Article

Journal of Cardiovascular
Pharmacology and Therapeutics
Metabolic Syndrome: Clinical and Policy 1-3
ª The Author(s) 2017
Reprints and permission:
Implications of the New Silent Killer sagepub.com/journalsPermissions.nav
DOI: 10.1177/1074248416686187
journals.sagepub.com/home/cpt

Dawn Harris Sherling, MD1, Parvathi Perumareddi, DO1,

and Charles H. Hennekens, MD, DrPH1

Abstract
The United States is experiencing its greatest life expectancy ever. Nonetheless, the general health of the US population is far
from at an all-time high. An important contributor to the pandemic of cardiovascular disease is that overweight and obesity are
also the major determinants of metabolic syndrome, an all too common and all too serious clinical and public health challenge.
Clinicians have traditionally evaluated each of the major risk factors contributing to metabolic syndrome on an individual basis.
There is evidence, however, that the risk factors are more than additive. The overlap of these factors in each disease state,
resulting in increased atherogenic risks, is worth examining as a broader entity rather than separately. While therapeutic lifestyle
changes (TLCs) should be strongly recommended, clinicians should not let the perfect be the enemy of the possible. Evidence-
based doses of statins, aspirin and angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers should be
prescribed as adjuncts, not alternatives, to TLCs. In fact, there is cogent evidence that the benefits of these pharmacologic
therapies may also be at least additive.

Keywords
obesity, statin, metabolic syndrome

The United States is experiencing its greatest life expectancy
ever. Nonetheless, the general health of the US population is far
from at an all-time high. The gains in United States life expec-
tancy have been less than those realized by other industrialized
nations, mostly owing to a stagnation or even a decline in the
life expectancy among a number of US counties, especially
among women. The poor health in these counties is correlated
with many factors, including rising rates of overweight and
obesity, especially in women.1 Overweight and obesity are
major risk factors for many major causes of US deaths, as well
as worldwide, including coronary heart disease, stroke, and
cancers of the large intestine, kidney, uterus, and breast in
postmenopausal women. In fact, obesity is emerging as perhaps
the leading avoidable cause of premature death in the United
States as well as worldwide.2
An important contributor to the pandemic of cardiovascular
disease (CVD) is that overweight and obesity are also the major
determinants of metabolic syndrome, an all too common and all
too serious clinical and public health challenge. As defined by
the US National Heart, Lung and Blood Institute and American
Heart Association Consensus Statement, metabolic syndrome
is a constellation of 3 or more risk factors, which include
abdominal obesity, high triglycerides, low- and high-density
lipoprotein cholesterol, high blood pressure, and elevated fast-
ing blood glucose (Table 1). From the perspectives of both
individual clinicians as well as the health of the general public,
metabolic syndrome is a major contributor to the epidemic of
CVD in the United States as well as the emerging pandemic.
Alarmingly, in the US National Health and Nutrition Examina-
tion Survey, more than 1 in 3 adults have metabolic syndrome.
More alarmingly, about 40% of adults aged 40 and older have
metabolic syndrome. Finally, and most alarmingly, participants
with metabolic syndrome are largely asymptomatic but have a
10-year risk of a first coronary event, based on the Framingham
Risk Score, of 16% to 18% which is nearly as high as a patient
who has already experienced a prior coronary event. At present,
however, there is underdiagnosis and undertreatment of meta-
bolic syndrome.3 This situation is somewhat analogous to that
of hypertension, the original silent killer, in the 1970s at the
time of the establishment of the National High Blood Pressure
Education Program. At that time, only 51% of individuals were
aware of their diagnosis and only slightly more than half of
1
Integrated Medical Sciences Department, Charles E. Schmidt College of
Medicine, Florida Atlantic University, Boca Raton, FL, USA
Manuscript submitted: August 12, 2016; accepted: October 19, 2016.
Corresponding Author:
Dawn Harris Sherling, Charles E. Schmidt College of Medicine, Florida Atlantic
University, Room 216, Building ME-104, 777 Glades Road, Boca Raton,
FL 33431, USA.
Email: dsherling@health.fau.edu
2 Journal of Cardiovascular Pharmacology and Therapeutics
Table 1. Clinical Diagnosis of the Metabolic Syndrome.
Risk Factors Defining Level
Abdominal obesity, given as waist
circumferencea,b
Men >102 cm (>40 in)
Women >88 cm (>35 in)
Triglycerides 150 mg/dL
HDL cholesterol
Men <40 mg/dL
Women <50 mg/dL
Blood pressure 130/85 mm Hg
Fasting glucose 110 mg/dL
Abbreviations: BMI, body mass index; HDL, high-density lipoprotein.
a
Overweight and obesity are associated with insulin resistance and the
metabolic syndrome. However, the presence of abdominal obesity is more
highly correlated with the metabolic risk factors than is an elevated BMI.
Therefore, the simple measure of waist circumference is recommended to
identify the body weight component of the metabolic syndrome.
b
Some male patients can develop multiple metabolic risk factors when the waist
circumference is only marginally increased, for example, 94 to 102 cm (37 to 39
in). Such patients may have a strong genetic contribution to insulin resistance.
They should benefit from changes in life habits, similarly to men with categorical
increases in waist circumference.
these were treated and still less than half of these patients were
adequately treated for hypertension.4
Clinicians have traditionally evaluated each of the major
risk factors contributing to metabolic syndrome on an individual
basis. There is evidence, however, that the risk factors are more
than additive.5 One of the main factors thought to accelerate the
pathway is insulin resistance, which to a certain degree is geneti-
cally predetermined. It is the presence of specifically a high
waist circumference which appears to contribute to the process.
The visceral fat component of abdominal obesity leads to not
only insulin resistance but also the release of nonesterified free
fatty acids from adipose tissue. Thus, lipids accumulate in other
sites such as liver and muscle, further predisposing to insulin
resistance and dyslipidemia. Additionally, adipose tissue may
produce various adipokines that may separately impact insulin
resistance and CVD risk factors. These characteristics coupled
with elevated blood pressure and dyslipidemia tend to be com-
monly manifested as prothrombotic and proinflammatory states.
It is the cascade of these closely coupled states that further
increase the rate of atherogenesis. The overlap of these factors
in each disease state, resulting in increased atherogenic risks, is
worth examining as a broader entity rather than separately.5
With respect to the pathophysiology of metabolic syndrome,
visceral fat and its clinically more easily measured correlate of
waist circumference are gaining increasing attention as strong
predictors of the metabolic syndrome, even independent of
body mass index (BMI).6 Increased interleukin 6 and other
inflammatory markers increase with metabolic syndrome
scores that have a positive predictive value for coronary heart
disease diagnosed angiographically.7 These correlations offer a
plausible explanation for the observed increased risk of CVD
among participants with so-called normal weight central
obesity. These high-risk patients represent an important
population for clinicians to screen for the metabolic syndrome
despite their normal BMI.
Though this may produce many more millions of Americans
classified as having metabolic syndrome, fortunately metabolic
syndrome is not a condition without treatment options. The
Diabetes Prevention Program regimen, published in 2002,
showed that therapeutic lifestyle changes (TLCs) had a far
greater impact than pharmacologic options. Thus, their key
interventions included dietary modifications and 150 minutes
of physical activity a week. The recommendations also
included individual case management and frequent contact
with lifestyle coaches.8 Today, however, even getting 1 visit
to a nutritionist paid for by health insurance presents a chal-
lenge to clinicians. Thus, while TLCs should be strongly rec-
ommended, clinicians should not let the perfect be the enemy
of the possible. Evidence-based doses of statins, aspirin and
angiotensin-converting enzyme inhibitors, or angiotensin II
receptor blockers should be prescribed as adjuncts, not alterna-
tives, to TLCs. In fact, there is cogent evidence that the benefits
of statins and aspirin are at least additive. Specifically, in data
from 2 large randomized trials of statins and a meta-analysis of
5 trials, patients on aspirin who were randomized to a statin
experienced greater benefits than those on each agent alone on
myocardial infarction, stroke, and a composite CVD end point.
These findings were also apparent among those randomized to
a statin who did or did not take aspirin. In these data, the
probability of synergy, or an effect greater than additivity, was
0.92.5 Furthermore, it has recently been estimated that 44% of
the decrease seen in CVD mortality from 1980 to 2000 is
attributable to risk factor modification, with 24% (of the
44%) being attributed to reductions in cholesterol and 20%
attributed to reductions in blood pressure.9 Statins produce
statistically significant and clinically important reductions in
risks of CVD, including myocardial infarction, stroke, and CV
death, in women and men in secondary prevention, in high-risk
primary prevention participants, including those with diabetes
and those at high risk of developing diabetes, as well as in low-
risk primary prevention participants. In contrast, the totality of
evidence is unclear about whether there is a valid statistical
association between statins and newly diagnosed diabetes. Spe-
cifically, the data from trials not designed a priori to test a
hypothesis should be viewed as hypothesis formulating, not
hypothesis testing. Furthermore, with respect to the rando-
mized evidence, there should be substantial differences
between how trial evidence is interpreted for the prespecified
main effects of statins on CVD in contrast to somewhat unex-
pected side effects of statins on newly diagnosed diabetes for
which no trial has been designed a priori to test the hypothesis.
Furthermore, some trials show inverse relationships or no asso-
ciation. From the perspective of individual patients as
well as the health of the general public, there is marked under-
utilization of statins in the United States. Many premature
deaths will occur needlessly if patients for whom statins should
be prescribed do not agree to take the drug or if patients pre-
scribed statins stop taking the drug as a result of concerns about
the development of diabetes.5 Even if real, the most plausible
Sherling et al
estimate of increased risk is about 9%.10 The authors of this
meta-analysis concluded that, even if causal, 255 patients
would have to be treated with a statin for 4 years to produce
1 case of diabetes whereas 9 vascular events would have been
prevented. Despite this persuasive totality of randomized
evidence on benefits in clinical CVD outcomes and controversy
about whether there is an increase in diabetes, there has been
hesitancy to prescribe statins. One hypothesis generated but not
tested relates to increases in plasma adenopectin.11 Thus, from a
clinical perspective, it seems prudent to use the particular statin
best suited to the needs of an individual patient rather than relying
on a particular brand related to the hypothesized but unproven risk
of diabetes and inconsistent data on glycemic parameters.
In conclusion, the clinical and public health challenges in
metabolic syndrome include prevention, early diagnosis, and
aggressive multifactorial medical management. These strate-
gies must include the adoption of the TLCs of weight loss and
increased physical activity as well as the use of adjunctive
pharmacologic therapies for many patients with metabolic
syndrome, whose risks of a first coronary event are almost as
high as those who have survived a prior event.
Author Contributions
D. Sherling and C. Hennekens contributed to conception or design,
acquisition, analysis, or interpretation and critically revised the manu-
script. P. Perumareddi contributed to acquisition, analysis, or interpreta-
tion. All authors drafted the manuscript, gave final approval, and agree to
be accountable for all aspects of work ensuring integrity and accuracy.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
References
1. Wang H, Schumacher AE, Levitz CE, Mokdad AH, Murray CJ.
Left behind: widening disparities for males and females in US
3
county life expectancy, 1985-2010. Popul Health Metr. 2013;
11(1):8. doi:10.1186/1478-7954-11-81.
2. Hennekens CH, Andreotti F. The leading avoidable cause of pre-
mature mortality in the world: the case for obesity. Am J Med.
2013;126(2):97-98. PMID: 23331432.
3. Aguilar M, Bhuket T, Torres S, Liu B, Wong RJ. Prevalence of
the metabolic syndrome in the United States, 2003-2012. JAMA.
2015;313(19):1973-1974. doi:10.1001/jama2015.4260.3.
4. The Seventh Report of the Joint National Committee on Preven-
tion, Detection, Evaluation, and Treatment of High Blood Pres-
sure. National High Blood Pressure Education Program. http://
www.nhlbi.nih.gov/files/docs/guidelines/jnc7full.pdf. Published
2004. Accessed May 22, 2016.
5. Hennekens C, Lieberman E, Rubenstein M, et al. Lipid Modifica-
tion in the Treatment and Prevention of Cardiovascular Diseases:
New emerging clinical and public health challenges. In: Watson
RR, ed. Handbook of Cholesterol. Urbana, IL: AOCS Press; 2016:
155-181. Chap 9.
6. Shah RV, Murthy VL, Abbasi SA, et al. Visceral adiposity and the
risk of metabolic syndrome across body mass index: the MESA
Study. JACC Cardiovasc Imaging. 2014;7(12):1221-1235. doi:
10.1016/j.jcmg.2014.07.017.6.
7. Kim JY, Choi EY, Mun HS, et al. Usefulness of metabolic syn-
drome score in the prediction of angiographic coronary artery
disease severity according to the presence of diabetes mellitus:
relation with inflammatory markers and adipokines. Cardiovasc
Diabetol. 2013;12:140. doi:10.1186/1475-2840-12-140.7.
8. Diabetes Prevention Program (DPP) Research Group. The Dia-
betes Prevention Program (DPP): description of lifestyle interven-
tion. Diabetes Care. 2002;25(12):2165-2171.
9. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in
U.S. deaths from coronary disease, 1980-2000. N Engl J Med.
2007;356(23):2388-2398. doi:10.1056/NEJMsa053935.9.
10. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident
diabetes: a collaborative meta-analysis of randomized trials.
Lancet. 2010;375(9716):735-742.
11. Arnaboldi L, Corsini A. Could changes in adiponectin drive the
effect of statins on the risk of new-onset diabetes? The case of
pitavastatin. Atheroscler Suppl. 2015;16:1-27. doi:10.1016/
S1567-5688(14)70002-9.