Elevation of FFA and other components of the lipid tri-
by Feingold et al. 65 analyzing LDL subclasses and ad are associated with endothelial dysfunction and inti-
triglyceride metabolism in normolipidemic subjects ma media thickening of the common carotid arteries and
Dyslipidemia in the Metabolic Syndrome • 355
Aa. femoralis75-77. In the CATHAY study78, in apparently the risk for coronary heart disease and stroke was in-
healthy Chinese subjects the Metabolic Syndrome was creased threefold in patients with the Metabolic Syn-
associated with impaired flow-mediated vasodilatation. drome applying the WHO definition. Dyslipidemia as
In addition to the well- known effect of “high normal” an individual trait had the highest relative risk for coro-
glucose the coexistence of dyslipidemia was also related nary heart disease (RR = 1.73) and myocardial infarction
to endothelial dysfunction in multiple regression analy- (RR = 1.71), whereas microalbuninuria was the strongest
sis. In a comparative CLAMP study of patients with individual predictor of cardiovascular mortality (RR =
type 2 diabetes73 the reduction of FFA by rosiglitazone 2.80). Insulin resistance was another independent risk
was associated with improved endothelial function, factor for coronary heart disease (RR for myocardial in-
whereas nateglinide with the same level of glucose con- farction 2.02) but not for mortality. There was a stepwise
trol neither affected dyslipidemia nor endothelium-de- increase in major cardiovascular events in patients with
pendent, flow-mediated vasodilatation or nitric oxide the Metabolic Syndrome from normal glucose tolerance
release. to prediabetes and to type 2 diabetes.
In the RIAD study79 dyslipidemia was associated The Verona Diabetes Complication study 55 con-
with an additional increase of intima-media thickness firmed insulin resistance as measured by HOMAIR as an
within the frame of the Metabolic Syndrome. In multi- independent risk factor together with HDL/total choles-
variate analysis with intima media thickness as the de- terol ratio for cardiovascular disease. The odds ratio for
pendent variable, HDL-cholesterol was a highly signifi- total/HDL-cholesterol was 1.22. Thus among the other
cant determinant of IMT. In univariate analysis both traits of the Metabolic Syndrome dyslipidemia along with
triglycerides and HDL-cholesterol were significantly insulin resistance were the only independent risk factors
correlated to intima media thickness mean. The HDL- for cardiovascular disease. In a population-based study81
cholesterol/triglycerides ratio showed the best predic- with middle-aged Finnish men free of clinical cardiovas-
tive power80. cular disease at baseline, the Metabolic Syndrome by
In a population based study77 in Swedish men aged NCEPIII and by WHO criteria was associated with a high-
58 years LDL particle size was significantly lower in pa- ly significant cardiovascular mortality: OR 2.9 and 2.9
tients with the Metabolic Syndrome as defined by the resp. After adjustment for conventional risk factors the
WHO definition. This was associated with a higher inti- WHO definition predicted more consistently cardiovas-
ma media thickness and plaque occurrence in the com- cular and all cause mortality. This study provides no data
mon carotid and femoral arteries. There was a signifi- on the contribution of the individual traits of the Meta-
cant but weak inverse relationship between LDL-parti- bolic Syndrome to the risk of cardiovascular diseases. The
cle size and intima media thickening. In the Baltimore impact of the Metabolic Syndrome by NCEPIII criteria on
longitudinal study on aging75 the presence of the Meta- coronary risk was analyzed in a population with low cho-
bolic Syndrome by NCEPIII criteria was associated with lesterol levels in Turkey82. In this population with low
higher intima media thickness and arterial stiffness. In HDL and low LDL the Metabolic Syndrome was an inde-
multiple regression analysis, taking into account each pendent predictor of subsequent coronary heart disease
individual component of the Metabolic Syndrome, the (RR 1.71). In men but not in women dyslipidemia as a sin-
clustering of traits in Metabolic Syndrome remained an gle trait was a risk factor for CHD.
independent risk factor for intima media thickness. This Finally, in the VAHIT- a secondary intervention trial
suggests that the traits act synergistically on endothelial of coronary heart disease in men with low HDL-hyper-
function and on intima media thickness, which is an es- triglyceridemia- the effect of genfibrozil was strongly
tablished surrogate parameter of systemic atherosclero- dependent on the status of insulin sensitivity. Patients
sis. This hypothesis is supported by a few prospective with insulin resistance benefited more from gemfibrozil,
studies with major cardiovascular events as hard end- a drug specifically acting on triglycerides and HDL-cho-
points. A prospective analysis of the insulin resistance lesterol, than those without insulin resistance83. The au-
syndrome in the San Antonio Heart Study51 has shown thors conclude that, independently of triglycerides and
that hyperinsulinemia at baseline was associated with HDL-cholesterol values at baseline or as a result of ther-
the subsequent development of multiple traits of the apy, insulin resistance is associated with a higher inci-
Metabolic Syndrome in particular of high triglycerides dence of major cardiovascular events.
and low HDL-cholesterol. Patients with dyslipidemia In conclusion, dyslipidemia may amplify the risk as
and the Metabolic Syndrome also had a higher risk for an individual component of the Metabolic Syndrome for
the development of cardiovascular disease. In the both diabetes and atherosclerotic vascular disease.
Bothnia study in a high risk Scandinavian population13 However it remains open to discussion to what extent
356 • Related Diseases in the Metabolic Syndrome
the risk of cardiovascular disease in the Metabolic Syn- sulin resistance syndrome. Diabetes Metab 2002
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