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DOI: 10.1161/CIRCULATIONAHA.106.671057
2007;115;32-35 Circulation
Lionel H. Opie
Metabolic Syndrome
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Metabolic Syndrome
Lionel H. Opie, MD, DPhil, FRCP
Case presentation: The patientwas a 38-year-old constructioncompany manager who pre-
sented with mild stage 1 hypertension
(office blood pressure [BP] ranging
from 145/92 to 150/105 mm Hg) with-
out end-organ damage. He worked
long and irregular hours. Being single
and often very tired at the end of the
day, he simply bought take-away fast
food as often as needed. He seldom
drank alcohol except at weekend par-
ties, when he had an excess. He
smoked 15 to 20 cigarettes per day. He
was overweight (body mass index�29
kg/m2), with an enlarged waist circum-
ference (42.5 inches [108 cm]). His
plasma triglyceride level was 281
mg/dL (3.19 mmol/L), high-density li-
poprotein (HDL) cholesterol was 35
mg/dL (0.9 mmol/L), calculated low-
density lipoprotein cholesterol was
135 mg/dL (3.5 mmol/L), total choles-
terol was 175 m/dL (4.5 mmol/L), and
fasting plasma glucose was 101 mg/dL
(5.6 mmol/L). Thus, he met the modi-
fied criteria of the Adult Treatment
Panel III for clinical identification of
the metabolic syndrome,1 as he had 4
of the 5 components (hypertension,
increased waistline, low HDL-choles-
terol, and high triglyceride values [Fig-
ure], with borderline elevated plasma
glucose). Of these, hypertension and
lowered HDL values best predict cor-
onary heart disease (CHD).2
Differing Definitions of the
Metabolic Syndrome
Abdominal obesity is most strictly
defined by the International Diabetes
Federation, with different cut-off
levels for different ethnicities.3 The
International Diabetes Federation
emphasizes abdominal obesity as the
initiating factor in the metabolic syn-
drome. Because risk factors cluster,
and because the cardiovascular risk
factors for the metabolic syndrome
are linear in their damaging effects
(Table 1), different definitions of the
metabolic syndrome make little dif-
ference in the prognostic implications.4
Some argue that the syndrome
does not exist, saying that the 5
components are merely borderline
cardiovascular risk factors. However,
if taken together, they significantly
augment risk. The large international
INTERHEART study has shown lin-
ear relationships between these risk
factors and myocardial infarction.5
Specifically, linear cardiovascular
risks are (1) the degree of abdominal
obesity6; (2) fasting or 2-hour post-
prandial glucose values7; (3) ele-
vated average BP8; (4) decreased cir-
culating HDL9; and (5) high
triglyceride levels.10 The metabolic
syndrome gives a 2- to 3-fold in-
creased risk for CHD, a similar risk
for future ischemic stroke,11 and a
much greater risk for future diabe-
tes.4,12 The more features of the met-
abolic syndrome a patient has, the
greater the risk, which is made much
worse by concomitant low-density li-
poprotein cholesterol elevation.10
Mechanism of
Metabolic Syndrome
The syndrome can best be explained
by viewing abdominal adipose tissue
as an endocrine organ13 that releases
into the circulation excess harmful free
fatty acids (FFA), angiotensin II, and
adipokines. First, the increased blood
FFA inhibit the uptake of glucose by
muscle.14,15 Excess FFA and angioten-
sin II damage the pancreas.16 Although
the pancreas manufactures extra insu-
lin, there is not enough to counter the
hyperglycemia, thus explaining the
paradox of fasting hyperglycemia de-
spite increased plasma insulin levels,
which is known as insulin resistance.
Angiotensin II increases BP through
its vasoconstrictive effects. Tumor ne-
crosis factor-� and other cytokines (in-
terleukins) provoke inflammatory reac-
tions that also lessen the efficacy of
insulin and may promote hypertension.
Hyperglycemia and increased circulat-
ing FFA provide the correct substrates
From the Cape Heart Center, Hatter Institute and Department of Medicine, University of Cape Town Medical School, Cape Town, South Africa.
Correspondence to Lionel H. Opie, MD, DPhil, FRCP, Cape Heart Center, Hatter Institute and Department of Medicine, University of Cape Town
Medical School, Observatory, Cape Town 7925, South Africa. E-mail Lionel.Opie@uct.ac.za
(Circulation. 2007;115:e32-e35.)
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.106.671057
CLINICIAN UPDATE
CLINICIAN UPDATE
e32
for increased manufacture of triglycer-
ides by the liver. Circulating triglycer-
ides increase so that lipoproteins carry
more triglycerides and less HDL (note
the complex reciprocal relationship be-
tween circulating triglyceride and
HDL).17
Therapy
Lifestyle
Regular exercise is the first step in
treating the metabolic syndrome be-
cause it increases glucose metabolism
by muscle and helps in weight reduc-
tion (Table 2). Dietary therapy has 2
components. The first is weight reduc-
tion, which is chiefly a matter of
achieving a sustained negative calorie
balance, and the second is adherence to
the Mediterranean diet, which is espe-
cially high in olive oil and nuts.18 This
enriched Mediterranean diet reduces
BP, as well as fasting glucose and
insulin and therefore the HOMA index
(Homeostasis Model Assessment, cal-
culated as a product of these 2 mea-
sures). It modestly increases HDL
while decreasing triglyceride levels
when compared with a low-fat diet19 in
a study that only lasted 3 months.
When specifically applied to patients
with the metabolic syndrome over 2
years, the Mediterranean diet de-
creased body weight and inflammatory
markers.20 In an observational study,
those Greek subjects who adhered
more closely to the Mediterranean
style of diet had a 20% lower risk of
the metabolic syndrome.21 Healthy
food choices together with regular ex-
ercise and not smoking reduce the risk
of CHD, in part through antiinflamma-
tory mechanisms.22 Thus, the Mediter-
ranean diet seems to be a good and
palatable dietary choice, usually very
acceptable to patients. Its major defect
is that it does not result in weight
reduction, which requires exercise and
a decreased calorie intake.
Lessening the Risk of
Future Diabetes
In the study by Tuomilehto et al,23
those prediabetic patients with meta-
bolic syndrome in the intervention
group had a mean waist circumference
of 102 cm, a fasting glucose level of
109 mg/dL, an HDL level of 46 mg/
dL, and a triglyceride level of 154
mg/dL, with BP values of 140/
86 mm Hg. The aims of the study were
to reduce weight by more than 5%,
reduce the fat intake, reduce the satu-
rated fat intake, increase the fiber in-
take, and increase exercise to more
than 4 hours per week. The exercise
goal was the one most often achieved
(86%), followed by reduction of the fat
intake (47%), modest weight reduction
(43%), decreased saturated fat intake
(26%), and increased fiber intake
(25%). The relative risk for diabetes in
the intervention groups was 0.4 (ie, a
60% reduction). In another similar
study,24 metformin also reduced new
diabetes but less so than did lifestyle
measures. The glitazones (rosiglita-
zone and pioglitazone) specifically re-
duce hyperglycemia at the small risks
of weight gain and increased heart
failure. However, they decrease FFA
levels, lessen insulin resistance, reduce
triglycerides, and increase HDL.25
Antihypertensives
Here the risk of future diabetes also
needs consideration. The combination
of diuretics and ß-blockers should be
avoided (Table 2). Angiotensin-
The diagnosis of metabolic syndrome requires a tape measure or accurate eye; fasting lipo-
gram and plasma glucose measurements; and BP measurements. A-II indicates angioten-
sin-II; FFA, free fatty acids; BP, blood pressure; FPG, fasting plasma glucose; TG, triglycer-
ides; and HDL, high-density lipoproteins. Figure modified with permission from Opie LH.
The metabolic syndrome, does it exist? In: Opie LH, Kasuga M, Yellon DM, eds. Diabetes at
the Limits. Cape Town, South Africa: University of Cape Town Press; 2006:95–110.
TABLE 1. Linearity of Features of the
Metabolic Syndrome as Risk Factors for
Cardiovascular Disease
1. Plasma glucose levels and cardiovascular risk7
2. Waist measurements6
3. Blood pressure8
4. Serum triglycerides levels10
5. HDL-cholesterol, reflected in the plasma
apolipoprotein B to A ratios5
TABLE 2. Metabolic Syndrome:
Therapeutic Strategies
1. Lifestyle changes,31 exercise, adherence to
the Mediterranean diet, and weight loss 3
less new diabetes
2. Metformin (less new diabetes, not as good
as lifestyle changes)
3. Glitazones, for non-diabetics with high
cardiovascular risk: 2 fatty free acids, 2
insulin resistance, 1 HDL,25 balancing
these against possible weight gain
4. Rimonabant, cannabinoid receptor blocker;
waist measurement 2,TG 2, 1 HDL29
5. Glucagon-like peptide (future therapy,
decreases plasma glucose and induces
weight loss)
6. Choice of antihypertensives:
�-blocker/diuretic much more likely to
cause metabolic syndrome than calcium
channel blockers/angiotensin-converting
enzyme inhibitors32
Opie Metabolic Syndrome e33
converting enzyme inhibitors and an-
giotensin-receptor blockers should
lessen the risk of new diabetes,26 even
though the absolute cardiovascular
benefit is small.27
Low HDL and High
Triglyceride Levels
This is a difficult problem to tackle.
Powerful investigational HDL-
elevating agents such as torcetrapib, an
inhibitor of cholesterol ester transfer
protein,28 have the potential to increase
HDL by about 50%. Formal outcome
trials have resulted in drug withdrawal
because of increased mortality. Exist-
ing agents that increase HDL and de-
crease triglyceride levels by about
10% include nicotinic acid and glita-
zones.25 Fibrates have less effect on
HDL and are especially active on tri-
glycerides. In overly obese persons,
high-dose rimonabant, the endocan-
nabinoid receptor inhibitor, increases
HDL by 19% and decreases triglycer-
ides by 16%, with only modest weight
loss.29 Modest alcohol consumption
increases HDL moderately. Geneti-
cally decreased hepatic alcohol dehy-
drogenase slows ethanol catabolism to
give higher HDL levels and lower
rates of myocardial infarction.30 Al-
monds decrease the low-density li-
poprotein:HDL ratio.18
What Therapy Was Chosen for
Our Patient?
Besides candesartan as the antihyper-
tensive, he was advised to exercise
regularly on the way to work and to
switch to a Mediterranean diet. He was
encouraged to dine at a Greek restau-
rant, add high-quality olive oil and
almonds to his Mediterranean food,
emphasize vegetables and fruit, and
have 1 or 2 glasses of wine but only
with his food. On this regimen, his
fasting glucose decreased to 96 mg/dL
and his HDL rose to 40 mg/dL
(1.1mmol/L). He did not stop smoking
but genuinely cut down by half, there-
fore reducing this linear risk by half.
Although therapy and lifestyle advice
countered all the abnormal compo-
nents of the metabolic syndrome, the
effort required for a busy person to
keep up the exercise routine in the
morning and frequent restaurant dining
in the evening may be too difficult to
sustain. Hence, if hyperglycemia re-
turns and worsens, he will be given
metformin. If metformin does not lead
to an adequate response, we may
switch to rosiglitazone.
Conclusion
The untreated metabolic syndrome
places individuals at risk both for dia-
betes and cardiovascular disease. Of
the 5 features of the metabolic syn-
drome, abdominal obesity, high tri-
glycerides, and modest elevations of
blood glucose were not part of the
original Framingham risk factor score,
nor did Framingham prognosticate on
the risks of future diabetes or ischemic
stroke. For these reasons, diagnosing
the metabolic syndrome extends our
concepts of cardiovascular risk.31,32
Disclosures
None.
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Opie Metabolic Syndrome e35