Managing Cardiometabolic Risk: An Evolving Approach to Patient Care

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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
  approach.
• 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.

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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.

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Introduction

• 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
  2002.
• DM had the sixth highest mortality rate in US,
  with T2DM contributing to more than 200,000
  deaths in 2002.

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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.

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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
  attention.

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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.

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• 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.

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• 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.

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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

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• 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
  obesity.
• 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
  factors
• Sowers also refers to this condition as
  cardiometabolic risk syndrome.

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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.

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• 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

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ATP III-BP

• 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
  atherosclerosis.
• 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.

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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
  T2DM
• All the independent risk factors associated with
  T2DM risk, glucose level is the strongest
  predictor.
• 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

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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
  TG
• 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
  level

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• 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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Controversies

• 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.

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• 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
  treatment.

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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.

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• 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.

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

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• Cardiometabolic risk not only involves multiple
  risk factors, but also multiple physiologic
  systems.
• 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
  hormones.
• 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.

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• 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.

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• 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
  adiposity.

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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.

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• 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
  adiposity.
• 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
  finding.
• 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.

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• 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
  hypertension.

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• 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
  management.
• 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
  WC.

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• 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.

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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.

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• 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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Adiponectin

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

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Adiponectin

• 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
  adiponectin.
• Increased adiponectin determined associated with
  improved insulin sensitivity.

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Adiponectin

• Adiponectin shown to have antiatherogenic
  properties, preventing or slowing the progression
  of the formation of lipids deposits in the
  arteries.
• 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.

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• 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.

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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
  T2DM

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• 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
  homeostasis.
• IL-6 is 2-3 times more abundant in visceral
  adipose tissue than in subcutaneous adipose
  tissue.
• 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.

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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.

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• 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
  morbidity.
• 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.

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• 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.

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• 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
  practice.
• There currently are no pharmacologic agents
  approved for reduction of these risk factors.

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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.

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• 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.

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• 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
  options.