Dyslipidemia

Purwoadi)Sujatno)
SMF)Penyakit)Dalam)RS)BETHESDA)Yogyakarta)
 What is Dyslipidemia
Dyslipidemia :
Total Cholesterol
Low Density Lipoprotein –Cholesterol
Triglycerides
High Density Lipoprotein - Cholesterol
!
Small!dense!LDL!is!more!atherogenic!than!LDL!due!to:!!
1.!Easier!penetra9on!to!the!arterial!wall!
2.!Endothelial!cell!toxicity!!
3.!Promo9on!of!synthesis!of!PAICI!and!the!Thromboxane!by! !endothelial!
cells!!
4.!Easier!oxida9on!
5.!Easier!adhesion!to!glycosaminoglycans!of!the!arterial!wall!
6.!Easier!connec9on!with!macrophage!scavenger!receptors!than!with!the!
LDL!receptor!!
!
 Manifesta9ons!of!Dyslipidemia!
Xanthelasmas!and!
tendon!xanthomata!
in!pa9ents!with!
severe!↑LDL!
(the!pa9ent!at!the!
boNom!has!
heterozygous!familial!
hypercholC
esterolemia)!

Erup9ve!xanthomata!on!the!
forearm!of!a!pa9ent!with!
severe!↑TGs%
How%it%can%be%Happen?%

PRIMARY%DYSLIPIDEMIA%
Gene!Muta9on!resul9ng!in!
disturbance!of!lipids!produc9on!
and!clearance!
! "  Sedentary)lifestyle)
Should be suspected in
patients with
! premature heart disease
! family history of
atherosclerotic diagnose
! Or serum cholesterol
level >240mg/dl.
SECONDARY%%
DYSLIPIDEMIA%%
Most%adult%cases%of%dyslipidemia%
are%secondary%in%nature%in%
western%civilizaEons%
"  Excessive)consumpDon)of)cholesterol)
–)saturated)fats)and)transGfaHy)
acids.))
Medical%CondiEons%Associated%
with%dyslipidemia%
Diabetes,)Hypothyroidism,)
CholestaDc)liver)disease.,)NephroDc)
syndrome!
%
 Whom!to!Screen!for!Dyslipidemia?!
Influenced!by!cardiac!risk!factors:!
1.  By!age!alone!(Canadian!Guidelines):!
–  Men!over!age!40!
–  Women!over!age!50!(or!postCmenopausal)!
2.  Adults!at!any!age!if:!
1.  At!least!2!risk!factors!!
•  DM,!HTN,!Smoking,!Abdominal!Obesity!
•  Family!history!of!early!CVD!
2.  Physical!signs!of!hyperlipidemia!!
•  Xanthomata,!xanthelasmas,!arcus!corneae,!etc!
3.  Evidence!of!exis9ng!atherosclerosis!
 SCREENING (AACE 2012)

•  More! frequent! assessments! for! all! pa9ents! with! a!

family!history!of!premature!CAD:!
1.  definite!myocardial!infarc9on!!
2.  or!sudden!death!<age!55!years!in!father!or!
other!male!1stCdegree!rela9ve,!
3.  !or!<age!65!years!in!mother!or!other!female!
firstCdegree!rela9ve!!
•  Suggest! considering! more! frequent! tes9ng! for!
individuals!with!CAD!risk!factors!!
 Adults With Diabetes

Annually!screen!all!adult!pa9ents!with!
diabetes!mellitus!for!dyslipidemia!!
WHICH SCREENING TESTS
ARE RECOMMENDED
FOR THE DETECTION OF
CARDIOVASCULAR RISK?
 Fasting Lipid Profile

•  Use!a!fas9ng!lipid!profile!to!ensure!the!
most!precise!lipid!assessment.))
•  This!should!include:!!
– total!cholesterol,!LDLCC,!triglycerides,!and!
HDLCC!!

Fas9ng!:!8C12!hrs!
 Triglycerides!
•  Increasing!clinical!evidence!suggests!that!
elevated!triglycerides!may!be!an!independent!
risk!factor!for!CAD.!!
•  Triglyceride!levels!200!mg/dL!or!greater!may!
indicate!a!substan9al!increase!in!CAD!risk!!
 Follow-up and Monitoring

•  Reassessing!pa9ents’!lipid!status!6!weeks!ager!therapy!
ini9a9on!and!again!at!6Cweek!intervals!un9l!the!
treatment!goal!is!achieved.!!
•  Thereager,!that!pa9ents!be!tested!at!6C!to!12Cmonth!
intervals.!!
•  The!specific!interval!should!depend!on!pa9ent!
adherence!to!therapy!and!lipid!profile!consistency.!!
•  If!adherence!is!a!concern!or!the!lipid!profile!is!
unstable,!the!pa9ent!will!probably!benefit!from!
biannual!assessment!!
 More frequent lipid status evaluation

•!Deteriora9on!of!diabetes!control.!
•!The!use!of!a!new!drug!known!to!affect!lipid!levels.!
•!Progression!of!atherothrombo9c!disease.!
•!Considerable!weight!gain.!
•An! unexpected! adverse! change! in! any! lipid!
parameter.!
•!Development!of!a!new!CAD!risk!factor.!
•! Convincing! new! clinical! trial! evidence! or!
guidelines!that!suggest!stricter!lipid!goals.!
 Liver Enzyme
•  Measured!before!and!3!months!ager!sta9n!or!fibric!
acid! treatment! ini9a9on,! because! most! liver!
abnormali9es! occur! within! 3! months! of! treatment!
ini9a9on.!!
•  Niacin:! baseline! and! every! 3! months! thereager! for!
the!first!year,!followed!by!periodic!(eg,!semiannual!)!

SGOT/AST!and!SGPT/ALT:!>!3!x!N!!!!!!
Treatment!stop!(!by!FDA!)!
 Renal function test

•  Should!be!tested!before!
treatment!
•  Increase!risk!of!myopathy!when!
GFR!decreased!
How%to%approach%the%management?%
•  Asses the risk factors and comorbidity
•  Determine the target
•  What is the lipid profile main problem
•  How to choose the lipid lowering drug
•  How to evaluate
•  Does the patient need titrating dose or switch to
another drug
•  Special consideration
GOALS%OF%THERAPY%

19
 NCEP–ATP III REVISED FOUR CATEGORIES OF
RISK THAT MODIFY LDL CHOLESTEROL GOALS

LDL%Goal%
Risk%Category%
(mg/dl)%

Very high risk CHD + DM < 70

High risk CHD and DM < 100

Multiple (2+) risk factors* < 130

0 – 1 risk factor < 160

Circula)on!2004!;!110:!2273239!
Goals of Therapy based on CHD Risk
( ESC 2011 Guidelines)

Reiner%Z,%et%al,%EHJ%2011:%32:%1769%[%1818%
AMERICAN!DIABETES!ASSOCIATION!!
CURRENT!CLINICAL!GUIDELINES!TYPE!2!DIABETES!!

•  Treatment goals:
–  LDL-C <100 mg/dL
•  Initiation threshold for pharmacologic therapy:
–  LDL-C >100 mg/dL for diabetes and CVD
–  LDL-C >130 mg/dL for diabetes without preexisting CVD
•  Encourages use of statins to reduce LDL-C >30% in …
people with diabetes over the age of 40 …
regardless of baseline LDL-C levels

American Diabetes Association. Diabetes Care. 2004;27(S1):S68-S71.

How%to%choose%%the%treatment%?%
ESC Treatment Strategies Depend On
Total CV Risks & LDL-C Level
Non[Pharmacologic%Treatment%

!  DIET% easy!to!say!but!
so!hard!to!do!
!  EXERCISE% it!
!  SMOKING%CESSATION%
!  STRESS%REDUCTION%
!  WEIGHT%CONTROL%
!  BEHAVIOR%CHANGE%
!  NUTRITIONAL%GENOMICS%%
%
 Life Style Intervention
Lifestyle to be modified Clinical approach

Individualized diet counseling that provides

Diet acceptable substitutions for favorite foods

Recommend 30 minutes of regular moderate intensity activity

Physical activity on most, if not all, days of the week

Discuss 10% weight loss goals for persons who are

Body Weight overweight

Follow ATP III guidelines for detection, evaluation, and

Cholesterol treatment of persons with lipid disorders.

Blood Pressure Follow BP guidelines

Smoking Cessation Promote smoking cessation

 NCEP ATP III. JAMA 2001; 285 (19) : 2486 - 2496
 A Model of Steps in
Therapeutic Lifestyle Changes (TLC)

Visit%1%Begin%TLC%

•  Emphasize!reduc9on!
in!saturated!fat!&! Visit 2 (6 wks)
chol.!
•  Encourage!moderate! •  Eval.!LDL!response!
Physical!ac9vity! •  Intensify!Tx!if!not! Visit 3 (6 wks)
•  Consider!referral!to! to!goal!
•  Eval.!LDL!response!
die9cian! •  Reinforce!dietary!
•  Consider!adding!Rx!if!not!
recommenda9ons!
to!goal!
•  Consider!adding!
plant!stanols/
sterols! • Evaluate!for!
•  Increase!fiber! Metabolic!syndrome!
intake! • Intensify!wt!mgmt!&!
•  Consider!die9cian! physical!ac9vity!
• Consider!die9cian!
 Some!moderateCintensity!physical!ac9vi9es!
150%calories%of%energy%per%day%

Daily life Sports

Washing%car,%45–60%min% Walking%3%mph,%35%min% Less vigorous
Washing%windows%or% Bicycling%10%mph,%30%min%
floors,%45–60%min%
Gardening,%30–45%min% Dancing,%30%min%
Raking%leaves,%30%min% Water%aerobics,%30%min%
Swimming,%20%min%
Jogging%1%mile,%15%min% More vigorous

NHLBI. www.nhlbi.nih.gov.
 Possible%Benefits%From%Other%Therapies%
%%%%%%%%%%%%%%%%Therapy % % % %%%% % %Result%

•  Soluble fiber in diet (2–8 g/d) ↓!LDLCC!1%!to!10%!

(oat bran, fruit, and vegetables) !
!
•  Soy protein (20–30 g/d) ↓!LDLCC!5%!to!7%!
!
•  Stanol esters (1.5–4 g/d) (inhibit ↓!LDLCC!10%!to!15%!
cholesterol absorption) !
!
•  Fish oils (3–9 g/d) ↓!Triglycerides!25%!to!35%!
(n-3 fatty acids) !

Jones PJ. Curr Atheroscler Rep. 1999;1:230-235.

Lichtenstein AH. Curr Atheroscler Rep. 1999;1:210-214.
Rambjor GS et al. Lipids. 1996;31:S45-S49.
Ripsin CM et al. JAMA. 1992;267:3317-3325.
Pharmacologic%Treatment%

Sta9ns!(HMGCCoA!reductase!inhibitors)!
Fibrates!
Niacin!
Bile!acid!sequestrants!
Cholesterol!absorption!Inhibitor!
Probucol!!
 Pharmacologic!Therapy:!!
HMGCCoA!Reductase!Inhibitor!

•  Inhibit hepatic Chol. production

•  Decrease APO B100 syntesis
•  Increase LDL receptor on liver surface
•  Side effects
–  Myopathy (Increased with fibrates)

•  Contraindicated in patients with severe renal or

hepatic disease

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA.
2001;285:2486.
Clinical!Reviews!
Fibrates!
 Effect%of%Lipid[modifying%Therapies%

Patient
Therapy TC LDL HDL TG
tolerability

Bile acid Neutral or

sequestrants
↓ 7-10% ↓ 10-18% ↑ 3% Poor
↑#

Poor to
Nicotinic acid ↓ 10-20% ↓ 10-20% ↑ 14-35% ↓ 30-70%
reasonable

Fibrates
(gemfibrozil)
↓ 19% ↓ 4-21% ↑ 11-13% ↓ 30% Good

Statins* ↓ 19-37% ↓ 25-50% ↑ 4-12% ↓ 14-29% Good

Ezetimibe ↓ 13% ↓ 18% ↑ 1% ↓ 9% Good

 combina9on!therapy!

•  Few patients achieve LDL-C goal on monotherapy

•  Uptitration of dosage is rare
•  LDL-C goals are getting more aggressive
•  High-dose statins increase risk of side effects
•  Can address mixed dyslipidemia (e.g., few pts
achieve adequate control of HDL-C and
triglycerides on monotherapy)
combina9on!therapy!
 Combina9on!Therapy!
Combination Drug Therapy (Limited if any
evidence):
! Moderate ↑TGs -> add salmon oil (1-3g tid) to statin
! ↓HDL -> combine statin with niacin.
! Caution:
!  1) niacin can cause increased insulin resistance
!  2) niacin-statin combination increases risk of hepatotoxicity
! If intolerant to niacin:
!  consider statin-fibrate combination
!  (simvastatin or pravastatin with fenofibrate, NOT gemfibrozil)
!  lowest possible doses of each
!  very close follow-up watching for hepatotoxicity and myositis
!  if no CRF
 Combina9on!Therapy!
•  If ↑TGs:
–  Ideal target <150 mg/dl
•  1st line: lifestyle modification
•  Treatments aimed at lowering the TC/HDL ratio usually
also help lower TGs

–  If TGs >500 mg/dl despite lifestyle changes, need drug

treatment even if the TC/HDL ratio is acceptable
•  Treatment is needed to avoid pancreatitis
•  Options:
–  Fibrate
–  Niacin
–  Salmon oil
 Specific!Dyslipidemias:!Elevated!Triglycerides!

Management of Very High Triglycerides

(>500 mg/dl)
•  Goal of therapy: Prevent acute pancreatitis
•  Very low fat diets (< 15% of caloric intake)
•  Triglyceride-lowering drug usually required (fibrate
or nicotinic acid)
•  Reduce triglycerides before lowering LDL
•  If a patient also has a high risk for a cardiovascular
event, LDL-lowering therapy should be considered.
! Gemfibrozil is extremely effective in reducing
cardiovascular risk in people with features of the
metabolic syndrome such as overweight,
hypertriglyceridemia, and low HDL-C (HPS and VA-
HIT)
! The observation that muscle problems appear to be
less of an issue when fenofibrate is combined with
a statin (VA-HIT)
! To be consider about myopathy event and
increasing of creatinine
 Follow[Up%
Which!blood!work!should!be!ordered!in!
followCup?!How!frequently?!
 FollowCUp!Recomenda9on!
! Lipids
!  6 weeks after start / change of dose (levels reach steady
state within 6 weeks of start/change of medication)
!  Long-term follow-up every 6-12 months

! AST / ALT (0.5 –3% incidence)

!  Get baseline
!  Use with caution if AST/ALT > 3 x normal
!  At 12 weeks after initiation or change in dose (FDA)

! CK (< 0.5% incidence)

!  Get baseline
!  Check only if symptomatic with myalgias (ATP III guideline)
!  More attention in elderly patient
Special!Considera9on!
 Sta9n!in!Elderly!
•  older chronological age in and of itself should not
exclude patients from receiving therapy, especially
if an otherwise healthy older patient s remaining
years of life may benefit from prevention of the
morbidity associated with a coronary event.

Elderly%with%AMI%
Scandinavian!Simvasta9n!Survival!Study!
CARE!(Cholesterol!and!Recurrent!Events)!Trial!
LIPID!(Long!Term!Interven9on!with!Pravasta9n!in!Ischemic!Disease)!Trial!
HPS!(Heart!Protec9on!Study)!
PROSPER!(Prospec9ve!Study!of!Pravasta9n!in!the!Elderly!at!Risk)!
 NKF%RecommendaEons%
for%StaEn%Dose%Adjustment%in%CKD%
Adjust%for%reduced%GFR%(mL/min/1.73%m2)%

30–90 <30% <15%

AtorvastaEn% No%adjustment% No%adjustment% No%adjustment%

PravastaEn% No%adjustment% No%adjustment% No%adjustment%

SimvastaEn% No%adjustment% StarEng%dose%5%mg%daily%in%paEents%with%%

severe%kidney%disease%
LovastaEn% No%adjustment% Use%doses%>20%mg/day%cauEously%%
in%paEents%with%GFR%<30%
No%dose%adjustments%needed%for%mild%to%moderate%
kidney%disease;%use%cauEon%in%paEents%with%severe%
FluvastaEn% No%adjustment%
kidney%disease;%fluvastaEn%not%studied%at%doses%%
>40%mg%in%these%paEents%
StarEng%dose%5%mg%and%NOT%to%exceed%10%mg%%
RosuvastaEn% No%adjustment%
in%paEents%with%GFR%<30%
NaEonal%Kidney%FoundaEon.%Am!J!Kidney!Dis.%2007;49(suppl%2):S1[S180!
 How%to%Titrate%dose%or%switch%to%%
another%staEn%

Some!adverse!effects!associated!with!sta9n!drugs!are!dosage[related!(eg,!
myopathy/rhabdomyolysis),!and!with!some!sta9ns,!liver!dysfunc9on!may!
increase!with!increased!dosage!!
If!sta9n!tolerability!is!a!concern,!a!combina9on!of!drugs!at!lower!dosages!
may!be!effec9ve!