13/04/2020

Metabolic Syndrome
&
Dyslipidemia

Sarah Firdausa
FK Unsyiah – RSUZA
April 2020
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Metabolic Syndrome
• The metabolic syndrome is a cluster of the most dangerous risk
factors that occur together and increase the risk for cardiovascular
disease, stroke, and type 2 diabetes,

• Epidemiology
• Around 20-25 %: adult population
• Risk of twice likely to die from heart attack
• Risk of three times likely to have a heart attack or stroke
• Risk of 5 fold developing diabetes
• Compared with people without the syndrome

The IDF consensus worldwide definition of the Metabolic Syndrome, 2006

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Definition = criteria

NCEP
WHO EGIR ATP III
1998 1999 2001 - 2005
World Health Organization European Group for study of National Cholesterol Education
Insulin resistance Program
Adult Treatment Panel III

Canada IDF AACE

2018 2005 2003

International Diabetes Federation Americon Associotion

of Clinical Endocrinologist

WHO
1998

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IDF
2005

The IDF consensus worldwide definition of the Metabolic Syndrome, 2006

The IDF consensus worldwide definition of the Metabolic Syndrome, 2006

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NCEP
ATP III
2005

Circulation 106, 3143-3421

Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada

Definition of Metabolic Syndrome Canada

Measure Categorical thresholds
2018
Elevated waist circumference (population/country specific) Men Women

Canada, United States of America ≥102 cm ≥88 cm

Middle Eastern, Sub-Saharan African, Mediterranean, Europids ≥94 cm ≥80 cm

Asians, Japanese, South and Central Americans

≥90 cm ≥80 cm
Elevated TG (drug treatment for elevated TG is an alternate ≥1.7 mmol/L
indicator†)
Reduced HDL-C (drug treatment for reduced HDL-C is an <1.0 mmol/L in males;
alternate indicator†) <1.3 mmol/L in females
Elevated BP (antihypertensive drug treatment in a person with systolic ≥130 mmHg or
a history of hypertension is an alternate indicator) diastolic ≥85 mmHg
Elevated FPG (drug treatment of elevated glucose is an ≥5.6 mmol/L
alternate indicator)
Adapted from: Alberti KG, et al. Circulation 2009;120:1640
† Commonly used drugs for elevated TG and reduced HDL-C are fibrates and nicotinic acid. A person taking one of these
drugs can be presumed to have high TG and reduced HDL-C. High-dose omega-3 fatty acids presumes high TG

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Huang, Paul L, Disease models & mechanisms 2, no. 5-6 (2009): 231-237
Huang, Paul L. Disease models & mechanisms 2, no. 5-6 (2009): 231-237

How to measure waist

circumference?
• Stand and place a tape measure around
your middle, just above your hipbones.
• Make sure tape is horizontal around the
waist.
• Keep the tape snug around the waist,
but not compressing the skin.
• Measure your waist just after a normal
breathe out.

https://www.cdc.gov/healthyweight/assessing/index.html
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Pathophysiology of Mets?

Insulin resistance Central obesity

Endothelial Dysfunction
Atherogenic Dyslipidemia

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Pathophysiology of Mets

Insulin Resistance

?
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Insulin resistance
Normal setting: insulin is produced in response to hyperglycemia and stimulates glucose use differently in various tissues.

- Stimulates glucose uptake (GLUT4) - Stimulates glucose uptake (GLUT4)

- Stimulates the synthesis of glycogen
- Inhibits fat breakdown, or lipolysis,
- Stimulates the synthesis of from glucose
and stimulates glucose uptake.
glycogen from glucose - Inhibits glycogenolysis
- Inhibits glycogenolysis - Decreases hepatic gluconeogenesis
- preventing an influx of more glucose
into the bloodstream
The net effect of all of these changes 

- increase glucose uptake

- reduce circulating glucose levels
- increase the conversion of glucose into the storage molecules, glycogen or fat

Insulin resistance: adipose, muscle and liver cells do not respond appropriately to insulin
- Effect: circulating glucose levels remain high Huang, Paul L. Disease models & mechanisms 2, no. 5-6 (2009): 231-237

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What is the marker for Insulin resistance?

• HOMA IR
• To evaluate insulin resisance
• HOMA B
• To evaluate β-cell disfunction

Tjokroprawiro, A., Formula Klinis Praktis, 2017

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Pathophysiology of Mets

Visceral obesity

?
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What is
visceral obesity?

- Body fat that is stored within the

abdominal cavity
- Stored around important internal
organs such as the liver, pancreas
and intestines

https://www.diabetes.co.uk/body/visceral-fat.html

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Visceral adiposity
• Visceral obesity causes a decrease in insulin-mediated glucose uptake 
clearly related to insulin resistance
• The probable mechanisms: involve adipokines (made by adipose tissue) that
modulate crosstalk between metabolism and vascular function
• Incuding: TNFα, IL-6  proinflammatory marker which contribute to insulin resistance
and vascular dysfunction
• The renin angiotensin system is also activated in adipose tissue, leading to
hypertension and insulin resistance.
• By contrast, adiponectin is a protective adipokine that couples insulin
sensitivity with energy metabolism.
• Adiponectin levels are decreased in obesity, T2D and metabolic syndrome.

Huang, Paul L. Disease models & mechanisms 2, no. 5-6 (2009): 231-237

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Pathophysiology of Mets

Atherogenic dyslipidemia

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What is Atherogenic dyslipidemia?

• The key features of atherogenic dyslipidemia:
• High plasma TG levels
• Low HDL
• Increase LDL
• Insulin resistance and visceral obesity are associated with
atherogenic dyslipidemia

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Atherogenic dyslipidemia
• Insulin resistance leads to atherogenic dyslipidemia in several ways.
1. Insulin normally suppresses lipolysis in adipocytes, so impaired insulin signaling
increases lipolysis, resulting in increased FFA levels.
In the liver, FFAs serve as a substrate for synthesis of TGs. FFAs also stabilize the production of apoB,
the major lipoprotein of very-low-density lipoprotein (VLDL) particles, resulting in more VLDL
production
2. Insulin normally degrades apoB through PI3K-dependent pathways, so insulin
resistance directly increases VLDL production
3. Insulin regulates the activity of lipoprotein lipase, the rate-limiting and major
mediator of VLDL clearance.

Thus, hypertriglyceridemia in insulin resistance is the result of both: ↑ VLDL production & ↓ VLDL clearance

Huang, Paul L. Disease models & mechanisms 2, no. 5-6 (2009): 231-237

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Pathophysiology of Mets

Endothelial dysfunction

?
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Endothelial dysfunction
Endothelial cells in Normal setting
• It lines the inner surface of blood vessels
• It serves important mechanical, as well as biological, functions.
• Some of Endothelium functions:
• It senses and responds to physiological and pathological stimuli
• It produces vasoactive substances, including NO, prostacyclin and endothelins.
• Endothelial expression of cell adhesion molecules governs interactions with circulating
leukocytes and monocytes, affecting inflammation, and with circulating platelets, affecting
hemostasis and thrombosis.
• It also modulates the response of the vascular smooth muscle layer, which may contribute
to intimal formation during the development of atherosclerotic plaques.
• Normal endothelial function protects against these processes, and endothelial
dysfunction is central to the pathogenesis of atherosclerotic lesion development.

Huang, Paul L. Disease models & mechanisms 2, no. 5-6 (2009): 231-237

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Endothelial dysfunction...?
• Endothelial dysfunction is the final common pathway
between many cardiovascular risk factors and
the development of atherosclerosis

• Endothelial dysfunction occurs when the endothelium fails to serve its

normal physiological and protective mechanisms.
• This might be because the endothelium is damaged or missing

• It occurs when the normal responses of the endothelium are affected, for
example by oxidative stress, hyperglycemia, advanced glycation products,
FFAs, inflammatory cytokines or adipokines.
• A common feature of endothelial dysfunction is the reduced bioavailability
of NO in the vasculature.

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Management of Mets
• The primary goal: reduce risk for clinical atherosclerotic disease.
• First-line therapy is directed toward the major risk factors: LDL-C above goal, hypertension,
and diabetes.
• Secondary goal: prevention of type 2 diabetes mellitus
• Individuals with established diabetes, risk factor management must be intensified to diminish
their higher risk for ASCVD.

• The prime emphasis in management of the metabolic syndrome per se is to

mitigate the modifiable, underlying risk factors (obesity, physical inactivity, and
atherogenic diet) through lifestyle changes.
• Effective lifestyle change will reduce all of the metabolic risk factors. Then, if
absolute risk is high enough, consideration can be given to incorporating drug
therapy to the regimen.

Circulation 106, 3143-3421

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Recommendations for treatment

Including
- Primary intervention
- Secondary intervention

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Primary intervention

A healthy lifestyle
• Moderate calorie restriction (7-10% BW loss in 1st year)
• Moderate increase in physical activity
• Change in dietary composition
• Smoking cessation

The IDF consensus worldwide definition of the Metabolic Syndrome, 2006

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Circulation 106, 3143-3421

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Secondary intervention

Drug therapy
• Treatment that could modulate the underlying
mechanisms of the metabolic syndrome as a whole
• However, these mechanisms are currently unknown
and specific pharmacological agents are not yet
available
• Therefore, treat the individual components of the
syndrome
The IDF consensus worldwide definition of the Metabolic Syndrome, 2006

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IDF recommended treatment of the individual

components of the metabolic syndrome

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Primary aims for therapy:

• Lower TG
• Raise HDL-c levels
• Reduce LDL-c levels

Atherogenic
dyslipidemia

The IDF consensus worldwide definition of the Metabolic Syndrome, 2006

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Konsensus Pengelolaan dan Pencegahan DMT2 di Indonesia 2019

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Konsensus Pengelolaan dan Pencegahan DMT2 di Indonesia 2015

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Target terapi dyslipidemia untuk resiko Penyakit Kardiovakular

Konsensus Pengelolaan dan Pencegahan DMT2 di Indonesia 2019

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• Hypertension (BP ≥ 140/≥ 90 mm Hg) should be

treated JNC 7
• Patients with DM, antihypertensive therapy
should be introduced at BP ≥ 130/≥ 80 mm Hg

Options:
Elevated Blood • ARB
• ACE-i
Pressure

The IDF consensus worldwide definition of the Metabolic Syndrome, 2006

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• Metformin in prediabetes pts will prevent

Insulin resistance
and hyperglycaemia
or delay the development of diabetes
• Thiazolidinedione  efficacy in delaying
or preventing T2DM in people with IGT
and insulin resistance
• Acarbose & Orlistat  can be used to
delay the development of T2DM in people
with IGT.

The IDF consensus worldwide definition of the Metabolic Syndrome, 2006

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Circulation 106, 3143-3421

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Circulation 106, 3143-3421

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Conclusions
• The central features of the metabolic syndrome are insulin resistance, visceral
adiposity, atherogenic dyslipidemia and endothelial dysfunction.
• These conditions are interrelated and share common mediators, pathways and
pathophysiological mechanisms.
• Of the various definitions for the metabolic syndrome, the NCEP ATP III definition is
the easiest to apply clinically and epidemiologically, because it uses straightforward
criteria that are measured readily.

• Consideration of metabolic syndrome as a specific entity allows for research on the

genetic basis for susceptibility to this syndrome, a better understanding of its
underlying pathophysiology and the development of treatment approaches

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References
• Huang, Paul L. "A comprehensive definition for metabolic syndrome." Disease models & mechanisms 2, no. 5-6 (2009): 231-
237.
• National Cholesterol Education Program (NCEP): Expert Panel on Detection and Treatment of High Blood Cholesterol in Adults
(2002). 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) final report. Circulation 106, 3143-3421.
• Zimmet, P., Magliano, D., Matsuzawa, Y., Alberti, G. and Shaw, J. (2005). The metabolic syndrome: a global public health
problem and a new definition. J. Atheroscler. Thromb. 12, 295-300
• Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the
Prevention and Management of Diabetes in Canada. Can J Diabetes. 2018;42(Suppl 1):S1-S325.
• Grundy, S. M., Cleeman, J. I., Daniels, S. R., Donato, K. A., Eckel, R. H., Franklin, B. A., Gordon, D. J., Krauss, R. M., Savage, P. J.,
Smith, S. C., Jr et al. (2005). Diagnosis and management of the metabolic syndrome: an American Heart Association/National
Heart, Lung and Blood Institute scientific statement. Circulation 112, 2735-2752.
• Dandona, Paresh, Ahmad Aljada, Ajay Chaudhuri, Priya Mohanty, and Rajesh Garg. "Metabolic syndrome: a comprehensive
perspective based on interactions between obesity, diabetes, and inflammation." Circulation 111, no. 11 (2005): 1448-1454.
• Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications, part 1: diagnosis and
classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15:539–553.
• Alberti, Kurt George Matthew Mayer, Paul Zimmet, and Jonathan Shaw. "Metabolic syndrome—a new world-wide definition. A
consensus statement from the international diabetes federation." Diabetic medicine 23, no. 5 (2006): 469-480.

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Thank you

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