Transcript Treatment of Lipid Disorders

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
 30% of total calories
Total fat
Saturated fatty acids
Step II Diet
<10% of
total calories
< 7% of
total calories
Carbohydrates
 55% of total calories
Protein
~ 15% of total calories
Cholesterol
< 300 mg/day
Total calories
< 200 mg/day
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
PRODUCTION
LIPOLYSIS
apo C
CE
SHUNT PATHWAY
Liver
VLDL
Remnant
+
LDL
CLEARANCE
Other sites
CONVERSION
LDL
Currently Available
HMG CoA Reductase Inhibitors
Generic Trade Dose % LDL
Atorvastatin
Lipitor
Simvastatin
Zocor
Lovastatin
Mevacor
10-80 mg
Cost
37-55
5-80 mg
24-51%
Formulary
10-80 mg
19-40%
Dependent
Pravastatin
Pravachol 10-40 mg
20-30%
Fluvastatin
Lescol
20-80 mg
15-25%
10-40 mg
46-55%
Resuvastatin Crestor
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
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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
Treat to prevent/
reverse ASCVD
Triglycerides
> 1,000 mg/dl
Treat to prevent
pancreatitis
Hypertriglyceridemia
Drug Therapy - High Risk CAD
TG  200
Statin
Resin
Niacin
TG 200-400 TG  400
Statin
Combined
Drug Therapy
Niacin
Consider High
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
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Primary target of therapy: identification of LDL-C; goal
for persons with diabetes: <100 mg/dL
Therapeutic options:
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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
HDL-C
LDL-C
20-50 %
10-15 %
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
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May raise homocysteine levels
Fibric Acid Derivatives
• Side Effects
Myopathy
Hepatitis (increases in transaminases)
Gallstones, Nausea, Diarrhea
•Contraindications
Absolute:
Gallstones
Hepatic Insufficiency
Pregnancy
Relative:
Use with statins
Inhibitors of CYP 3A4
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)
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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
Cumulative Incidence
0.07
0.06
37% Risk Reduction
0.05
Placebo
(p = 0.00008)
0.04
0.03
Lovastatin
0.02
0.01
0.00
0
# At Risk
Lovastatin
Placebo
1
2
3
4
5
5+ Years
Years of Follow-up
N=3304
N=3301
N=3270
N=3251
N=3228
N=3211
N=3184
N=3159
N=3134
N=3092
N=1688
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
14
-44%
risk reduction
patient-years at risk
Event rate per 1,000
16
-45%
risk reduction
12
Lovastatin
-15%
risk reduction
10
8
6
4
2
0
 34
35–39
HDL-C (mg/dL)
Downs JR et al. JAMA 1998;279:1615–1622
 40
Placebo
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
% with CAD event
HPS: Primary and Secondary
Prevention Implications
25
4S
20
15
LIPID
CARE
10
HPS
WOSCOPS
HPS
5
AFCAPS
0
50
70
90
110
130
150
LDL-C (mg/dL)
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
At: http://www.hpsinfo.org.
170
190
210
Simvastatin: Major Vascular Events
in Upper and Lower Thirds of Baseline LDL
(Heart Protection Study)
% with Major
Vascular Events
30
25
Statin-allocated
Placeboallocated
Upper
third LDL
Lower
third LDL
20
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
(mg/dl)
Statin
(10,269)
Placebo
(10,267)
<100
282
358
100–129
668
871
1083
1356
130
All patients
2033
(19.8%)
2585
(25.2%)
Statin
better
Statin
worse
24% SE 3
reduction
(2P<0.00001)
0.4 0.6 0.8 1.0 1.2 1.4
www.hpsinfo.org
Simvastatin: Major Vascular Events by Year
People Suffering Events
(%)
30
25
Placebo
20
15
Simvastatin
10
5
0
0
Benefit/1000
(SE)
1
5
(3)
2
3
4
5
6
20
(4)
35
(5)
46
(5)
54
(7)
60
(18)
Years of Follow-up
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22.
Simvastatin: Cause-Specific Mortality
Risk ratio and 95% CI
Simvastatin
(10,269)
Placebo
(10,267)
Coronary
587
707
Other vascular
194
230
Cause of Death
Vascular
ANY VASCULAR
STATIN
Better
781 (7.6%)
937 (9.1%)
359
345
Respiratory
90
114
Other medical
82
90
Nonmedical
16
21
PLACEBO
Better
17% SE 4
reduction
(2P<0.0001)
Nonvascular
Neoplastic
NONVASCULAR
ALL CAUSES
547 (5.3%)
570 (5.6%)
1328 (12.9%) 1507 (14.7%)
5% SE 6
reduction
(NS)
13% SE 4
reduction
(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
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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:
Rx:
?other diagnostic and lab tests
?Diet
?Drug therapy
Lipoprotein electrophoresis (Kaneka, HELP)
Evaluation for Hyperlipidemia
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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
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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
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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
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Lab:
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Dx:
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Rx:
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
?other diagnostic and lab tests
Refrigeration test
Lipoprotein electrophoresis (chylomicrons)
Apolipoprotein electrophoresis (apo C2)
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.