Treatment of Lipid

Disorders
Ulrich K. Schubart
AECOM/JMC
 Proposed Mechanisms of Event
Reduction by Lipid Lowering Therapy
• Prevention, slowed progression, or regression of
atherosclerotic lesions
• Stabilization of atherosclerotic lesions
- Especially non-obstructive , vulnerable plaques

• Improved endothelium dependent vasodilation

• Reduction in inflammatory stimuli

- Lipoproteins and modified lipoproteins
• Reduced thrombotic and increased fibrinolytic potential

adapted from Libby P. Circulation1995; 91:2844-2850

 % Reductions in CV
Events depends upon:

• Percent cholesterol (and LDL) lowering

• Absolute Level of Baseline cholesterol
• Duration of cholesterol lowering
• Presence of other lipid abnormalities
Dietary Therapy for Elevated Blood Cholesterol
Nutrient* Recommended intake
Step I Diet Step II Diet

Total fat  30% of total calories

Saturated fatty acids <10% of < 7% of
total calories total calories

Carbohydrates  55% of total calories

Protein ~ 15% of total calories
Cholesterol < 300 mg/day < 200 mg/day
Total calories To achieve and maintain
desirable weight

* Calories from alcohol not included.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 1993;269:3015-3023.
 Drugs to lower LDL
Cholesterol
% LDL Reduction

• Statins (HMG-CoA Reductase Inhibitors) 25-55%

• Bile Acid Resins 15-30%

• Cholesterol Absorption Inhibitors 15-20%

• Niacin 15-25%

• Combinations >60%

• Estrogen 10-15%
 Synergistic effects of diet and
drug therapy

• Dietary therapy reduces LDL cholesterol

by 7-10%

• This is the equivalent of doubling the

daily dose of a statin

• Therefore, successful dietary therapy

reduces drug therapy by over 50%
 Common Final Mechanism of Statin/BAR/CAI
reduction in LDL-C
apo B-100 apo E

VLDL VLDL
LIPOLYSIS
PRODUCTION

apo C

CE SHUNT PATHWAY
Liver
VLDL
Remnant
+
LDL
CONVERSION
CLEARANCE

Other sites LDL

 Currently Available
HMG CoA Reductase Inhibitors
Generic Trade Dose % LDL Cost
Atorvastatin Lipitor 10-80 mg 37-55

Simvastatin Zocor 5-80 mg 24-51% Formulary

Lovastatin Mevacor 10-80 mg 19-40% Dependent

Pravastatin Pravachol 10-40 mg 20-30%

Fluvastatin Lescol 20-80 mg 15-25%

Resuvastatin Crestor 10-40 mg 46-55%

 Side Effects of HMG CoA
Reductase Inhibitors
• Myopathy (0.1%)
• Abnormal Liver Function Tests (1-2%)
• Gastrointestinal Distress and Diarrhea
• CNS – Insomnia
• Diabetes
Statins and Myopathy

Precipitating Factors:
• Liver Disease
• Multisystem Disease
• Drugs:
- Cyclosporin; tacrolimus
- Fibrates
- Erythromycin
- Itraconazole, ketoconazole
- Mibefradil (Posicor)
- ? Protease inhibitors
 Statins and Myopathy

Check CK
prior to initiating statin therapy
 Significant Inhibitors of CYP3A4:
Potential for interaction with statins
Antibiotics clarithromycin* erythromycin* metronidazole
Antifungals ketoconazole* itraconazole** miconazole
Protease Inhibitors indinivir ritonavir nelfinivir
CCB’s mibefradil**
Immunosuppressant cyclosporin A*
H2 Blockers cimetidine
Antidepressants fluoxetine fluvoxamine
Food grapefruit grapefruit juice
 Hypertriglyceridemia
Treatment
 Hypocaloric, low fat (10-20%), alcohol restricted diet.
Avoid saturates, simple Carbs. Exercise and weight
loss.
 In DM: Optimize glycemic control
 Consider metformin or thiazolidenedione for
IGT/insulin resistance
 Assess meds: oral estrogens/OCPs, steroids,
Retin A, thiazides or B blockers
 Drugs: 1 : Fibrates or Niacin (unless DM)
2 : High dose statins, Fish Oils
 Hypertriglyceridemia
Drug Therapy: High Risk Patients

R/O
Secondary Hyperlipidemia
Diet/Lifestyle Modification

<800 mg/dl Triglycerides > 1,000 mg/dl

Treat to prevent/ Treat to prevent
reverse ASCVD pancreatitis
 Hypertriglyceridemia
Drug Therapy - High Risk CAD
TG  200 TG 200-400 TG  400
Statin Statin Combined
Drug Therapy
Resin Niacin Consider High
Niacin Gemfibrozil DoseStatins

Useful Combinations: Statins+Resins/Ezitamibe

Hypercholesterolemia: Statins/Ezit+Niacin, or
Mixed HLD: Statins/Ezit+ Fibrates*
 Hypertriglyceridemia
The bottom line

• Triglycerides 150 -1000. Treat to prevent CAD*

• Triglycerides > 1000. Treat to prevent

pancreatitis

* If in doubt measure Apo B 100.

Median 100 mg/dl; > 125 mg/dl likely atherogenic
 ATP III: Management of
Diabetic Dyslipidemia
 Primary target of therapy: identification of LDL-C; goal
for persons with diabetes: <100 mg/dL
 Therapeutic options:
 LDL-C 100–129 mg/dL: increase intensity of TLC; add
drug to modify atherogenic dyslipidemia (fibrate or
nicotinic acid); intensify risk factor control
 LDL-C 130 mg/dL: simultaneously initiate TLC and
LDL-C–lowering drugs
 TG 200 mg/dL: non–HDL-C* becomes secondary
target
Note: Diabetic dyslipidemia is essentially atherogenic dyslipidemia in persons with type 2
diabetes.
*Non–HDL-C goal is set at 30 mg/dL higher than LDL-C goal.
JAMA. 2001;285:2486-2497.
 Fibric Acid Derivatives
• Gemfibrozil (Lopid) 600-1200 mg/day
Clofibrate (Atromid S) 1000-2000 mg/day
Fenofibrate (Tricor) 54-160 ug/ day

• Mechanism: Increases clearance of

triglyceride-rich lipoproteins (Chylos, VLDL,
remnants) through downregulation of Apo CIII
and increased LPL activity

• Effects on Lipids:
TG 20-50 %
HDL-C 10-15 %
LDL-C variable
 Fibric Acid Derivatives -
Indications
• Severe Hypertriglyceridemia (TG > 1000 mg/dl)

• ? Combination therapy for mixed hyperlipidemia or

moderate hypertriglyceridemia

• Reduces risk of CHD in subjects with High TG

/Low HDL-C

• May raise homocysteine levels

 Fibric Acid Derivatives
• Side Effects
Myopathy
Hepatitis (increases in transaminases)
Gallstones, Nausea, Diarrhea

•Contraindications
Absolute: Relative:

Gallstones Use with statins

Hepatic Insufficiency Inhibitors of CYP 3A4
Pregnancy
 Niacin - Indications

• Mixed hyperlipidemia
• Hypertriglyceridemia
• Low HDL (hypoalphalipoproteinemia)
• Combination therapy for hypercholesterolemia,
mixed hyperlipidemia
 Niacin - Mechanism of Action
• Inhibition of hormone-sensitive lipase in fat cells
• Reduction of VLDL production rates from liver
• Activation of LPL and accelerated
TG rich lipoprotein clearance.
• Increased clearance of remnants and LDL
• Mechanism of HDL-C increase unknown, but may
be related to decreased TG- cholesterol exchange
 Niacin - Side effects
• Flushing, pruritis - almost universal, harmless
• Insulin resistance/ worsened glucose tolerance
• Hyperuricemia/ gout
• Hepatitis (fulminant hepatic failure with SR niacin)
• Dyspepsia, Exaccerbation of IBD
• Toxic ambliopia (rare)
 Niacin - Contraindications
• Active liver disease, alcoholism
• Hx of neural tube defect or hyperhomocysteinemia
• Gout or active hyperuricemia
• Active peptic ulcer disease (caution if prior Hx)
• Inflammatory bowel disease
• Pregnancy
• Poorly controlled diabetes
 Niacin - Prescribing Hints
• Dose 1.5 - 6 gms/ day divided t.i.d. IR niacin
• Max dose 2.0 gm/day SR niacin (and give folate)
• Titrate dose up slowly
• Benefit on HDL seen at < 1.5 gms/day;
TG effect dose dependent.
• Take with meals; pretreat_~1 hour earlier with NSAID
• Avoid alcohol (flushing, hepatitis)
 Bile Acid Binding Resins

Cholestyramine (Questran)
Colestipol (Colestid)
Colesevelam (Welchol)
• Indicated for treatment of hypercholesterolemia
• Proven efficacy to prevent CHD
• Safest agent for reducing cholesterol
(except bran foods and garlic)
• Ideal for the young, healthy patient
Ge et al Cell Metab 2008
 Other Drugs, etc
• Estrogen replacement therapy
oral estrogens vs transdermal
selective estrogen receptor modulators
(raloxifene)
- risk of TG’s with oral estrogens

• Vitamin E (400 - 800 I.U./ day)

• Vitamin C 1-2 gm/day
• Folic acid (1-2 mg/day), B 2-5 mg/day
• Aspirin
• ACE inhibitors
• LDL apheresis
Statins in CAD
Statin Tx Metaanalysis Lancet 2005
Statin Tx Metaanalysis Lancet 2005
Statin Tx Metaanalysis
Lancet 2005
 Statins for
Primary Prevention
 Air Force/Texas Coronary Atherosclerosis
Prevention Study (AFCAPS/TexCAPS)

 Randomized, double-blind trial to

compare lovastatin with placebo for
prevention of first acute major coronary
event in men and women without clinically
evident atherosclerotic CVD
 5,608 men and 997 women with average
Total-C and LDL-C and below-average
HDL-C

Downs JR et al. JAMA 1998;279:1615–1622

 Primary Endpoint
First Acute Major Coronary Event
0.07
Cumulative Incidence

0.06

0.05 37% Risk Reduction

Placebo (p = 0.00008)
0.04

0.03
Lovastatin
0.02

0.01

0.00

0 1 2 3 4 5 5+ Years

# At Risk
Years of Follow-up
Lovastatin N=3304 N=3270 N=3228 N=3184 N=3134 N=1688
Placebo N=3301 N=3251 N=3211 N=3159 N=3092 N=1644

Downs JR et al. JAMA 1998;279:1615–1622

 Air Force/Texas Coronary Atherosclerosis
Prevention Study (AFCAPS/TexCAPS)
Event Rates by Baseline HDL-C Tertile
-45%
16 risk reduction -44%
risk reduction
14 Lovastatin
Event rate per 1,000
patient-years at risk

12 -15% Placebo
risk reduction
10
8
6
4
2
0
 34 35–39  40
HDL-C (mg/dL)
Downs JR et al. JAMA 1998;279:1615–1622
 Heart Protection Study
 Primary prevention with risk factors
(hypertension, diabetes, and CVA)
 2x2 factorial design
simvastatin 40 mg/day, antioxidant cocktail
(600 mg vitamin E, 250 mg vitamin C, 20 mg beta
carotene)
 N = 20,000; subgroups include:
Women (n ~ 5,000)
Elderly (>65, n ~ 10,000)
Diabetics (n ~ 6,000)
Stroke (n ~ 3,000)
Hypertension (n ~ 8,000)
Noncoronary vascular disease (n ~ 7,000)
Low to average blood cholesterol (n ~ 8,000)
 FPI – 1996, fully enrolled, results 2001
Heart Protection Collaborative Group. Lancet 2002;360:7–22. Study
 HPS: Primary and Secondary
Prevention Implications
25 4S
% with CAD event

20

15 LIPID
CARE

10 HPS WOSCOPS
HPS
5
AFCAPS
0
50 70 90 110 130 150 170 190 210
LDL-C (mg/dL)
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
At: http://www.hpsinfo.org.
 Simvastatin: Major Vascular Events
in Upper and Lower Thirds of Baseline LDL
(Heart Protection Study)
30
Statin-allocated
Placebo-
Vascular Events
% with Major

allocated
25 Upper
third LDL

20 Lower
third LDL

15
60 80 100 120 140 160
Average LDL Cholesterol (mg/dl)
 HPS: Statin Benefit is Entirely
Independent of Baseline LDL
Risk ratio and 95% CI
Baseline LDL Statin Placebo Statin Statin
(mg/dl) (10,269) (10,267) better worse

<100 282 358

100–129 668 871

130 1083 1356

24% SE 3
All patients 2033 2585 reduction
(19.8%) (25.2%) (2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

www.hpsinfo.org
 Simvastatin: Major Vascular Events by Year
30
People Suffering Events

25
Placebo
20
(%)

15 Simvastatin
10

0
0 1 2 3 4 5 6
Years of Follow-up
Benefit/1000 5 20 35 46 54 60
(SE) (3) (4) (5) (5) (7) (18)

Heart Protection Study Collaborative Group. Lancet 2002;360:7–22.

 Simvastatin: Cause-Specific Mortality
Risk ratio and 95% CI
Simvastatin Placebo STATIN PLACEBO
(10,269) (10,267) Better Better
Cause of Death
Vascular
Coronary 587 707
Other vascular 194 230
17% SE 4
ANY VASCULAR 781 (7.6%) 937 (9.1%) reduction
(2P<0.0001)
Nonvascular
Neoplastic 359 345
Respiratory 90 114
Other medical 82 90
Nonmedical 16 21
5% SE 6
NONVASCULAR 547 (5.3%) 570 (5.6%) reduction
(NS) 13% SE 4
reduction
ALL CAUSES 1328 (12.9%) 1507 (14.7%) (2P<0.001)

0.4 0.6 0.8 1.0 1.2 1.4

Taggart
Lancet
2009
 Statins in Diabetes
Metaanalysis Lancet 2008
 Statins
in Diabetes
Metaanalysis
Lancet 2008
 Statins
in Diabetes
Metaanalysis
Lancet 2008
 Statins
in Diabetes
Metaanalysis
Lancet 2008
Statins in CKD
Metaanalysis
BMJ 2008
Statins in CKD
Metaanalysis
BMJ 2008
Statins in CKD
Metaanalysis
BMJ 2008
 Fibrate Trials
CVD Mortality

Metaanalysis: Ajoy Saha et al Am Heart J 2007

 Fibrate Trials
Non-fatal MI

Metaanalysis: Ajoy Saha et al Am Heart J 2007

 Fibrate Trials
All Outcomes

Metaanalysis: Ajoy Saha et al Am Heart J 2007

 COMBINATION LIPID THERAPY
For Patients with Metabolic Syndrome

Zhao et al. Am J Cardiol 2009

 COMBINATION LIPID THERAPY
With and Without Metabolic Syndrome

Zhao et al. Am J Cardiol 2009

COMBINATION LIPID THERAPY
With and Without Metabolic Syndrome

Zhao et al.
Am J Cardiol 2009
Sharma et al
Framingham CHD Score for Men
Framingham CHD Score for Men
Conroy et al.
Eur Heart J
2003
Conroy et al.
Eur Heart J
2003
Hayward et al Ann Int Med 2010
Hayward et al Ann Int Med 2010
Case Studies
 An Employment Physical
 24 yo ♂ construction worker.
 Sx: vague joint pains which he treats with NSAIDS without much relief and which he attributes
to work
 PMH: “high cholesterol”
 FHx: F died of MI at 40. 2 paternal aunts with MI aged 60,70. 2 sisters A&W.
 Diet: Likes fast food. Non smoker
 PE: BMI 25. BP 130/80
+ arcus, xanthelasma
soft S2
thickened achilles tendons
 Lab:
Chol 360 TSH 2.9
TG 100 glucose 100
LDL 290 urine μalb - neg
HDL 50

 Dx: ?other diagnostic and lab tests

 Rx: ?Diet
?Drug therapy
Lipoprotein electrophoresis (Kaneka, HELP)
 Evaluation for Hyperlipidemia
 34 yo ♂ ICU Physician of Asian Indian background
 Sx:: None. Does c/o of decreased exercise tolerance
 PMH: Hyperlipidemia in past: - 2 years ago: Chol 200, TG 250, HDL 40, LDL 110; wt 165#
 SHx: 20 lb weight gain since finishing Medical School. Was avid runner/biker in past. Now
works night shift, rarely exercises, eats lots of pizza, hamburgers, frozen foods due to stress and
lack of time. Non smoker.
 FHx: F CABG aged 50, one paternal uncle with high cholesterol on Zocor. Sister with
hypertriglyceridemia, 2 brothers A&W, no known problems..
 Diet: Likes fast food, icecream. Non smoker
 PE: BMI 27. Wt. 170. WHR 0.92. BP 135/85
o/w unremarkable
 Lab:
Chol 252 TSH 2.9 Lp(a) 10 mg/dl
TG 210 glucose 105 apoB 125 mg/dl
LDL 175 urine μalb – 15 ug/g VLDL-C 53 mg/dl (beta quant)
HDL 35 Hyc – 7 μmole/L
 Dx: ?other diagnostic and lab tests
 Rx: ?Diet
?Drug therapy
 Evaluation for Hyperlipidemia
 54 yo AA♀ Diabetic
 Sx: polyuria, polydipsia. 10# weight loss over last 3-6 months. Pain in the legs when walking.
 PMH: DM2 Dx’d 5 years ago. Post menopausal x 5 years. HTN x 3 years.
Meds: glyburide 10 mg qd x 5 years
premarin/provera 0.625/10 mg x 5 years
HCTZ 25 mg qd x 3 years
metoprolol 50 mg bid x 6 months
 SHx: On a 1800 kcal ADA low fat diet but is “frequently hungry”. Weight maxed out at 230# 1
year ago. Non smoker
 FHx: M with PVD who is diabetic and smokes. Currently on Tricor.
 PE: BMI 28. Wt. 190. WHR 0.93. BP 140/85
+ arcus corniae
liver edge 2 FB below RCM
+ bruit over R femoral artery
o/w unremarkable
 Lab:
Chol 310 TSH 2.9 Alk Phos 185
TG 450 glucose 210 VLDL-C 144 mg/dl (beta quant)
LDL - HbA1C 9.5% LP Electrophoresis: broad beta band
HDL 30 urine μalb – 150 ug/g
 Evaluation for Hypertriglyceridemia
 21 yo ♀
 Px: pancreatitis, lipemic serum.
 HPI: Has noted abd pains increasing over last 3-6 months. Noted mild SOB, difficulty
concentrating in school and pruritic rash over her sides and buttocks prior to onset of abd pain.
No history of gallstones.
 PMH: Appendicitis in El Salvador at age 13.
Meds: Orthotricyclin x 6 months.
 ROS: Onset abd pains around puberty when eating fatty meals. Pain seemed to wax and wane in
monthly intervals and was worse when she ate more at celebrations. Stopped eating porc and fried
foods after appendicitis and has felt well since.
 SHx: Comes from a small town in the highlands of El Salvador. No ETOH. Eats low fat diet.
Has remained slim all her life. No regular exercise except regular walking. Recently married but
wants to finish school before starting a family.
 FHx: F died at age 50 of “abdominal pain”. He liked to drink alcohol. Has 10 brothers and
sisters. All in good health except her brother who came to US with her and was recently
hospitalized with pancreatitis.
 PE: BMI 18. Wt. 110. BP 100/65
Fundiscopic exam: lipemia retinalis
fading eruptive xanthomata over the buttocks and flanks.
distended abdomen with peritoneal findings.
 Evaluation for Hypertriglyceridemia
continued

 Lab: Chol 252 TSH 2.9 Lipase 15

TG 5200 glucose 155 Na 125 K 3.8 Cl 99 CO2 20
LDL - HbA1C 4.6%
HDL 15
 Dx: ?other diagnostic and lab tests
Refrigeration test
Lipoprotein electrophoresis (chylomicrons)
Apolipoprotein electrophoresis (apo C2)
 Rx: acute – starvation plus insulin/glucose to maintain normoglycemia
– Consider plasma for known apo CII deficiency
discontinue/reverse predisposing drugs and/or causes of hyperlipidemia
?Diet- very low fat < 20g fat/day. Supplement with MCT fat soluble vitamins prn
?Drug therapy
fibrates
niacin
+/- statins
consider fish oils, androgenic progestins/steroids in ♀/♂
 Evaluation for Hypertriglyceridemia

Continued

Other Therapy:
consider anti-oxidant therapy:
Vit E 300 IU/qd
Vit C 500/qd
Β-carotene 9000 i.u.qd
methionine 500 mg qd in divided doses.

Heaney AP et al.
Prevention of recurrent pancreatitis in familial lipoprotein lipase deficiency
with high-dose antioxidant therapy.
JCEM. 1999 Apr;84(4):1203-5.