High Profile Call Girls Coimbatore Saanvi☎️ 8250192130 Independent Escort Se...
Dyslipidemia [Compatibility Mode]
1. DYSLIPIDEMIA
Integrated Therapeutics I Seminar
Msc, Clinical Pharmacy PG Study
School of Pharmacy, JU
Moti Deressa hundera
Jimma, Oromia, Ethiopia
September 2009
3. Cholesterol – A Hot Topic
CVD & death
Prevalence of CVD is worldwide.
Major,independent risk factors of
ajor,i
atherosclerosis
Hypertriglyceridemia :acute pancreatitis
Robs dollar: 17% of total direct health care
costs
Huge profit: WOW! PROVE-IT Trial 4
4. CHD Risk Factors ranking - PROCAM Study
Risk factor Relative risk P Value
Smoking 2.3 0.001
LDL cholesterol (mg%)
> 100 but < 160 1.9 0.01
> 160 4.3 0.001
Hypertension (SBP > 140; DBP > 90) 1.8 0.001
HDL cholesterol (mg%)
40 to 55 1.7 0.01
< 40 2.7 0.001
Triglycerides (mg%)
105- 167 1.6 0.01
>167 2.6 0.001
Fasting blood glucose (mg%)
110 - 126 1.4 0.05
> 126 1.9 0.01
Family history of MI 1.4 4
0.05
5. 5
Why much concern…?
Relative risk of CHD
Additive Effect
4.5 3
1.6
Smoking 16 SBP >160
6
5
4
Dyslipidemia
With DM all risks are doubled
5
6. Definition: Hyperlipidemia
abnormal levels of lipids in blood
TC, LDL-cl, TG, apo-B, or Lp(a) above the 90th
percentile
,Or HDL-c or apo A-1 <10th percentile
several forms:
– Hyperlipoproteinemia: lipoprotein
– Hyperlipidemia: TG & cholesterol
– Hypertriglyceridemia: TG only
– Hypercholesterolemia: cholesterol 6
1
7. Major Plasma & lipoproteins:
Typetypes
Source Major lipid Apoproteins ELFO
Athero-
genicity
–
Chylomicr Dietary A-I, B-48, no
Gut
ons TGs C-I, C-III, E mobility (pancreat
itis)
Endogeno B-100, E,
VLDL Liver us C-II, C- Pre-β +
TGs III,
VLDL Ch esters, B-100, C- Slow
IDL +
remnant TGs III, E pre- β
VLDL, 7
LDL Ch esters B-100 β +++ 7
IDL
anti-
8. Epidemiology
Prevalence ???
2002 audit of GP practices in England >50% US adults > 20 yrs have
TC ≥200 mg/dL.
Patients with CVD
Detected & Controlled > 1/2 of borderline to high risk
remain unaware
Detected & Uncontrolled <1/2 of highest-risk are on
drug therapy
only 1/3 are achieving their
LDL goal
Undetected <20% of CHD patients are at
their LDL goal
NHANES, : 199-2000
Br J Cardiol 2006;13:145
9. 9
Intestinal Cholesterol Absorption
Intestinal Biliary Dietary
epithelial cell cholesterol cholesterol
Through
lymphatic
system to
the liver MTP
CM Cholesteryl esters
Luminal
cholesterol
ACAT excretion Bile
(esterification)
acid
ABCG5 Micellar
ABCG8
cholesterol
Free
cholesterol uptake
Bays H et al. Expert Opin Pharmacother 2003;4:779-790.
20. Screening
Diagnosis: ATP III of NCEP
- For all above 20 yrs
Symptoms: once in q 5 years
– asymptomatic,
– xanthomas, enlargement of
liver or spleen, pancreaitis, - For those above 45
Atherosclerosis yrs – once in 2 years
FMH
- For those with
PE already known lipid
abnormality follow-up q
lipid panel 3-6 months
LDL = TC– (HDL +
TG/5)
21. Management: principle
Treat according to global risk level, not only cholesterol value
Achieve at least a 30% to 40% reduction in LDL-C
Initial therapy for any lipoprotein disorder is therapeutic
lifestyle changes, TLC
TLC in all patients with lifestyle-related risk factors regardless of
LDL-C level
any potential underlying medical problems
Initiation & Selection of Drug therapy
Monitor for efficacy and safety
22. Mgt: Goals for Lipids
LDL HDL
– < 100 →Optimal
– < 40 → Low
– 100-129 → Near optimal
– 130-159 → Borderline – ≥ 60 → High
– 160-189→ High Serum Triglycerides
– ≥ 190 → Very High – < 150 → normal
Total Cholesterol – 150-199 →
– < 200 → Desirable Borderline
– 200-239 → Borderline – 200-499 → High
– ≥240 → High
– ≥ 500 → Very High
23. 23
Treatment Strategy
Lipid Profile, Risk Assessment
LDL > 100 Look For Sec. Causes
Treat the cause, if found
Treatment
NO CHD
CHD +
Primary Prevention
Sec. Prevention
LDL < 130
2 or more < 2 RF
RF
High Risk Low Risk
LDL > 100 LDL <160
25. Updated NCEP ATP III: Risk Categories,
LDL-C Goals, Treatment Cutpoints
LDL-C goal Initiate TLC* Consider drug Tx
Risk category (mg/dL) (mg/dL) (mg/dL)
High risk
CHD and CHD <100 ≥100 ≥100
risk equivalents (optional goal: <70) (<100: drug optional)
(10-year risk >20%)
Moderately high risk
≥2 risk factors <130 ≥130 ≥130
(10-year risk 10%-20%) (optional goal: <100) (100-129: drug optional)
Moderate risk
≥2 risk factors ≥130 ≥130 ≥160
(10-year risk <10%)
Lower risk
0–1 risk factor† <160 ≥160 ≥190
(160-189: drug optional)
*TLC=therapeutic lifestyle changes
†Almost all people with a 0–1 risk factor have a 10-year risk 25
<10%; thus, risk calculations are not necessary Grundy SM et al. Circulation. 2004;110:227-239.
26. Therapeutic Lifestyle Changes ,TLC
TLC Nutrient Recommended Intake
TLC Diet Saturated fat < 7% of calories
PUFA fat Up to 10% of calories
MUFA fat Up to 20% of calories
Weight Total fat 25–35% of calories
reduction Carbohydrate 50–60% of calories
Fiber 20–30 grams per day
Protein Approx. 15% of calories
physical Cholesterol Less than 200 mg/day
activity
DIETARY THERAPY
26
28. Progression of Drug Therapy for
LDL-C Lowering
Visit 1 Visit 2 Visit 3 F/U
q
6 6 Visits
Initiate LDL-
LDL- If LDL goal If LDL goal 4–6 Monitor
lowering wks not achieved, wks not achieved, mo response &
drug intensify LDL-
LDL- drug therapy adherence
therapy lowering or refer to a to therapy
therapy lipid specialist
Start statin Consider If LDL goal
or bile acid higher dose of has been
resin or the statin or achieved,
nicotinic add a bile acid treat other
acid resin or lipid risk
nicotinic acid factors
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA 2001;285:2486-2497.
29.
30. 30
Treatment of ↓ HDLc
Low HDLc
Therapeutic Lifestyle Change
Drug Therapy
Therapy of Choice : Niacin
Add on drug - Finofibrate
31. 31
Treatment of ↑ TG
High TG
Therapeutic Lifestyle Change
Drug Therapy
Therapy of Choice : Fibrate
Add on drug – Statin, Niacin
32. Treatment of Mixed Hyperlipidemia
High LDL-C and TGs
LDL-
Therapeutic Lifestyle Change
Drug Therapy
STEP 1 Achieve the LDL-C goal: statins
LDL-
Therapy of Choice : Statin + Fibrate
Achieve the non-HDL-C goal
non-HDL-
STEP 2 Increase LDL-C lowering or
LDL-
Add a fibrate, niacin or fish oils
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA 2001;285:2486-2497.
33. ATP III: The Metabolic Syndrome
Diagnosis is established when ≥3 of these risk factors are present.
Risk Factor Defining Level
Abdominal obesity
(Waist
circumference) >102 cm (>40 in)
Men >88 cm (>35 in)
Women
TG ≥150 mg/dL
HDL-C
Men <40 mg/dL
Women <50 mg/dL
Blood pressure ≥130/≥85 mm Hg
Expert Panel on Detection, Evaluation, and Treatment of High 33
≥110
Cholesterol in Adults. JAMA 2001;285:2486-2497. mg/dL
Blood Fasting glucose
34. 34
Statins – Mechanism of Action
Cholesterol VLDL
synthesis LDL receptor–mediated
receptor–
LDL receptor Apo
VLDLR
B hepatic uptake of LDL& VLDL
HMGCoA (B–E receptor)
(B– Apo remnants
E Serum LDL-C
LDL-
Intracellular synthesis Apo
Cholesterol LDL Serum VLDL remnants
B
Serum IDL
Hepatocyte Systemic Circulation
1. Reduce hepatic cholesterol synthesis (HMG CoA),
CoA),
2. lowering intracellular cholesterol,
3. Upregulation of LDL receptor and
4. ↑ the uptake of non-HDL from circulation.
non-
35. The LDL-C–Lowering Efficacy of the
Currently Available Statins
Daily Atorv
Dose a Fluva Lova Prava Simva
10 mg –39% –22% –30%
20 mg –43% –22% –27% –32% –38%
40 mg –50% –25% –32% –34% –41%
80 mg –60% –36% –42% –47%
Physician’s Desk Reference. 55th ed. Montvale, NJ: Medical 35
Economics, 2001.
36. 36
CHD Risk Reduction – Statin Therapy
Relative Risk Reduction (%)
Endpoints +20 0 –5 –10–15–20–25–30–35–40–45–50
Major coronary events
Coronary deaths
Cardiovascular deaths
Non_CV events
Total mortality
Strokes
Intermittent
claudication
Angina
La Rosa JC et al. JAMA 1999;282:2340-2346.
37. Fibrates
⇑ FA oxidation in muscle and liver and lipogenesis in the liver
Most effective at reducing VLDL (TG); smaller ↓ in LDL-chol but
useful ↑ in HDL-chol
α
Act as PPARα ligands (cf glitazones) -
38. Fibric Acid Derivatives
Indications: Adjunctive therapy to diet
Hypertriglyceridemia (Type IV and V)
Combined hyperlipidemia (Type IIb) with low
HDL-C who do not respond to nicotinic acid
Mechanism of Increase peripheral lipolysis and decrease
Action: hepatic TG production
Efficacy: Decrease TG 25–50%
LDL-C decreases, remains the same, or increases
Increase HDL-C 15–25% in hypertriglyceridemia
Side Effects: GI upset (8%), cholelithiasis, myositis, abn LFTs
Contraindications: Hepatic or renal dysfunction
Pre-existing gallbladder disease
Intervention Trials: HHS, VA-HIT, BIP, LOCAT, BECAIT, DAIS
38
39. 39
Bile Acid Resins: Mechanism of Action
↑↑ Cholesterol 7-α
7-
Gall Bladder hydroxylase
Bile Acid ↑ Conversion of
cholesterol to BA
Enterohepatic Recirculation
↑ BA Secretion Liver
Terminal Ileum
↑ LDL Receptors
Reabsorption
of bile acids ↑ VLDL and LDL removal
↑ BA
Excretion
Net Effect - ↓ LDL-C
LDL-
40. 40
Nicotinic Acid – Mechanism of Action
Mobilization of FFA
Apo B
Serum VLDL
results in reduced
VLDL VLDL lipolysis to LDL
TG
synthesis VLDL Serum LDL
secretion
LDL
HDL
Liver Circulation
Hepatocyte Systemic Circulation
Decreases hepatic production of VLDL and of apo B
41. 41
Effect of Niacin on Lipoproteins
35%
HDL-
HDL-C with crystalline niacin
25%
HDL-
HDL-C with Niaspan®
12.5%
Baseline LDL-
LDL-C with Niaspan®
-15% LDL-
LDL-C with crystalline niacin
TG with Niaspan®
-30% TG with crystalline niacin
0 1g/d 2g/d 3g/d
Adapted from Knopp RH. N Engl J Med 1999;341:498-511..
43. Fish Oils
Indication Adjunctive therapy to diet
s: Hypertriglyceridemia (Type IV and
V)
With statins or other LDL-C–
lowering drugs in mixed
hyperlipidemia
Efficacy: Decrease TG 30–40%
LDL-C remains the same or
increases
No change in HDL-C
Side
GI upset and a “fish burp”
Effects:
43
Interventi Lyon Heart Study (dietary), GISSI
on Trials: Prevenzione Trial, others
45. Dyslipidemia and DM
Elevated TG
Elevated VLDL Type Rx used Effect on lipids
Insulin Favourable
Reduced HDL-C Metformin Mildly favourable
Increase in SD-LDL Sulfonylureas Not favourable
Decrease in Apo A I Glitazones Favourable
Acarbose No effect
Increase in Apo B
Apo A I / Apo B < 1
All Diabetics must be given STATIN 45
46. 46
Hypertension Treatment and Lipids
Type Rx used Effect on lipids
1. Diuretics Unfavourable
2. Indapamide Mildly favourable
3. ACEi and ARB Very favourable
4. Betablockers Unfavourable
5. Ca channel blockers No effect
47. Special consideration
Elderly: Women
– Start slow & go slow HDL > LDL ?
– ↓ absolute risk More responsive than
reduction ?? men
Children: Pregnancy: Not
– < 10 years: No drug recommended
therapy!
- High risk: BAR,
– 10-20: d/t guideline
Ezetimibe?
– First line: BAR→
statins Menopause?
48. BOTTOM LINE
Hyperlipidemia is a modifiable risk factor for
IHD and stroke
1° & 2° prevention of ASCVD are
possible!
TLC is a must !
Intervention with a statin is highly effective and
can reduce risk by ~ 1/3rd
Follow up
49. Where are we heading ? ?
20000 B.C. 2004
Paleolithic sup. age Neolithic age 19th century 21st century
Technology has changed a lot in the way we live
Processed
Hunting-gathering foods
subsistence
- Animal fats
and glucides
High level of
¯ Dietary fibre
physical activity Sedentary
But, we have not altered our life style
life
Thrifty genotype Susceptibility genotype
Journal of internal medicine 2003:254(2):114-25
50. References
Joseph T. DiPiro, Pharmacotherapy,A
Pathophysiologic Approach,Seventh Edition, 2008
Harrison's PRINCIPLES OF INTERNAL
MEDICINE, Seventeenth Edition, 2008
NCEP, www.
www.lipidsonline.org
51. Thanks for your Attention!
Questions are guaranteed in life; Answers aren’t!!