Acervo 2

S P E C I A L F E A T U R E
C l i n i c a l P r a c t i c e G u i d e l i n e
Primary Prevention of Cardiovascular Disease

and Type 2 Diabetes in Patients at Metabolic Risk:
An Endocrine Society Clinical Practice Guideline
James L. Rosenzweig, Ele Ferrannini, Scott M. Grundy, Steven M. Haffner, Robert J. Heine,
Edward S. Horton, and Ryuzo Kawamori
Boston Medical Center and Boston University School of Medicine (J.L.R.), Boston, Massachusetts 02118; University of Pisa School (E.F.),
56126 Pisa, Italy; University of Texas Southwestern Medical Center (S.M.G.), Dallas, Texas 75390; University of Texas Health Science
Center (S.M.H.), San Antonio, Texas 78249; *Vrije Universiteit Medical Center (R.J.H.), 1081 Amsterdam, The Netherlands; Joslin
Diabetes Center (E.S.H.), Boston, Massachusetts 02215; and Juntendo University School of Medicine (R.K.), 113-8421 Tokyo, Japan
Objective: The objective was to develop clinical practice guidelines for the primary prevention of
cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) in patients at metabolic risk.
Conclusions: Healthcare providers should incorporate into their practice concrete measures to
reduce the risk of developing CVD and T2DM. These include the regular screening and identifi-
cation of patients at metabolic risk (at higher risk for both CVD and T2DM) with measurement of
blood pressure, waist circumference, fasting lipid profile, and fasting glucose. All patients iden-
tified as having metabolic risk should undergo 10-yr global risk assessment for either CVD or
coronary heart disease. This scoring will determine the targets of therapy for reduction of apoli-
poprotein B-containing lipoproteins. Careful attention should be given to the treatment of ele-
vated blood pressure to the targets outlined in this guideline. The prothrombotic state associated
with metabolic risk should be treated with lifestyle modification measures and in appropriate
individuals with low-dose aspirin prophylaxis. Patients with prediabetes (impaired glucose toler-
ance or impaired fasting glucose) should be screened at 1- to 2-yr intervals for the development of
diabetes with either measurement of fasting plasma glucose or a 2-h oral glucose tolerance test.
For the prevention of CVD and T2DM, we recommend that priority be given to lifestyle manage-
ment. This includes antiatherogenic dietary modification, a program of increased physical activity,
and weight reduction. Efforts to promote lifestyle modification should be considered an important
component of the medical management of patients to reduce the risk of both CVD and T2DM.
(J Clin Endocrinol Metab 93: 3671–3689, 2008)
Summary of Recommendations of the risk factors for these conditions and be able to identify
patients at risk in order to initiate treatment to prevent these
The dramatic increase in the incidence of patients at risk for the diseases. This guideline focuses on the population of individuals
development of cardiovascular disease (CVD) and type 2 diabe- with the components of the metabolic syndrome who do not yet
tes mellitus (T2DM) throughout the developed and developing have diagnosed CVD or T2DM and on the steps that can be taken
world requires that physicians and other care providers be aware to prevent these two diseases. Several risk factors for CVD and
0021-972X/08/$15.00/0 Abbreviations: AHA/NHLBI, American Heart Association/National Heart, Lung, and Blood
Printed in U.S.A. Institute; ALT, alanine transferase; apo B, apolipoprotein B; ATP, Adult Treatment Panel;
BMI, body mass index; CHD, coronary heart disease; CRP, C-reactive protein; CVD, car-
Copyright © 2008 by The Endocrine Society diovascular disease; DPP, Diabetes Prevention Program; FPG, fasting plasma glucose;
doi: 10.1210/jc.2008-0222 Received January 29, 2008. Accepted July 17, 2008. HDL-C, high-density lipoprotein cholesterol; IDF, International Diabetes Foundation; IFG,
First Published Online June 29, 2008 impaired fasting glucose; IGT, impaired glucose tolerance; IRS, insulin resistance syndrome;
JNC7, Seventh Report of the Joint National Committee on Prevention, Detection, Evalu-
ation, and Treatment of High Blood Pressure; LDL, low-density lipoprotein; MR, magnetic
resonance; NCEP, National Cholesterol Education Program; OGTT, oral glucose tolerance
test; PAI-1, plasminogen activator inhibitor-1; PROCAM, Prospective Cardiovascular Mun-
ster; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione; UKPDS, United Kingdom
Prospective Diabetes Study; VFA, visceral fat area; VLDL, very-low-density lipoprotein.
J Clin Endocrinol Metab, October 2008, 93(10):3671–3689 jcem.endojournals.org 3671
The Endocrine Society. Downloaded from press.endocrine.org by [Ines Donangelo] on 10 November 2015. at 18:04 For personal use only. No other uses without permission. . All rights reserved.
3672 Rosenzweig et al. Guidelines for Patients at Metabolic Risk J Clin Endocrinol Metab, October 2008, 93(10):3671–3689
T2DM– hypertension, lipid abnormalities, hyperglycemia, and be at least 102 cm for men and at least 88 cm for women in Cau-
abdominal adiposity–tend to cluster together. We recommend casian, African-American, Hispanic, and Native American popu-
that physicians screen for these key risk factors for CVD and lations (3). We recommend that the cutoffs for waist circumference
T2DM at routine clinical visits when they obtain a patient’s in Asian populations (both East Asian and South Asian) be at least
history and perform physical examinations. 90 cm for men and at least 80 cm for women (1兩QEEE).
1.4 We suggest that individuals previously diagnosed with
1. Definitions and diagnosis prediabetes (IGT or IFG) be screened for the presence of overt
There is growing evidence that many patients who develop T2DM at 1- to 2-yr intervals (2兩QEEE). This can be done with
CVD or T2DM have common antecedents of metabolic origin. fasting plasma glucose (FPG) and, wherever possible, with an
Although the pathophysiology underlying these antecedents is oral glucose tolerance test (OGTT). For individuals at metabolic
not fully understood, there is a strong overlap between cardio- risk without IFG, there is less consensus on the recommended
vascular risk factors and prediabetes [impaired fasting glucose interval of screening.
(IFG) and impaired glucose tolerance (IGT)]. For this reason, it 1.5 A number of additional biological markers have been
is reasonable to identify a general condition called metabolic associated with metabolic risk: apo B, adiponectin, leptin, fasting
risk. The Endocrine Society has recognized the importance of insulin or proinsulin, free fatty acids, homocysteine, plasmino-
identifying patients who are at metabolic risk so that efforts can gen activator inhibitor-1 (PAI-1), fibrinogen, alanine transferase
be instituted to prevent both CVD and T2DM. This guideline (ALT) as a marker of liver fat, C-reactive protein (CRP), inflam-
follows the recommendations of the GRADE working group for matory cytokines (e.g. IL-6), liver or myocellular fat content by
grading of evidence and recommendations (see Appendix 1 for magnetic resonance (MR) spectroscopy, and microalbuminuria
presentation of symbols and language). (in patients without diabetes). Evidence that these markers
The Task Force decided to define metabolic risk as reflecting provide an indication of metabolic risk beyond routine mea-
an individual’s risk for CVD and T2DM (see Appendix 2 for a surements is limited. Their measurement is not recommended
full discussion of this choice of terminology). Individuals at high for routine evaluation of metabolic risk in clinical practice.
metabolic risk often have 1) elevations of apolipoprotein B (apo (2兩QEEE).
B)-containing lipoproteins [low-density lipoprotein (LDL) and Some of the above measurements may have utility for deter-
very-low-density lipoprotein (VLDL)] with elevated triglycer- mining the pattern or severity of metabolic risk, but must be
ides, 2) reduced levels of high-density lipoprotein cholesterol considered as optional based on clinical judgment. Although
(HDL-C), 3) increased plasma glucose levels, 4) hypertension, these measures are not recommended for routine measurement,
5) enlarged waist circumference, 6) a prothrombotic state, and one or more of them may be measured according to physician
7) a proinflammatory state. discretion to confirm or clarify estimates of metabolic risk.
1.1 The Task Force did not attempt to reach consensus on
endorsement of a specific definition of the metabolic syndrome. 2. Absolute risk assessment
The two currently used definitions describe closely overlapping 2.1 We recommend that all patients identified as having met-
but not identical populations (Table 1). Of the most commonly abolic risk undergo global risk assessment for 10-yr risk for ei-
used definitions of the metabolic syndrome, we suggest that ther coronary heart disease (CHD) or CVD. Framingham and
physicians screen for the components of the American Heart Prospective Cardiovascular Munster (PROCAM) scoring as-
Association/National Heart, Lung, and Blood Institute (AHA/ sesses 10-yr risk for CHD. The European SCORE algorithm
NHLBI) definition at the clinical visit, because of its ease of use predicts 10-yr risk for total cardiovascular mortality. Risk factor
and convenience of implementation in the office setting. The scoring with these algorithms can be easily carried out. Global
finding of at least three components especially should alert the risk assessment for cardiovascular outcomes is recommended
clinician to a patient at metabolic risk (at higher risk for CVD and before starting preventative treatment (1兩QEEE).
T2DM) (2兩QEEE).
1.2 We recommend that providers screen for the main com- 3. Treatment to prevent atherosclerotic CVD (especially
ponents of the metabolic syndrome at regular intervals CHD and stroke)
(1兩QQQE). We suggest that this should be done at least every 3 3.1.1 We recommend that apo B-containing lipoproteins
yr (2兩QEEE) in those individuals who have one or more risk (LDL and VLDL) be lowered in patients at metabolic risk to
factors but do not meet the established definitions of the syn- reduce risk for CVD (1兩QQQQ).
drome. These components include measurement of blood pres- 3.1.2 We recommend that LDL cholesterol (LDL-C) be the
sure, waist circumference, fasting lipid profile, and fasting primary target of lipoprotein-lowering therapy (1兩QQQQ) and
glucose. that non-HDL-C (an indicator for all apo B-containing lipopro-
1.3 We recommend that waist circumference be measured teins) be the secondary target (1兩QQQE). Furthermore, if
by clinicians as a routine part of the clinical examination. This HDL-C remains reduced after treatment of non-HDL-C, con-
measurement does not replace the routine measurement of sideration can be given to therapies designed to raise HDL-C
weight or calculation of body mass index (BMI) but can pro- (2兩QQEE).
vide more focused information regarding risk for CVD and 3.1.3 We recommend that intensity of lipoprotein-lowering
T2DM (1兩QEEE). therapy be adjusted to the absolute 10-yr risk for CVD.
We recommend that the cutoffs for elevated waist circumference (1兩QQEE) We suggest that intensity of lipoprotein-lowering
therapy further be adjusted to the absolute lifetime risk for CVD of carbohydrates in the diet. We were unable to reach consensus
(2兩QEEE). on the optimal ratio of carbohydrates to fats in the diet. We
3.2.1 We recommend that when blood pressure is elevated, it recommend that individuals at metabolic risk increase the pro-
be lowered to reduce the risk for CVD (1兩QQQQ). portion of fiber, unprocessed grains, and unsaturated fat in their
3.2.2 We recommend that type and intensities of blood pres- diet. Avoiding foods with high glycemic index may help lower
sure-lowering therapies be selected to optimize risk reduction, metabolic risk.
safety, and cost-effectiveness. We recommend that blood pres- 4.2 We recommend that priority be given to reducing risk for
sure be treated to a target of less than 140/90 mm Hg (or diabetes with lifestyle therapies rather than drug therapies
⬍130/80 in individuals with diabetes or chronic kidney disease). (1兩QQQE).
If weight loss or lifestyle modifications are not successful, then The dramatic increase in the incidence of patients at risk for
antihypertensive medications should be instituted and dose ad- the development of CVD and T2DM throughout the developed
justed to treat to target (1兩QQQE). and developing world requires that physicians and other care
3.3 We recommend that lifestyle management be consid- providers be aware of the risk factors for these conditions and be
ered first-line therapy for patients at increased metabolic risk able to identify patients at risk to initiate treatment to prevent
(1兩QEEE). these diseases. This guideline focuses on the population of indi-
3.4.1 We recommend that the prothrombotic state be treated viduals with the components of the metabolic syndrome who do
with lifestyle therapies to reduce risk for CVD (1兩QEEE). not yet have diagnosed CVD or T2DM, and on the steps that can
3.4.2 In individuals at metabolic risk who are over age 40 and be taken to prevent these two diseases. Several risk factors for
whose 10-yr risk is more than 10%, we recommend that low- CVD and T2DM, hypertension, lipid abnormalities, hypergly-
dose aspirin prophylaxis for primary prevention of CVD (75– cemia, and abdominal adiposity, tend to cluster together. We
162 mg/d) be considered if there are no contraindications recommend that physicians screen for these key risk factors for
(1兩QQQE). CVD and T2DM at routine clinical visits when they obtain a
There is no consensus on the specific recommended dose patient’s history and perform physical examinations.
within this range.
4. Treatment to prevent T2DM

4.1.1 For primary prevention of T2DM, we recommend that Complete Recommendations with Evidence
patients found to be at higher metabolic risk on the basis of
multiple metabolic syndrome components be started on a clinical 1. Definitions and diagnosis
program of weight reduction (or weight maintenance if not over- There is growing evidence that many patients who develop
weight or obese) through an appropriate balance of physical CVD or T2DM have common antecedents of metabolic origin
activity, caloric intake, and formal behavior modification pro- (4, 5). Although the pathophysiology underlying these anteced-
grams to achieve a lowering of body weight/waist circumference ents is not fully understood, there is a strong overlap between
below the targets indicated (see 1.3 for waist circumference and cardiovascular risk factors and prediabetes (IFG and IGT). Ac-
4.1.2 for weight) (1兩QQEE). cordingly, it is reasonable to identify a general condition called
Although it is important to aim for these targets, any lowering metabolic risk. The Endocrine Society has recognized the im-
of body weight/waist circumference is beneficial, and we recom- portance of identifying patients who are at metabolic risk so that
mend use of lifestyle modification programs for this purpose efforts can be instituted to prevent both CVD and T2DM. This
(1兩QQEE). guideline follows the recommendations of the GRADE working
4.1.2 In individuals at metabolic risk who have abdominal group for grading of evidence and recommendations (see Ap-
obesity, we suggest that body weight be reduced by 5–10% dur- pendix 1 for presentation of symbols and language).
ing the first year of therapy (2兩QEEE). Efforts to continue weight The Task Force decided to define metabolic risk as reflecting
loss or maintain the weight loss over the long term should be an individual’s risk for CVD and T2DM (see Appendix 2 for a
encouraged. full discussion of the choice of terminology). Individuals at high
4.1.3 We recommend that patients at metabolic risk undergo metabolic risk often have 1) elevations of apo B-containing li-
a program of regular moderate-intensity physical activity poproteins (LDL and VLDL) with elevated triglycerides, 2) re-
(1兩QQEE). This activity would be for at least 30 min, but pref- duced levels of HDL-C, 3) increased plasma glucose levels, 4)
erably 45– 60 min, at least 5 d/wk. It could include brisk walking hypertension, 5) enlarged waist circumference, 6) a prothrom-
or more strenuous activity. It can be supplemented by an increase botic state, and 7) a proinflammatory state.
in physical exercise as part of daily lifestyle activities. 1.1 The Task Force did not attempt to reach consensus on
4.1.4 We recommend that all individuals at metabolic risk endorsement of a specific definition of the metabolic syndrome.
follow a diet that is low in total and saturated fat, is low in trans The two currently used definitions describe closely overlapping
fatty acids, and includes adequate fiber (1兩QQEE). We suggest but not identical populations (Table 1). Of the most commonly
that saturated fat be less than 7% of total calories and dietary used definitions of the metabolic syndrome, we suggest that phy-
cholesterol less than 200 mg/d (2兩QEEE). We recommend that sicians screen for the components of the AHA/NHLBI definition
trans fat in the diet should be avoided as much as possible at the clinical visit because of its ease of use and convenience of
(1兩QEEE). There is much controversy regarding the proportion implementation in the office setting. The finding of at least three
TABLE 1. Criteria proposed for clinical diagnosis of the metabolic syndrome
Clinical measure AHA/NHLBI (1): any 3 of the following 5 features IDF (2)
Waist circumference ⱖ102 cm in men or ⱖ88 cm in women (non-Asian origin); ⱖ94 cm in men or ⱖ80 cm in women (Europids, Sub-
ⱖ90 cm in men or ⱖ80 cm in women (both East Asians Saharan Africans, and Middle Eastern); ⱖ90 cm in men
and South Asians) or ⱖ80 cm in women (both East Asians and South
Asians; South and Central Americans); ⱖ85 cm in men
or ⱖ90 cm in women (Japanese), plus any 2 of the
following:
Triglycerides (fasting) ⱖ150 mg/dl or on drug therapy for high triglycerides ⱖ150 mg/dl or on drug therapy for high triglycerides
HDL-C ⬍40 mg/dl in men or ⬍50 mg/dl in women or on drug ⬍40 mg/dl in men or ⬍50 mg/dl in women or on drug
therapy for low HDL-C therapy for low HDL-C
Blood pressure ⱖ130 mm Hg systolic or ⱖ85 mm Hg diastolic or on drug ⱖ130 mm Hg systolic or ⱖ85 mm Hg diastolic or on drug
therapy for hypertension therapy for hypertension
Glucose (fasting) ⱖ100 mg/dl or drug therapy for elevated glucose ⱖ100 mg/dl (includes diabetes)
components especially should alert the clinician to a patient at visceral adiposity, resting heart rate as a proxy of cardiorespi-
metabolic risk (at higher risk for CVD and T2DM) (2兩QEEE). ratory fitness, etc.) and/or from the large pool of biochemical
markers (e.g. CRP, adiponectin, HDL-C, triglycerides, apo
Evidence A/apo B ratio, fibrinogen, etc.) does not require assumptions
Of the various proposed definitions of the metabolic syn- about etiology or pathogenesis. As long as the aim is to configure
drome, only two are currently of practical use in the clinical a risk syndrome (7), all that matters is the ability of its compo-
setting (1, 2) (see Table 1). Although there are numerous analyses nents to consistently and substantially contribute to the identi-
of the various components of these definitions to independently fication of those who may be at risk for CVD and T2DM. Data
predict risk for CVD and T2DM, there are very few that inves- from the Framingham Study indicate that the AHA/NHLBI def-
tigate the definitions as a whole or compare them with each other inition of the metabolic syndrome may be associated with in-
with regard to effectiveness. The major difference between the creased risk for CVD independent of insulin resistance (8). Al-
AHA/NHLBI and the International Diabetes Foundation (IDF) though the currently available definitions of the metabolic
definitions is that the former posits the presence of three of five syndrome are not yet validated as quantifiable predictors of risk,
possible components, whereas the latter requires that central and more study is necessary to test their ability to predict CVD
obesity, as defined by waist circumference, be present first before and T2DM, they can be used to identify more susceptible pop-
examining for the other components. Because some individuals ulations for more intensive screening.
at risk for CVD and T2DM do not have obesity, and a substantial 1.2 We recommend that providers screen for the main
number of obese individuals may not be at higher risk, we believe components of the metabolic syndrome at regular intervals
that the AHA/NHLBI definition might identify a better popula- (1兩QQQE). We suggest that this should be done at least every
tion for further targeted screening for CVD and T2DM. Using 3 yr (2兩QEEE) in those individuals who have one or more risk
the AHA/NHLBI definition, metabolic syndrome is common factors but do not meet the established definitions of the syn-
and is associated with increased risk for T2DM and CVD in both drome. These components include measurement of blood pres-
sexes, accounting for up to half of new cases of T2DM and up to sure, waist circumference, fasting lipid profile, and fasting
one third of new CVD cases, over 8 yr of follow-up (6). glucose.
The concept of the metabolic syndrome has been, and con-
tinues to be, very useful to the medical community to enhance Evidence
awareness of risk clustering and to promote thorough screening The suggested time frames for screening are based on clinical
in individuals presenting with risk factors for CVD and T2DM. consensus, without established evidence from controlled clinical
Although such a benefit appears likely, no study has formally studies. Epidemiological evidence suggests that approximately
addressed this issue. Focusing on the metabolic syndrome should 30% of the people with T2DM in the United States have not had
not divert attention from other major, established CVD risk fac- their disease diagnosed (9) and that regular screening with fast-
tors such as LDL-C and family history. Therefore, the concept of ing blood glucose could identify those individuals for appropri-
metabolic risk has value only when these additional clinical fac- ate treatment, which could delay or decrease the development of
tors are considered by the physician. related complications. In addition, the identification of individ-
It remains possible that some combination of subclinical ab- uals with prediabetes (IFG or IGT) could allow for those indi-
normalities, more or less closely related to insulin resistance/ viduals to be treated with lifestyle modification and exercise to
hyperinsulinemia/visceral obesity, may signal a significant sur- prevent the development of diabetes in the future.
plus of CVD risk that is not predicted by the classical risk engines 1.3 We recommend that waist circumference be measured by
[Framingham, United Kingdom Prospective Diabetes Study clinicians as a routine part of the clinical examination. This mea-
(UKPDS), PROCAM, etc.]. This hypothesis must be rigorously surement does not replace the routine measurement of weight or
tested. In general, the concept of identifying predictors from the calculation of BMI but can provide more focused information
physical/lifestyle domain (e.g. waist circumference as a proxy of regarding risk for CVD and T2DM (1兩QEEE).
We recommend that the cutoffs for elevated waist circumfer- ference cutoff of at least 90 cm in men and at least 80 cm in
ence be at least 102 cm for men and at least 88 cm for women in women seems to be comparable to that in U.S. people. On the
Caucasian, African-American, Hispanic, and Native American other hand, according to the reports from the examination com-
populations (3). We recommend that the cutoffs for waist cir- mittee of Criteria for Obesity Disease in Japan, Japanese people
cumference in Asian populations (both East Asian and South with visceral fat area (VFA) of more than 100 cm2 have more
Asian) be at least 90 cm for men and at least 80 cm for women than one of the obesity-related disorders such as hyperglycemia,
(1兩QEEE). dyslipidemia, and hypertension. Correlation between VFA and
waist circumference in men and women showed 85 cm of waist
Evidence circumference in men and 90 cm of waist circumference in
Numerous studies have indicated that waist circumference women correspond to a VFA of 100 cm2 (12). There are several
and waist-to-hip ratio are better predictors of risk for CVD and studies showing the rationale for using different cutoff points of
diabetes than weight or BMI (10). We advocate waist measure- waist circumferences in different ethnic groups in Asian popu-
ment because of its ease of use in the clinical setting, when per- lations (13, 14). The Task Force recognizes that East Asian and
formed properly. Currently, waist circumference is rarely used South Asian populations may have significant differences in lipid
by clinicians in the primary care setting. Greater use would help indices, fat mass as a proportion of BMI, and cardiovascular
identify those individuals at higher risk who should receive fur- morbidity. More studies are necessary to clarify these differences
ther screening. It should not replace weight measurement or before consensus on separate cutoffs for waist circumference
BMI, because longitudinal measurement of weight is important might be established for these ethnic groups. It can be argued
for follow-up of any major clinical interventions to treat obesity. whether cutoff points should vary according to race or ethnicity.
Both AHA/NHLBI and IDF recognize that the definition of However, because of the huge variation of standard waist cir-
elevated waist circumference is variable among different popu- cumference depending on race, it is practical to use the ethnicity-
lations. The IDF suggests that for Europids the threshold for specific values for waist circumferences in the AHA-NHLBI def-
increased waist circumference be at least 94 cm in men and at initions of the metabolic syndrome until more specific data are
least 80 cm in women. For the U.S. population, the AHA/NHLBI available.
defines elevated waist circumference as at least 102 cm for men
and at least 88 cm for women (Table 2). Values
To assess the implication of metabolic syndrome in different Our recommendation that physicians routinely measure
ethnic populations, there is some concern that the recommended waist circumference for determination of metabolic risk places a
cutoff for waist circumference is inappropriate for different eth- higher value on use of this measure in risk scoring to identify
nic groups, especially for Asian individuals. There are two im- appropriate patients for further screening and more intensive
portant studies showing the rationale for using different cutoff goals of therapy to treat blood pressure and hyperlipidemia and
points of waist circumferences in people of Asian extraction. Tan a lower value on the fact that this measurement is not routinely
et al. (11) used receiver operating characteristic analysis to iden- performed in most practices at the present time. We also recog-
tify the level of waist circumference in people living in Singapore nize that practicality in the clinical setting is an important de-
(mainly composed of Chinese, Malay, and Asian Indian popu- terminant in the use of a measurement like waist circumference.
lations) that best predicted the clustering of impaired glucose We also place high value on the need to identify risk for diabetes
metabolism and low HDL-C. They found that a waist circum- and CVD in ethnic populations where the incidence is increasing
especially rapidly.
TABLE 2. Recommended waist circumference thresholds to Remarks

define abdominal obesity Waist circumference can be easily measured in the clinical
Waist circumference setting according to the NHANES III Protocol (15). To define the
Recommending threshold for level at which waist circumference is measured, a bony landmark
Region/ethnicity body abdominal obesity is first located and marked. The subject stands, and the examiner,
United States AHA/NHLBI ⱖ102 cm in men; ⱖ88 cm positioned at the right of the subject, palpates the upper hip bone
in womena to locate the right iliac crest. Just above the uppermost lateral
Europe/Europids IDF ⱖ94 cm in men; ⱖ80 cm border of the right iliac crest, a horizontal mark is drawn and
in women
then crossed with a vertical mark on the midaxillary line. The
Asia AHA/NHLBI IDF ⱖ90 cm in men; ⱖ80 cm
in womenb measuring tape is placed in a horizontal plane around the ab-
domen at the level of this marked point on the right side of the
Data are not available for Sub-Saharan Africans, Eastern Mediterranean and
Middle East (Arab) populations, and Ethnic South and Central Americans. IDF trunk. The plane of the tape is parallel to the floor, and the tape
suggests using waist thresholds for Europe/Europids for populations in these is snug but does not compress the skin. The measurement is made
regions. at a normal minimal respiration (see Fig. 1).
a
AHA/NHLBI guidelines indicate that waist circumference thresholds of at least 1.4 We suggest that individuals previously diagnosed with
94 cm in men and at least 80 cm in women are optional in persons who show
clinical evidence of insulin resistance. prediabetes (IGT or IFG) be screened for the presence of overt
b
In Japan, national recommendations for waist circumference thresholds for T2DM at 1- to 2-yr intervals (2兩QEEE). This can be done with
abdominal obesity are at least 85 cm in men and at least 90 cm in women. FPG and, wherever possible, with an OGTT. For individuals
diagnose diabetes is well known, but that in itself does not warrant
universal implementation of the OGTT in clinical practice.
There is less information on progression to metabolic syn-
drome than on progression to diabetes in various populations. In
the Framingham Offspring Study of 2848 adult men and women
who did not have diabetes or CVD at their baseline examination,
it was found that 12.5% of women and 21.4% of men had
metabolic syndrome (or metabolic risk as defined in this docu-
ment) according to the modified National Cholesterol Education
Program (NCEP) Adult Treatment Panel (ATP) III criteria (8,
18). When these patients were reexamined 8 yr later, the per-
centages had increased to 23.6 and 33.9% (after direct adjust-
ment to the baseline age) or by 47 and 56%, respectively (6).
When Framingham Offspring Study patients satisfying ATP III
criteria for metabolic syndrome were followed for up to 11 yr, it
was found that metabolic syndrome criteria increased the risk for
developing diabetes 6-fold, regardless of the degree of insulin
resistance (19).
In the Diabetes Prevention Program (DPP) study, 53% of
subjects met the ATP III criteria for metabolic syndrome at base-
line, and approximately 60% of those who initially did not meet
the criteria did meet them after 4 yr (20).
On the basis of these data, it is suggested that people with IFG
or IGT be screened for metabolic risk factors at 1- to 2-yr inter-
vals so that the presence of new risk factors can be identified and
treated appropriately.
1.5 A number of additional biological markers have been
FIG. 1. Measuring waist circumference according to the National Health associated with metabolic risk: apo B, adiponectin, leptin, fasting
Information Survey III protocol.
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid⫽obesity.figgrp.237. insulin or proinsulin, free fatty acids, homocysteine, PAI-1, fi-
brinogen, ALT as a marker of liver fat, CRP, inflammatory cy-
tokines (e.g. IL-6), liver or myocellular fat content by MR spec-
with metabolic syndrome without IFG, there is less consensus on troscopy, and microalbuminuria (in patients without diabetes).
the recommended interval of screening. Evidence that they provide an indication of metabolic risk be-
yond routine measurements is limited. Measurement of these
Evidence markers is not recommended for routine evaluation of metabolic
The natural history of both IFG and IGT can be defined in risk in clinical practice (2兩QEEE).
terms of progression to T2DM. The majority of people with Some of the above measurements may have utility for deter-
IFG/IGT will eventually meet the criteria for T2DM. Early di- mining the pattern or severity of metabolic risk but must be
agnosis of T2DM should result in a decrease in duration-depen- considered as optional based on clinical judgment. Although
dent diabetes-related microvascular complications; however, di- these measures are not recommended for routine measurement,
rect data are not available to determine whether this decrease one or more of them may be measured according to physician
occurs. Published trials have not been sufficiently powered to discretion to confirm or clarify estimates of metabolic risk.
show a reduction in these hard outcomes. One of the other major
reasons to recommend early therapeutic interventions for indi-
viduals with diabetes is the potential to reduce the increased risk Evidence
of CVD. A large number of different markers of CVD risk have been
The OGTT is more sensitive but also more time-consuming identified. Some of these have also been identified as markers of
and costly than the FPG test. Some evidence suggests that the high diabetes risk. Still, we cannot recommend the measurement
OGTT is more sensitive for identifying those individuals with a of these markers for routine clinical practice for several reasons.
higher degree of cardiovascular risk, but as a screening test for The so-called classic risk factors are used in clinical practice
cardiovascular risk in the clinical, nonresearch setting, it is not to estimate the absolute risk of CVD. The most widely applied
always practical. Recently, the suggestion has been made to use prediction equation is the Framingham risk score (21). This score
OGTTs in populations at high risk for diabetes, as for example is less well validated for persons with T2DM. More recently, the
persons with hypertension (16, 17). The main reason for this UKPDS risk engine has been developed with validated CVD risk
suggestion is the high prevalence of glucose abnormalities in estimates for people with T2DM (22, 23). Both methods apply
hypertensive patients attending hospital clinics and the low sensi- easy-to-collect clinical parameters, for example, age, use of cig-
tivity of the FPG test. The relatively low sensitivity of the FPG to arettes, blood pressure, and serum lipid levels. The UKPDS risk
engine also includes duration of diabetes and glycemia, additions 10-yr risk for total cardiovascular mortality. Risk factor scoring
based on the earlier observations of that study (24). with these algorithms can be easily carried out. Global risk as-
The main question is whether the addition of one or more of sessment for cardiovascular outcomes is recommended before
the new markers will enhance the predictive power of these sim- starting preventative treatment (1兩QEEE).
ple equations. Another relevant question is whether these mark-
ers will affect the therapeutic intervention. The ability to estimate Evidence
the risk of a CVD event will determine whether the patient re- Several risk assessment algorithms have been published for
quires intervention to lower that risk. If the marker is causally estimating 10-yr risk for CHD. These include Framingham scor-
related to the disease process, then it will also determine which ing for the United States (21) and PROCAM (28) and SCORE for
therapeutic intervention is indicated. Europe (29). These methods use easy-to-collect clinical param-
An example of a widely debated marker is CRP (25). A high eters, for example, age, use of cigarettes, blood pressure, and
CRP level is indicative of a high CVD risk. The therapeutic con- serum lipid levels. Others that are less widely used also have been
sequence may be that general therapy to lower CVD risk should published. The UKPDS risk engine has been developed with val-
be initiated earlier than would be done without an elevated CRP idated CVD risk estimates for people with T2DM (22, 23), but
level for a given Framingham risk score. In that case, measures the population with previously diagnosed diabetes is outside the
might need to be taken to decrease LDL-C and blood pressure to framework of the primary prevention population considered in
lower targets, but the specific evidence for lower targets has not this guideline. We recommend that 10-yr risk for CHD be as-
yet been identified. sessed for individuals using published algorithms that best per-
Are these new markers, and CRP in particular, able to en- tain to the individuals from a particular population group. Clin-
hance the risk estimates of the well-known risk scores/engines? ical judgment or national or regional recommendations can be
Recent studies have addressed this clinically important question used for making these assessments. The Task Force made no
(26). The main and consistent conclusion of these studies is that attempt to compare the different algorithms among different
adding CRP, or in fact other novel risk markers, to more basic population groups. Data are not available for making these
risk models does not improve prediction of CVD risk. This is not comparisons.
very surprising. Most of the risk factors are interrelated and by Currently accepted categories of risk for primary prevention
themselves not able to provide a good prediction. This means in patients with metabolic syndrome are high risk, moderately
that in a clinical setting we can rely on simple, less expensive high risk, and moderate risk. The absolute cutoff points of 10-yr
measures, as for example asking about family history, cigarette risk to define these three categories vary somewhat from one
smoking, and measuring blood pressure and serum lipids. These country to another. Currently accepted categories of Framing-
simple measures will enable us to identify those patients at high- ham risk for patients with metabolic syndrome are high risk
est CVD risk, thus the persons who will benefit the most from any (10-yr risk for major coronary events, ⬎20%), moderately high
medical intervention to lower that risk (27). risk (10 –20%), and moderate risk (⬍10%).
Traditionally recognized risk factors (such as those included
in CVD risk calculators) explain a large proportion of the vari-
ation in CVD risk across individuals. Researchers have shown an Values
association between abnormalities in other biological markers Our recommendations place high value on the need for early
and elevated metabolic risk. These include apo B, LDL fraction- preventative care in vulnerable populations and the need for
ation, adiponectin, leptin, fasting insulin or proinsulin, free fatty simple, easy-to-measure tools in the clinical setting. We place
acids, homocysteine, PAI-1, fibrinogen, ALT as a marker of liver relatively low value on the burden of early therapy with medi-
fat, CRP, inflammatory cytokines (e.g. IL-6), liver or myocellular cations to lower blood pressure and cholesterol and the lack of
fat content by MR spectroscopy, and microalbuminuria (in pa- data to compare the relative efficacy of the different scoring
tients without diabetes). Ease of measurement, convenience, systems.
cost, and extent to which changes in these markers enhance our
ability to identify individuals at different CVD risk above and 3. Treatment to prevent atherosclerotic CVD (especially
beyond the information traditional risk factors provide will de- CHD and stroke)
termine their future role in practice. 3.1.1 We recommend that apo B-containing lipoproteins
In conclusion, none of the mentioned markers can be recom- (LDL and VLDL) be lowered in patients at metabolic risk to
mended for routine clinical use. The readily available simple and reduce risk for CVD (1兩QQQQ).
much less expensive parameters are able to provide a risk as- 3.1.2 We recommend that LDL-C be the primary target of
sessment that enables the physician to target treatment to those lipoprotein-lowering therapy (1兩QQQQ) and that non-HDL-C
who will experience the most benefit. (an indicator for all apo B-containing lipoproteins) be the sec-
ondary target (1兩QQQE). Furthermore, if HDL-C remains re-
2. Absolute risk assessment duced after treatment of non-HDL-C, consideration can be given
2.1 We recommend that all patients identified as having met- to therapies designed to raise HDL-C (2兩QQEE).
abolic risk undergo global risk assessment for 10-yr risk for ei- 3.1.3 We recommend that intensity of lipoprotein-lowering
ther CHD or CVD. Framingham and PROCAM scoring assess therapy be adjusted to the absolute 10-yr risk for CVD
10-yr risk for CHD. The European SCORE algorithm predicts (1兩QQEE). We suggest that intensity of lipoprotein-lowering
therapy further be adjusted to the absolute lifetime risk for CVD with diabetes must be carefully monitored because some patients
(2兩QEEE). show a worsening of glucose control.
Fibrates may be considered as an option as an add-on drug to
Evidence statins (or LDL-lowering drugs) in patients who persist with high
3.1.1 Elevations of apo B-containing lipoproteins (LDL and triglycerides and low HDL after LDL-lowering therapy. This
VLDL), which are characteristic of most patients at metabolic choice depends on physician judgment. It is supported by a meta-
risk, are associated with increased CVD risk. A large number of analysis of fibrate trials (30) that show fibrates in general reduce
randomized controlled clinical trials document that the lowering risk by 15–20%. If a fibrate is used with the statin, fenofibrate is
of apo B-containing lipoproteins will reduce risk for CVD (30). the drug of choice. It is recommended because of evidence of
For this reason, we recommend that in patients at metabolic risk, minimal interaction with statins and decreased risk of myopathy
an effort be made to reduce apo B-containing lipoproteins. with this drug (49).
3.1.2 Non-HDL-C is highly correlated with apolipoprotein B 3.1.3 If it is accepted (3.1.1) that patients with metabolic risk
levels. Recent evidence shows that non-HDL-C is a better pre- deserve therapies to reduce CVD risk, we recommend that in-
dictor of future CHD events than is LDL-C (31– 40). The NCEP tensity of lipoprotein-lowering therapy be adjusted to the abso-
recommends that in patients with elevated triglycerides non- lute 10-yr risk for CVD. The purpose is to optimize risk reduc-
HDL-C be a secondary target of cholesterol-lowering therapy, tion, safety, and cost-effectiveness. The NCEP has identified
after LDL-lowering treatment. In patients at metabolic risk, most LDL-C as the primary target of therapy and has made non-
of whom have some elevation of triglycerides, treatment to lower HDL-C a secondary target in patients with elevated triglycerides
both non-HDL-C and LDL-C to appropriate targets is prudent. (50). The NCEP has made recommendations for balancing these
A low level of HDL-C is a well-accepted risk factor for CVD three factors for achieving these objectives based on 10-yr risk
(41). In a post hoc analysis of the Treating to New Targets study, projections for CHD. The Task Force accepted these recommen-
low HDL-C was shown to be a risk factor for future CHD, even dations as reasonable treatment goals for elevations of apo B-
among CHD subjects who have an LDL-C less than 70 mg/dl containing lipoproteins.
who were treated on statins. However, no clinical trials have One of the major aims of this guideline is to reduce lifetime
definitively shown that raising HDL-C has reduced CHD in statin- risk for CVD in patients with increased metabolic risk. Prospec-
treated subjects, although such trials are currently underway (42). tive studies suggest that evidence of metabolic risk is associated
Evidence that raising HDL-C with specific therapies will re- with an increase in lifetime risk for CVD. We suggest that in-
duce risk for CVD has not been documented adequately in con- tensity of lipoprotein-lowering therapy further be adjusted to the
trolled clinical trials. Smaller clinical trials are supportive of ben- absolute lifetime risk for CVD. Evidence to support this sugges-
efit, but they do not provide the strength of evidence necessary to tion comes from prospective epidemiological and genetic studies
make a strong recommendation. Nonetheless, on the basis of but not from long-term controlled clinical trials. If absolute risk
epidemiological evidence and smaller trials, we suggest that ther- scoring reveals a person at metabolic risk to be at moderately
apy be instituted to raise serum levels of HDL-C to reduce the risk high or high risk (i.e. 10-yr risk for CHD ⱖ10%), the treatment
for CVD in patients at metabolic risk. goals outlined in Table 3 pertain. Here the LDL-C goal is less
HDL-C levels can be raised with both lifestyle therapies and than 130 mg/dl, but an optional goal is LDL-C less than 100
drugs. Lifestyle therapies include weight reduction, increased mg/dl. Corresponding goals for non-HDL-C are 30 mg/dl higher
physical activity, and avoidance of very low fat diets. Drugs that than the LDL-C goal. If 10-yr CHD risk is less than 10%, which
will raise HDL-C levels include nicotinic acid and, to a lesser can be called moderate risk for patients found to be at metabolic
extent, fibrates and statins (43– 46). All of these agents will re- risk, the ranges for LDL-C and non-HDL-C defined by NCEP
duce apo B-containing lipoproteins, and thus the possibility can- guidelines can be taken as a guide to evaluate therapy. Here the
not be ruled out that their actions to lower risk for CVD is due LDL-C and non-HDL-C goals are less than 130 mg/dl and less
to this mechanism and not to raising HDL-C. Furthermore, ac- than 160 mg/dl, respectively.
cording to practice norms, drug therapies to raise HDL-C levels To achieve the goals of therapy outlined in 3.1.3, we recom-
generally are limited to patients at higher risk for CVD. mend that for adjustment of intensity of lipoprotein-lowering
The recent Fenofibrate Intervention and Event Lowering in therapy the therapies be selected that optimize risk reduction,
Diabetes (FIELD) trial (47) tested the efficacy of fenofibrate for safety, and cost-effectiveness. Depending on the level of risk,
reducing CVD risk in patients with established T2DM. In that several therapeutic options are available. For patients at mod-
trial, fenofibrate therapy failed to reduce CHD events as the erate risk for CVD (10-yr risk for CHD ⬍10%), lifestyle ther-
primary endpoint. It did, however, significantly lower total CVD apies (antiatherogenic diet and weight reduction) may be suffi-
and microvascular complications as secondary endpoints. In cient to lower LDL-C and non-HDL-C adequately to reduce
contrast, subgroup analysis of the Veterans Affairs High-Density long-term risk. Table 4 outlines strategies for use of lifestyle
Lipoprotein Intervention Trial (VA-HIT) trial indicated that therapies for reduction in apo B-containing lipoproteins in clin-
gemfibrozil reduced risk for CHD/CVD events in patients with ical practice. This table also shows the degree of reduction of
diabetes (48). In a post hoc analysis of the Coronary Drug LDL-C accompanying each dietary change; it also shows the
Project, nicotinic acid was found to reduce risk for CHD events estimated reduction in risk for CHD accompanying the dietary
in patients with diabetes (45). Although nicotinic acid produces change projected from the change in LDL-C levels. Increased
a favorable effect on the lipoprotein pattern, its use in patients physical activity can also be recommended simultaneously with
TABLE 3. Treatment goals for apo B-containing lipoproteins the LDL-C remains more than 130 mg/dl on maximal lifestyle
therapy. For patients at higher risk (10-yr risk for CHD ⱖ10%),
Therapeutic target and lifestyle therapy still should be employed to maximize lowering
goals of therapy for apo of lipoproteins. However, consideration can be given to using
B-containing lipoproteins
cholesterol-lowering drugs if LDL-C is at least 130 mg/dl on
LDL-C goals lifestyle therapies, with an optional goal of less than 100 mg/dl
High-risk patientsa ⬍100 mg/dl (2.6 mmol/liter)
(51– 65). It must be recognized that cholesterol-lowering drugs
(for very-high-risk patientsb
in this category, optional have not been studied in all subgroups of the population or in
goal is ⬍70 mg/dl) many different populations, but that they have the ability to
Moderately high-risk patientsc ⬍130 mg/dl (3.4 mmol/liter) reduce risk for CVD under a broad range of circumstances is
(for higher-risk patients beyond doubt (66 – 68). For this reason, the Task Force does not
in this category, optional goal
exclude patients on the basis of ethnicity, gender, or age. None-
is ⬍100 mg/dl 关2.6 mmol/liter兴)
Moderate-risk patientsd ⬍130 mg/dl (3.4 mmol/liter) theless, different subgroups of the population may require spe-
Non-HDL-C goals cial considerations, as discussed below.
High-risk patientsa ⬍130 mg/dl (3.4 mmol/liter)
(optional: ⬍100 mg/dl for
very high risk patientsb)
Women
Moderately high-risk patients c
⬍160 mg/dl (4.1 mmol/liter); In women, onset of CHD is delayed by 10 –15 yr as compared
therapeutic option: ⬍130 mg/dl with men in general (69). However, management for risks is as
(3.4 mmol/liter) important for women as for men. To prevent premature CHD
Moderate-risk patientsd ⬍160 mg/dl (4.1 mmol/liter) (i.e. before age 65 yr), metabolic syndrome in women should be
a
High-risk patients are those with established atherosclerotic CVD, diabetes, or treated the same as in men.
10-yr risk for CHD higher than 20%. For cerebrovascular disease, high-risk
condition includes transient ischemic attack or stroke of carotid origin or more
than 50% carotid stenosis. Ethnic groups
b
Very-high-risk patients are those who are likely to have major CVD events in Despite relatively higher rates of CHD in African-Americans
the next few years, and diagnosis depends on clinical assessment. Factors that as compared with Caucasians (69), typically the triglyceride lev-
may confer very high risk include recent acute coronary syndromes and
established CHD along with any of the following: multiple major risk factors
els in African-Americans are lower and the HDL-C levels are
(especially diabetes), severe and poorly controlled risk factors (especially higher than those in Caucasians (70). These lipid profiles are not
continued cigarette smoking), and metabolic syndrome. explained by differences in BMI or other factors (71). It is not
c
Moderately high-risk patients are those with 10-yr risk for CHD 10 –20%. clear whether this lipid pattern works protectively. On the other
Factors that favor the therapeutic option of non-HDL-C less than 100 mg/dl are
those that can raise persons to the upper range of moderately high risk: multiple
hand, African-Americans have long been known to have the
major risk factors, severe and poorly controlled risk factors (especially continued highest prevalence of hypertension of all ethnic groups. This
cigarette smoking), metabolic syndrome, and documented advanced subclinical higher incidence might cancel the favorable lipid profile.
atherosclerotic disease (e.g. coronary calcium or carotid intimal-medial thickness
⬎75th percentile for age and sex).
d
Moderate-risk patients are those with at least two major risk factors and 10-yr Younger adults
risk less than 10%. In the younger population, CHD is rare. However, years of
life lost, defined as the difference between the number of years a
other lifestyle therapies because of prospective studies that sug- person would be expected to live if he/she were not obese,
gest it will reduce cardiovascular risk. Furthermore, in all pa- showed that the younger population lost more years than the
tients, cessation of cigarette smoking is mandatory to reduce older population (72). Thus, the younger population with met-
CVD risk. In patients at moderate metabolic risk, ATP III guide- abolic syndrome should be treated more strictly than the older
lines recommend reserving cholesterol-lowering drugs to those population.
with higher cholesterol levels, e.g. LDL-C at least 160 mg/dl Table 5 summarizes the available cholesterol-lowering drugs.
(non-HDL-C ⱖ190 mg/dl). On the basis of recent clinical trials, It also provides estimated reductions in LDL-C accompanying
many authorities favor employing cholesterol-lowering drugs if each therapeutic regimen as well as projected reductions in CHD.
TABLE 4. Recommended dietary changes to reduce apo B-containing lipoproteins and estimated reduction in CHDa
Dietary factor Suggested change LDL-C reduction (%) Estimated CHD reductionb (%)
Saturated fat reduction Reduce saturated fat to ⬍7% of total energy 8 –10 ⬎8 –10
Trans fat reduction Reduce trans fat to ⬍1% of total energy 2 ⬵2
Dietary cholesterol reduction Reduce dietary cholesterol to ⬍200 mg/d 3–5 ⬎3
Plant stanols/sterols Add plant stanols/sterols 2 g/d 6 –10 ⬎6
Dietary fiber Add viscous fiber 5–10 g/d 3–5 ⬎3
Weight reduction Reduce body weight by 7–10% 5– 8 ⬎5
Total ⬃25–35 ⬃25
a
LDL-C is used as a surrogate marker for apo B-containing lipoproteins because the available data are more robust for this marker than for other lipoprotein fractions.
b
Estimate based on results of controlled clinical trials that a 1% reduction in LDL-C reduces risk for CHD by approximately 1%.
TABLE 5. Summary of efficacy of drugs that reduce apo B-containing lipoproteins
Standard dose: LDL-C Standard dose: estimated High dose: LDL-C High dose: estimated
Drug category reduction (%) CHD reductiona (%) reduction (%) CHD reductiona (%)
Statins 30 – 40b 30 – 40 45–55h 45–55
(for more potent statins)
Cholesterol-absorption blocker 18 –25c 18 –25
(ezetimibe)
Bile acid sequestrants 15–20d 15–20 20 –25i 20 –25
Niacin 10 –15e 10 –15g 15–20 j 15–20
Fibrates 5–15f 10 –20g
a
The estimated reduction in CHD is based on clinical trial evidence that a 1% reduction in LDL-C is associated with a 1% reduction in CHD risk. However, because LDL-
lowering drugs also reduce VLDL-C, some of the risk reduction attributed to LDL-C lowering may be the result of a simultaneous reduction in VLDL-C.
b
Lovastatin 40 mg, pravastatin 40 mg, simvastatin 20 – 40 mg, fluvastatin 40 – 80 mg, atorvastatin 10 mg, rosuvastatin 5–10 mg.
c
Ezetimibe 10 mg.
d
Cholestyramine 4 –16 g, colestipol 5–20 g, colesevelam 2.6 –3.8 g.
e
Extended release niacin (Niaspan) 2 g.
f
Gemfibrozil 1200 mg, fenofibrate 145–200 mg.
g
A portion of the reduction in CHD risk may be related to a rise in HDL.
h
Simvastatin 80 mg, atorvastatin 80 mg, rosuvastatin 40 mg.
i
Cholestyramine 24 g, colestipol 30 g, colesevelam 4.4 g.
j
Crystalline nicotinic acid 4.5 g.
3.2.1 We recommend that when blood pressure is elevated, it to reduce the risk for CVD in patients at metabolic risk. The
be lowered to reduce the risk for CVD (1兩QQQQ). primary goal for blood pressure lowering according to JNC7 is
3.2.2 We recommend that type and intensities of blood pres- a level of less than 140/90 mm Hg. However, because even milder
sure-lowering therapies be selected to optimize risk reduction, forms of elevated blood pressure are accompanied by increased
safety, and cost-effectiveness. We recommend that blood pres- risk for CVD, reducing blood pressure to the normal range
sure be treated to a target of less than 140/90 mm Hg (or (⬍120/⬍80 mm Hg) is considered optimal for long-term pre-
⬍130/80 in individuals with diabetes or chronic kidney disease). vention of CVD. Still, the incremental benefit of achieving nor-
If weight loss or lifestyle modifications are not successful, then mal blood pressure levels, compared with the prehypertensive
antihypertensive medications should be instituted and dose ad- range, has not been documented in controlled clinical trials. This
justed to treat to target (1兩QQQE). potential benefit can be extrapolated from prospective studies in
which people with normal blood pressure have the lowest rates
Evidence of CVD.
3.2.1 An elevated blood pressure is a major risk factor for 3.2.2 Blood pressure can be lowered by both lifestyle and drug
CVD. Its effect on CVD risk has been documented in many pro- therapies (74 –78). For this reason, we recommend that the type
spective studies. The higher the blood pressure is, the greater will and intensities of blood pressure-lowering therapies be selected
be the risk for both CHD and stroke. This fact has led treatment
to optimize risk reduction, safety, and cost-effectiveness. For
guidelines to classify severity of hypertension according to in-
example, for patients at metabolic risk whose blood pressures are
creasing levels of blood pressure. The Seventh Report of the Joint
in the prehypertensive range, lifestyle therapies are preferable to
National Committee on Prevention, Detection, Evaluation, and
drug treatment for both safety and cost reasons. The extent to
Treatment of High Blood Pressure (JNC7) (73) provides an ac-
which various lifestyle therapies can lower blood pressure was
ceptable classification of progressively elevated blood pressure
estimated by JNC7 (73) and is shown in Table 7. When blood
(Table 6). Furthermore, a large number of controlled clinical
pressure reaches the hypertensive range, lifestyle therapies
trials demonstrate that lowering of blood pressure will reduce
should be continued, but consideration can be given to adding
risk for CVD, both CHD and stroke. For these reasons, we rec-
drug therapy. Dietary sodium restriction is an important com-
ommend that when the blood pressure is elevated, it be lowered
ponent of lifestyle therapies to control blood pressure, and we
support the recommendations of JNC7 with respect to this. Tai-
TABLE 6. Categories of blood pressure loring drug therapy to treat hypertension is beyond the scope of
this document and has been outlined in detail in the JNC7 report.
Systolic and/or diastolic blood
Blood pressure category pressures (mm Hg) There is controversy as to whether certain antihypertensive drugs
Normal ⬍120 and ⬍80 are to be preferred in patients at metabolic risk. Some investi-
Prehypertension 120 –139 or 80 – 89 gators favor use of angiotensin-converting enzyme inhibitors
Hypertension, stage 1 140 –159 or 90 –99 and angiotensin receptor blockers over diuretics and ␤-blockers
Hypertension, stage 2 ⱖ160 or ⱖ100 (77, 79 – 81). However, in practice, treatment of hypertension
Blood pressure categories based on the JNC7 (73). often requires multiple drugs to achieve the goal of therapy, and
TABLE 7. Projected reductions in blood pressure accompanying lifestyle therapies
Projected reduction in systolic

Lifestyle therapy Specific recommendation blood pressure (mm Hg)
Weight reduction Weight reduction of 7–10% of body weight 5–20
Moderate exercise Moderate exercise (30 min/d) 4 –9
Reduce dietary sodium ⬍2 g/d (100 mmol/d) 2– 8
Other nutrient change Increased fruits and vegetables (e.g. DASH Diet) 5 servings per day 8 –14
Moderation of alcohol intake 2– 4
Total Total BP lowering ⬎10 mm Hg
Estimations of efficacy of lifestyle modification taken from the JNC7 (73). BP, Blood pressure.
preferences must give way to the priority of attaining the desired 3.4.1 We recommend that the prothrombotic state be treated
blood pressure (82– 85). with lifestyle therapies to reduce risk for CVD (1兩QEEE).
3.3 We recommend that lifestyle management be consid- 3.4.2 In individuals at metabolic risk who are over age 40 and
ered first-line therapy for patients at increased metabolic risk whose 10-yr risk is more than 10%, we recommend that low-
(1兩QEEE). dose aspirin prophylaxis for primary prevention of CVD (75–
162 mg/d) be considered if there are no contraindications
Evidence (1兩QQQE).
Lifestyle therapies (weight reduction, increased physical ac- There is no consensus on the specific recommended dose
tivity, and antiatherogenic diet) have been shown to reduce all of within this range.
the components of the metabolic syndrome simultaneously (86 –
91). The only drugs that have the same effects are weight reduc- Evidence
tion drugs. However, currently available drugs of this type are 3.4.1 A prothrombotic state is recognized as a significant risk
associated with side effects that limit their use in many patients. factor for CVD. Patients with metabolic syndrome exhibit an
In addition, drugs that treat individual risk components do not increase in coagulation factors and antifibrinolytic factors.
modify all of them simultaneously. For these reasons, lifestyle These factors can be reduced by weight loss (95–99). In addition,
therapies clearly have priority over drug treatment. Nonetheless, aspirin therapy will reduce the likelihood of cardiovascular
in patients at increased risk for CVD or those with clinically thrombosis (coronary thrombosis and stroke) (100, 101). We
significant risk factors (e.g. elevated cholesterol or blood pres- therefore recommend that the prothrombotic state be treated to
sure), drug therapy targeted to treat those specific risk factors reduce risk for CVD. Lifestyle therapies should be introduced in
may be required to achieve current goals of therapy. all patients at metabolic risk to reduce coagulation factors and
Although one study has suggested, in a secondary analysis, a antifibrinolytic factors.
beneficial effect of a thiazolidinedione (TZD) in reduction of 3.4.2 Several analyses suggest that if the 10-yr risk for CHD
cardiovascular risk (92), we cannot recommend such use for is 10% or more, the risk-to-benefit ratio is favorable for preven-
primary prevention at this time. Concerns related to the in- tion of CVD. Therefore, we suggest that aspirin therapy be in-
creased risk of fractures with these agents, the possibility of ex- stituted (if not contraindicated) when 10-yr risk for CHD ex-
acerbation of previously undetected congestive heart failure with ceeds 10%. The existing evidence indicates that aspirin therapy
thiazolidinedione, and the possible increased risk of cardiovas- will reduce risk for CVD in primary prevention. On the other
cular events with rosiglitazone (93) make inadvisable the use, at hand, a small fraction of treated subjects will experience major
present, of this class of medications in large populations for bleeding episodes including stroke. Even so, the aspirin prophy-
prevention. laxis option is favored by the American Heart Association. It
Complete cessation of smoking and elimination of exposure must be noted nonetheless that some authorities express caution
to tobacco smoke in the environment are important goals of about the use of aspirin for primary prevention; they contend
lifestyle intervention to reduce the risk of cardiovascular disease that the benefit-to-risk ratio is not high enough to justify as-
and stroke. We support the recommendations of the American pirin therapy in this risk category. One report also suggests
Heart Association with respect to smoking cessation (94). that aspirin therapy may be only marginally efficacious for
CVD reduction in women. Despite these caveats, the Task
Values Force favors institution of aspirin treatment for patients at
Our recommendations for lifestyle management as first-line metabolic risk when their 10-yr risk for CHD is more than 10%.
therapy place high value on avoiding the potential risks and side
effects of the use of TZDs and metformin in very large popula- Values
tions, in which the relationship of risk to potential benefit is not Our recommendation for the use of lifestyle therapies to re-
yet established. We also place high value on the relative safety duce the prothrombotic state places a higher value on the use of
and public health benefit of lifestyle modification measures in the exercise, fitness, and behavior modification for CVD and T2DM
clinical setting and low value on the current difficulties of insti- prevention because of its multiple health benefits as part of a
tuting these measures in the clinical office setting. coordinated plan of care. We place a lower value on the evidence
for specific benefits with regard to reduction of the prothrom- progression to diabetes was significantly lower in all three in-
botic state and the difficulties in instituting such therapies in the tervention groups than in the control group: 44% in the diet-only
medical office setting. group, 41% in the exercise-only group, and 46% in the com-
bined diet and exercise group, as compared with 68% in the
4. Treatment to prevent T2DM control group.
4.1.1 For primary prevention of T2DM, we recommend that The Finnish Diabetes Prevention Study (107) was a random-
patients found to be at higher metabolic risk on the basis of ized clinical trial conducted in overweight men and women with
multiple metabolic syndrome components be started on a clinical IGT who were identified by screening high-risk populations.
program of weight reduction (or weight maintenance if not over- Subjects were randomized to usual care or to an individualized
weight or obese) through an appropriate balance of physical lifestyle modification program that emphasized weight reduc-
activity, caloric intake, and formal behavior modification pro- tion of at least 5% by reduced caloric intake, decreased intake of
grams to achieve a lowering of body weight/waist circumference dietary fat and saturated fats, increased fiber intake, and the
below the targets indicated (see 1.3 for waist circumference and addition of 4 h/wk moderate-intensity exercise. After a mean 3.2
4.1.2 for weight) (1兩QQEE). yr follow-up, the risk of developing diabetes was decreased by
Although it is important to aim for these targets, any lowering 58% in the intensive lifestyle modification group. Moreover, in
of body weight/waist circumference is beneficial, and we rec- those subjects who exceeded the weight loss goal of 5%, the risk
ommend use of lifestyle modification programs for this pur- reduction was 74%, and in those who exceeded the exercise goal
pose (1兩QQEE). of 4 h/wk, the relative risk reduction was 80%. In follow-up
4.1.2 In individuals at metabolic risk who have abdominal studies done 3 yr after completion of active counseling, the ben-
obesity, we suggest that body weight be reduced by 5–10% dur- eficial effects of the lifestyle program persisted with 36% risk
ing the first year of therapy (2兩QEEE). Efforts to continue weight reduction (110).
loss or maintain the weight loss over the long term should be The DPP (103), conducted in 27 centers in the United States,
encouraged. randomized 3234 adults with IGT to groups receiving an inten-
4.1.3 We recommend that patients at metabolic risk undergo sive lifestyle modification intervention, treatment with met-
a program of regular moderate-intensity physical activity formin, or placebo. Initially, there was also a group treated with
(1兩QQEE). This activity would be for at least 30 min, but pref- troglitazone, but this was discontinued early in the study before
erably 45– 60 min, at least 5 d/wk. It could include brisk walking recruitment was completed, and follow-up of this group was less
or more strenuous activity. It can be supplemented by an increase than 1 yr compared with a mean of 2.8 yr for the three completed
in physical exercise as part of daily lifestyle activities. groups, which included over 1000 subjects per group. The goals
4.1.4 We recommend that all individuals at metabolic risk for the group receiving the intensive lifestyle modification inter-
follow a diet that is low in total and saturated fat, is low in trans vention were to lose at least 7% of body weight through a 24-wk
fatty acids, and includes adequate fiber (1兩QQEE). We suggest program of diet and exercise and to maintain this weight loss
that saturated fat be less than 7% of total calories and dietary throughout the duration of the study (111). Lifestyle modifica-
cholesterol less than 200 mg/d (2兩QEEE). We recommend that tion emphasized reducing caloric intake, principally by reduc-
trans fat in the diet should be avoided as much as possible tion of fat to less than 25% of energy, decreasing saturated fats,
(1兩QEEE). There is much controversy regarding the proportion increasing dietary fiber, and increasing physical activity by at
of carbohydrates in the diet. We were unable to reach consensus least 150 min/wk moderate-intensity exercise equivalent to brisk
on the optimal ratio of carbohydrates to fats in the diet. We walking (20). The intensive lifestyle modification intervention
recommend that individuals at metabolic risk increase the pro- decreased the risk of developing diabetes by 58% as compared
portion of fiber, unprocessed grains, and unsaturated fat in their with the placebo-treated control group. The intensive lifestyle
diet. Avoiding foods with high glycemic index may help lower modification intervention was significantly more effective than
metabolic risk. treatment with metformin, up to 850 mg, which reduced the risk
of diabetes by 31% (103, 112).
Evidence In the DPP, 53% of subjects met the NCEP ATP III criteria for
During the past 20 yr there have been numerous studies of the the metabolic syndrome at baseline, whereas 47% did not. This
effects of weight reduction and increased physical activity on the provided an opportunity to evaluate the effects of the treatment
development of T2DM in high-risk populations (102–107). strategies to prevent or reverse the features of the metabolic syn-
These have been reviewed by Norris and colleagues (108) and by drome and other metabolic risk factors in this high-risk popu-
Yamaoka and Tango (109). At least three of these trials, the Da lation. Post hoc analyses found that in subjects without meta-
Qing Study (105), The Finnish Diabetes Prevention Study (107), bolic syndrome at baseline, approximately 60% of the control
and the DPP in the United States (103), have demonstrated that group developed it over 4 yr. Metformin treatment reduced the
weight reduction and increased physical activity significantly de- risk by 17% and the intensive lifestyle modification intervention
crease the risk of progression from IGT to diabetes by 40 –58%. decreased it by 41%. Furthermore, in subjects who had meta-
In the Da Qing Study, subjects with IGT were assigned by clinic, bolic syndrome at baseline, the intensive lifestyle modification
rather than individually, to one of four treatment groups: a cal- intervention resulted in a reversal of the syndrome in 38%,
orie-restricted diet, an exercise program, a combined program of whereas reversal occurred in 18% of the control group (20).
diet and exercise, or a control group. During this 6-yr study, the In other analyses of the DPP data (113), it was found that
hypertension was present in 30% of subjects at baseline. Over 3 TABLE 8. Recommendations for lifestyle reduction of plasma
yr, it increased in the placebo- and metformin-treated groups but glucose to lower risk for T2DMa
significantly decreased in the group receiving the intensive life-
style modification intervention. Serum triglycerides decreased in Dietary recommendation Goals of therapy
all groups but significantly more in the intensive lifestyle mod- Weight reduction Achieve and maintain a weight loss
ification intervention group. This group also had significantly of 7% with healthy eatingb
Physical activity Maintain physical activity at least
increased HDL-C levels and decreased small dense LDL-C. After
150 min/wk with moderate
3 yr, the quantity of medications used to control blood pressure exercise, such as walking or
and dyslipidemia was reduced by 25–28% in the group receiving biking
intensive lifestyle modification intervention. At baseline, high- a
Recommendations correspond to the intervention arm of the DPP (111).
sensitivity CRP was increased in all groups and was correlated b
For healthy eating, follow dietary guidelines for lowering cholesterol and blood
with BMI, waist circumference, FPG, and insulin resistance pressure (see Tables 3 and 6).
(114). After 1 yr, use of metformin resulted in a modest 7–14%
reduction in high-sensitivity CRP, but the intensive lifestyle mod-
confirmed in two other clinical TZD trials, the TRIPOD study
ification intervention resulted in a 29 –33% reduction.
using troglitazone (118) and the DREAM trial using rosiglita-
Thus, there is convincing evidence from well-conducted ran-
zone (119). One clinical trial with a TZD provided suggestive
domized controlled trials that weight reduction of 5–10% of
evidence that treatment of diabetes with pioglitazone may also
initial body weight in overweight subjects with metabolic risk is
reduce the risk for CVD (92, 120), but such a result has not been
effective in decreasing the development of T2DM and reducing
confirmed in patients at metabolic risk without diabetes. More-
multiple CVD risk factors. In general, weight loss programs are
over, recent studies with rosiglitazone have raised questions
designed to achieve a negative energy balance of 500 –1000
about the long-term safety of this drug for diabetes prevention or
kcal/d, which results in a weight loss of 1–2 lb/wk (0.5–1.1 kg/
treatment (93, 121). We suggest that priority be given to reducing
wk). Both the DPP and the Finnish Diabetes Prevention Study
risk for diabetes with lifestyle therapies rather than drug thera-
used a diet with 25% of energy from fat (7% from saturated fats)
pies. There are three reasons for this suggestion. First, lifestyle
and increased amounts of fiber. Consumption of high-fructose
therapies appear to be as effective as drug treatment for reducing
corn syrup-containing beverages has been associated with obe-
conversion to diabetes (20). Second, there are limited data on the
sity and T2DM (115, 116), and restriction of their use is recom-
long-term safety of drug therapy for the treatment of prediabetes.
mended in most weight-loss programs. Considerable contro-
Third, the cost-effectiveness and long-term risks of drug therapy
versy exists on the amounts and types of carbohydrates that
in these populations have not been adequately assessed.
should be incorporated into weight-loss diets. This controversy
includes the use of low glycemic index foods, glycemic load, and
percentage of energy from carbohydrate sources.
Appendix 1: Method of Development of
Values Evidence-Based Guidelines
Our recommendations for dietary modification and exercise
The Clinical Guidelines Subcommittee of the Endocrine Society deemed
to reduce the risk of diabetes place high value on the use of these therapy of metabolic risk a priority area in need of practice guidelines and
programs in a coordinated manner to improve health and reduce appointed a seven-member Task Force to formulate evidence-based rec-
multiple risk factors simultaneously and low value on the socio- ommendations. The Task Force elected to use the approach recom-
economic factors that currently tend to prevent these interven- mended by the GRADE group, an international group with expertise in
tions from being implemented. We believe that proper imple- development and implementation of evidence-based guidelines (122).
The Task Force reviewed the available literature to inform its key rec-
mentation of these recommendations extends beyond the realm ommendations and used consistent language and graphical descriptions
of the medical office practice and enters the areas of public health of both the strength of recommendation and the quality of evidence. The
and public policy. strength of a recommendation is indicated by the number 1 (strong rec-
4.2 We recommend that priority be given to reducing risk ommendation, associated with the phrase “we recommend”) or 2 (weak
for diabetes with lifestyle therapies rather than drug therapies recommendation, associated with the phrase “we suggest”). The quality
of the evidence is indicated by cross-filled circles, such that Q䡬䡬䡬
(1兩QQQE). denotes very low quality evidence, QQ䡬䡬 low quality, QQQ䡬 moderate
quality, and QQQQ high quality. Recommendations are followed by a
Evidence description of the evidence, and in some instances the values, that the
There is growing clinical trial evidence, particularly the DPP, Expert Panel considered in making the recommendation. A detailed de-
that risk for diabetes can be reduced by lowering plasma glucose scription of this grading scheme has been published elsewhere (123).
levels in patients with prediabetes. Glucose concentrations can
be reduced by either lifestyle therapies or by drug therapy. Life-
style therapy consists of weight reduction and increased physical Appendix 2: Choice of Terminology
activity (Table 8). In addition, glucose concentrations can be
In this guideline, we focus on a specific set of risk factors for CVD and
reduced by either metformin or a TZD. In the DPP, both met- T2DM. The term metabolic syndrome has been used to describe a set of
formin and a TZD (troglitazone) were shown to delay the con- clinical features clustered in individuals, most of whom have abdominal
version of prediabetes to diabetes (103, 117). This delay was adiposity, conferring an increased risk for CVD and T2DM. There are
various definitions of the metabolic syndrome; they all include a subset 1997–1999 despite increasing central obesity. The metabolic syndrome
of the relevant risk factors for CVD and T2DM. Although these risk by itself offers little substantial advantage in CVD risk prediction over
factors (high triglycerides/low HDL, increased small dense LDL, elevated available algorithms (e.g. the Framingham score). However, a careful
blood pressure, elevated plasma glucose, abdominal obesity, insulin re- metaanalysis has shown that depending on the definition (and modifi-
sistance, and inflammatory and thrombotic markers) tend to occur to- cations thereof), sample size, subject selection, duration of follow-up,
gether in the same individuals, the etiology is not fully understood. Fur- outcome event, and type of statistical analysis, using the metabolic syn-
thermore, because these definitions do not contain all CVD risk factors drome as a predictor may provide some improvement in risk assessment
and dichotomize the population into those with and without the meta- (141). To predict diabetes, on the other hand, the current definitions of
bolic syndrome, it should not be used as an indicator of absolute, short- metabolic syndrome do not offer any significant advantage over other
term risk for CVD. The occurrence of multiple metabolic risk factors in algorithms (142, 143), although they efficiently detect impaired glucose
one individual, nonetheless, does indicate the presence of a higher long- tolerance (19), which is an important antecedent of diabetes. Which
term risk for both CVD and T2DM. component of the syndrome carries what weight has not been
The concept that insulin resistance clusters with glucose intolerance, established.
dyslipidemia, and hypertension to enhance CVD risk was proposed by For the metabolic syndrome to be a better predictor of risk for CVD
Reaven in 1988 (124). At that time, it was presumed that the various and T2DM, its criteria must be unambiguously defined (144). Physio-
clinical characteristics were linked by an overriding pathophysiological logical parameters should not be dichotomized unless independent evi-
mechanism tied to insulin resistance, hence the term insulin resistance dence proves the existence of a threshold in their relation to risk. Mod-
syndrome (IRS). In IRS, the primacy of insulin resistance is posited on the eling should explore nonlinearities and weighting, and established
grounds that insulin resistance is an effective transducer of environmen- predictors (e.g. age, familial diabetes, premature CVD, etc.) should be
tal influences, obesity (especially visceral) (10), cardiorespiratory fitness included in the model.
(125), and stress (126) being the most important ones. On the effector In this document, the term metabolic risk is employed so as not to
side, insulin exerts potent actions not only in pathways of glucose ho- favor one term over another. One reason for avoiding use of metabolic
meostasis but also on lipid turnover, blood pressure control, and vascular syndrome, the most popular term, is that major organizations that have
reactivity. Moreover, chronic hyperinsulinemia, the in vivo adaptive re- produced guidelines for the metabolic syndrome allow its diagnosis to be
sponse to insulin resistance, has been shown to have pathogenic potential extended to patients with T2DM. The Endocrine Society recognizes
in its own right [for example, by down-regulating insulin action (127), T2DM as a separate disease entity, for which other guidelines specific
strengthening antinatriuresis (128), or stimulating the adrenergic ner- to diabetes are applicable. Therefore, to avoid any confusion, meta-
vous system (129)], thereby creating reinforcement circuits in the net- bolic risk is restricted to patients who do not manifest clinical dia-
work (130). These facts are supported by a wealth of experimental and betes. It does not, however, exclude prediabetes from the category of
clinical investigation (131). However, it is crucial to emphasize that just metabolic risk.
as insulin resistance alone is insufficient to alter glucose tolerance, for
which some degree of ␤-cell dysfunction is required, insulin resistance/
hyperinsulinemia is neither strictly necessary nor sufficient to alter lipid
metabolism, blood pressure, or vascular function. Each of these homeo- Acknowledgments
static systems is under the control of multiple factors. Also, each of these
systems is redundant, with plenty of interactions. The members of the Task force thank Dr. Robert Vigersky, the members
More recently, the pathophysiological IRS has been replaced by com- of the Clinical Guidelines Subcommittee, the Clinical Affairs Core Com-
binations of clinical criteria, defined by various organizations, which mittee, and the Council of the Endocrine Society for their careful reading
attempt to describe a clinical entity, the metabolic syndrome. The major of and very useful suggestions for improving the guideline. We thank the
purpose initially was to use clinical signs and symptoms to identify people members of the Endocrine Society at large for their input when the draft
with a clustering of risk factors, with a higher risk for CVD and T2DM guideline was posted on the Society’s website; all the responses received
than the general population. were considered by the authors, and many incorporated. We greatly
In fact, hyperinsulinemia predicts diabetes, dyslipidemia (132), and appreciate the help of Dr. Victor Montori, who provided review of the
to a lesser extent hypertension (133), and it is an independent, if weak, evidence and grading of the recommendations of the guideline and par-
CVD predictor (134). Measuring insulin resistance directly (by the glu- ticipated actively in our discussions. We thank Lisa Marlow of the En-
cose clamp technique or by glucose tolerance testing) is too difficult for docrine Society, who has provided superb administrative support for this
practical clinical use. Using fasting plasma insulin levels as a proxy for project, without which such a geographically dispersed international
insulin resistance introduces confounding, due to the partly different group would have found the task of producing this guideline insur-
physiology of hyperinsulinemia and insulin resistance (135) as well as mountable. Finally and most importantly, we are greatly indebted to Dr.
lack of measurement standardization across studies. Patricia A. Stephens, medical writer, for her meticulous editing of the
These practical hurdles have prompted the search for practical, easily document, checking of both text and references, and her help in improv-
measured surrogates of insulin resistance, among which the waist girth ing the clarity and quality of this manuscript.
or the waist-to-hip ratio seemed best in certain epidemiological studies
(136). Thus, anthropometric measures have tended to replace insulin Address all correspondence to: The Endocrine Society, 8401 Con-
resistance in various definitions of the syndrome, such as those from necticut Avenue, Suite 900, Chevy Chase, Maryland 20815. E-mail: govt-
AHA/NHLBI (1), WHO (137), NCEP ATP III (50), IDF (2), European prof@endo.society.org. Telephone: 301-941-0200. Address all reprint re-
Group for the Study of Insulin Resistance (138), and American College quests for orders of 101 and more to: Heather Edwards, Reprint Sales
of Endocrinology (139). These varying definitions have adopted mix- Specialist, Cadmus Professional Communications, Telephone: 410-691-
tures of anthropometric, pathophysiological, and clinical criteria. Pre- 6214, Fax: 410-684-2789 or by E-mail: endoreprints@cadmus.com. Ad-
dictors (waist girth, insulin, and triglycerides) and outcomes (diabetes dress all reprint requests for orders of 100 or less to Society Services, Tele-
and hypertension) have been dichotomized (thresholds rather than con- phone: 301-941-0210 or by E-mail: societyservices@endo-society.org.
tinuous variables), assembled (any two of three or three of five criteria),
and even prioritized (e.g. waist girth first, then any two of three) as a
result of clinical consensus, without hard evidence for their usefulness.
The stability of the metabolic syndrome over time is ill defined; it may Disclaimer
display a relatively high rate of spontaneous regression (as is the case with
IGT). In the only relevant study (140), the prevalence of the metabolic Clinical Practice Guidelines are developed to be of assistance to endo-
syndrome did not increase in Mexico City between 1990 –1992 and crinologists by providing guidance and recommendations for particular
areas of practice. The Guidelines should not be considered inclusive of all Diagnosis and management of the metabolic syndrome: an American Heart
proper approaches or methods, or exclusive of others. The Guidelines Association/National Heart, Lung, and Blood Institute Scientific Statement.
cannot guarantee any specific outcome, nor do they establish a standard Circulation 112:2735–2752
2. Alberti KG, Zimmet P, Shaw J 2005 The metabolic syndrome: a new world-
of care. The Guidelines are not intended to dictate the treatment of a
wide definition. Lancet 366:1059 –1062
particular patient. Treatment decisions must be made based on the in-
3. 1998 Clinical Guidelines on the Identification, Evaluation, and Treatment of
dependent judgment of health care providers and each patient’s individ- Overweight and Obesity in Adults: The Evidence Report. National Institutes
ual circumstances. of Health. Obes Res [Erratum (1998) 6:464] 6(Suppl 2):51S–209S
The Endocrine Society makes no warranty, express or implied, re- 4. Gami AS, Witt BJ, Howard DE, Erwin PJ, Gami LA, Somers VK, Montori VM
garding the Guidelines and specifically excludes any warranties of mer- 2007 Metabolic syndrome and risk of incident cardiovascular events and
chantability and fitness for a particular use or purpose. The Society shall death: a systematic review and meta-analysis of longitudinal studies. J Am
not be liable for direct, indirect, special, incidental, or consequential Coll Cardiol 49:403– 414
damages related to the use of the information contained herein. 5. Meigs JB, Rutter MK, Sullivan LM, Fox CS, D’Agostino Sr RB, Wilson PW
2007 Impact of insulin resistance on risk of type 2 diabetes and cardiovascular
disease in people with metabolic syndrome. Diabetes Care 30:1219 –1225
6. Wilson PW, D’Agostino RB, Parise H, Sullivan L, Meigs JB 2005 Metabolic
syndrome as a precursor of cardiovascular disease and type 2 diabetes mel-
Financial Disclosure of Task Force litus. Circulation 112:3066 –3072
7. Ferrannini E, Stern MP 1995 Primary insulin resistance: a risk syndrome. In:
James L. Rosenzweig, M.D. (chair) – Significant Financial Interests: none Leslie RDG, Robbins DC, eds. Diabetes: clinical science in practice. Cam-
declared; Governance: National Diabetes Quality Improvement Alli- bridge, UK: Cambridge University Press; 200 –220
ance; Consultation or Advisement: AMA Physician Consortium for Per- 8. Rutter MK, Meigs JB, Sullivan LM, D’Agostino Sr RB, Wilson PW 2005
formance Improvement Advisory Committee, Alere Medical Scientific Insulin resistance, the metabolic syndrome, and incident cardiovascular
events in the Framingham Offspring Study. Diabetes 54:3252–3257
Advisory Board, Blue Cross-Blue Shield of Massachusetts Advisory
9. Cowie CC, Rust KF, Byrd-Holt DD, Eberhardt MS, Flegal KM, Engelgau
Board, National Quality Forum Technical Advisory Panel, Disease Man-
MM, Saydah SH, Williams DE, Geiss LS, Gregg EW 2006 Prevalence of
agement Association of America Advisory Board; Grant or Other Re- diabetes and impaired fasting glucose in adults in the U.S. population: Na-
search Support: Ruby Linn Foundation; Honoraria: Alere Medical, tional Health and Nutrition Examination Survey 1999 –2002. Diabetes Care
Merck, Healthways; Philips Medical, Sanofi-Aventis; Speakers Bureau: 29:1263–1268
Bristol-Myers Squibb; Merck, Sanofi-Aventis; Ele Ferrannini, M.D. – 10. Lebovitz HE, Banerji MA 2005 Point: visceral adiposity is causally related to
Significant Financial Interests: none declared; Governance: none de- insulin resistance. Diabetes Care 28:2322–2325
clared; Consultation or Advisement: none declared; Grant or Other Re- 11. Tan CE, Ma S, Wai D, Chew SK, Tai ES 2004 Can we apply the National
search Support: none declared; Honoraria: none declared; Speakers Bu- Cholesterol Education Program Adult Treatment Panel definition of the met-
reau: none declared; Scott Grundy, M.D. – Significant Financial abolic syndrome to Asians? Diabetes Care 27:1182–1186
12. Examination Committee of Criteria for ‘Obesity Disease’ in Japan; Japan
Interests: none declared; Governance: none declared; Consultation or
Society for the Study of Obesity 2002 New criteria for ‘obesity disease’ in
Advisement: Pfizer, Abbott, Astra Zeneca, Sanofi Aventis, Merck, Grant
Japan. Circ J 66:987–992
or Other Research Support: Merck, Abbott, Kos, GlaxoSmith Kline, 13. Ko GT, Cockram CS, Chow CC, Yeung V, Chan WB, So WY, Chan NN,
Donald W. Reynolds Fund, Veterans Affairs, National Institutes of Chan JC 2005 High prevalence of metabolic syndrome in Hong Kong Chi-
Health; Honoraria: Merck, Pfizer, Sankyo, Merck/Schering-Plough, nese: comparison of three diagnostic criteria. Diabetes Res Clin Pract 69:
Kos, Abbott, Bristol-Myers Squibb, AstraZeneca; Speakers Bureau: none 160 –168
declared; Steven M. Haffner, M.D. – Significant Financial Interests: none 14. Ramachandran A, Snehalatha C, Vijay V 2004 Low risk threshold for ac-
declared; Governance: none declared; Consultation or Advisement: quired diabetogenic factors in Asian Indians. Diabetes Res Clin Pract 65:
Pfizer, Merck & Company, Inc.; Grant or Other Research Support: Na- 189 –195
tional Institutes of Health, GlaxoSmithKline, Novartis, Pfizer, Astra- 15. U.S. Department of Health and Human Services, Public Health Service 1996
NHANES III anthropometric procedures video. Washington, DC: U.S. Gov-
Zeneca; Honoraria: none declared; Speakers Bureau: Sanofi-Aventis,
ernment Printing Office
Novartis, GlaxoSmithKline, Merck & Company, Inc., Pfizer, Eli Lilly,
16. Salmasi AM, Alimo A, Dancy M 2004 Prevalence of unrecognized abnormal
AstraZeneca; Robert J. Heine, M.D., Ph.D. – Significant Financial In- glucose tolerance in patients attending a hospital hypertension clinic. Am J
terests: Eli-Lilly*; Governance: none declared; Consultation or Advise- Hypertens 17:483– 488
ment: Novartis, Merck, Sanofi-Aventis, Bristol-Myers Squibb, Novo Nor- 17. Salmasi AM, Dancy M 2005 The glucose tolerance test, but not HbA1c,
disk, Amylin; Grant or Other Research Support: Novartis, Sanofi-Aventis, remains the gold standard in identifying unrecognized diabetes mellitus and
Merck, Novo Nordisk, Eli Lilly; Honoraria: none declared; Edward S. Hor- impaired glucose tolerance in hypertensive subjects. Angiology 56:571–579
ton, M.D. – Significant Financial Interests: none declared; Governance: none 18. Meigs JB, Wilson PW, Fox CS, Vasan RS, Nathan DM, Sullivan LM,
declared; Consultation or Advisement: Novartis, Merck, Takeda, Novo D’Agostino RB 2006 Body mass index, metabolic syndrome, and risk of type
Nordisk, Sankyo, Pfizer; Grant or Other Research Support: none declared; 2 diabetes or cardiovascular disease. J Clin Endocrinol Metab 91:2906 –2912
19. Meigs JB, Williams K, Sullivan LM, Hunt KJ, Haffner SM, Stern MP, Gonzalez
Honoraria: Advisory Boards, Data Safety Monitoring Boards, Novartis,
Villalpando C, Perhanidis JS, Nathan DM, D’Agostino Jr RB, D’Agostino Sr
Merck, Takeda, Novo Nordisk, Sankyo, Pfizer; Ryuzo Kawamori, M.D. –
RB, Wilson PW 2004 Using metabolic syndrome traits for efficient detection
Significant Financial Interests: none declared; Governance: none declared; of impaired glucose tolerance. Diabetes Care 27:1417–1426
Consultation or Advisement: Takeda, Astra Zeneca; Grant or Other Re- 20. Orchard TJ, Temprosa M, Goldberg R, Haffner S, Ratner R, Marcovina S,
search Support: none declared; Honoraria: none declared. Speakers Bureau: Fowler S 2005 The effect of metformin and intensive lifestyle intervention on
Takeda, Novo Nordisk. the metabolic syndrome: the Diabetes Prevention Program randomized trial.
* As of January 1, 2008, Robert J. Heine joined Eli Lilly in Indianapolis Ann Intern Med 142:611– 619
as the Executive Medical Director of the Diabetes and Endocrine Divi- 21. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel
sion, but retained his affiliation with the Vrije Universiteit Medical Cen- WB 1998 Prediction of coronary heart disease using risk factor categories.
ter in Amsterdam, The Netherlands. Circulation 97:1837–1847
22. Kothari V, Stevens RJ, Adler AI, Stratton IM, Manley SE, Neil HA, Holman
RR 2002 UKPDS 60: risk of stroke in type 2 diabetes estimated by the UK
Prospective Diabetes Study risk engine. Stroke 33:1776 –1781
23. Stevens RJ, Kothari V, Adler AI, Stratton IM 2001 The UKPDS risk engine:
References a model for the risk of coronary heart disease in type II diabetes (UKPDS 56).
Clin Sci (Lond) 101:671– 679
1. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, 24. Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR,
Gordon DJ, Krauss RM, Savage PJ, Smith Jr SC, Spertus JA, Costa F 2005 Holman RR 1998 Risk factors for coronary artery disease in non-insulin
dependent diabetes mellitus: United Kingdom Prospective Diabetes Study 46. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH,
(UKPDS: 23). BMJ 316:823– 828 Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J 1999 Gemfibrozil for
25. Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, the secondary prevention of coronary heart disease in men with low levels of
Lowe GD, Pepys MB, Gudnason V 2004 C-reactive protein and other cir- high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipopro-
culating markers of inflammation in the prediction of coronary heart disease. tein Cholesterol Intervention Trial Study Group. N Engl J Med 341:410 – 418
N Engl J Med 350:1387–1397 47. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai
26. Folsom AR, Chambless LE, Ballantyne CM, Coresh J, Heiss G, Wu KK, A, Davis T, Glasziou P, Drury P, Kesaniemi YA, Sullivan D, Hunt D, Colman
Boerwinkle E, Mosley Jr TH, Sorlie P, Diao G, Sharrett AR 2006 An assess- P, d’Emden M, Whiting M, Ehnholm C, Laakso M 2005 Effects of long-term
ment of incremental coronary risk prediction using C-reactive protein and fenofibrate therapy on cardiovascular events in 9795 people with type 2
other novel risk markers: the atherosclerosis risk in communities study. Arch diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366:
Intern Med 166:1368 –1373 1849 –1861
27. Davey Smith G, Timpson N, Lawlor DA 2006 C-Reactive protein and cardio- 48. Barter PJ, Rye KA 2008 Is there a role for fibrates in the management of
vascular disease risk: still an unknown quantity? Ann Intern Med 145:70 –72 dyslipidemia in the metabolic syndrome? Arterioscler Thromb Vasc Biol
28. Assmann G, Cullen P, Schulte H 2002 Simple scoring scheme for calculating 28:39 – 46
the risk of acute coronary events based on the 10-year follow-up of the 49. Zambon A, Cusi K 2007 The role of fenofibrate in clinical practice. Diab Vasc
prospective cardiovascular Munster (PROCAM) study. Circulation 105: Dis Res 4(Suppl 3):S15–S20
310 –315 50. National Cholesterol Education Program 2002 Third Report of the National
29. Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De Backer G, De Cholesterol Education Program (NCEP) Expert Panel on Detection, Evalu-
Bacquer D, Ducimetiere P, Jousilahti P, Keil U, Njolstad I, Oganov RG, ation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment
Thomsen T, Tunstall-Pedoe H, Tverdal A, Wedel H, Whincup P, Wilhelmsen Panel III) final report. Circulation 106:3143–3421
L, Graham IM 2003 Estimation of ten-year risk of fatal cardiovascular disease 51. ALLHAT Officers and Coordinators for the ALLHAT Collaborative
in Europe: the SCORE project. Eur Heart J 24:987–1003 Research Group 2002 Major outcomes in moderately hypercholester-
30. Grundy SM, Cleeman JI, Merz CN, Brewer Jr HB, Clark LT, Hunninghake olemic, hypertensive patients randomized to pravastatin vs usual care: The
DB, Pasternak RC, Smith Jr SC, Stone NJ 2004 Implications of recent clinical Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack
trials for the National Cholesterol Education Program Adult Treatment Panel Trial (ALLHAT-LLT). JAMA 288:2998 –3007
III Guidelines. J Am Coll Cardiol 44:720 –732 52. Amarenco P, Bogousslavsky J, Callahan 3rd A, Goldstein LB, Hennerici M,
31. Cui Y, Blumenthal RS, Flaws JA, Whiteman MK, Langenberg P, Bachorik PS, Rudolph AE, Sillesen H, Simunovic L, Szarek M, Welch KM, Zivin JA 2006
Bush TL 2001 Non-high-density lipoprotein cholesterol level as a predictor High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med
of cardiovascular disease mortality. Arch Intern Med 161:1413–1419 355:549 –559
32. Frost PH, Havel RJ 1998 Rationale for use of non-high-density lipoprotein
53. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R,
cholesterol rather than low-density lipoprotein cholesterol as a tool for li-
Joyal SV, Hill KA, Pfeffer MA, Skene AM 2004 Intensive versus moderate
poprotein cholesterol screening and assessment of risk and therapy. Am J
lipid lowering with statins after acute coronary syndromes. N Engl J Med
Cardiol 81:26B–31B
350:1495–1504
33. Jiang R, Schulze MB, Li T, Rifai N, Stampfer MJ, Rimm EB, Hu FB 2004
54. Deedwania P, Barter P, Carmena R, Fruchart JC, Grundy SM, Haffner S,
Non-HDL cholesterol and apolipoprotein B predict cardiovascular disease
Kastelein JJ, LaRosa JC, Schachner H, Shepherd J, Waters DD 2006 Reduc-
events among men with type 2 diabetes. Diabetes Care 27:1991–1997
tion of low-density lipoprotein cholesterol in patients with coronary heart
34. Liu J, Sempos C, Donahue RP, Dorn J, Trevisan M, Grundy SM 2005 Joint
disease and metabolic syndrome: analysis of the Treating to New Targets
distribution of non-HDL and LDL cholesterol and coronary heart disease risk
study. Lancet 368:919 –928
prediction among individuals with and without diabetes. Diabetes Care 28:
55. Heart Protection Study Collaborative Group 2002 MRC/BHF Heart Protec-
1916 –1921
tion Study of cholesterol lowering with simvastatin in 20,536 high-risk in-
35. Liu J, Sempos CT, Donahue RP, Dorn J, Trevisan M, Grundy SM 2006
dividuals: a randomised placebo-controlled trial. Lancet 360:7–22
Non-high-density lipoprotein and very-low-density lipoprotein cholesterol
56. Law MR, Wald NJ, Rudnicka AR 2003 Quantifying effect of statins on low
and their risk predictive values in coronary heart disease. Am J Cardiol 98:
density lipoprotein cholesterol, ischaemic heart disease, and stroke: system-
1363–1368
atic review and meta-analysis. BMJ 326:1423
36. Lu W, Resnick HE, Jablonski KA, Jones KL, Jain AK, Howard WJ, Robbins
57. Law MR, Wald NJ, Thompson SG 1994 By how much and how quickly does
DC, Howard BV 2003 Non-HDL cholesterol as a predictor of cardiovascular
disease in type 2 diabetes: the Strong Heart Study. Diabetes Care 26:16 –23 reduction in serum cholesterol concentration lower risk of ischaemic heart
37. Pischon T, Girman CJ, Sacks FM, Rifai N, Stampfer MJ, Rimm EB 2005 disease? BMJ 308:367–372
Non-high-density lipoprotein cholesterol and apolipoprotein B in the pre- 58. LIPID Study Group 1998 Prevention of cardiovascular events and death with
diction of coronary heart disease in men. Circulation 112:3375–3383 pravastatin in patients with coronary heart disease and a broad range of initial
38. Schulze MB, Shai I, Manson JE, Li T, Rifai N, Jiang R, Hu FB 2004 Joint role cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic
of non-HDL cholesterol and glycated haemoglobin in predicting future cor- Disease (LIPID) Study Group. N Engl J Med 339:1349 –1357
onary heart disease events among women with type 2 diabetes. Diabetologia 59. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG,
47:2129 –2136 Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E 1996
39. Simon A, Chironi G, Gariepy J, Del Pino M, Levenson J 2005 Differences The effect of pravastatin on coronary events after myocardial infarction in
between markers of atherogenic lipoproteins in predicting high cardiovas- patients with average cholesterol levels. Cholesterol and Recurrent Events
cular risk and subclinical atherosclerosis in asymptomatic men. Atheroscle- Trial investigators. N Engl J Med 335:1001–1009
rosis 179:339 –344 60. Sacks FM, Tonkin AM, Shepherd J, Braunwald E, Cobbe S, Hawkins CM,
40. Xydakis AM, Ballantyne CM 2003 Role of non-high-density lipoprotein Keech A, Packard C, Simes J, Byington R, Furberg CD 2000 Effect of
cholesterol in prevention of cardiovascular disease: updated evidence from pravastatin on coronary disease events in subgroups defined by coronary
clinical trials. Curr Opin Cardiol 18:503–509 risk factors: the Prospective Pravastatin Pooling Project. Circulation 102:
41. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, 1893–1900
Jacobs Jr DR, Bangdiwala S, Tyroler HA 1989 High-density lipoprotein 61. Scandinavian Simvastatin Survival Study Group 1994 Randomised trial of
cholesterol and cardiovascular disease. Four prospective American studies. cholesterol lowering in 4444 patients with coronary heart disease: the Scan-
Circulation 79:8 –15 dinavian Simvastatin Survival Study (4S). Lancet 344:1383–1389
42. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein 62. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R,
JJ, Bittner V, Fruchart JC 2007 HDL cholesterol, very low levels of LDL Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien
cholesterol, and cardiovascular events. N Engl J Med 357:1301–1310 E, Ostergren J 2003 Prevention of coronary and stroke events with atorva-
43. 1975 Clofibrate and niacin in coronary heart disease. JAMA 231:360 –381 statin in hypertensive patients who have average or lower-than-average cho-
44. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, lesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–
Friedewald W 1986 Fifteen year mortality in Coronary Drug Project patients: Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled
long-term benefit with niacin. J Am Coll Cardiol 8:1245–1255 trial. Lancet 361:1149 –1158
45. Canner PL, Furberg CD, McGovern ME 2006 Benefits of niacin in patients 63. Shepherd J, Barter P, Carmena R, Deedwania P, Fruchart JC, Haffner S, Hsia
with versus without the metabolic syndrome and healed myocardial infarc- J, Breazna A, LaRosa J, Grundy S, Waters D 2006 Effect of lowering LDL
tion (from the Coronary Drug Project). Am J Cardiol 97:477– 479 cholesterol substantially below currently recommended levels in patients with
coronary heart disease and diabetes: the Treating to New Targets (TNT) 81. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins
study. Diabetes Care 29:1220 –1226 R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien
64. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, E, Ostergren J 2005 Prevention of cardiovascular events with an antihyper-
Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, tensive regimen of amlodipine adding perindopril as required versus atenolol
Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac
C, Westendorp RG 2002 Pravastatin in elderly individuals at risk of vascular Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicen-
disease (PROSPER): a randomised controlled trial. Lancet 360:1623–1630 tre randomised controlled trial. Lancet 366:895–906
65. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, 82. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research
McKillop JH, Packard CJ 1995 Prevention of coronary heart disease with Group 2002 Major outcomes in high-risk hypertensive patients randomized
pravastatin in men with hypercholesterolemia. West of Scotland Coronary to angiotensin-converting enzyme inhibitor or calcium channel blocker vs
Prevention Study Group. N Engl J Med 333:1301–1307 diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent
66. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Heart Attack Trial (ALLHAT). JAMA [Errata (2003) 289:178; (2004) 291:
Langendorfer A, Stein EA, Kruyer W, Gotto Jr AM 1998 Primary prevention 2196] 288:2981–2997
of acute coronary events with lovastatin in men and women with average 83. Black HR, Elliott WJ, Grandits G, Grambsch P, Lucente T, White WB, Neaton
cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary JD, Grimm Jr RH, Hansson L, Lacourciere Y, Muller J, Sleight P, Weber MA,
Atherosclerosis Prevention Study. JAMA 279:1615–1622 Williams G, Wittes J, Zanchetti A, Anders RJ 2003 Principal results of the
67. Frost PH, Davis BR, Burlando AJ, Curb JD, Guthrie Jr GP, Isaacsohn JL, Controlled Onset Verapamil Investigation of Cardiovascular End Points
Wassertheil-Smoller S, Wilson AC, Stamler J 1996 Serum lipids and incidence (CONVINCE) trial. JAMA 289:2073–2082
of coronary heart disease. Findings from the Systolic Hypertension in the 84. Verdecchia P, Reboldi G, Angeli F, Gattobigio R, Bentivoglio M, Thijs L,
Elderly Program (SHEP). Circulation 94:2381–2388 Staessen JA, Porcellati C 2005 Angiotensin-converting enzyme inhibitors and
68. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme calcium channel blockers for coronary heart disease and stroke prevention.
I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J 2005 High-dose Hypertension 46:386 –392
atorvastatin vs usual-dose simvastatin for secondary prevention after myo- 85. Wright Jr JT, Agodoa L, Contreras G, Greene T, Douglas JG, Lash J, Randall
cardial infarction: the IDEAL study: a randomized controlled trial. JAMA O, Rogers N, Smith MC, Massry S 2002 Successful blood pressure control in
294:2437–2445 the African American Study of Kidney Disease and Hypertension. Arch Intern
69. Cooper R, Cutler J, Desvigne-Nickens P, Fortmann SP, Friedman L, Havlik Med 162:1636 –1643
R, Hogelin G, Marler J, McGovern P, Morosco G, Mosca L, Pearson T, 86. Balagopal P, George D, Patton N, Yarandi H, Roberts WL, Bayne E, Gidding
Stamler J, Stryer D, Thom T 2000 Trends and disparities in coronary heart S 2005 Lifestyle-only intervention attenuates the inflammatory state associ-
disease, stroke, and other cardiovascular diseases in the United States: find- ated with obesity: a randomized controlled study in adolescents. J Pediatr
ings of the national conference on cardiovascular disease prevention. Circu-
146:342–348
lation 102:3137–3147
87. De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R,
70. Hutchinson RG, Watson RL, Davis CE, Barnes R, Brown S, Romm F, Spencer
Dallongeville J, Ebrahim S, Faergeman O, Graham I, Mancia G, Manger Cats V,
JM, Tyroler HA, Wu K 1997 Racial differences in risk factors for athero-
Orth-Gomer K, Perk J, Pyorala K, Rodicio JL, Sans S, Sansoy V, Sechtem U,
sclerosis. The ARIC Study. Atherosclerosis Risk in Communities. Angiology
Silber S, Thomsen T, Wood D 2003 European guidelines on cardiovascular
48:279 –290
disease prevention in clinical practice. Third Joint Task Force of European
71. Sprafka JM, Norsted SW, Folsom AR, Burke GL, Luepker RV 1992 Life-style
and Other Societies on Cardiovascular Disease Prevention in Clinical Prac-
factors do not explain racial differences in high-density lipoprotein choles-
tice. Eur Heart J 24:1601–1610
terol: the Minnesota Heart Survey. Epidemiology 3:156 –163
88. Esposito K, Pontillo A, Di Palo C, Giugliano G, Masella M, Marfella R,
72. Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB 2003 Years of
Giugliano D 2003 Effect of weight loss and lifestyle changes on vascular
life lost due to obesity. JAMA 289:187–193
inflammatory markers in obese women: a randomized trial. JAMA 289:
73. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr JL,
1799 –1804
Jones DW, Materson BJ, Oparil S, Wright Jr JT, Roccella EJ 2003 Seventh
89. Hamdy O, Ledbury S, Mullooly C, Jarema C, Porter S, Ovalle K, Moussa A,
report of the Joint National Committee on Prevention, Detection, Evaluation,
Caselli A, Caballero AE, Economides PA, Veves A, Horton ES 2003 Lifestyle
and Treatment of High Blood Pressure. Hypertension 42:1206 –1252
modification improves endothelial function in obese subjects with the insulin
74. Appel LJ, Champagne CM, Harsha DW, Cooper LS, Obarzanek E, Elmer PJ,
resistance syndrome. Diabetes Care 26:2119 –2125
Stevens VJ, Vollmer WM, Lin PH, Svetkey LP, Stedman SW, Young DR 2003
Effects of comprehensive lifestyle modification on blood pressure control: 90. Selvin E, Paynter NP, Erlinger TP 2007 The effect of weight loss on C-reactive
main results of the PREMIER clinical trial. JAMA 289:2083–2093 protein: a systematic review. Arch Intern Med 167:31–39
75. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, 91. Wadden TA, Butryn ML, Byrne KJ 2004 Efficacy of lifestyle modification for
Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A long-term weight control. Obes Res 12(Suppl):151S– 62S
2004 Outcomes in hypertensive patients at high cardiovascular risk treated 92. Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK,
with regimens based on valsartan or amlodipine: the VALUE randomised Skene AM 2007 The effect of pioglitazone on recurrent myocardial infarction
trial. Lancet 363:2022–2031 in 2,445 patients with type 2 diabetes and previous myocardial infarction:
76. Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, Black results from the PROactive (PROactive 05) Study. J Am Coll Cardiol 49:
HR, Grimm Jr RH, Messerli FH, Oparil S, Schork MA 2006 Feasibility of 1772–1780
treating prehypertension with an angiotensin-receptor blocker. N Engl J Med 93. Nissen SE, Wolski K 2007 Effect of rosiglitazone on the risk of myocardial
354:1685–1697 infarction and death from cardiovascular causes. N Engl J Med 356:2457–2471
77. Julius S, Weber MA, Kjeldsen SE, McInnes GT, Zanchetti A, Brunner HR, 94. Pearson TA, Blair SN, Daniels SR, Eckel RH, Fair JM, Fortmann SP, Franklin
Laragh J, Schork MA, Hua TA, Amerena J, Balazovjech I, Cassel G, Herczeg BA, Goldstein LB, Greenland P, Grundy SM, Hong Y, Miller NH, Lauer RM,
B, Koylan N, Magometschnigg D, Majahalme S, Martinez F, Oigman W, Ockene IS, Sacco RL, Sallis Jr JF, Smith Jr SC, Stone NJ, Taubert KA 2002
Seabra Gomes R, Zhu JR 2006 The Valsartan Antihypertensive Long-Term AHA Guidelines for Primary Prevention of Cardiovascular Disease and
Use Evaluation (VALUE) trial: outcomes in patients receiving monotherapy. Stroke. 2002 Update: Consensus Panel Guide to Comprehensive Risk Re-
Hypertension 48:385–391 duction for Adult Patients without Coronary or Other Atherosclerotic Vas-
78. Law MR, Wald NJ, Morris JK, Jordan RE 2003 Value of low dose combi- cular Diseases. American Heart Association Science Advisory and Coordi-
nation treatment with blood pressure lowering drugs: analysis of 354 ran- nating Committee. Circulation 106:388 –391
domised trials. BMJ 326:1427 95. Folsom AR, Qamhieh HT, Wing RR, Jeffery RW, Stinson VL, Kuller LH, Wu
79. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, KK 1993 Impact of weight loss on plasminogen activator inhibitor (PAI-1),
Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S 2001 Effects of losartan on factor VII, and other hemostatic factors in moderately overweight adults.
renal and cardiovascular outcomes in patients with type 2 diabetes and ne- Arterioscler Thromb 13:162–169
phropathy. N Engl J Med 345:861– 869 96. Hamalainen H, Ronnemaa T, Virtanen A, Lindstrom J, Eriksson JG, Valle
80. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist TT, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Rastas M, Aunola S,
F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Uusitupa M, Tuomilehto J 2005 Improved fibrinolysis by an intensive life-
Omvik P, Oparil S, Wedel H 2002 Cardiovascular morbidity and mortality in the style intervention in subjects with impaired glucose tolerance. The Finnish
Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a Diabetes Prevention Study. Diabetologia 48:2248 –2253
randomised trial against atenolol. Lancet 359:995–1003 97. Lindahl B, Nilsson TK, Jansson JH, Asplund K, Hallmans G 1999 Improved
fibrinolysis by intense lifestyle intervention. A randomized trial in subjects ␤-cell function and prevention of type 2 diabetes by pharmacological
with impaired glucose tolerance. J Intern Med 246:105–112 treatment of insulin resistance in high-risk Hispanic women. Diabetes
98. Marckmann P, Toubro S, Astrup A 1998 Sustained improvement in blood 51:2796 –2803
lipids, coagulation, and fibrinolysis after major weight loss in obese subjects. 119. DREAM Trial Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan
Eur J Clin Nutr 52:329 –333 P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman
99. Rissanen P, Vahtera E, Krusius T, Uusitupa M, Rissanen A 2001 Weight B, Holman RR 2006 Effect of rosiglitazone on the frequency of diabetes in
change and blood coagulability and fibrinolysis in healthy obese women. Int patients with impaired glucose tolerance or impaired fasting glucose: a random-
J Obes Relat Metab Disord 25:212–218 ised controlled trial. Lancet 368:1096 –1105
100. Antithrombotic Trialists’ Collaboration 2002 Collaborative meta-analysis 120. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M,
of randomised trials of antiplatelet therapy for prevention of death, myocar- Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox
dial infarction, and stroke in high risk patients. BMJ 324:71– 86 RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L,
101. Hayden M, Pignone M, Phillips C, Mulrow C 2002 Aspirin for the primary Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum
prevention of cardiovascular events: a summary of the evidence for the U.S. W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J 2005 Secondary
Preventive Services Task Force. Ann Intern Med 136:161–172 prevention of macrovascular events in patients with type 2 diabetes in the
102. Eriksson KF, Lindgarde F 1991 Prevention of type 2 (non-insulin-dependent) PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular
diabetes mellitus by diet and physical exercise. The 6-year Malmo feasibility Events): a randomised controlled trial. Lancet 366:1279 –1289
study. Diabetologia 34:891– 898 121. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP,
103. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Kravitz BG, Lachin JM, O’Neill MC, Zinman B, Viberti G 2006 Glycemic
Walker EA, Nathan DM; Diabetes Prevention Program Research Group durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl
2002 Reduction in the incidence of type 2 diabetes with lifestyle intervention J Med 355:2427–2443
or metformin. N Engl J Med 346:393– 403 122. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, Guyatt GH,
104. Kosaka K, Noda M, Kuzuya T 2005 Prevention of type 2 diabetes by lifestyle Harbour RT, Haugh MC, Henry D, Hill S, Jaeschke R, Leng G, Liberati A,
intervention: a Japanese trial in IGT males. Diabetes Res Clin Pract 67: Magrini N, Mason J, Middleton P, Mrukowicz J, O’Connell D, Oxman AD,
152–162 Phillips B, Schunemann HJ, Edejer TT, Varonen H, Vist GE, Williams Jr
105. Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, Hu ZX, Lin J, Xiao JW, Zaza S 2004 Grading quality of evidence and strength of recommenda-
JZ, Cao HB, Liu PA, Jiang XG, Jiang YY, Wang JP, Zheng H, Zhang H, tions. BMJ 328:1490
Bennett PH, Howard BV 1997 Effects of diet and exercise in preventing 123. Swiglo BA, Murad MH, Schunemann HJ, Kunz R, Vigersky RA, Guyatt GH,
NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Montori VM 2008 A case for clarity, consistency, and helpfulness: state-of-
Diabetes Study. Diabetes Care 20:537–544 the-art clinical practice guidelines in endocrinology using the GRADE system.
106. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V J Clin Endocrinol Metab 93:666 – 673
2006 The Indian Diabetes Prevention Programme shows that lifestyle mod- 124. Reaven GM 1988 Banting lecture 1988. Role of insulin resistance in human
ification and metformin prevent type 2 diabetes in Asian Indian subjects with disease. Diabetes 37:1595–1607
impaired glucose tolerance (IDPP-1). Diabetologia 49:289 –297 125. LaMonte MJ, Barlow CE, Jurca R, Kampert JB, Church TS, Blair SN 2005
107. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne- Cardiorespiratory fitness is inversely associated with the incidence of meta-
Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, bolic syndrome: a prospective study of men and women. Circulation 112:
Salminen V, Uusitupa M 2001 Prevention of type 2 diabetes mellitus by 505–512
changes in lifestyle among subjects with impaired glucose tolerance. N Engl 126. Bjorntorp P 1995 Insulin resistance: the consequence of a neuroendocrine
J Med 344:1343–1350 disturbance? Int J Obes Relat Metab Disord 19 Suppl 1:S6 –S10
108. Norris SL, Zhang X, Avenell A, Gregg E, Bowman B, Schmid CH, Lau J 2005 127. Del Prato S, Leonetti F, Simonson DC, Sheehan P, Matsuda M, DeFronzo
Long-term effectiveness of weight-loss interventions in adults with pre-dia- RA 1994 Effect of sustained physiologic hyperinsulinaemia and hyper-
betes: a review. Am J Prev Med 28:126 –139 glycaemia on insulin secretion and insulin sensitivity in man. Diabetologia
109. Yamaoka K, Tango T 2005 Efficacy of lifestyle education to prevent type 2 37:1025–1035
diabetes: a meta-analysis of randomized controlled trials. Diabetes Care 28: 128. Ferrannini E 1995 The phenomenon of insulin resistance: its possible rele-
2780 –2786 vance to hypertensive disease. In: Laragh JH, Brenner BM, eds. Hypertension:
110. Lindstrom J, Ilanne-Parikka P, Peltonen M, Aunola S, Eriksson JG, Hemio K, pathophysiology, diagnosis, and management. 2nd ed. New York: Raven
Hamalainen H, Harkonen P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta Press; 2281–2300
A, Mannelin M, Paturi M, Sundvall J, Valle TT, Uusitupa M, Tuomilehto J 2006 129. Muscelli E, Emdin M, Natali A, Pratali L, Camastra S, Gastaldelli A, Baldi
Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: S, Carpeggiani C, Ferrannini E 1998 Autonomic and hemodynamic responses
follow-up of the Finnish Diabetes Prevention Study. Lancet 368:1673–1679 to insulin in lean and obese humans. J Clin Endocrinol Metab 83:2084 –2090
111. Diabetes Prevention Program Research Group 2002 The Diabetes Pre- 130. Ferrannini E 2006 Is insulin resistance the cause of the metabolic syndrome?
vention Program (DPP): description of lifestyle intervention. Diabetes Ann Med 38:42–51
Care 25:2165–2171 131. Reaven GM, Laws A, eds. 1999 Insulin resistance: the metabolic syndrome
112. Herman WH, Hoerger TJ, Brandle M, Hicks K, Sorensen S, Zhang P, Hamman X. Totowa, NJ: Humana Press
RF, Ackermann RT, Engelgau MM, Ratner RE 2005 The cost-effectiveness 132. Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP
of lifestyle modification or metformin in preventing type 2 diabetes in adults 1992 Prospective analysis of the insulin-resistance syndrome (syndrome X).
with impaired glucose tolerance. Ann Intern Med 142:323–332 Diabetes 41:715–722
113. Ratner R, Goldberg R, Haffner S, Marcovina S, Orchard T, Fowler 133. Haffner SM, Ferrannini E, Hazuda HP, Stern MP 1992 Clustering of car-
S, Temprosa M 2005 Impact of intensive lifestyle and metformin therapy on diovascular risk factors in confirmed prehypertensive individuals. Hyperten-
cardiovascular disease risk factors in the Diabetes Prevention Program. Di- sion 20:38 – 45
abetes Care 28:888 – 894 134. Hu G, Qiao Q, Tuomilehto J, Eliasson M, Feskens EJ, Pyorala K 2004 Plasma
114. Haffner S, Temprosa M, Crandall J, Fowler S, Goldberg R, Horton E, insulin and cardiovascular mortality in non-diabetic European men and
Marcovina S, Mather K, Orchard T, Ratner R, Barrett-Connor E 2005 In- women: a meta-analysis of data from eleven prospective studies. Diabetologia
tensive lifestyle intervention or metformin on inflammation and coagulation 47:1245–1256
in participants with impaired glucose tolerance. Diabetes 54:1566 –1572 135. Ferrannini E, Balkau B 2002 Insulin: in search of a syndrome. Diabet Med
115. Elliott SS, Keim NL, Stern JS, Teff K, Havel PJ 2002 Fructose, weight gain, 19:724 –729
and the insulin resistance syndrome. Am J Clin Nutr 76:911–922 136. Despres JP 2006 Is visceral obesity the cause of the metabolic syndrome? Ann
116. Gross LS, Li L, Ford ES, Liu S 2004 Increased consumption of refined car- Med 38:52– 63
bohydrates and the epidemic of type 2 diabetes in the United States: an eco- 137. Alberti KG, Zimmet PZ 1998 Definition, diagnosis and classification of di-
logic assessment. Am J Clin Nutr 79:774 –779 abetes mellitus and its complications. Part 1: diagnosis and classification of
117. Knowler WC, Hamman RF, Edelstein SL, Barrett-Connor E, Ehrmann DA, diabetes mellitus provisional report of a WHO consultation. Diabet Med
Walker EA, Fowler SE, Nathan DM, Kahn SE 2005 Prevention of type 2 15:539 –553
diabetes with troglitazone in the Diabetes Prevention Program. Diabetes 54: 138. Balkau B, Charles MA 1999 Comment on the provisional report from the
1150 –1156 WHO consultation. European Group for the Study of Insulin Resistance
118. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa (EGIR). Diabet Med 16:442– 443
C, Tan S, Berkowitz K, Hodis HN, Azen SP 2002 Preservation of pancreatic 139. Einhorn D, Reaven GM, Cobin RH, Ford E, Ganda OP, Handelsman Y,
Hellman R, Jellinger PS, Kendall D, Krauss RM, Neufeld ND, Petak SM, 142. Saaristo T, Peltonen M, Lindstrom J, Saarikoski L, Sundvall J, Eriksson JG,
Rodbard HW, Seibel JA, Smith DA, Wilson PW 2003 American College of Tuomilehto J 2005 Cross-sectional evaluation of the Finnish Diabetes Risk
Endocrinology position statement on the insulin resistance syndrome. Endocr Score: a tool to identify undetected type 2 diabetes, abnormal glucose toler-
Pract 9:237–252 ance and metabolic syndrome. Diab Vasc Dis Res 2:67–72
140. Lorenzo C, Williams K, Gonzalez-Villalpando C, Haffner SM 2005 The 143. Stern MP, Williams K, Gonzalez-Villalpando C, Hunt KJ, Haffner SM 2004
prevalence of the metabolic syndrome did not increase in Mexico City be- Does the metabolic syndrome improve identification of individuals at risk of
tween 1990 –1992 and 1997–1999 despite more central obesity. Diabetes type 2 diabetes and/or cardiovascular disease? Diabetes Care 27:2676 –2681
Care 28:2480 –2485 144. Kahn R, Buse J, Ferrannini E, Stern M 2005 The metabolic syndrome: time
141. Ford ES 2005 Risks for all-cause mortality, cardiovascular disease, and di- for a critical appraisal. Joint statement from the American Diabetes Associ-
abetes associated with the metabolic syndrome: a summary of the evidence. ation and the European Association for the Study of Diabetes. Diabetologia
Diabetes Care 28:1769 –1778 48:1684 –1699

Acervo 2

Uploaded by

Copyright:

Available Formats

Acervo 2

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Acervo 2

Uploaded by

Copyright:

Available Formats

S P E C I A L F E A T U R E

Primary Prevention of Cardiovascular Disease

J Clin Endocrinol Metab, October 2008, 93(10):3671–3689 jcem.endojournals.org 3671

4. Treatment to prevent T2DM

TABLE 1. Criteria proposed for clinical diagnosis of the metabolic syndrome

TABLE 2. Recommended waist circumference thresholds to Remarks

TABLE 5. Summary of efficacy of drugs that reduce apo B-containing lipoproteins

TABLE 7. Projected reductions in blood pressure accompanying lifestyle therapies

Projected reduction in systolic

You might also like