John Hyer
University of Georgia College of Pharmacy
Doctor of Pharmacy Candidate, 2012
Preceptor: Ali R. Rahimi, MD, FACP, AGSF
Objectives
• Define metabolic syndrome (MetS)
• Examine the risk and prevalence associated with
Metabolic syndrome (MetS)
• Evaluate current treatment strategies for efficacy
• Our role in prevention
Epidemiology
 Approximately 25% of the world’s population has
metabolic syndrome

Interestingly enough (but not surprisingly), more than half of
the adults in U.S. are overweight or obese
 Same or greater primary risk factor as smoking for CVD
(cardiovascular disease)
 Numbers will increase with aging population and
increasing rates of childhood obesity

Peaks in mid to late 60’s
Epidemiology
 Most common in men and Hispanics
 Increases with age
 Native Americans have highest recorded prevalence of
MetS
 60% or women aged 45-49
 45% of men aged 45-49
 Cardio-Metabolic Syndrome risk is based on global
risk of metabolic syndrome
Risk factors
 Central adiposity (waist
circumference)
 Better association with MetS
than BMI

Peripheral adiposity is a weaker
predictor of MetS
 Obesity
 Sedentary lifestyle
 Type 2 diabetes mellitus (T2DM)
 Est. that up to 75% of patients
with T2DM or impaired
glucose tolerance have MetS
 Lipodystrophy
 Genetic or HAART induced
 Aging
 Postmenopausal status
 Smoking
 Low household income
 Antipsychotic medications
 Clozapine
 Olanzapine
Pathophysiology of MetS
 Widely debated

Most accepted hypothesis is insulin resistance
 Insulin resistance precluded by:


Postprandial hyperinsulinemia followed by
Fasting hyperinsulinemia and hyperglycemia
Diabetes
obesity
diabesity
Insulin resistance
 Increases with increasing body fat
 Excess adipose tissue releases
 Nonesterified fatty acids (NEFA)

High level overloads muscle and liver with lipids
 Cytokines –
 Increase glucose and VLDL-C production by liver
 Plasminogen activator inhibitor-1 (PAI-1)
 High levels contribute to a prothrombotic state
 Adiponectin
 Plays a role as an anti-inflammatory and insulin sensitizing agent
 Reduced
 Interleukin (IL)-6 elevation
 Stimulate insulin resistance and lypolysis of adipose tissue TG
 C-reactive protein (CRP)
 Signifies cytokine excess and a proinflammatory state
Insulin resistance
 Free fatty acids - contributor
 Released from enlarged adipose tissue mass
 Insulin responsible for


Antilipolysis
 Most sensitive pathway of insulin action
Stimulation of hormone sensitive lipoprotein lipase
 Mobilizes fatty acids from triglyceride rich stores
 Insulin resistance = increased lipolysis produces more
FFA= further decreases antipolytic effect of insulin
Insulin resistance -FFAs
 In muscle
 High NEFA levels in muscle are diverted to the liver

Promoting fatty liver and atherogenic dyslipidemia
 In the liver increases production of
 Glucose
 Triglycerides
 Secretion of very-low-density lipoproteins
Insulin resistance
 In muscle
 FFA’s reduce insulin sensitivity by inhibiting insulinmediated glucose uptake

Leads to increased circulating glucose
 Increases pancreatic insulin secretion – hyperinsulinemia
 Results in enhanced sodium reabsorption and increased
sympathetic nervous system activity

Hypertension?
 Take home Point!!!
 Insulin resistance leads to oxidative stress which leads to
endothelial cell dysfunction, promoting vascular damage and
atheroma formation
Diagnosing Metabolic Syndrome
Metabolic Syndrome Defined
 According to the National Cholesterol Education Program Adult
Treatment Panel III (NCEP ATP III) presence 0f 3 of the
following:
ATP III Criteria
Abdominal Obesity
Waist circumference > 40 inches
in men and 35 inches in female
Fasting plasma glucose (FPG)
FPG ≥ 100 mg/dL or drug
treatment for elevated blood
glucose
Blood pressure (BP)
BP > 130/85 mmHg or drug
treatment for blood pressure
Serum high-density lipoprotein
cholesterol (HDL-C)
HDL-C < 40 mg/dL in men and
< 50 mg/dL in women
Serum triglycerides
≥ 150 mg/dL or drug treatment
for elevated triglycerides
Evaluation
 The American Heart Association
 Recommends measurement of high-sensitivity CRP for risk
stratification in patients at high risk of CVD
 Is patient ready to make therapeutic lifestyle






modifications? (i.e. reduce dietary fat)
Fasting glucose
Fasting lipid panel
Waist circumference
Height and weight (BMI)
Frammingham Risk Assessment for 10 Year CVD risk
Coronary Artery Calcium (CAC) scan (AHA/ACC)
 Good in asymptomatic low-risk patients
Clinical Consequences
MetS
CVD and T2DM
 Cardiovascular Disease (CVD)
 High risk for developing CVD

MetS and the Framingham Risk Score
 Which is better at predicting CVD?
 Evidence for both camps in the literature
 Relative risk for CVD events or death is 1.78 in patients
with MetS
Clinical Consequences
 Type II Diabetes Mellitus
(T2DM)
 Presence of MetS is
highly predictive of
developing new-onset
T2DM


75-85% of patients with
MetS will progress to
T2DM
Relative risk of 3.53-5.17 for
development of diabetes
T2DM
Insulin
resistance
Hyperinsulinemia
Dyslipidemia
Obesity
Therapy
 Difficult
 No randomized controlled trials for specific treatment
options
 Goal
 Reduce the risk for or preventing CVD and T2DM
NCEP ATP III Major Therapeutic Goals in Patients with
MetS
1. Treat underlying causes (overweight/obesity and
physical inactivity) by intensifying weight management
and increasing physical activity
2. Treating cardiovascular risk factors if they persist
despite lifestyle modification
*** lifestyle modifications, pharmacologic therapy, and
bariatric surgery***
Lifestyle Modifications
Lifestyle Modifications
 Diet
 Even a modest weight loss significantly reduced prevalence of
MetS
 Diet rich in complex, unrefined carbs, high in fiber
(14 g/1000
cal consumed daily), and low in added sugar (<25% of caloric
intake)

Recommended by Diabetes Prevention Program
 Fat
 Saturated fat <7% of caloric intake
 Increase of unsaturated fat
 linoleic acid should be 5-10% of caloric intake (i.e. safflower oil)
 alpha-linolenic acid 0.7-1.6% of calories (i.e. kiwifruit seeds and flax)
Lifestyle Modifications
 Sodium
 DASH (Dietary Approaches to Stop Hypertension)

Restrict sodium intake to no more than 1500 to 2000mg/day
Lifestyle Modifications
 Physical activity
 Improves glucose transport and insulin action in
working skeletal muscle
 AHA guidelines on exercise

≥ 30 min/day most days of the week (brisk activity; 5 days)
 Dose-response effect of aerobic exercise on visceral
adiposity
 7-10% reduction in BW during one year of therapy
Pharmacologic Therapy
 Lifestyle modifications can have amazing clinical
benefits… but often met with failure
 Noncompliance

Journal keeping and classes?
 Excess adiposity
 Currently only one FDA drug approved for long term
management – Orlistat (Rx - Xenical, OTC - Alli)

The National Institutes of Health guidelines
 BMI ≥ 30 kg/m2
Pharmacologic Therapy
 Insulin resistance/hyperglycemia
 First line treatment
1.
2.
3.
•
•
4.
•
5.
Weight loss – 5-10% of baseline weight
Lifestyle modifications
Metformin – indicated for patients with both impaired
fasting glucose (IFG) and impaired glucose tolerance (IGT)
DPP study found metformin reduced progression of diabetes
by 31% for those at risk (53% whom had MetS)
Also reduced incidence of MetS by 17%
Pioglitazone – increase BW, but reduces waist to hip ratio
Improves: BP, TGs, HDL-C, carotid intima-media thickness
Acarbose – STOP-NIDDM trial – many benefits, but very
poor patient tolerability (FLUTALANCE, abdominal pain)
Pharmacologic Therapy
 Dyslipidemia
 Elevated TGs, low HDL-C, and small, dense LDL-C
 MetS is not currently a coronary risk equivalent for
managing lipid goals
 Calculate LDL goal and secondary Non-HDL goal using
ATP III guidelines



Very high risk – LDL < 70 mg/dL
Moderate high risk LDL < 100 mg/dL
Moderate risk LDL < 130mg/dL
Pharmacologic Therapy
 Dyslipidemia – treatment
1. Statins
Reduce LDL-C 15 to 60%
•
Increase HDL-C 5 to 10%
•
Reduce triglycerides 7 – 30%
•
Pleiotropic effects on inflammation, endothelial function,
and CVD events
•
4S* trial- Those with MetS had both the highest risk of
major coronary events and the greatest benefit from statin
therapy
*Scandinavian Simvastatin Survival Study
•
Pharmacologic Therapy
 Dyslipidemia
 Bile acid sequestrants (Welchol, Questran, Colestid)

LDL-C reduction of 15 to 30%
 Ezetimibe (Zetia)
 LDL-C reduction of 15 to 25%
***CONTROVERSY***
 ENHANCE study showed no differences in carotid intima-media
thickness when given with simvastatin; no reduction in events…
 ARBITER 6-HALTS trial
 Showed that ezetimibe increased carotid intima-media artery
wall thickness compared to niacin
 SHARP study – Simvastatin and ezetimibe in renal disease
 Upcoming IMPROVE-IT Trial
Pharmacologic Therapy
 Dyslipidemia
 Fibrates




Reduce triglycerides 25 to 50%
Increase HDL-C 5 to 15%
Reduce LDL 0 to 30%
Useful to reach non-HDL-C goal when statins are not enough
 Niacin
 Most effective FDA approved agent for raising HDL-C and increasing HDL-C particle
size
 15-35%
 Lowers TGs 20 to 50%
 Reduction of LDL-C 5 to 25%
 Note: caution in liver dx, gout, DM (hyperglycemia and hyperuricemia)
 AIM-HIGH trial – halted prematurely
 No benefit over statin alone in reduction CV related complications, despite
increases in HDL and decreases in triglycerides
 A small and unexplained increase in ischemic stroke rates in high dose niacin
group
Pharmacologic Therapy
• Hypertension/Elevated Blood Pressure
• First line – in patients with MetS, especially in setting of
CVD or T2DM
1.
2.
A.
•
•
Angiotensin-converting enzyme (ACE) inhibitors
Angiotensin receptor blockers (ARB)
Shown to be effective in reducing rates of albuminuria or
progression of nephropathy in patients with diabetes
Thiazide type diuretic
ALLHAT* trial – superior CVD outcomes compared to CCB,
B-B, or ACE-I; even in diabetes
*Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial
Pharmacologic Therapy
 Antiplatelets (ASA)
 Treating the prothrombotic state of MetS
 low-dose aspirin reduces CVD events in both secondary
and primary prevention
 Favorable efficacy/side effect ratio when 10-year risk for
CVD is ≥10%.
 AHA/ACC class 1b recommendation for women less than
65 years old with intermediate risk
Bariatric Surgery
 In a recent meta-analysis of 22,094 morbidly obese
patients:
 T2DM resolved in 76.8% and improved in 86% of cases
 Swedish Obese Subjects study – 10 year follow up
surgery
 Overall reduction in mortality due to CVD and T2DM
 Associated with improvement and/or resolution of
multiple comorbidities associated with obesity
Controversy About MetS
1. The definition
2. The ability or inability of MetS to predict CVD or
T2DM
•
Should T2DM be part of the definition?
Is MetS greater than the sum of its parts?
•
•
•
Weakness:
•
•
i.e. greater risk than its individual abnormalities
Treatment is no different than treatment for each of its
components
NCEP ATP III associates MetS with a 2-fold increase in
CVD
Conclusion
 Treatment strategies must focus on identifying and




managing individual components of metabolic
syndrome
Aggressive therapy must be optimized for each
individual patient and characteristics to reduce risk
No direct marker for insulin resistance to diagnose
metabolic syndrome
Further research is needed to better define metabolic
syndrome, the exact pathophysiology, and treatment
algorithms
Use care with lipid lowering agents
References
 Prasad, H, et al. Metabolic Syndrome: Definition and
Therapeutic Implications. Postgraduate Medicine 2012; Jan. vol.
124, issue I. Pg. 21-30.
 Well, CC, et al. Obesity, race, and risk for death or functional
decline among Medicare beneficiaries. Annals. 2011 May; Vol 154,
num 10: 645-654.
 SHARP Collaborative Group. Study of Heart and Renal
Protection (SHARP): Randomized trial to assess the effects of
lowering low-density lipoprotein cholesterol among 9438
patients with chronic kidney disease. Am Heart J 2010;
DOI:10.1016/j.ahj.2010.08.012.
 The AIM-HIGH investigators. Niacin in patients with low HDL
cholesterol levels receiving intensive statin therapy. N Engl J
Med2011; DOI:10.1056/oa1107579
References
 Taylor AJ, Villines TC, Stanck EJ, et al. Extended-
release niacin or ezetimibe and carotid intima-media
thickness. N Engl J Med 2009;
DOI:10.1056/NEJMoa907569
 National Health Disparities Research Center of
Excellence Meharry Medical College. Cardio
Metabolic. Accessed March 2012.
http://www.hdrcoe.org/CardioMetabolic.html
 Bruce Goldfarb. Metabolic Syndrome Debate Defused.
Diabetes Journals. March 2012.
http://docnews.diabetesjournals.org/content/3/9/1.1.f
ull
References
 Expert Panel On Detection, Evaluation, And Treatment Of High
Blood Cholesterol In Adults (May 2001). "Executive Summary of
the Third Report of the National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation, and Treatment
of High Blood Cholesterol in Adults (Adult Treatment Panel
III)". JAMA: the Journal of the American Medical
Association 285 (19): 2486–9
 Ashen, DM. Management of cardiometabolic syndrome in the
primary and secondary prevention of cardiovascular disease.
Journal for Nurse Practitioners. 2008;4(9):673-680.
 Metabolic syndrome shown to increase risk of kidney problems.
Worldwide-Medicine.com. Aug 26, 2011. Accessed 10 March 2012.
http://www.worldwide-medicine.com/diseasesconditions/metabolic-syndrome-shown-to-increase-risk-ofkidney-problems/
References
 Sulaiman N, Mahmood DA. Cardiometabolic
Syndrome. HOD Family and Community Medicine,
Sharjah University of Melbourne. Access 10 March 2012.