CURRICULUM VITAE

• SALLY AMAN NASUTION, MD, FINASIM, FACP

- Born in Medan, August 8th 1967
- Internist – Cardiologist
- Faculty Member Division of Cardiology,
Department of Internal Medicine at
Faculty of Medicine University of
Indonesia, Jakarta
- Head of Intensive Coronary Care Unit
(ICCU), Cipto Mangunkusumo National
General Hospital Jakarta
- Secretary General of Indonesian Society
of Internal Medicine
 The New Horizon
in Metabolic Syndrome Management

Dr Sally Aman Nasution, SpPD-KKV, FINASIM, FACP

Cardiology Division Department of Internal Medicine
Faculty of Medicine Universitas Indonesia
Cipto Mangunkusumo National General Hospital
Jakarta
Definition

Constellation of metabolic
abnormalities that confer increased
risk of cardiovascular disease(CVD) and
diabetes mellitus.
 Sindrom Metabolik (SM)

• Adalah kondisi yang ditandai adanya beberapa

faktor risiko mayor penyakit kardiovaskular
(PKV)
• Berhubungan secara etiologi dengan resistensi
insulin
• Genetik juga berperan
• Munculnya fenotip ini dipicu oleh kenaikan
berat badan, terutama dengan akumulasi
lemak
Han TS, Lean intraabdomen
MEJ. Metabolic Syndrome. 2014. Obesity anddengan lingkar
Metabolic Complication. pinggang
2014. Elsevier
International Diabetes Federation Definition:
Abdominal obesity plus two other components: elevated BP, low
HDL, elevated TG, or impaired fasting glucose
 Alternative names

• Metabolic syndrome

• Syndrome X

• Insulin resistance syndrome

• Deadly quartet
 Other associated
conditions
1) Cardiovascular disease
increased risk for new onset CVD, ischemic stroke,
PVD
2) Type 2 diabetes mellitus
increased risk by 3-5 folds
3) NAFLD and/or NASH
4) Hyperuricemia
 Pathogenesis

• Insulin resistance
• Increased waist circumference
• Dyslipidemia
• Glucose intolerance
• Hypertension
• Decreased adiponectin levels
 Pathogenesis contd…

• 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
Pathogenesis contd…
 Pathogenesis contd…

Insulin resistance pp/fasting hyperinsulinemia

Lipolysis by LPL Abundance of FFA’s

Impaired insulin Toxic injury to

mediated glucose Increased insulin
resistance pancreatic islets
uptake

Hyperglycemia Type 2 DM
Pathogenesis contd…
http://www.myhealthywaist.org/documentation-
centre/index.html?no_cache=1&tx_stdoccenter_pi1%5Buid%5D=58&tx_stdoccenter_pi1%5Bmo
Grundy SM. Pre-Diabetes, Metabolic Syndrome, and Cardiovascular Risk. JACC. 2012
http://www.myhealthywaist.org/documentation-
centre/index.html?no_cache=1&tx_stdoccenter_pi1%5Buid%5D=58&tx_stdoccenter_pi1%5Bmo
CVD risk markers that contribute
to global cardiometabolic risk

Can J Cardiol. 2011 Mar-Apr;27(2):e1-e33

 Prevalensi SM

Prevalensi USA 22%

Age dependent increase:

– 20-29 tahun: 6.7%

– 60-69 tahun: 43.5%

– >70 tahun : 42%

 Prevalensi SM meningkat pada TGT dan GDPT

NFG: Normoglycemia
IFG: impaired fasting glucose
Grundy SM. Pre-Diabetes, Metabolic Syndrome, and Cardiovascular Risk. 2012. JACC IGT: impaired glucose tolerance
 Faktor Risiko SM

Lingkungan:
“westernized” lifestyle (inaktivitas & unlimited high fat food supply) Genetik
Obesitas saat kanak2
Stress psikososial Mempengaruhi
Bertambahnya BB 30-40% variasi BMI
Diet tinggi lemak jenuh
Merokok 70% variasi distribusi l
Inaktivitas Usia
Kelebihan konsumsi alkohol
Impaired Fetal Growt

Han TS, Lean MEJ. Metabolic Syndrome. 2014. Obesity and Metabolic Complication. 2014. Elsevier
 SM terdiri dari penyakit metabolik di bawah ini, yang
semuanya adalah faktor risiko ASCVD

Timbul dan beratnya komponen di atas bergantung pada usia dan kenaikan
BB. Akumulasi lemak sentral lebih berperan dibandingkan lemak tubuh total,
baik pada orang kurus maupun overweight
Han TS, Lean MEJ. Metabolic Syndrome. 2014. Obesity and Metabolic Complication. 2014. Elsevier
 Kriteria SM yang paling sering digunakan:

Kombinasi fitur tersebut secara signifikan meningkatkan risiko DM tipe 2 dan PJK
prematur
 NCEP ATP III (2005) vs IDF (2006)

Kriteria IDF memiliki batas lebih rendah dgn tujuan

mencegah DM tipe 2 dan PJK. Tujuan kriteria diagnostik ini
yaitu untuk meningkatkan kesadaran inisiasi intervensi BB
Han TS, Lean MEJ. Metabolic Syndrome. 2014. Obesity and Metabolic Complication. 2014. Elsevier
untuk pencegahan DM tipe 2 dan PJK.
 Ukuran Lingkar Pinggang berdasarkan Etnis

IDF. The IDF consensus worldwide definition of the Metabolic Syndrome. 2006
The metabolic syndrome was associated with an increased risk of
• Cardiovascular disease (CVD) (RR: 2.35; 95% CI: 2.02 to 2.73)
• CVD mortality (RR: 2.40; 95% CI: 1.87 to 3.08)
• All-cause mortality (RR: 1.58; 95% CI: 1.39 to 1.78)
• Myocardial infarction (RR: 1.99; 95% CI: 1.61 to 2.46)
• Stroke (RR: 2.27; 95% CI: 1.80 to 2.85)

Patients with the metabolic syndrome, but without diabetes,

maintained a high cardiovascular risk.
 SM juga berhubungan dengan:

• Perlemakan hati dengan steatosis, fibrosis,

dan sirosis
• Karsinoma hepatoselular dan
kolangiokarsinoma intrahepatik
• CKD dan mikroalbuminuria.
– Pada studi NHANES III, SM pada analisis
multivariat secara signifikan meningkatkan risiko
CKD dan mikroalbuminuria (adjusted OR 2.6 dan
1.9). Risiko meningkat dengan meningkatnya
Meigs JB. The metabolic syndrome (insulin resistance syndrome or syndrome X). 2016. Uptodate. Diunduh dari:
https://www.uptodate.com/contents/the-metabolic-syndrome-insulin-resistance-syndrome-or-syndrome-
x?source=search_result&search=metabolic%20syndrome&selectedTitle=1~150
 Hubungan Obesitas Sentral dan
Penyakit Metabolik
• Struktur dan fungsi jaringan lemak bervariasi
pada berbagai situs anatomik
• Lemak intraabdomen adalah organ endokrin
aktif mensekresi sitokin (adipokin): leptin,
adiponektin, resistin, IL-1 dan IL-6, TNF-a yang
penting pada regulasi energi, juga
angiotensinogen dan PAI-1 (protrombotik)
• Peningkatan adipokin berhubungan dengan
Grundy SM.berbagai penyakit
Pre-Diabetes, Metabolic metabolik
Syndrome, and Cardiovascular Risk. 2012. JACC
 How to diagnose?

• IDF criteria
• H/o symptoms of OSA in all patients
• H/o PCOS in premenopausal women
• Family H/o CVD and DM
• Waist circumference and BP measurement
• Laboratory investigations
 Fasting lipid profile and fasting glucose
TREATMENT
 Terapi

• ATP III tahun 2001, didukung AHA, NIH, dan

The Endocrine Society merekomendasikan 2
tujuan utama terapi:
– Terapi kausa utama (kelebihan berat
badan/obesitas) dengan intensifikasi manajemen
berat bedan dan meningkatkan aktivitas fisik
– Terapi faktor risiko KV yang menetap setelah
modifikasi gaya hidup
Meigs JB. The metabolic syndrome (insulin resistance syndrome or syndrome X). 2016. Uptodate. Diunduh dari:
https://www.uptodate.com/contents/the-metabolic-syndrome-insulin-resistance-syndrome-or-syndrome-
x?source=search_result&search=metabolic%20syndrome&selectedTitle=1~150
 LIFESTYLE
MODIFICATIONS

• Weight reduction- include a combination of caloric restriction,

increased physical activity, and behavior modification.
 Modifikasi Gaya Hidup
Modifikasi Gaya Hidup
Fokus: penurunan BB dan peningkatan
aktivitas fisik u/pencegahan progresi SM.
• Studi The Coronary Artery Risk Development in
Young Adults (CARDIA)Pada 5115 dewasa muda
18-30 thn, peningkatan BMI dalam 15 tahun
berhubungan dengan progresi SM dibandingkan
dewasa muda dengan BMI stabil (tak peduli
berapapun BMI awal).
• Penurunan BB meningkatkan sensitivitas insulin
Meigs JB. The metabolic syndrome (insulin resistance syndrome or syndrome X). 2016. Uptodate. Diunduh dari:
https://www.uptodate.com/contents/the-metabolic-syndrome-insulin-resistance-syndrome-or-syndrome-
x?source=search_result&search=metabolic%20syndrome&selectedTitle=1~150
 OBESITY

• Appetite
suppressants-
phentermine and
sibutramine.

• Absorption inhibitors-
Orlistat

• Bariatric surgery is
also an option for
patients with BMI >40
 Modifikasi Gaya Hidup – Diet

• Diet Mediterranean (tinggi buah, sayur,

kacang, gandum utuh, minyak zaitun) lebih
banyak menurunkan BB, TD, profil lipid,
resistansi insulin, peradangan, dan disfungsi
endotel dibandingkan diet rendah lemak.
• Diet DASH (membatasi natrium harian 2400
mg, lebih tinggi produk susu dibanding diet
Mediterranean) memperbaiki trigliserida, TD
diastolik, GDP, dan BB.
Meigs JB. The metabolic syndrome (insulin resistance syndrome or syndrome X). 2016. Uptodate. Diunduh dari: https://www.uptodate.com/contents/the-metabolic-
syndrome-insulin-resistance-syndrome-or-syndrome-x?source=search_result&search=metabolic%20syndrome&selectedTitle=1~150
 Modifikasi Gaya Hidup – Olahraga
– Bermanfaat untuk BB dengan menghilangkan
secara selektif, terutama lemak abdomen.
Rekomendasi: setidaknya 30 menit aktivitas
intensitas moderat (seperti berjalan cepat) per
hari.
– Liposuction tidak meningkatkan sensitivitas insulin
atau memperbaiki faktor risiko PJKdiperlukan
balans energi negatif dengan diet dan olahraga
untuk mendapatkan manfaat metabolik
penurunan BB.
Meigs JB. The metabolic syndrome (insulin resistance syndrome or syndrome X). 2016. Uptodate. Diunduh dari:
https://www.uptodate.com/contents/the-metabolic-syndrome-insulin-resistance-syndrome-or-syndrome-
x?source=search_result&search=metabolic%20syndrome&selectedTitle=1~150
 PHYSICAL ACTIVITY
• 60–90 min of daily activity (At least 30 min.)
Gradual increases in physical activity should be
encouraged to enhance adherence and avoid
injury.

• Some high-risk patients should undergo formal

cardiovascular evaluation before initiating an
exercise program.

• Physical activity could be formal exercise such

 Modifikasi Gaya Hidup
Pencegahan DM Tipe 2
• Modifikasi gaya hidup secara bermakna
menurunkan risiko DM tipe 2 dan faktor risiko
KV pada uji klinis
• Obat hipoglikemik oral yang berefek pada
toleransi glukosa & sensitivitas insulin yaitu
metformin dan thiazolidinediones.
• Metformin dapat mencegah terjadinya DM pd TGT
• Metformin+edukasi diet & olahraga menurunkan risiko
Meigs JB. The metabolic syndrome (insulin resistance syndrome or syndrome X). 2016. Uptodate. Diunduh dari:
DM sebesar 31% dibandingkan plasebo (insidens DM
https://www.uptodate.com/contents/the-metabolic-syndrome-insulin-resistance-syndrome-or-syndrome-
x?source=search_result&search=metabolic%20syndrome&selectedTitle=1~150
 Modifikasi Gaya Hidup
Pencegahan DM Tipe 2
• Obat hipoglikemik oral yang berefek pada
toleransi glukosa & sensitivitas insulin –
thiazolidinediones.
• Thiazolidinediones mengalihkan lemak intra-abdomen
ke jaringan subkutan (lebih baik secara metabolik) dan
meningkatkan toleransi glukosa dan memperbaiki
profil lipid.

Meigs JB. The metabolic syndrome (insulin resistance syndrome or syndrome X). 2016. Uptodate. Diunduh dari:
https://www.uptodate.com/contents/the-metabolic-syndrome-insulin-resistance-syndrome-or-syndrome-
x?source=search_result&search=metabolic%20syndrome&selectedTitle=1~150
 INSULIN RESISTANCE

• Insulin resistance is the primary Patho-physiologic mechanism for the

metabolic syndrome.

• Several drug classes [biguanides, thiazolidinediones (TZDs)] increase insulin

sensitivity.

• Both metformin and TZDs enhance insulin action in the liver and suppress
endogenous glucose production. TZDs, but not metformin, also improve
insulin-mediated glucose uptake in muscle and adipose tissue.

• Benefits of both drugs have also been seen in patients with NAFLD and PCOS,
 GLYCEMIC CONTROL

• In patients with the metabolic syndrome and Type 2 diabetes,

aggressive glycemic control decreases cardiovascular risk..

• In patients with IFG without a diagnosis of diabetes, a lifestyle

intervention has been shown to reduce the incidence of Type 2
diabetes.
 Pencegahan
Penurunan
Modifikasi
Olahraga
Diet Gayarisiko
Hidup KV
DM tipe 2

Terapi SM

Meigs JB. The metabolic syndrome (insulin resistance syndrome or syndrome X). 2016. Uptodate. Diunduh dari:
https://www.uptodate.com/contents/the-metabolic-syndrome-insulin-resistance-syndrome-or-syndrome-
x?source=search_result&search=metabolic%20syndrome&selectedTitle=1~150
 Modifikasi Gaya Hidup
Pencegahan DM Tipe 2
• Belum ada data target kontrol gula darah
pasien SM nondiabetik.
Rekomendasimemperbaiki GDPT dan TGT
dengan penurunan BB sekitar 5-10% dari BB
awal, dengan diet dan olahraga.
• Farmakoprevensi DM dengan obat tidak
direkomendasikan, tetapi metformin dapat
dipertimbangkan untuk individu tertentu
dengan
Meigs JB. The GDPT
metabolic syndrome dan syndrome
(insulin resistance TGT. orPasien yang
syndrome X). 2016. baru
Uptodate. Diunduh dari:
https://www.uptodate.com/contents/the-metabolic-syndrome-insulin-resistance-syndrome-or-syndrome-
terdiagnosis DM perlu mendapat terapi
x?source=search_result&search=metabolic%20syndrome&selectedTitle=1~150
 Penurunan Risiko KV
Penurunan Risiko KV—Perbaikan Lipid

– ATP III merekomendasikan target LDL <100 mg/dL

untuk pencegahan sekunder pasien dengan DM
tipe 2, disarankan dari beberapa studi bahwa
target yang lebih agresif (<70 mg/dL) dengan
regimen statin
– Pada pasien PJK dengan LDL tinggi, pasien dengan
karakteristik SM (HDL rendah, trigliserida tinggi)
berisiko paling tinggi mengalami MACE dan paling
mendapat manfaat dari terapi statin.
Meigs JB. The metabolic syndrome (insulin resistance syndrome or syndrome X). 2016. Uptodate. Diunduh dari:
– Terapi pasien PJK dan SM dengan atorvastatin 80
https://www.uptodate.com/contents/the-metabolic-syndrome-insulin-resistance-syndrome-or-syndrome-
x?source=search_result&search=metabolic%20syndrome&selectedTitle=1~150
 TRIGLYCERIDES

• A fasting triglyceride value of <150 mg/dL is

recommended. A weight reduction of >10% is
necessary to lower fasting triglycerides.

• A fibrate (gemfibrozil or fenofibrate) is the drug of

choice to lower fasting triglycerides and typically
achieve a 35–50% reduction.
 HDL Cholesterol

• For rise in HDL cholesterol, weight reduction is an important

strategy.

• Nicotinic acid is the only currently available drug with

predictable HDL cholesterol-raising properties.

• Statins, fibrates, and bile acid sequestrants have modest

effects (5–10%), and there is no effect on HDL cholesterol with
ezetimibe or omega-3 fatty acids.
 LDL Cholesterol

For patients with the metabolic

syndrome and diabetes, LDL
cholesterol should be reduced to
<100 mg/dL.
 Penurunan Risiko KV
Penurunan Risiko KV—Terapi Hipertensi

– Peran ACE-I atau ARB menurunkan resistansi

insulin pada DM Tipe 2 masih kontroversial.
– Kontrol hipertensi penting pada pasien DM. Target
TD lebih rendah dibandingkan populasi umum dan
bergantung pada ada/tidaknya nefropati diabetik.
Target TD belum jelas pada SM, untuk sementara
dapat mengikuti panduan untuk populasi umum.
– Peran ACE-I atau ARB pada pasien hipertensi
dengan SM tanpa CVD atau diabetes belum
Meigs JB. The metabolic syndrome (insulin resistance syndrome or syndrome X). 2016. Uptodate. Diunduh dari:
diketahui.
https://www.uptodate.com/contents/the-metabolic-syndrome-insulin-resistance-syndrome-or-syndrome-
x?source=search_result&search=metabolic%20syndrome&selectedTitle=1~150
 BLOOD PRESSURE

• The direct relationship between blood pressure and all-cause

mortality rate has been well established.

• Best choice for the first antihypertensive should usually be an

angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II
receptor blocker.

• In all patients with hypertension, a sodium-restricted diet enriched

in fruits and vegetables and low-fat dairy products should be
advocated.
Meigs JB. The metabolic syndrome (insulin resistance syndrome or syndrome X). 2016. Uptodate. Diunduh dari:
https://www.uptodate.com/contents/the-metabolic-syndrome-insulin-resistance-syndrome-or-syndrome-
x?source=search_result&search=metabolic%20syndrome&selectedTitle=1~150
 PROTHROMBOTIC & PROINFLAMMATORY STATE

• Most patients with metabolic syndrome exhibit a prothrombotic state

characterized by elevations of plasminogen activator inhibitor-1 and
fibrinogen.

• Use of low dose aspirin can be recommended for patients with

metabolic syndrome, who have a high CV risk, those with overt type 2
diabetes mellitus, or atherosclerotic cardiovascular diseases.

• Metabolic syndrome frequently is accompanied by a pro-inflammatory

state, characterized by increased CRP levels. No specific treatment
available.
Han TS, Lean MEJ. Metabolic Syndrome. 2014.
Obesity and Metabolic Complication. 2014.
Elsevier
 Pencegahan
• Walaupun gangguan metabolik memburuk dengan usia,
banyak faktor yang dapat diimiodifikasi untuk mencegah
progresinya.
• Individu risiko tinggi dapat diidentifikasi dari riwayat
keluarga dan besarnya lingkar pinggang
• Aktivitas fisik teratur (jalan cepat 2-4 jam/minggu) dapat
mencegah SM
• Penurunan BB sedang (±5kg) dapat menghilangkan SM,
dan mencegah 60% insidens DM.
• Penurunan BB sedang dengan orlistat didapatkan
menurunkan insidens SM dan diabetes 30-40%
• Metformin dapat mencegah progresi prediabetes,
Han TS, Lean MEJ. Metabolic Syndrome. 2014. Obesity and Metabolic Complication. 2014. Elsevier
menghilangkan SM pada 5% kasus
 Terapi SM Potensial

• Testosteron
– Pada uji klinis kecil individu dengan konsentrasi
testosteron rendah, testosteron replacement
mengurangi lemak intra-abdomen, meningkatkan
massa otot, dan meningkatkan sensitivitas insulin.
Masih diperlukan RCT

• Bromocriptine mesylate (centrally-acting

dopamine D2 receptor agonist)
– dipikirkan dapat mereset organisasi sirkadian
Han TS, Lean MEJ. Metabolic Syndrome. 2014. Obesity and Metabolic Complication. 2014. Elsevier
hipotalamus abnormal sehingga memperbaiki
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