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Managing Cardiometabolic Risk: An Evolving Approach to Patient Care


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Title: Managing Cardiometabolic Risk: An Evolving Approach to Patient Care

Managing Cardiometabolic Risk An Evolving
Approach to Patient Care
  • Karol Watson, MD, PhD
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Abstract (1)
  • Cardiometabolic risk (CMR)-encompasses a cluster
    of risk factors- predispose individuals to CV
    disease and T2DM.
  • These risk factors-currrently undermanaged-involve
    multiple pathways and physiologic systems and
    point to a need for a comprehensive management
  • Abdominal obesity-key component of
    cardiometabolic risk- increasing the incidence of
    insulin resistance, vascular inflammation,
    dyslipidemia, and hypertension.
  • Adipose tissue-now recognized as an endocrine
    organ, and its hormonal products appear to play a
    significant role in the regulation of fat and
    glucose metabolism throughout the body.

Abstract (2)
  • These mechanisms are clearly involved in the
    development of CV and metabolic disease
  • Current treatment protocols-generally involve a
    fragmented approach to care, management only
    clinically evident conditions.
  • As cardiometabolic risk factors tend to
    cluster-patients often have additional
    subclinical conditions that would be discovered
    through comprehensive evaluation for the entire
    constellation of risk factors-thereby enabling
    clinicians to recommend optimal treatment to
    prevent CV and metabolic morbidities.

  • Key point
  • Progress in detection treatment of CV disease
    has not kept it from being the deadliest disease
    in US, causing an estimated 927,000 deaths in
  • DM had the sixth highest mortality rate in US,
    with T2DM contributing to more than 200,000
    deaths in 2002.

Introduction (2)
  • Cardiometabolic risk-constellation of CV and
    metabolic risk factors
  • CVD-remains the leading cause of mortality in US
  • gt70 million Americans (34.2) have some form of
    CVD (NHANES 1999-2002), 927,000 Americans died
    from CVD-related causes in 2002.

Introduction (3)
  • DM-6th highest mortality rate in US in 2002,
    contributing gt224,000 deaths.
  • 90-95 are T2DM-contributed gt200,000 deaths.
  • NHANES 1999-2002 documented a marked increase in
    overall prevalence of DM and obesity, 2 trends
    are closely related.
  • The age-adjusted prevalence of obesity, (BMIgt30
    kg/m2), has doubled in last quarter century, from
    15 in 1976-1980 to 30 in 1999-2002. (Figure 1)

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Introduction (4)
  • Obesity-primary pathogenetic mechanisms of both
    CVD T2DM.
  • The 2 conditions share a number of other
    underlying factors-insulin resistance,
    hypertension, and dyslipidemia-when occur
    concomitantly-constitute metabolic syndrome.
  • Metabolic syndrome-identified in ATPIII as a
    complex risk factor for CVD warrants clinical

Economic Burden
  • Key point
  • Direct indirect US health-care costs associated
    with CVDestimated at 393.5 billion for 2005.
  • Costs associated with DM underestimated at 132
    billion for 2002.

  • In addition to mortality rates with
    cardiometabolic risk, CVD T2DM are responsible
    for a major portion of disabilities in the US
  • Direct costs-physician visits, hospital stays,
    and other health-care expenses
  • Indirect costs-lost productivity due to illness
  • Health-care spending for individuals with DM is
    more than 2 X that of individuals without DM.

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  • McKenna-analyzed data from multiple health
    surveys-NHANES, hospital discharge reports,
    National Health Interview Survey to determine
    disability-adjusted life years (DALYs) lost to
    various disease and events.
  • DALYs-combination of productive years lost to
    premature death or to disability.
  • CV conditions leading cause of DALYs in
    mi-1990s, DM-9th for women, 11th for men.

  • Wang-conducted an analysis of National Health
    Interview Survey and the 1996 Medical Expenditure
    Panel Survey to determine health-care costs
    associated with excess weight
  • Prevalence of CVD increase with BMI
  • 20 normal-weight (BMI 18-lt25) were diagnosed
    with CVD, 28 in overweight (BMI 25-lt30) 39 in
    obese (BMIgt30).
  • It is clear, cardiometabolic risk factors
    associated with CVD T2DM, add up to a
    substantial economic burden to society.

Cardiometabolic Risk
  • Key Point
  • Cardiometabolic risk goes beyond metabolic
    syndrome to encompass a cluster of 9 modifiable
    CV and metabolic risk factors that increase an
    individuals risk of developing CVD and T2DM

  • Cardiometabolic risk-evolved from an enhanced
    understanding of established emerging risk
    factors associated with a predisposition to CV
    metabolic disease (Figure 2)
  • Cardiometabolic risk-defined as a cluster of
    modifiable risk factors and markers that identify
    individuals at increased risk for CVD MI,
    stroke, PAOD and T2DM.
  • This cluster of risk factors-include ATP III
    definition of metabolic syndrome as well as other
    risk factors also identified in ATP III as
    significantly contributing to cardiometabolic
    morbidity (Table 2)

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  • 2000 Pescatello-coin the term cardiometabolic
    disease-a clustering group of disorders lead to
    CVD and/or T2DM.
  • The disorders-insulin resistance, hypertension,
    LDL-C TG elevation, low HDL-C, and abdominal
  • 2001 Sowers-used the term cardiometabolic
    syndrome in the context of cardiovascular risk
    factors that cluster with microalbuminuria
  • They cited central obesity, insulin resistance,
    low HDL-C, high TG, systolic hypertension,
    increased CV oxidative stress, and impaired
    endothelial function among the cluster of risk
  • Sowers also refers to this condition as
    cardiometabolic risk syndrome.

Metabolic Syndrome (MS) A Component of
Cardiometabolic Risk
  • Key Point
  • There are multiple definitions of metabolic
    syndrome, all of which include obesity,
    dyslipidemia, hypertension, and elevated
    glucose/insulin resistance as risk factors.

  • There are several definitions of metabolic
    syndrome-ATP III, WHO, AACE, IDF. All 4
    definitions include measures of obesity,
    dyslipidemia, elevated BP, and elevated glucose
    (include insulin resistance).

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ATP III guidelines
  • ATP III guidelines identified metabolic syndrome
    as a risk reduction target second only to
    elevated LDL-C.
  • The components include abdominal obesity (more
    highly associated with metabolic risk factors
    other than overall obesity).
  • WC gt40 inches in men, gt35 inches in women.
  • Abdominal adiposity is linked to insulin
    resistance, T2DM, elevated inflammatory markers,
    dyslipidmeia, and hypertension.
  • ATP III characterized metabolic syndrome as
    metabolic complications of abdominal obesity

  • BP gt130/85 mmHg
  • Hypertension is also a powerful risk factor for
    CV morbidity mortality.
  • Untreated hypertension is associated with
    enlargement of the heart and heart failure,
    aneurysm, renal failure, vision impairment, and
  • 1/3 US adult has high BP.
  • 70 American recognizing hypertension as medical
    condition, 59 with high BP receiving Tx, 34 had
    BP under adequate control.

ATP III-Fasting Blood Glucose
  • FBG gt100 mg/dl.
  • Growing evidence-even prediabetes levels of
    elevated glucose significantly increase the risk
    of CVD.
  • ADA defines prediabetes-IGT (glucose levels
    100-125 mg/dl).
  • Other CV risk factors more prevalent in
    prediabetes, thereby exacerbating the risk of
    heart disease.
  • IGT is significantly related to development of
  • All the independent risk factors associated with
    T2DM risk, glucose level is the strongest
  • ADA National Institute of Diabetes and
    Digestive and Kidney Diseases strongly recommend
    glucose screening in persons gt45 y/o who are
    overweight have gt1 other risk factor for DM

TG and HDL-C
  • Elevated TG HDL-C both considered independent
    risk factors for CVD.
  • TG gt150mg/dl.
  • Factors contributing to elevated TG-obesity,
    physical inactivity, tobacco use, excess alcohol
    consumption, high-CHO diets.
  • T2DM chronic renal failure often have elevated
  • HDL-Clt40 mg/dl in men, lt50 mg/dl in women.
  • Insulin resistance, elevated TG, obesity,
    physical inactivity T2DM are commonly
    associated with low HDL-C.
  • No specific therapeutic goal for raising HDL-C

  • Nnumerous other cardiometabolic risk factors
    identified by ATP III predisposing to
    CVD-physical inactivity, atherogenic diet,
    proinflammatory state, family history of CAD,
    insulin resistance.
  • Applying ATP III definition to NHANES data,
    Ford-determined prevalence of MS is on the rise.
  • Among US adults gt20 y/o, unadjusted prevalence of
    MS was 23.1 in NHANES III (1988-1994), in HNANES
    1999-2000, the prevalence was 26.7 (relative
    increase 15.7) (Figure 3)

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  • Ford conducted review of 7 prospective
    studies-relative risk associated with MS-1.65
  • 4 prospective studies-relative risk for DM-2.99
  • He concluded that MS has a strong association
    with DM and is moderately predictive of CVD.
  • Malik-in subjects with gt3 risk factors, the
    hazard ratio was 2.71 (Figure 4)-concluded that
    MS confers a risk profile that is greater than
    that posed by its individual components
  • Relly also noted that evidence suggests MS is
    more than the sum of its parts

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  • Dx of MS could enhance prevention of CVD T2DM.
  • In ADA EASD joint statement-Kahn-lack of a
    consensus on the definition, as well as ambiguous
    or incomplete criteria. Treatment of the syndrome
    was identical to Tx of individual risk factors.
  • ADA/EASD took the position that until additional
    data are available regarding MS its clinical
    utility, clinicians should avoid applying this
    diagnostic label to their pts.
  • AHA and NHLBI Grundy-ATP III diagnosis of MS to
    be clinically usefulit is associated with
    increased risk of atherosclerotic CVD and T2DM
    warrants attention by clinicians.

  • Key Point
  • Despite the ongoing debate regarding the clinical
    utility of the metabolic syndrome (MS), experts
    agree that its constituent risk factors are
    predictive of CVD and T2DM and therefore warrant

Clustering of Risk factors
  • Key Point
  • Cardiometabolic risk factors tend to cluster. A
    patient with 1 or 2 clinically evident risk
    factors is likely to have more and should be
    evaluated for the full spectrum of
    cardiometabolic risk.

  • It is widely accepted that certain
    cardiometabolic risk factors tend to cluster-such
    that a patient with 1 or 2 risk factors is likely
    to have others.
  • Meigs-offer a classic description of the
    clustering concept in a factor analysis of the
    Framingham Offspring Study.
  • 3 factors underlying the clustering of certain
    risk variables were identified (Figure 5).

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  • To determine whether clusters of risk factors
    predict the development of T2DM.
  • Hanley-conducted a factor analysis with data
    from 1087 nondiabetic participants in the Insulin
    Resistance Atherosclerosis Study (IRAS).
  • The analysis identified 3 factors metabolic,
    inflammation, and blood pressure.
  • Each was determined to be a significant predictor
    of diabetes after a median follow-up period of
    5.2 years, and each remained significant in a
    multivariate model that included all 3 factors.

  • Key Point
  • Cardiometabolic risk involves multiple
    physiologic pathways, indicating a need for
    comprehensive management that addresses all
    pathogenetic mechanisms

  • Cardiometabolic risk not only involves multiple
    risk factors, but also multiple physiologic
  • Endocrine system is a major piece of
    cardiometabolic risk paradigm.
  • Adipose tissue-recognized as endocrine
    organ-secretes adipokines with endocrine
    functions expresses receptors enable it
    respond to afferent signals from numerous
  • Renin-angiotensin system (RAS)-a network of
    hormones regulates BP-known to be present in
    human adipose tissue, offering a potential link
    between obesity hypertension, as well as the
    prothrombotic properties of CVD.
  • RAS has been called a crucial driver of the
    pathophysiologic mechanisms associated with
    diabetic heart disease.

  • Immune system plays an integral role-mediating
    inflammatory cytokines associated with obesity.
  • Adipose tissue secretes signaling
    molecules-TNF-a, IL-6, and CRP.
  • Conditions associated with obesity-DM, HTN, and
    atheroclerosis-increases these inflammatory
    markers and cytokines, which have been shown to
    be predictive of both CVD and T2DM.
  • Dyslipidemia represents the circulatory component
    of cardiometabolic risk.

  • Arterial buildup of detrimental lipids and the
    deficit of beneficial lipids are well known
    causes of atherosclerosis, the building block of
    heart disease.
  • The endocannabinoid system (ECS) (a newly
    identified physiologic system) hosts receptors
    throughout the body (eg, brain, liver, pancreas,
    adipocytes, GI tract)
  • ECS plays a role in regulating satiety signals
    food intake-influencing BW and abdominal

Abdominal Adiposity A key Component in
Cardiometabolic Risk
  • Key Point
  • Abdominal adiposity is considered to be the
    high-risk fat. It is associated with insulin
    resistance, elevated inflammatory markers,
    dyslipidemia, and hypertension. Studies show
    abdominal fat to be more predictive of CVD and
    T2DM than subcutaneous fat.

  • Abdominal (visceral) fat is associated with
    insulin resistance, elevated inflammatory
    markers, dyslipidemia, and hypertension.
  • Abdominal adiposity is now recognized to be a
    greater risk for CVD and T2DM than overall
  • Despres-abdominal obesity as a major clinical and
    public health issue.
  • WC is considered to be the prime clinical
    indicator of abdominal adiposity, compared with
    BMI, which has been the traditional measure of
    overall obesity.

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Abdominal adiposity and FFA
  • The precise mechanisms behind increased risk from
    abdominal adiposity vs subcutaneous adiposity is
    not known, but numerous studies support this
  • The link to insulin resistance is partly
    explained by the increased levels of FFA that
    typically accompany excess abdominal adiposity.
  • Elevated FFA inhibit the insulin signaling
    mechanism, which causes decreased glucose
    transport to skeletal muscle.
  • FFA also play a mediating role between insulin
    resistance and b-cell dysfunction-indicating that
    a reduction in FFA levels could be a desirable
    therapeutic goal.

  • Abdominal obesity is also associated with
    decreased levels of adiponectin, which also
    contributes to insulin resistance.
  • Elevated CRP believed to be triggered by excess
    abdominal adiposity it is indicative of
    inflammation in the body and shown to be
    predictive of CVD and an insulin resistance.
  • Obesity has been shown to be associated with the
    inflammation cascade, with adipose tissue
    expressing a number of inflammatory cytokines.
  • Obesity associated with dyslipidemia and

  • Abdominal obesity specifically linked with
    elevations in total cholesterol, LDL-C, TG, and
    apolipoprotein-B, low HDL-C. It is also
    associated with elevated BP
  • Zhu evaluated data from NHANES III-WC more highly
    correlated with hypertension than BMIas a
    screening tool for pts in need of weight
  • Han-determined WC more predictive of MS than BMI
    in an 8-year follow up study of 1968 adults in
    San Antonio Heart Study.
  • Among BMIlt30 kg/m2, 8-year incidence of MS was
    20 in those with high WC 10 in those without
    high WC
  • Among BMIgt30 kg/m2, 8-years incidence was 33
    with high WC vs 20 without.

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  • Abdominal adiposity shown to have a stronger
    association with T2DM than overall adiposity.
  • Wang-evaluate BMI, WHR, and WC as predictors of
    T2DM in 27,270 participants in prospective
    male-cohort Health Professionals Follow-up Study
    (Figure 7). WC with the sharpest increase, high
    WC conferred a relative risk of 20.4, compared
    with 16.5 for BMI and 8.7 for WHR.

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  • Abdominal adiposity has also been determined to
    be more predictive of CVD than overall adiposity.
  • Lakka-analyzed CVD outcome in 1346 Finnish men
    with no history of CVD-BMI was measured as an
    indicator of overall obesity, WHR WC for
    abdominal obesity-men with 3 higher quartiles of
    WHR had 3 X risk of coronary events than lowest
    quartiles. Men in 2 highest quartiles of WC had 2
    X risk of events significant linear correlation
    between WC number of events. BMI was less
    consistently associated with CVD risk than WHR or

  • The risk of becoming obese was recently
    determined to increase considerably with age.
  • Vasan-4117 Framingham Heart Study, aged 30-59
    years, normal weight-4-year rates becoming
    overweight 14-19 in women 26-30 in men.
    4-year rate developing obesity 5-7 in women,
    7-9 in men. 30 yrs obesity rate 25 in men 30
    in women. More than ½ became overweight at 30yrs.

Adipose Tissue as an Endocrine Organ
  • Key Point
  • Adipose tissue has been shown to act as an
    endocrine organ, expressing proteins that act as
    a signaling mechanism throughout the body and
    playing a significant role in metabolism of fat
    and glucose.

  • Adipose tissue composed of adipocytes, a
    connective tissue matrix, nerve tissue,
    stromavascular cells, and immune cells
  • Adipose tissue secretes endocrine proteins
    hormonal receptors
  • Many proteins, or adipokines, secreted by adipose
    tissue (Figure 4), act as a metabolic signaling
    mechanism, interacting with CNS and organs
    throughout the body.
  • TNF-a inhibits the uptake and storage of glucose
    and FFA it also inhibits metabolism and fatty
    acid oxidation.
  • Leptin plays a role in perceived satiety-its
    effects are mediated via hypothalamic pathways
    through actions on peripheral tissues such as
    muscle pancretic b-cells.

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  • Key Point
  • Adiponectin has been shown to have
    antiatherogenic, antidiabetic, and
    anti-inflamamtory properties, with decreased
    levels being associated with abdominal obesity.

  • Adiponectin plays a key role in regulation of fat
    glucose metabolism.
  • Decreased plasma adiponectin strongly associated
    with insulin resistance in animal models, while
    increased improved insulin sensitivity.
  • Study of obese Japanese T2DM and CVD, 2
    conditions commonly associated with insulin
    resistance and hyperinsulinemia, plasma
    adiponectin decreased.
  • 352 nondiabetci women study, hypertriglyceridemia
    and reduced HDL-C associated with low
  • Increased adiponectin determined associated with
    improved insulin sensitivity.

  • Adiponectin shown to have antiatherogenic
    properties, preventing or slowing the progression
    of the formation of lipids deposits in the
  • Multiple mechanisms of adiponectin
  • Inhibit expression of adhesion molecules
  • Inhibit TNF-a-induced nuclear factor-kB
    activation, inhibit
  • adhesion of monocytes to endothelial cells,
  • Inhibit expression of macrophage scavenger
    receptor class A-1,
  • in turn inhibit uptake of oxidized LDL-C,
    as well as formation
  • of foam cells,
  • Inhibits the migration and proliferation of
    smooth muscle cells.

  • Adiponectin demonstrated antidiabetic properties
  • In high fat/high sucrose mice, globular
    adiponectin resulted weight loss and decrease
    plasma glucose, FFA, and TG.
  • Adiponectin increase FFA oxidation, glucose
    uptake, and lactate production in monocytes and
    reduce expression of molecules involved in
    hepatic gluconeogenesis
  • This leads to decreased glucose levels in vivo.

Inflammatory and Thrombotic factors
  • Key Point
  • Proinflammatory and prothrombotic cytokines are
    associated with obesity and insulin resistance.
    They have been shown to be predictive of CVD and

  • The proinflammatory/prothrombotic state is
    identified as a prominent component of
    cardiometabolic risk, adiponectin shown to have
    anti-inflammatory properties.
  • Xydakis-evaluated relationship of adiponectin
    with inflammation, adiposity, and insulin
    resistance in 40 subjects with metabolic
    syndrome, adiponectin was low.
  • Adiponectin decreased and TNF-a increased with
    the number of metabolic syndrome factors present
    (high TG, low HDL-C, elevated BP, elevated BG,
    and high WC). (Figure 8)
  • Increase number of metabolic syndrome factors
    results in greater proinflammatory state.

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Other adipokines
  • Other adipokines are also linked to inflammation.
  • IL-6 associated with obesity and insulin
    resistance, playing a complex role in energy
  • IL-6 is 2-3 times more abundant in visceral
    adipose tissue than in subcutaneous adipose
  • PAI-1 is one of fibrinolytic proteins, is a
    primary inhibitor of fibrinolysis, giving it
    prothrombotic properties, elevated PAI-1
    associated with obesity and insulin resistance
    and believed to play a causal role in CVD.

Residual Risk
  • Key Point
  • Despite great advances in prevention and
    treatment of CVD and T2DM, no treatment is
    effective in all patients. There is a residual
    risk with any given therapy, indicating an
    opportunity for additional intervention.

  • Reduction of cardiometabolic risk factors is a
    critical patient management goal of clinicians.
  • Recommendations commonly include therapeutic
    lifestyle changes such as a healthier diet and
    exercise regimen, as well as pharmacologic
    treatment for the more commonly addressed risk
    factors (eg, LDL-C, hypertension).
  • But even the best established treatment are not
    100 effective-leaving a certain proportion of
    treated patients vulnerable to CV or metabolic
  • There is a residual risk factors-also been
    documented in patients receiving highly effective
    pharmacologic treatment for hypertension.
  • Therapeutic gaps exist-agents most commonly
    prescribed for CVD and T2DM are generally
    indicated for only 1 or 2 risk factors-meaning
    multiple cardiometabolic risk factors often
    require multiple medications.

  • Key Point
  • Standards of care involve a fragmented approach
    to management, ie, treating only the clinically
    evident conditions.
  • As cardiometabolic risk also involves developing
    conditions, patient would likely benefit from
    comprehensive evaluation for all cardiometabolic
    risk factors.

  • Modern treatment paradigms encourage a fragmented
    approach to patient management.
  • Clinicians often treat individual risk factors
    without evaluating for the full constellation of
    cardiometabolic risk factors, possibly
    overlooking developing subclinical conditions
    that might benefit from early intervention.
  • Emerging cardiometabolic risk factors, such as
    inflammation, insulin resistance, and abdominal
    adiposity, are often underaddressed in clinical
  • There currently are no pharmacologic agents
    approved for reduction of these risk factors.

Proactive Management of Cardiometabolic Risk
  • Key Point
  • Comprehensive evaluation for cardiometabolic risk
    represents a preventive approach to CVD and T2DM,
    potentially leading to decreased morbidity and
    mortality, as well as decreased health-care costs.

  • Proactive management of CMR-offers potential
    identify subclinical morbidities before
    significant health threat-thereby reducing
    morbidity, mortality, economic costs.
  • Key to identification of CMR-recognition patient
    with 1 or 2 clinically evident risk factors
    likely has more, as these risk factors have been
    shown to cluster.
  • Full evaluation for CMR enables clinicians to
    move beyond the fragmented approach to patient
    management (targeting only the clinically evident
    conditions) more comprehensive Tx.
  • In addition to pts with subclinical morbidities,
    this approach is also appropriate for established
    CVD or T2DM as a means of preventing future
    events or progression of disease.

  • CMR involves multiple pathogenic pathways and
    physiologic systems, with abdominal adiposity
    playing a key role.
  • The complex nature of this constellation of risk
    factors presents a special challenge to
    clinicians, necessitating a better understanding
    of conditions and their markers that may have
    previous been considered outside the scope of
    their practices.
  • Successful management of CMR depends partly on
    the physicians enhanced ability to identify all
    appropriate risk factors, as well as on the
    development of more comprehensive management
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