CURRICULUM VITAE SINGKAT

Nama : TONY SUHARTONO dr.SpPD KEMD, FINASIM

Tempat, tgl lahir : Yogyakarta, 10 Desember 1948.
Pekerjaan : Dosen Fakultas Kedokteran UNDIP/ RS Dr Kariadi
Alamat : Jl. Lampersari No.35 Semarang.
Riwayat pendidikan :
- Dokter umum (FK UNDIP) 1975.
- Dokter Spesialis Penyakit Dalam (FK UNDIP) 1994
- Konsultan Endokrin Metabolisme Diabetes 2003
Pendidikan tambahan :
- Biokimia Kedokteran FK UI : 1977-1978
- Gerontological Nursing (Chiang May University) : 1992.
- Dyslipidemic management (Frieberg Hospital) : 1998
- Clinical Endocrinology (Royal Adelaide Hospital) : 2002
Anggota organisasi profesi:
- IDI
- PBBMI
- PAPDI
- PERKENI
- PERGEMI
- PERALMUNI
Medical approach to Dyslipidemia

Tony Suhartono

Sub Bag. Endokrinologi-Metabolisme, Bag Penyakit Dalam,

Bagian Biokimia
Fakultas Kedokteran Universitas Diponegoro/RS dr Kariadi
Semarang
 DISLIPIDEMIA
Kelainan metabolisme lipid, ditandai dengan
peningkatan serta penurunan fraksi lipid
plasma.

TRIAD LIPID
Kol-total/ kol-LDL
Trigliserid (TG)
Kol-HDL.
Lipemia is normal , however dyslipidemia is abnormal. We need lipid for
normal body metabolism ? There are several kinds of lipids. Lipids are
hydrophobic therefore its must be transferred in a hydrophilic form as
lipoprotein 11
Bile Acids
Dietary + LIVER
Cholesterol 7 LDL
Fat
2 Apo, B-100
1
Endogenous
Cholesterol

INTESTINES EXTRAHEPATIC
10 TISSUES

3 5

NASCENT HDL

LPL LPL
4 6
HDL3
LDL
REMNANTS VLDL 8 9
CHYLOMICRONS Apo E, B-100
Apo E, B-48 Apo E, C-II, LCAT HTGL
Apo E, C-II, B-48 B-100

Exogenous Endogenous CETP

HDL2
Pathway Pathway
Diagrammatic representation of lipoprotein metabolism. (Oberman, 1992)
 Exogenous Pathway of Lipid
Metabolism

Cholest
AA
FA
Vessel wall
P,
glycerol
Digestion and metabolism of dietary fat
Endogenous Pathway of Lipid
Metabolism
HDL metabolism and reverse cholesterol transport
 Mechanism of reverse
cholesterol transport
Esterified
cholesterol

Liver
Hepatic
Free catabolism
cholesterol Apo A-I
HDL
CETP
ABC-1
receptor Free
cholesterol VLDL
Apo A-II

Peripheral cell
Cholesterol
efflux
pre -HDL
HDL formation

The role of adenosine triphosphate-binding cassette transporter-1 (ABC-1) in cholesterol efflux.

Apo = apolipoprotein; CETP = cholesterol-ester transfer protein; HDL = high-density lipoprotein;
VLDL = very-low-density lipoprotein.
HDL Metabolism
Key Enzymes and Cofactors in Lipid
Metabolism
HMG-CoA reductase-reduces HMG-CoA to mevalonic acid in the
rate-limiting step of cholesterol biosynthesis (mainly liver and
intestine)
Lipoprotein Lipase- digests TG core of CMC and VLDL

Hepatic Lipase-conversion of IDL to LDL

CETP-transfers cholesteryl esters from HDL to other lipoproteins in
exchange for TG
LCAT(lecithin cholesterol acyl transferase) conversion of cholesterol
to cholesterol esters
Apolipoprotein A-major protein of HDL activating many reactions
Apo-B-major protein of VLDL, IDL, and LDL

Apo-CII and Apo E obtained from HDL by CMC and VLDL for
activation of LPL and receptor recognition respectively
LDL Oxidation and Atherosclerosis
 Mechanism of Atherogenic
Dyslipidemia
Insulin resistance
Increased
increased NEFA and VLDL
glucose flux to liver

IR impairs
LDLR
Insulin resistance
Insulin
and decreased FCHL
resistance
apo-B and DM II
degradation decreased
LPL Metabolic
syndrome
 Increased Atherogenicity of Small
Dense LDL
Direct Association Indirect Association
Longer residence time in Inverse relationship with HDL
plasma than normal sized LDL Marker for atherogenic TG
due to decreased recognition remnant accumulation
by receptors in liver Insulin resistance
Enhanced interaction with
scavenger receptor promoting
foam cell formation
More susceptible to oxidation
due to decreased antioxidants
in the core
Enter and attach more easily
to arterial wall
Endothelial cell dysfunction
 High Density Lipoprotein and
Atherosclerosis
Reverse cholesterol transport

Maintenance of endothelial function

Protection against thrombosis

With Apo A-I inhibits generation of calcium-induced
procoagulant activity on erythrocytes by stabilizing
cell membrane

Low blood viscosity via permitting red cell deformability

Anti-oxidant properties-may be related to enzymes called

paraoxonase
 Lipoprotein (a)
Specialized form of LDL
(apolipoprotein (a) covalently bound to
apo B by disulfide bridge)
Structural similarity to plasminogen,
thus interfering with fibrinolysis
Macrophage binding and cholesterol
deposition
Measured by ELISA
Cross-sectional and retrospective
epidemiologic studies have shown
association between excess Lp (a) and
CHD while prospective results are
conflicting
Associated with unstable angina and
presence of complex coronary lesions
Commonly detected in premature CHD
Possible role in target organ damage
in presence of HTN
Indications for screening:
CHD and no other identifiable
dyslipidemia
Strong CHD family history and no
other dyslipidemia
HTN and early premature target
organ damage
Hypercholesterolemia refractory to
statins and bile acid sequestrants
Treatment guidelines
Primary goal is to lower LDL to
target and lowering to <80 may
reduce risk
If LDL cannot become optimized,
then Lpa loweing with nicotinic
acid (38%) shoud be tried
Goal <20 in whites
 Primary Disorders of
LDL-Cholesterol Metabolism
Familial hypercholesterolemia
- Defect in gene coding for apo B/E LDL receptor thus reduced clearance of LDL from circulation
Homozygotes with higher LDL-C levels
Excess LDL deposited in arteries as atheroma and in tendons and skin as xanthomata and
xanthelasma
Hypercholesterolemia, normal TG, genetic or cellular confirmation of LDL receptor defect
Usually serum cholesterol levels AND premature CHD in first-degree or 2 second-degree
relatives
Usually requires multiple drugs for treatment

Familial defective apolipoprotein B-100

Mutation in apo-B 100 ligand and impaired binding to LDL receptor with decreased clearance of
LDL and 2-3 fold increase
Similar clinical manifestation as FH and only distinguished by molecular biology techniques

Familial combined hyperlipidemia

Usually associated with metabolic syndrome
1-2% general population
1/3-1/2 familial causes of CHD and 10% of premature cases
Overproduction of hepatically derived apo-B 100 associated with VLDL +/- decreased LDL
receptor activity
LDL phenotype B, increased TG, decreased HDL (atherogenic dyslipidemia)
Phenotypic heterogeneity depends on problems with VLDL or LDL metabolism
Elevated TG and cholesterol
Elevated LDL
Isolated hypertriglyderidemia (rise in VLDL)
 Statins
Competitive inhibitors of HMG CoA reductase, rate-limiting step in
cholesterol biosynthesis

Reduction in intrahepatic cholesterol leading to increased LDL

receptor turnover

Most powerful for lowering LDL cholesterol

Modest effect on raising HDL

Reduction in TG due to decreased VLDL synthesis and clearance of

VLDL remnants by apo B/E (LDL) receptors

Reduction in oxidized and small dense LDL subfractions and

reduce remnant lipoprotein cholesterol levels (reduction of CE
transfer from LDL to VLDL)
 Acetyl-CoA + Acetoacetyl-CoA

HMG-CoA
HMG-CoA X Statin
reductase
Mevalonate

PI3-Kinase/ Protein kinase Akt eNOS

BMP-2/ Bone formation
Dolichol
Angiogenesis
Haem
Ubiquinone
Farnesyl-PP Ras Cellular growth
Proliferation

Squalene
Geranylgeranyl-PP

RhoA Rac1 Cdc42

Lipoprotein eNOS t-PA
Vit D
Cholesterol
Bile acid
PAI-1, ET-1 Actin
Steroid hormones
cytoskeleton
Proliferation NADPH oxydase
and migration

Oxydative stress
Liao JK J Clin Invest 2002; 110:285-288
 HMG-CoA Reductase Inhibitors

RhoA

TXA2 t-PA Macrophage growth Rac1 RhoA ET-1

PAI-1 AT1 receptor

MMPS hs-CRP
Adhesion molecules ROS NO
TF

Platelet Thrombotic Plaque Vascular SMC Endothelial SMC
Vasoconstriction
activation effect stability inflammation hypertrophy dysfunction proliferation

Atherosclerosis Hypertension

Cardiovascular
disease

Takemoto MArterioscler. Thromb Vasc Biol. 2001; 21:1712-1719

Comparative efficacy of available statins.
(Davidson 2002)

Doses of agent (mg) % reduction

Rosuvastatin Atorvastatin Simvastatin Lovastatin Pravastatin Fluvastatin TC LDL-C

- - 10 20 20 40 22 27
- 10 20 40 40 80 * 27 34
5 20 40 80 160 # 32 41
10 40 80 37 48
20 80 42 55
40 49 62
80 54 65

LDL-C low density lipoprotein TC=total cholesterol, 80mg XL formulation 2x80mg XL not yet approved
Comparable Efficacy of Statins

Special considerations:
No renal dosing: Atorvastatin and Fluvastatin
Use in chronic liver disease: pravastatin or rosuvastatin
Less drug interactions: pravastatin, fluvastatin, rosuvastatin
(not metabolized via CYP3A4)
Less muscle toxicity: Pravastatin and Fluvastatin
Cost-effectiveness: Rosuvastatin, atorvastatin, fluvastatin
 Evidence in Primary Prevention
Name of Study Design Outcome
West of Scotland 6595 men 31 % risk reduction in
Coronary Prevention Mean TC 272; LDL>155 coronary deaths and
Study (WOSCOPS) diet + placebo nonfatal MI
Diet + pravastatin Benefit >treating mild
HTN but 3 x less than
that in 4S study
Air Force/Texas Coronary 5614 Men; 991 women 37 % risk reduction in
Atherosclerosis 45-73 y.o. coronary events
Prevention Study mean TC 221; LDL 150
(130-190)
Diet + placebo
Diet + lovastatin
 Evidence in Secondary Prevention
Name of Study Design
Scandinavian Simvastatin 4444 patients (angina or h/o
Survival Study (4S) MI)
TC 212-309; 5 year f/u
Placebo v. simvastatin 20-40 qd
Goal TC <200
CARE 4159 h/o MI 2 yrs prior
Borderline Average TC 209;
LDL 139; HDL 39
Pravastatin 40 qhs x 5 yrs
LIPID 9014 men and women with
recent MI or unstable angina
TC 155-270
Pravastatin or placebo
Heart Protection Study 20,536; simvastatin 40 qd; 33%
LDL<116;25% 116-135; 42%
LDL>135 h/o CVD, DM, or
treated HTN; 5.5 yrs
Outcome
Total mortality (8 v.12%)
Major events (19 v. 28%)
CHD deaths 42% lower
Revascularization 37%
CVA (2.7 vs 4.3)
1% LDL decrease=1.7% RR
Coronary death/MI 10.2 v. 13.2
Revascularization 14.1 v. 18.8
Stroke frequency 2.6 v. 3.8
% LDL reduction unrelated
to events
CHD deaths 6.4 v. 8.3
Total mortality 11 v. 14
Stroke 20% decrease
Bypass 8.9 v. 11.3
All cause mortality RRR 13%
CHD death RRR 17%
Major events RRR 24%
Similar in 3 tertiles of LDL
and in those with LDL<100
Mechanism of Benefit of Statins in
Secondary Prevention
Regression of atherosclerosis
Plaque stabilization
Reduced inflammation
Decreased thrombogenicity
Reversal of endothelial dysfunction
Others
Reduced monocyte adhesion to endothelium
Reduced oxidative modification of LDL
Increased mobilization and differentiation of
endothelial progenitor cells leading to new vessel
formation
 Adverse Effects of Statins
In general, less than with other agents. Fairly tolerable and safe
Myopathy
Ranges from myalgias (2-11%), myositis(0.5%) to rhabdomyolysis (<0.1%)
(possibly ARF)
Few weeks-4 months onset
Symptoms and CK should normalize over days to one month after d/c
Pravastatin and Fluvastatin less risk
Increased risk in
ARF/CRF
Obstructive liver disease
Hypothyroidism
Concomittant use of drugs interfering with CYP3A4??
Gemfibrozil combined therapy
Hepatic
0.5 to 3% persistent elevations in amino-transferases in first 3 months and dose-
dependent
Several randomized trials have found no difference compared with placebo
FDA recommends LFTs before and 12 weeks after starting and with any dose
elevation and periodically
CNS
Case reports of memory loss associated with statins (mainly lipophilic)
If memory loss and recent initiation of statin, then d/c and use a hydrophilic
statin such as pravastatin or rosuvastatin
No significant difference with placebo in trials
 Fibric Acid Derivatives
Decrease Triglycerides (35-50%)
Reduced hepatic secretion of VLDL through activation of PPAR-alpha receptors in liver
Stimulate lipoprotein lipase and thus clearance of TG-rich lipoproteins

Raise HDL (15-25%)

Direct stimulation of HDL apolipoprotein synthesis A-I,II
Increased transfer of apo A-I with diminished cholesterol transfer from HDL to VLDL

Increases LDL buoyancy

May also improve endothelial function and favorable effect on macrophage responses (possible
reduction in CHD risk independent of effect on lipoproteins)

Agents
Gemfibrozil- 600 mg po BID (11% raise in HDL). Modest LDL reduction but little effect in
combined hyperlipidemia. Can increase LDL in pure hypertriglyderidemia
Fenofibrate 200 mg capsules or iii caps 67 mg qd (renal dosing and can decrease Cyclosporin
levels). Better for LDL lowering

Side effects
Gallstone formation
Dyspepsia, diarrhea, nausea, vomiting, abdominal pain, eczema, rash, vertigo and myalgias

Adverse drug interaction

Gemfibrozil- inhibits glucuronidation of lipophilic statins and increases levels thus increasde
risk of myopathy. Also decreases warfarin by 30%
 Bile Acid Sequestrants
Lower LDL (10-15%)
BINDING BILE ACIDS IN INTESTINE CAUSING A DECLINE IN HEPATIC CHOLESTEROL
POOL; THUS SYNTHESIS OF apo B/E (LDL) RECEPTORS
Max doses cause 30% reduction
Raise HDL
Intestinal formation of nascent HDL

Available agents
Cholestyramine 8 grams/day. 24-30 grams/day can lower LDL up to 24%
Colestipol 10 grams/day
Colesevelam 1.5-4.5 grams/d

Adverse effects
Usually limit use
Mainly GI (nausea, bloating, cramping)- least problematic with colesevelam
Increased liver enzymes
Also drug interactions (impair absorption)
Digoxin, warfarin, and fat soluble vitamins (give one hour before or 4 hours after bile
acid sequestrant)
Contraindications: pts with elevated TG
 Nicotinic Acid
Mechanism of Action
Inhibits hepatic VLDL production and its metabolite LDL
Raises HDL by reducing lipid transfer of cholesterol from HDL to VLDL and by delaying HDL
clearance
Increase in LDL size
Reduction in plasma fibrinogen levels

Formulations and dosing

Immediate release (crystalline): 100 TID and titrated to tolerance
Sustained release
Niacor
Niaspan: 500 mg qhs x one month and then titrated to 1000 mg usually given daily
after evenng meal

1-1.5 grams/day for HDL raising

3 grams/day for VLDL and LDL lowering and possibly lowering lipoprotein a levels
OTC IR preps are cheaper and effective
OTC preps labeles NO FLUSH usually not efficacious

Side effects
Flushing (less common with controlled release) minimized with ASA 30 minutes before and
limited in 7-10 days
Nausea, paresthesias, pruritis (20% each)
Elevation of hepatocellular enzymes and possible hepatotoxicity, jaundice and fulminant
hepatitis (generally less common with Niaspan and crystalline niacin)
Insulin resistance and worsening hyperglycemia (less with crystalline Niaspan)
Hyperuricemia (AVOID IF H/O GOUT)
Hypotension in combination with other vasodialtors (can increase unstable angina)
 NICOTINIC PERIPHERAL
ADIPOCYTE TISSUES
ACID
* Cholesterol
TG
HDL
HSL

FFA Acyl Acetyl

CoA CoA

DGAT2
TG DG
HDL
Cholesterol
VLDL
PL HEPATOCYTE
Cholesterol
B100

Mechanisms of action of nicotinic acid on lipoprotein physiology. Nicotinic acid inhibits hepatic TG synthesis at the
level of fatty acid synthesis and esterification of diglyceride. Nicotinic acid also blocks apoAI-containing HDL
holoparticle uptake at the liver without altering the transport of cholesterol from HDL to the liver by way of SRB1.
Finally, nicotinic acid acutely inhibits adipocyte lipolysis, but the significance of this effect on lipoprotein physiology
is unclear. B100, apoprotein B100; CoA, coenzyme A; DG, diglyceride; HSL, hormone sensitive lipase; PL,
phospholipid. (Meyers. EMCNA 33 (2004):561)
 Ezetimibe
(Zettia)
Mechanism:
impairs dietary and biliary cholesterol absorption at the brush border of the
intestines without affecting TG or fat-soluble vitamins
possible Niemann-Pick C1 like protein involved in cholesterol transport
LDL decrease 15-20%
Trivial effects on HDL and TG

Also adjunctive therapy to statins but same effect with higher dose of statin as in one
study 10 zettia and 10 atorvastatin same effect as 80 atorvastatin
Indications
Avoiding high doses of statins
Very high LDL (FCH) not sufficiently controlled on statins
Adverse effects
Only 20% absorption so lower side-effect profile
Higher incidence of myopathy and elevated transaminases when coadministered
with a statin

Should not be used as the first-line agent in lowering LDL

Check LFTs prior to starting in combo with statins
No definite clinical outcome studies available
 Effect of Lifestyle Modification
Diet
Decreased saturated fat (decrease LDL)
Replacing saturated and trans unsaturated fats with unhydrogenated
monounsaturated or polyunsaturated fats
Recommended diet
Dietary cholesterol <200 mg/d; total fat <30%; saturated fat <7%
CHO (whole grains, fruits,veggies) 50-60% total calories
Dietary fiber 20-30 g/d
Protein 10-25 g/day
Plant stanols/sterols 2 grams/day
Effect of LDL lowering should be evident in 6-12 months
Elevated BMI associated with decreased dietary response
Referral to dietitian helpful

Exercise
In a prospective study of 111 sedentary men and women with dyslipidemia
randomized to different levels of exercise, decrease in VLDL TG and increase in
LDL size observed. Increase in HDL and size and largest effect on LDL seen with
high amount high intensity exercise
Mechanisms of benefit: reduction in CETP, elevation in LCAT, reduced hepatic
lipase and elevated LPL activity
Possible effect on LDL particle size
Moderate intensity exercise (3-4 mi/hr) for 30 minutes on most days of the week
 Diet Supplements
Fish Oil (source of omega-3 polyunsaturated fatty acids)
Salmon, flaxseed, canola oil, soybean oil and nuts
At high doses > 6 grams/day reduces TG by inhibition of VLDL-TG synthesis and
apolipoprotein B
Possibly decreases small LDL (by inhibiting CETP)
Several studies have shown lower risk of coronary events
2 servings of fish/week recommended??
Pharmacologic use restricted to refractory hypertriglyceridemia
Number of undesirable side effects (mainly GI)
Soy
Source of phytoestrogens inhibiting LDL oxidation
25-50 grams/day reduce LDL by 4-8%
Effectiveness in postmenopausal women is questionable
Garlic
Mixed results of clinical trials
In combination with fish oil and large doses (900-7.2 grams/d), decreases in LDL observed
Cholesterol-lowering Margarines
Benecol and Take Control containing plant sterols and stanols
Inhibit cholesterol absorption but also promote hepatic cholesterol synthesis
10-20% reduction in LDL and TC however no outcome studies
AHA recommends use only in hypercholesterolemia pts or those with a cardiac event
requiring LDL treatment
Other agents include soluble fiber, nuts (esp. walnuts), green tea
Overall a combination diet with multiple cholesterol-lowering agents causes much more significant
LDL reductions
 Measurement of Lipoproteins
Lipoprotein analysis 12-14 hours fasting
TC and HDL-C can be measured fasting or non-fasting
LDL-Cholesterol = Total cholesterol VLDL (1/5 TG)-HDL (Friedewalls)
Validity depends on TG <400 mg/dL
Measured directly if patients have profound hypertrig
Errors in TC, HDL, and TG can affect values
Non-HDL cholesterol= TC HDL-C
All cholesterol in atherogenic lipoproteins incl LDL, Lipoprotein (a), IDL, VLDL
Acute phase response (i.e. MI, surgical trauma or infection)
Can reduce levels of TC, HDL, LDL, apo A+B through impairment of hepatic
lipoprotein production and metabolism
Raise Lpa and TG
Lipoprotein analysis should be done as outpatient one month after event
 Screening Recommendations
Adult Treatment Panel III (NCEP)
Fasting lipid profile at least once q 5 years for all
persons 20 y.o. or older
If non-fasting obtained and TC >200 or HDL <40, f/u
panel recommended
If no known CHD and serum LDL <160 (0-1 risk
factors) or LDL <130 (2 or more risk factors) then re-
screen in 5 years
Borderline high cholesterol and <2 risk factors, re-
screen in 1-2 years
 Risk Assessment
CHD equivalents:
Symptomatic carotid artery disease
Peripheral arterial disease
AAA
DM
Multiple risk factors that confer a 10-year risk of CHD > 20%
Identify major risk factors other than LDL:
Smoking
HTN BP >140/90 or on anti-hypertensive medication
Low HDL <40 mg/dL
Family history premature CHD (CHD in men 1st degree relative <55;
women <65 y.o.)
Age (men > or =45; women >or =55)
Other potential risk factors
Chronic renal insufficiency (Cr > 1.5 mg/dL OR GFR <60 cc/min) per
Up-To-Date
Obesity, physical inactivity, impaired fasting glucose, markers for
inflammation
HDL > 60 mg/dL is a negative risk factor
If patient without CHD or equivalent has 2 or more major risk factors, then
calculate the Framingham risk (age,TC,HDL,smoking,SBP)
 New Guidelines for LDL Goal
Risk category Goal LDL (mg/Dl)
CHD (CHD risk equivalent) <100
<70 optional

2 or more major risk factors + 10 <100

yr >20% <70 optional

2 or more major risk factors +10 <130

yr 10-20% <100 optional

2 or more major risk factors +10 <130

yr risk <10%

0-1 major risk <160

 Basis of New Guidelines in July 2004
REVERSAL (secondary prevention)
Moderate tx (40 qd pravastatin)
Intensive tx (80 qd atorvastatin)
Coronary intravascular US after 18 months
Mod tx (: increase in atheroma volume 2.7%, mean LDL 110 mg/dL
Intensive tx: decrease in atheroma volume 0.4%, mean LDL 79
No clinical outcomes
PROVE-IT: 4162 patients with ACS measuring clinical outcomes
Moderate tx (40 qd pravastatin): median LDL-C 96
Intensive tx (80 qd atorvastatin): median LDL 62 AND 16% reduction of CV events (all
cause death, MI, UA, revasc, stroke)
Benefit of pushing LDL below 70
HPS: >20,000 patients with established CAD or CHD-equivalent
Simvastatin 40 qd
Placebo
27% reduction in nonfatal MI and coronary death in Tx group
Patients w/o CHD but with CHD equivalents benefited from treatment
Benefit was present regardless of pretreatment LDL <100
Application of New guidelines for LDL <70
Very high risk (established CHD plus multiple major risk factors)
CHD + smoking
CHD +metabolic syndrome
ACS
2004 ACC/AHA: for STEMI, LDL substantially <100 mg/Dl
 Elevated LDL
Statins are first choice and selection is based on extent of LDL
reduction, cost and reduction in clinical CHD events as well as
presence of renal impairment

30-35% decrease in LDL-C with equivalent doses

Titrate statin dose at 3-4 week intervals

Doubling statin dose reduced LDL an additional 6%

Consider adding second agent instead of dose increase
Variable drug response depending on endogenous v. exogenous
hypercholesterolemia

Second agents may include bile acid resins (15%), ezetimibe

(20%), or plant stenol/sterol margarine (10%)
Niacin may be added as a third agent if needed
 Mixed (Combined Hyperlipidemia)
Elevated LDL and/ or triglycerides

Objective is to achieve LDL goals

With very high TG> 400, start with fibrate or niacin

Then treat LDL with statin

If LDL-C goal achieved, but TG>200, non-HDL-C should be

targeted
Non-HDL goal 30 above LDL goal

Statin titration dose OR Statin-fibrate OR Statin-Niacin

combinations more effective in this type of dyslipidemia but
adverse reactions more common with combined treatment
so benefit/risk ratio considered
Titration for mild TG elevations
Combination TX for moderate to severe TG elevations
 Hypertriglyceridemia
Normal <150 mg/dL; very high >500
mg/dL
Evidence-Based Data
Evidence-Based studies include
Helsinki Heart Study and VA-HIT
trial assessing efficacy of
gemfibrozil and CV risk reduction
from lowering TG
In many large studies, elevated
TG were determined to be
independent risk factor for CHD
Rule out secondary causes and eliminate
Obesity
DM
Nephrotic syndrome
Hypothyroidism
Estrogen replacement
Beta blockers
Glucocorticoids, cyclosporin
Identify those with
hyperchylomicronemia: TG >1000
mg/dL, eruptive xanthomas,
pancreatitis
Familial hypertrig (200-500) or
combined hyperlipidemia
Treatment Recommendations:
After achievement of LDL goal
(150-199): emphasize weight
reduction and physical activity
(200-499): non-HDL second target
and pharmacologic tx for those
with h/o MI or at high risk
>500: prevention of pancreatitis
with non-pharmacologic and
pharmacologic therapy
Isolated hypertrig tx indications
Overt CHD
Strong FH of CHD
Multiple cardiac risk factors
Statins (atorvastatin or
rosuvastatin) if LDL elevated
Fibrates or nicotinic acid
Add fish oil for refractory cases
 Isolated Low HDL
Evidence in Treatment
Framingham Heart Study: MI risk VA-HIT trial: strong correlation
increases by 25% per 5 mg/Dl of reduction in MI and CHD death
decrease below mean HDL for men with serum HDL achieved with
and women gemfibrozil
LIPID and CARE trials: 10 increase in Simvastatin plus Niacin:
HDL, 29% decrease in event rate in higher reduction in events
LDL <125 vs 10% decrease in achieved than statin-only trial
LDL>125
HPS: vascular event rate in baseline
Familial h/o premature CHD HDL <35 was 29.9% vs 20.9% for
helpful in differentiating high from low HDL >42
risk pts with low HDL
HDL < 40 mg/Dl; if metabolic
Causes: syndrome <40 men and <50 women
Familial forms Treatment Indications of Isolated
Elevated CETP low HDL
LPL deficiency CHD OR CHD equivalent
Elevated hepatic TG lipase if first-degree relative early onset
LCAT deficiency CHD and similar lipid profile
Insulin deficiency Weight management, exercise, and
Drugs smoking cessation
Beta blockers Niacin +/- gemfibrozil
BDZ CETP inhibitors (NEW and
investigational)
Anabolic steroids
 Treatment Guidelines
Always Consider secondary causes of dyslipidemia (DM, hypothyroidism,
obstructive liver disease, CRF or nephrotic syndrome or drugs)
All patients with LDL above goal start with adequate trial of lifestyle
modification only but concomitant drug therapy may be appropriate if:
LDL >220 or > 190 if >= 2 risk factors
Pre-existing CHD or CHD equivalent
If CHD or risk equivalent and? significantly above goal, then start
pharmacotherapy (preferably statin) immediately
If CHD or equivalent and LDL goal <100 not achieved on maximal statin
(atorvastatin 80 or rosuvastatin 40), then additional agent should be
added based on abnormalities in other lipoproteins

In no CHD or CHD equivalent, consider drug therapy with statin if after

adequate lifestyle trial:
LDL >190 if 0 or 1 risk factor
LDL >160 if 2 or more risk factors if 10 yr risk <10%; 130 if risk 10-
20%
If persistent elevation in LDL purely, then add bile acid sequestrant or
zettia
In patients with ACS, atorvastatin 80 mg/day should be started soon after
hospitalization
PROVE-IT TIMI 22 Trial, MIRACLE, A to Z trial
When LDL goal reached but TG >200, then consider non-HDL cholesterol
and treat to goal 30 above LDL
In patients with ACS, atorvastatin 80 mg/day should be started soon after
hospitalization (event reduction and LDL lowering effect)
PROVE-IT TIMI 22 Trial, MIRACLE, A to Z trial
 Elderly
Should be individualized based on chronologic and physiologic age
Secondary prevention studies support treatment
CARE :50% patients >60 derived similar benefits as in younger patients
HPS :% reduction in events similar in < or > 65 y.o.
Cardiovascular Health Study showed benefit in primary prevention in >65
y.o.
All major statin trials and VA-HIT trial have shown reduction of
atherothrombotic stroke with lipid-lowering
ATP III recommends diet as first line of primary intervention but drugs can
be considered if multiple risk factors possibly with LDL >160
Underutilization of lipid-lowering drugs in elderly due to
Concern for safety (hapatic/renal impairment)
Time course to benefit
 Adults With DM
Both primary and secondary intervention trials have shown benefit and
reduction of CVD in diabetic subgroups treated with lipid-lowering agents
(HPS and CARE trial showed significant outcome improvement with statins
even at LDL <116)
Despite their often elevated TG and low HDL due to insulin resistance, etc.
LDL should be primary goal
Niacin-Statin combination can be particularly effective
LDL goal <100 and threshold for drug tx is 130 and optional 100-129 if diet
effective
ADA 2004 guidelines: adults >40 y.o. and TC >135, statin to lower LDL by
30%
Based on HPS, drug therapy should not be postponed if LDL goal unlikely
achieved by nonpharmacologic means
TZDs are insulin sensitizers and affect adipose tissue distribution by
decrease in intraabdominal fat; shown to increase HDL and peak LDL
buoyancy; rosiglitazone/atorvastatin led to reduction in TG/LDL and
elevation in HDL (Promising but more studies required)
 Metabolic Syndrome
ATP III criteria: (3 or more)
Abdominal obesity (waist circumference > 102 cm in men or > 88 cm
in women)
Hypertriglyceridemia (TG>150 mg/dL)
Low HDL <40 men; <50 women
SBP >130 or DBP >85
Fasting glucose >110 mg/dL
Increased risk of DM and cardiovascular disease although there has been
some controversy in the literature
Kuopio Ischemic Heart Disease Risk Factor Study: 1209 Finnish men
(42-60 y.o.) without CVD, cancer or DM at baseline followed for 11.4
years. Results showed that CVD and all-cause mortality are increased
in men with MS even in absence of CVD or DM at baseline
Dyslipidemia is atherogenic with low HDL, elevated TG, and small dense
LDL
Treatment Recommendations:
Weight reduction and exercise
LDL goal is same as in patient w/o MS
If LDL goal reached, then focus on TG if >200?
Calculate non-HDL and goal is 30 above LDL goal
Fibrates and nicotinic acid are good choices for elevated TG
 Hyperlipidemia in Nephrotic Syndrome
Marked hypercholesterolemia
Increased apo B lipoprotein synthesis by liver due to decreased oncotic
pressure
Decreased catabolism
Hypertriglyceridemia
Slow conversion of VLDL to IDL then LDL
Decreased LDL-receptor clearance of LDL and IDL
Associated Risks
Small study showed RR 5.5 for MI and 2.8 for coronary death
Possible progression of glomerular disease
Treatment rationale
Tx of underlying disease (i.e. steroids in minimal change disease)
Little benefit in diet therapy (vegetable soy diet rich in MUFA/PUFA) and
low protein with 20-30 % reduction in lipids
Best drug tx is statins
ACE-Inhibitor or ARB by decreasing protein excretion cause 10-20%
reduction in TC and LDL
 CRF and Dialysis
Hypertriglyceridemia
Diminished clearance due to apo C-III and reduction in
lipoprotein lipase and hepatic triglyceride lipase
Usually not enough elevation to increase coronary risk
Diet modification preferable over drug therapy because of risk of
rhabdomyolysis
Isolated marked hypertrig with cardiac risk factors may warrant
drug therapy
Modest decline in HDL raising LDL/HDL ratio
Elevated Lipoprotein a
Increase in oxidative modification of LDL
Statins should be used to lower LDL <100 or better yet <80 as CKD
considered CHD risk equivalent. Atorvastatin and fluvastatin better
choices. Hydrophilic statins safer and dose adjustment needed with
CrCl <30
EPO appears to have modest hypolipidemia effect though unknown
mechanisms

Evolving Methods of Risk Assessment
Total/HDL cholesterol ratio
Ratio <4.0 advocated by the Canadian guidelines
Aggressive lowering LDL vs raising HDL
Better epidemiologic predictor of CV events than LDL (Lipid Research Clinics and Framingham
Heart Study) however no trials based on this ratio

Non-HDL cholesterol (Total-HDL)

Includes all atherogenic cholesterol (LDL, lipoprotein a, IDL, VLDL)
Lipid Research clinics program showed slightly stronger predictor of CVD than LDL
Secondary target in pts with high triglycerides >200 mg/Dl (ATP III)
Goal 30 above LDL goal

Apolipoprotein measurement
Apo B/ Apo A-I found to be a better predictor of events than LDL and total/HDL in AMORIS
study; best predictor of events on statins in AFCAPS/TexCAPS study
<0.7 considered target in Canadian guidelines
Most useful in the hypertriglyceridemic patient (elevated apoB levels)
Not universally available and much more expensive
Needs more cost-benefit analysis before routine use
May be useful for determining the efficacy of novel therapies
Hs-CRP
Intensity of atherosclerotic process
Recommendation of AHA, should be measured in the patient with intermediate Framingham
risk (10-20%) with LDL below the cutoff point for tx
Would not add much to those already at high risk
questionable correlation with LDL levels
 Investigational Issues
To what extent should plasma levels of LDL-C be
lowered by therapy to afford optimal risk reduction?
Can risk assessment be improved by using novel risk
measures (such as hs-CRP) to indicate patients at higher
risk who may benefit from more aggressive intervention?
Should the metabolic syndrome be considered a high risk
state warranting aggressive intervention irrespective of
risk categorization using current scoring methods?
Awaiting prospective trials investigating the preventive
benefits of lipid-altering treatment in metabolic
syndrome (COMETS trial)
 Laki-laki 45 tahun. TB 170 cm BB 87 kg
(BMI=30). Tensi 140/80 m Hg. Cor &
pulmo dbn. Laboratorium: Glukosa darah
puasa 286 mg/dl. Glukosa darah 2 jam
post prandial 359. A1C 10,1%. Kolesterol
210 mg/dl. HDL 30 mg/dl. LDL 155 mg/dl.
TG 596 mg/dl. Riwayat DM 16 tahun.
Riwayat stroke (hemiparesis dextra) 8
bulan yang lalu.
a. diagnosis?
b. tata laksana.
 Gadis 27 tahun. Oedem anasarka. TB 155
cm. BB: 60 kg. BMI 25 kg/m2. Tensi:
130/80 mmHg. Protein total 6,3 gr%.
Albumin 2,8 gr%. Kolesterol 320 mg/dl.
HDL 50 mg/dl. LDL 170 mg/dl. TG 150
mg/dl. Urin: protein +4. Riwayat
kolesterol tinggi pada orang tuanya.
a. diagnosis
b. tata laksana.
 References
Management of atherogenic dyslipidemia of the metabolic syndrome: evolving rationale for
combined drug therapy. Endocrinology and Metabolism Clinics of North America 33 (2004) 525-
544
Obesity and dyslipidemia. Endocrinology and Metabolism Clinics of North America 32 (2003) 855-
867
Management of Metabolic Sydrome: statins. Endocrinology and Metabolism Clinics of North
America 33 (2004) 509-523
Emerging therapeutic strategies for the management of dyslipidemia in patients with the
metabolic syndrome. The American Journal of Cardiology June 3, 2004
Past, Present and Future Standards for Management of Dyslipidemia. The American Journal of
Medicine March 22, 2004
Cardiovascular Endocrinology: Special Features. Medical Management of
Hyperlipidemia/Dyslipidemia. Journal of Clinical Endocrinology and Metabolism, June 2003
Effects of Lipid-Altering Treatment in DM and the Metabolic Syndrome. American Journal of
Cardiology June 3, 2004
Statins as the cornerstone of drug therapy for dyslipidemia: Monotherapy and combination
therapy options
Use of combination Therapy for Dyslipidemia: A Lipid Clinic Approach
Clinical relevance of the biochemical, metabolic, and genetic factors that influence low-density
lipoprotein heterogenity. The American Journal of Cardiology October 2002
Up-To-Date
Emerging Lipoprotein Goal
Trials
Validation study
found Framingham
CHD predictor
worked well in
white and black
population but
overestimated risk
in Japanese
American,
Hispanic men and
native American
women and other
studies have
shown possible
overestimation in
European and
Asian populations
Cholesterol efflux and reverse cholesterol
transport is modulated by two receptors
Atherogenicity of small dense LDL