Metabolic

Syndrome

Citra Ayu Aprilia

March 1st, 2017
contents
Definition
Epidemiology
Diagnosticcriteria
Pathogenesis
Treatment
 Metabolic Syndrome definition
 A cluster of physiological and biochemical abnormalities associated with the
development of cardiovascular disease and type 2 diabetes.
 Metabolic syndrome occurs when a person has three or more of the following
measurements:
 Abdominal obesity (Waist circumference >40 inches in men, > 35 inches in
women)
 Triglyceride level of 150 milligrams per deciliter of blood (mg/dL) or greater
 HDL cholesterol of < 40 mg/dL in men or < 50 mg/dL in women
 Systolic blood pressure (top number) of 130 millimeters of mercury (mm Hg) or
greater, or diastolic blood pressure (bottom number) of 85 mm Hg or greater
 Fasting glucose of 100 mg/dL or greater
EPIDEMIOLOGY
Affects close to 25% of U.S. adults
Prevalence increases with weight.
Metabolic syndrome is noted in 5% of normal weight, 22% of
overweight, and 60% of obese individuals
EPIDEMIOLOGY

Patients with the metabolic syndrome are :

At twice the risk of developing cardiovascular Disease.

Seven fold increase in risk for type 2 diabetes .
1.5-fold increase in all-cause mortality compared to
patients without the syndrome.
Abdominal Adiposity Is
Associated
With Increased Risk of P value for trend <0.001
25
Diabetes
20

Relative Risk of Diabetes

15

10

0
<28 >28-29 30-31 32-33 34-35 36-37 ≥38
Waist Circumference (in)

Carey VJ, et al. Am J Epidemiol. 1997;145:614-619

The new international Diabetes Federation (IDF) definition
According to the new IDF definition , for a person to be defined as having the metabolic syndrome he/she must have :
Central Obesity (defined as waist circumference * with ethnicity specific values )
plus any two of the following four factors :

 150 mg/dL (1.7 mmol/L ) Raised

. or specifc treatment for this lipid abnormality triglycerides

 40 mg/dl ( 1.03 mmol/L ) in males Reduced HDL

mg/dL (1.29 mmol/L) in females 50 Cholesterol
 or specific treatment for this lipid abnormality
Systolic BP 130 or diastolic BP 85 mmHg Raised blood
Or treatment of previously diagnosed hypertension pressure

100 mg/dL (5.6 mmol/L) )FPG( Raised fasting

or previously diagnosed type 2 diabetes plasma glucose
Waist circumference Country / Ethnic group
cm 94 Male *Europids
In the USA, the ATP III values ( 102 cm male; 88
cm 80 Female cm female) are likely to continue to be used for
clinical purposes
cm 90 Male South Asians
cm 80 Female Based on a Chinese , Malay and Asian-Indian
population
cm 90 Male Chinese
cm 80 Female
cm 90 Male **Japanese
cm 80 Female
Use South Asian recommendations until Ethnic South and Central Americans
more specific data are available
Use European data until more specific data
Sub-Saharan Africans
are available
Use South Asian recommendations until EMME ( Arab) populations
more specific data are available
Intra-abdominal (Visceral) Fat
The dangerous inner fat! Front

Visceral AT

Subcutaneous
Back
 PATHOGENESIS
• Central obesity is the keystone for pathogenesis of “METABOLIC
SYNDROME”
• Central obesity leads to insulin resistance.
• Various factors that play a role in pathogenesis includes:
IL-1, IL-6, IL-18
Resistin
TNF-alpha
CRP
• Adiponectin an anti inflammatory cytokine is reduced in metabolic
syndrome.
The BP in these patients also increases because:

1-insulin stimulates increased sodium reabsorption .

2-there is reduced endothelial nitric oxide production .
3-there is increased vascular sympathetic tone.
Insulin-resistant adipose tissue is a potent source of
Angiotensinogen.
 Insulin resistance fasting hyperinsulinemia/

Lipolysis by LPL Abundance of FFA’s

Impaired insulin mediated Toxic injury to

glucose uptake Increased insulin resistance
pancreatic islets

Hyperglycemia Type 2 DM
DIFFERENTIAL DIAGNOSIS
Cushing’s syndrome
Hypothyroidism
familial hyperlipidemia
Hyperaldosteronism.
Prevention and general aspects of intervention
 Obesity, glucose intolerance, insulin resistance, diabetes mellitus type 2: correction
of overweight by adequate changes in diet (Mediterranean diet, less saturated fat,
fewer calories, reduction of alcohol consumption), and by more and regular physical
activity.
 Hyperlipidemia: as discussed above for obesity etc.
 Hypertension: as discussed above for obesity etc.; in addition, moderation of salt
(NaCl) and alcohol consumption.
 All patients are urgently advised to stop smoking
Prevention and general aspects of intervention
 On the basis of the concept that the metabolic syndrome is associated with
sympathetic hyperactivity, preventive measures aiming at reducing this hyperactivity
could be considered.

 Correctionof overweight and enhanced physical activity may be expected to reduce

sympathetic hyperactivity somewhat.

 Prevention of the prothrombotic condition can be achieved only by drug treatment.

ABC's for Providers
A A1c Target
Aspirin Daily
B Blood Pressure Control
C Cholesterol Management
Cigarette Smoking Cessation

D Diabetes and Pre-Diabetes

Management
E Exercise
F Food Choices
A1c Target
Diabetes and Pre-Diabetes
Management
 Glucose intolerance, insulin resistance, and type 2
diabetes mellitus
 The classical oral antidiabetic drugs (tolbutamide and related sulfonylurea
derivatives, glinides, and acarbose), the biguanide, metformin, exhibits insulin-
sensitizing activity.
 Metformin is considered the oral antidiabetic drug of choice in patients with
metabolic syndrome
 Glitazones, are the newer type of insulin sensitizer. They reduce insulin resistance
via the activation of the peroxisomeproliferator-activated receptor subtype g (PPAR-
g). They would be beneficial oral antidiabetic agents in patients with metabolic
syndrome. Their position will be established by means of current clinical trials
Insulin resistance
As insulin resistance is now widely recognized as an
important background to the various components of the
metabolic syndrome, it appears useful to review the
differential influences of the various cardiovascular and
antidiabetic drugs used in the management of the
metabolic syndrome
Aspirin Daily
Prothrombotic State
 A prothrombotic state in patients with the metabolic syndrome is characterized by
elevations of fibrinogen, PAI-1, and possibly other coagulation factors. However,
these are not measured routinely in clinical practice.

 The risk for thrombotic events can be reduced by aspirin therapy.

 The AHA currently recommends use of aspirin prophylaxis in most patients whose
10-year risk for CHD is 10% as determined by Framingham risk scoring.13
Including patients with metabolic syndrome when their 10-year risk for CHD is 10%
is appropriate
Blood Pressure
Control
Hypertension
 The Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)
introduced a new category of “prehypertension” (120 to 139/80 to 89
mm Hg), in recognition of the fact that underlying risk factors raise
blood pressure to ranges that increase risk for CVD.

 This
recognition accords with ATP III’s adding of blood pressures
130/85 mg/dL to the list of risk factors comprising the metabolic
syndrome.
 In persons with categorical hypertension (blood pressure 140/90 mm Hg),
drug therapies are required according to JNC 7 recommendations.
 In patients with established diabetes, antihypertensive drugs should be
introduced at even lower blood pressures (130/80 mm Hg).
 No particular antihypertensive agents have been identified as being
preferable for hypertensive patients who also have the metabolic syndrome.
 Angiotensin-converting enzyme inhibitors and angiotensin receptor
blockers are useful antihypertensive drugs, and some clinical trials (but
not all) suggest that they carry advantages over other drugs in patients
with diabetes.

 Diuretics and ẞ-blockers in high doses can worsen insulin resistance

and atherogenic dyslipidemia.
 For thiazide diuretics, doses should be kept relatively low in accord
with current recommendations.
 ẞ-Blockers are cardioprotective in patients with established CHD and
are no longer contraindicated in patients with type 2 diabetes.
Cholesterol
Management
Atherogenic Dyslipidemia
Beyond lifestyle modification, several drug alternatives may be
considered in patients with atherogenic dyslipidemia.
ATP III emphasized that LDL cholesterol is the primary target
of lipid-lowering therapy.
Statins will reduce all apolipoprotein B–containing lipoproteins
and often can achieve the ATP III goals for LDL cholesterol as
well as for non-HDL cholesterol.
 Fibratesimprove all components of atherogenic dyslipidemia and appear
to reduce the risk for CVD. Their use in combination with statins is
particularly attractive. However, both fibrates and statins have the
potential to produce myopathy, and when they are used together, risk for
myopathy is enhanced.

 The literature contains many isolated reports of severe myopathy

occurring from the combination of statin plus gemfibrozil. Recent
evidence further indicates that gemfibrozil interferes with catabolism of
statins in the liver, which can raise statin blood levels, thereby
predisposing to myopathy.
 Fenofibrate does not interact adversely with statin catabolism and thus may be safer
to use in combination therapy.

 Nicotinic acid has similar features to fibrates, and the combination of nicotinic acid
and statins is promising. Nicotinic acid is especially efficacious for raising HDL
cholesterol levels, but higher doses can raise plasma glucose levels. Therefore, if
nicotinic acid is used in patients with IFG, IGT, or diabetes, its dose should be kept
relatively low (eg, 1 to 2 g per day).
Exercise
 Lifestyle modification leading to weight reduction and increased
physical activity represents first-line clinical therapy of the metabolic
syndrome.
 Smoking cessation, of course, is paramount.
 A realistic goal for overweight/obese persons is to reduce body
weight by 7% to 10% over a period of 6 to 12 months.
 Weight reduction should be combined with a daily minimum of 30
minutes of moderateintensity physical activity.
Hyperuricemia
 Foryears, hyperuricemia has been identified with or thought to be
the same as gout, but uric acid has now been identified as a marker
for a number of metabolic and hemodynamic abnormalities
Hyperuricemia Medication
 Nonsteroidal Anti-Inflammatory Drugs
Management of pain and inflammation in gout. Have analgesic, anti-inflammatory,
and antipyretic properties. Inhibit the enzyme cyclooxygenase, thus inhibiting
biosynthesis of prostaglandins and thromboxanes from arachidonic acid.
Indomethacin (Indochron E-R, Indocin)
Rapidly absorbed. Metabolism occurs in liver by demethylation, deacetylation, and
glucuronide conjugation. Inhibits prostaglandin synthesis.

Discontinue 3-4 d following symptom resolution.

Indomethacin (Indochron E-R, Indocin)
Mechanism of Action
 Inhibits synthesis of prostaglandins in body tissues by inhibiting at least 2 cyclo-oxygenase (COX) isoenzymes,
COX-1 and COX-2
 May inhibit chemotaxis, alter lymphocyte activity, decrease proinflammatory cytokine activity, and inhibit
neutrophil aggregation; these effects may contribute to anti-inflammatory activity

 Absorption
 Bioavailability: ~100%
 Onset: 30 min
 Duration: 4-6 hr
 Peak plasma time: 0.5-2 hr; 1.67 hr (Tivorbex)
 Peak plasma concentration: 1.2 mcg/mL (20 mg PO); 0.8-2.5 mcg/mL (25 mg PO); 2.4 mcg/mL (40 mg PO);
2.5-4 mcg/mL (50 mg PO)
Indomethacin (Indochron E-R, Indocin)
 Distribution
 Protein bound: 99%
 Metabolism: liver

Metabolites: Desmethyl, desbenzoyl, desmethyl-desbenzoyl

Enzymes inhibited: COX-1, COX-2
 Elimination

Half-life: 4.5 hr (prolonged in neonates)

 Excretion: Urine (60%), feces (>33%)
Indomethacin (Indochron E-R, Indocin)
Dosage Forms & Strengths
 Capsule: 20mg (Tivorbex); 25mg; 40mg (Tivorbex); 50mg capsule, extended-
release 75mg
 powder for injection:1mg
 oral suspension: 25mg/5mL
 Suppository: 50mg

Inflammatory/Rheumatoid Disorders
 Immediate release: 25-50 mg PO/PR q8-12hr; not to exceed 200 mg/day
 Extended release: 75-150 mg/day PO in single daily dose or divided q12hr; not to
exceed 150 mg/day
Indomethacin (Indochron E-R, Indocin)
Bursitis/Tendinitis
 Immediate-release: 75-150 mg/day PO/PR divided q6-8hr
 Extended-release: 75-150 mg/day PO in single daily dose or divided q12hr

Acute Gouty Arthritis

 50 mg PO/PR q8hr for 3-5 days; reduced once pain is under control
 Nephrogenic Diabetes Insipidus
 2 mg/kg/day PO divided q8hr

Pain
 Tivorbex: Indicated for mild-to-moderate acute pain
 20 mg PO TID or 40 mg PO BID/TID
 Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals
Xanthine Oxidase Inhibitors
Prevent gouty arthritis attacks and nephropathy. Used to treat hyperuricemia secondary
to diuretics or antineoplastics.
Prevent recurrent uric acid nephrolithiasis.
Allopurinol (Zyloprim)
Inhibits xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine.
Reduces synthesis of uric acid without disrupting biosynthesis of vital purines.
Febuxostat (Uloric)
Xanthine oxidase inhibitor. Prevents uric acid production and lowers elevated serum
uric acid levels. Indicated for long-term management of hyperuricemia associated with
gout.
Allopurinol (Zyloprim)
Mechanism of Action
Xanthine oxidase inhibitor; inhibits conversion of hypoxanthine to xanthine to uric acid;
decreases production of uric acid without disrupting synthesis of vital purines

Pharmacokinetics
Bioavailability: 49-53%
Onset: 2-3 days
Peak plasma time: 0.5-2 hr
Time to peak effect: 7-14 days

Distribution
Protein bound: <1%
Allopurinol (Zyloprim)
 Metabolism: liver
 Metabolites: Oxypurinol (active), allopurinol riboside (activity unknown)

 Elimination
 Half-life:
Parent drug, 1-3 hr; active metabolite, 15-20 hr
 Dialyzable: Yes (both hemodialysis and peritoneal dialysis)
 Renal clearance: 30 mL/min
 Excretion: Urine (80%), feces (10-20%)
Allopurinol (Zyloprim)
Dosage Forms & Strengths
 Tablet: 100mg; 300mg
 powder for injection: 500mg/vial

Mechanism of Action
 Xanthine oxidase inhibitor; inhibits conversion of hypoxanthine to xanthine to uric acid; decreases
production of uric acid without disrupting synthesis of vital purines
Pharmacokinetics
 Bioavailability: 49-53%
 Onset: 2-3 days
 Peak plasma time: 0.5-2 hr
 Time to peak effect: 7-14 days
 Distribution: Protein bound: <1%
 Metabolism: liver

Metabolites: Oxypurinol (active), allopurinol riboside (activity unknown)

Allopurinol (Zyloprim
 Elimination
 Half-life:Parent drug, 1-3 hr; active metabolite, 15-20 hr
 Dialyzable: Yes (both hemodialysis and peritoneal dialysis)
 Renal clearance: 30 mL/min
 Total body clearance: 16 mL/min/kg
 Excretion: Urine (80%), feces (10-20%)
Uricosuric Agents
Competitively inhibit reabsorption of uric acid in proximal renal tubule. This
promotes excretion of uric acid and lowers serum uric acid levels.
Probenecid (Benemid)
 Used to treat and prevent hyperuricemia associated with gout and gouty
arthritis.
 250 mg PO twice daily for 1 week; increase to 500 mg PO twice daily to 2
g/day maximum with dosage increases of 500 mg q4weeks
 If gout attacks do not occur for 4 months and uric acid levels are within
normal may reduce dose by 500 mg q6monts
Probenecid (Benemid)
Mechanism of Action
 (Uricosuric) inhibits tubular reabsorption of urate; increasing uric acid excretion
 Also inhibits tubular secretion of weak organic acids like PCNs & cephalosporins

Pharmacokinetics
 Half-Life: 3-17 hr
 Onset: 2 hr (effect on penicillin levels)
 Peak Plasma Time: 2-4 hr
 Bioavailability: >90%
 Protein Bound: 85-95% (albumin)
 Metabolism: Liver
 Metabolites: hydroxylated metabolites, N-despropyl metabolite, probenecid acylglucuronide
 Excretion: Urine
 Probenecid (Benemid)
 Dosage Forms & Strengths
 Tablet: 500mg

Gout
 250 mg PO twice daily for 1 week; increase to 500 mg PO twice daily to 2 g/day
maximum with dosage increases of 500 mg q4weeks
 If gout attacks do not occur for 4 months and uric acid levels are within normal may
reduce dose by 500 mg q6monts
Food Choices
 Nutritional therapy calls for a lownintake of saturated fats, trans fats,
and cholesterol; reduced consumption of simple sugars; and
increased intakes of fruits, vegetables, and whole grains.
 Extremes in intakes of either carbohydrates or fats should be
avoided.
Thank you