THE METABOLIC SYNDROME AND CENTRAL OBESITY
From Scripps Clinic’s Primary Care Medicine: A Practical Approach
Educational Objectives
| The goal of this program is to improve management of the metabolic syndrome and lowe the risk for cardiovascular
disease. After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Recognize and manage conditions associated with the metabolic syndrome.
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| 2. Explain the role of the endocannabinoid system in regulating body weight.
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| 3. Understand the role of cannabinoid type-1 (CB1 ) agonists for treatment of obesity.
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| 4. Evaluate risk factors for cardiovascular disease.
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| 5. Employ therapeutic strategies to reduce risks for cardiovascular disease.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of
the planning committee to disclose relevant financial relationships within the past 12 months that might create
any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity
promotes quality in health care and not a proprietary business or commercial interest. For this program, the following
has been disclosed: Dr. Dailey—Bristol-Myers Squibb (Speakers Bureau; investigator; occasional consultant);
Merck (Speakers Bureau; investigator); Pfizer (occasional consultant; investigator; Speakers Bureau);
Sanofi-Aventist (occasional consultant; investigator; Speakers Bureau)
Acknowledgements
Drs. Dailey and Guarneri were recorded at Primary Care Medicine: A Practical Approach, sponsored by Scripps Clinic
in San Diego, CA, August 10-12, 2007. The Audio-Digest Foundation thanks the speakers and the Scripps Clinic for
their cooperation in the production of this program.
| RISKS AND TREATMENTS FOR METABOLIC SYNDROME AND CENTRAL OBESITY —George E.
Dailey III, MD, Senior Consultant in Diabetes and Endocrinology, Scripps Clinic, La Jolla, CA
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| Fat cell: more than passive storage reservoir for triglycerides; sends signals to brain and to other storage organs;
metabolically active; visceral adiposity difficult-to-mobilize central storage compartment that helps
withstand starvation; free fatty acids result from mobilization, stream out of visceral fat continually, but
mobilized from subcutaneous fat in response to epinephrine
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| Products of fat cell: lipoprotein lipase (found in blood vessels; cleaves triglycerides); angiotensinogen; free
fatty acids; plasminogen activator inhibitor-1 (PAI-1; precursor of thrombotic disease; inflammatory cytokine);
adiponectin; resulting cascade—hypertension; atherogenic dyslipidemia; insulin resistance; thrombotic
tendency; atherosclerosis
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| Adipokines: adiponectin—antiatherogenic; reduces foam cells; improves insulin sensitivity; reduces vascular
remodeling; decreases hepatic glucose output; interleukin (IL)-6 and tumor necrosis factor (TNF)-α—inflammatory
cytokines that increase vascular inflammation, reducing insulin signaling and sensitivity in intra-abdominal
adiposity
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| Adiponectin: circulating protein; development of standardized measurement would enable assay to measure
insulin resistance indirectly; involved in regulation of fat and glucose metabolism; decreased in type 2 diabetes;
increased by certain drugs, eg, thiazolidinediones and by blocking endocannabinoid type-1 (CB1 ) receptor
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| Abdominal obesity: visceral adiposity more common in men; genetic tendency to deposit visceral fat in some
groups, eg, Asians (more visceral fat for same waist circumference) upper limit of body mass index [BMI]
23 in Asians, 25 in whites)
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| Waist circumference: consider following in patients; correlates with intra-abdominal fat on computed tomography
(CT); criterion for metabolic syndrome (men, 40 in; women, 35 in); recommendation for measuring—
from National Institutes of Health (NIH); use top of iliac crest parallel to floor at end of expiration; obesity
increasing—≈1 lb per yr on average in general population; waist circumference increasing faster; correlates
with increase in prevalence of type 2 diabetes
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| History: first written description of use of cannabinoids (relief of menstrual and rheumatic pain) in China;
first record in Britain in 1839; active ingredient in Cannabis sativa identified in 1964; receptor cloned from
rat brain in 1988 (any plant-based substance with central nervous system [CNS] effect likely has endogenous
ligand that evolved for purpose); first human receptor identified in 1991; first endogenous cannabinoid
described in 1992
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| First CB1 -receptor inhibitor: developed in 1994; several manufacturers developing product
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| CB1 receptor: stimulating; enhances feeding behavior in animals; tendency seen in increased appetite
(“munchies”) in cannabis smokers; blocking receptor seen as therapeutic measure for obesity
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| CB1 receptors throughout body: rich source of CB1 in limbic system; peripheral adipocytes; skeletal muscle;
liver; pancreas
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| CB1 receptor agonist drugs: drug expected to be on market in 1.5 to 2 yr; Merck in phase 3 trials; rimonabant
on market for >2 yr in Europe (European agency to collect information about depression and anxiety); Sanofi-
Aventis started several-year study with 8000 participants (to assess long-term effects); Solvay, Bristol-Myers
Squibb, and Pfizer in phase 2 trials
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| Additional metabolic findings: hypothalamus—reacts to hunger and satiety signals from gut; average American
meal lasts ≈8 min (too short for satiety signal to reach brain; some drugs slow gastric emptying and gastrointestinal
[GI] motility in effort to synchronize with satiety signal); ghrelin—made in stomach; indicates
hunger; important for immediate food-seeking behavior; limbic system—alters type of food sought; activates
sweet and fat food-seeking, ie, concentrated sources of calories (thought to have evolved for survival in periods
of famine)
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| Fuel storage: glycogen—most immediately releasable energy source; deposited in skeletal muscle and fat; fat
cell—deeper storage reservoir; visceral fat difficult to mobilize; subcutaneus fat easily mobilized
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| Endocannabinoid system: injection of endogenous cannabinoid into hypothalamus increases food intake in
rats, while blocking with increasing drug doses produces dose-related decrease in food intake; knockout
mouse (CB1 receptor missing) cannot gain weight on high-fat diet
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| Rimonabant: increases glucose uptake by muscle in response to insulin (peripheral effect, independent of
brain)
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| Genetic finding: abnormal allele increased in obese people and disproportionately increased in blacks, even
those with BMI of 25 to 30
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| Summary: endocannabinoid system increased in genetic and diet-induced obesity; several cardiovascular and
metabolic variables improved with rimonabant, eg, increased high-density lipoprotein (HDL), decreased triglycerides;
improved glucose tolerance, reduced C-reactive protein (CRP), and adiponectin
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| Clinical investigation of rimonabant: Rimonabant in Overweight/Obesity (RIO) trials; large multicenter
studies; initial results reported as trials continue; patients receiving 5-mg or 20-mg doses; 20-mg dose most
effective but has more side effects than placebo or 5-mg dose
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| Results: weight loss persisted for 2 yr after drug discontinuation; weight eventually returns to baseline; ≈3 in
loss in waist circumference; weight loss, 5 to 6 kg; triglycerides reduced; discontinuation rate higher and
psychiatric side effects increased (depressed mood; anxiety) with 20-mg dose
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| Bariatric surgery: diet and exercise unable to solve problem of obesity; gastric bypass surgery only realistic
way to lose 50 lb; some patients may die unless other alternative emerges; pouch reduced from 1 L to 20 to
25 mL (ghrelin signaling of hunger to brain reduced); adjustable gastric band enables size of opening to be
varied; 2 to 3 mo after surgery, patients must restrict carbohydrates and fluid intake to avoid dumping syndrome;
some people “able to eat around it”
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| Is obesity curable? not curable; multisystem problem; gaining 1 lb per yr (on average) represents ≈10 excess
calories per day; most drugs produce ≈5% weight loss
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| Responders vs nonresponders: difficult to identify; some have different enzyme for degrading system; multiple
reasons likely
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| Site of visceral adipose tissue deposition: liters in peritoneum; in organs, eg, liver, skeletal muscles
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| Interaction with CB2 receptor: CB2 under investigation for modulating immune system in multiple sclerosis
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| Happiness after weight loss: cause unknown; quality of life improves in every study
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| Leptin: signals brain about amount of fat stores; brain responds only to long-term changes; most obese humans
not deficient in leptin; not practical for weight loss therapy
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| Rosiglitazone (Avandia) safety: evidence of 43% increase in risk for MI reported; being used in 4 large 5-yr
cardiovascular event reduction trials; remains on market; significant cardioprotection unlikely; speaker
continues to use drug; more postmarketing surveillance needed
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| FRESH PERSPECTIVES ON RISK FACTORS FOR CARDIOVASCULAR DISEASE —Erminia M. Guarneri,
MD, Medical Director, Scripps Center for Integrative Medicine, Scripps Clinic, La Jolla
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| Context: “Conventional medical care is geared toward dealing with long-term degenerative processes only after
they erupt into advanced clinical disease. It’s like approaching a cliff but walking backward. You need to
recognize that you are getting close to the edge and stop. Once you fall off it is difficult to do anything about
it.” Terri Grossman, MD
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| Advances in genetics: discovering genetic basis of disease opens possibility of early intervention to modify
risks; polymorphisms—recently identified in cardiology, eg, for homocysteine; apo E isoform predicts responders
to very low-fat diet and susceptibility to Alzheimer’s disease
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| Trial findings: Framingham study found 35% of coronary events occur with total cholesterol level between
150 and 200 mg/dL; prevention trials show statins decrease risk ≈33% (risks remain; patients on statins continued
to have events)
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| Key factors: low-density lipoprotein (LDL) subtypes; high triglycerides (particularly in women; along with
low HDL); some proteins run in families, eg, Lp(a); inflammation
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| What to evaluate: apoliprotein (apo) A/apo A-I ratio; CRP levels; insulin resistance; HDL2b ; small dense
LDL
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| Other considerations: anger; depression; level of stress; central obesity; sedentary lifestyle; purpose in life
(someone without purpose may choose not to live)
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| Environment and lifestyle: account for 70% to 90% of patient prospects; environment washes over genes
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| Obesity epidemic: driving increased heart disease, diabetes, and hypertension; definition of obesity—30 lb
greater than ideal body weight or BMI >30; as BMI increases, cholesterol, blood pressure, blood glucose
level, and triglycerides increase, while HDL decreases
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| Central obesity: weight in midline functions as endocrine organ, producing angiotensin II, tumor necrosis factor,
IL-6, and CRP
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| Resulting inflammation: starts plaque formation, including oxidation of LDL and expression of adhesion
molecules; inflammation may be most important risk factor
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| CRP level: as this rises, risk for first myocardial infarction (MI) increases; for postmenopausal women, undesirable
total cholesterol/HDL ratio and CRP level biggest predictors of future cardiovascular events
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| Statins and CRP: intravascular ultrasonography compared pravastatin (Pravachol) 40 mg with atorvastatin
(Lipitor) 80 mg in 502 patients with coronary disease; found more plaque regression with same LDL level in
Lipitor group (greater reduction in CRP); this study and PRavastatin Or AtorVastatin Evaluation and Infection
Therapy (Prove it) study demonstrated 30% to 40% reduction in CRP
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| Metabolic syndrome: includes reduced HDL, insulin resistance, and hypertension (eg, 145/80 mg/Hg); presence
confirmed in ≈50% of population 60 to 69 yr of age
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| Diabetes: Centers for Disease Control and Prevention (CDC) predicts 1 in 3 children born in 2000 will be diagnosed
with diabetes in lifetime; in patients with diabetes, speaker recommends simultaneously treating LDL
while raising HDL; risks persist after reduction in LDL and HDL levels; HDL2b now known to pull plaque
from vessels (associated with reverse cholesterol transport and bringing antioxidant enzymes to subendothelial
surface)
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Suggested Reading
Böhm M et al: Treating to protect: current cardiovascular treatment approaches and remaining needs. Medscape
J Med 10 Suppl:S3, 2008; Després JP et al: Effects of rimonabant on metabolic risk factors in overweight
patients with dyslipidemia. N Engl J Med 353:2121, 2005; Di Marzo V et al: Endocannabinoid control of food
intake and energy balance. Nat Neurosci 8:585, 2005; Eberly LE et al: Multiple-stage screening and mortality
in the Multiple Risk Factor Intervention Trial. Clin Trials1:148, 2004; Fernandez ML et al: The LDL to HDL
cholesterol ratio as a valuable tool to evaluate coronary heart disease risk. J Am Coll Nutr 27:1, 2008; Howlett
AC et al: International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev
54:161, 2002; Kempler P: Learning from large cardiovascular clinical trials: classical cardiovascular risk factors.
Diabetes Res Clin Pract 68 Suppl1:S43, 2005; Epub 2005 Apr 8. Review; Mozaffarian D et al: Metabolic
syndrome and mortality in older adults: the Cardiovascular Health Study. Arch Intern Med 168:969, 2008; Pi-Sunyer
FX: Pathophysiology and long-term management of the metabolic syndrome. Obes Res 12 Suppl:174S,
2004; Stern RH: Evaluating new cardiovascular risk factors for risk stratification. J Clin Hypertens (Greenwich)
10:485, 2008; Taylor AJ: Evidence to support aggressive management of high-density lipoprotein cholesterol:
implications of recent imaging trials. Am J Cardiol 101:36B, 2008; Van Gaal LF et al: Effects of the cannabinoid-1
receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients:
1-year experience from the RIO-Europe study. Lancet 365:1389, 2005; Erratum in: Lancet. 2005 Jul 30-
Aug5;366:370.
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