Comprehensive Lipid Management BEYON LDL
description
Transcript of Comprehensive Lipid Management BEYON LDL
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Indian SpecialtyIndian Specialty
↑ LDL
↓ HDL
↑ TG
The Triad
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JAPI 2008; 56: 99-102
Prevalence in Young Indian AdultsPrevalence in Young Indian Adults
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JAPI 2008; 56: 99-102
Prevalence in Young Indian AdultsPrevalence in Young Indian Adults
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Clinical Features & ComplicationsClinical Features & Complications
• Clinical symptoms/signs directly due to dyslipidemia is uncommon
• May include skin lesions (xanthomas, xanthelasmas etc.)
• Dyslipidemia is clinically important because of its direct association with risk of
atherosclerosis & associated complications (CAD, CVD & PVD)
• Hypertriglyceridemia (>1000 mg/dl) is also associated with increased risk for Pancreatitis
• Raised LDL has strongest known association with raised risk of Atherosclerosis
• Reduction of LDL has been shown to reduce its risk
• Decreased HDL has less strong evidence for its association with Atherosclerosis
• Raising HDL has given mixed results in modifying its risk
• Raised levels of TGs too is weakly associated with risk of Atherosclerosis
• No trial has ever studied effect of reducing TGs on risk of Atherosclerosis
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HDL-C vs. LDL-C as a predictor of CHD riskHDL-C vs. LDL-C as a predictor of CHD risk
*Men aged 50–70Am J Med 1977; 62: 707–714
100 mg/dl 160 mg/dl 220 mg/dl0
0.5
1
1.5
2
2.5
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Risk of CAD over 4years of follow-up*
LDL-C
85 mg/dl
65 mg/dl
45 mg/dl
25 mg/dl
HDL-C
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Eruptive xanthomata on the forearm of a patient
with severe ↑TGs↑TGs
Xanthelasmas
& tendon
xanthomata in
patients with
severe ↑LDL↑LDL
Cutaneous Manifestations of DyslipidemiaCutaneous Manifestations of Dyslipidemia
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Screening & Diagnosis of DyslipidemiaScreening & Diagnosis of Dyslipidemia
• Adult Treatment Panel III (NCEP)
• Fasting lipid profile at least once in 5 years for all persons 20 yrs. 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
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Lipid Profile TestingLipid Profile Testing
• Should be done after overnight (or 8 hours) fasting
• Commonly only Total Cholesterol, HDL Cholesterol & TGs are tested
• Value for VLDL & LDL are derived*
• VLDL C = TGs ÷ 5
• LDL C = TC – (TGs ÷ 5) – HDL C [Friedewald formula]
* This formula is reasonably accurate if test results are obtained on fasting plasma and if the triglyceride level does not exceed 400 mg/dL
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LDL Targets – NCEP ATP III GuidelinesLDL Targets – NCEP ATP III Guidelines
Risk Profiling
• Very High Risk– CHD + multiple risk factors (diabetes)– CHD + poorly controlled risk factor (smoking)– CHD + metabolic syndrome– CHD + ACS
• High Risk– CHD– CHD Equivalents
• Moderately High Risk– >2 Risk Factors + Framingham Risk of 10-20%
• Intermediate Risk– >2 Risk Factors + Framingham Risk of < 10%
• Low Risk– 0-1 Risk Factor
CHD Equivalents:
• Other clinical forms of
atherosclerotic disease (PAD,
abdominal aortic aneurysm,
symptomatic carotid artery disease)
• Diabetes
• Multiple risk factors that confer a
10-year risk for CHD >20%
Risk Factors: • Cigarette smoking
• Hypertension (BP 140/90 mmHg
or on antihypertensive medication)
• Low HDL cholesterol (<40 mg/dL)*
• Family history of premature CHD
• Age (men 45 yrs; women 55
yrs)
* HDL cholesterol 60 mg/dL counts as a “negative” risk factor; its presence removes one risk factor from the total count.
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LDL Targets – NCEP ATP III GuidelinesLDL Targets – NCEP ATP III Guidelines
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LDL Targets – NCEP ATP III GuidelinesLDL Targets – NCEP ATP III Guidelines
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LDL Targets – NCEP ATP III GuidelinesLDL Targets – NCEP ATP III Guidelines
Risk CategoryLDL Goal(mg/dL)
LDL Level at Which to Initiate Therapeutic Lifestyle Changes
(TLC) (mg/dL)
LDL Level at Which to Consider
Drug Therapy (mg/dL)
CHD or CHD Risk Equivalents
(10-year risk >20%)<100 100
130 (100–129: drug
optional)
2+ Risk Factors (10-year risk 20%) <130 130
10-year risk 10–20%: 130
10-year risk <10%: 160
0–1 Risk Factor <160 160
190 (160–189: LDL-lowering drug
optional)
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Lifestyle Modification (LSM)Lifestyle Modification (LSM)
• Diet
– Reduced intake of cholesterol-raising nutrients
• Saturated fats <7% of total calories
• Dietary cholesterol <200 mg per day
– LDL-lowering therapeutic options
• Plant stanols/sterols (2 g per day)
• Viscous (soluble) fiber (10–25 g per day)
• Weight reduction
• Increased physical activity
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Nutrient Recommended Intake
• Saturated fat Less than 7% of total calories
• Polyunsaturated fat Up to 10% of total calories
• Monounsaturated fat Up to 20% of total calories
• Total fat 25–35% of total calories
• Carbohydrate 50–60% of total calories
• Fiber 20–30 grams per day
• Protein Approximately 15% of total calories
• Cholesterol Less than 200 mg/day
• Total calories (energy) Balance energy intake and expenditure to maintain desirable body weight/prevent weight gain
Lifestyle Modification (LSM)Lifestyle Modification (LSM)
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Hypolipidemic Drugs – Classification Hypolipidemic Drugs – Classification
• HMG CoA Reductase Inhibitor (Statins)
• Lovastatin
• Simvastatin
• Atorvastatin
• Rosuvastatin
• Fibric Acid Derivatives (Fibrates)
• Clofibrate
• Gemfibrozil
• Fenofibrate
• Bile Acid Sequestrants – Cholestyramine, Colestipol, Colesevelam
• Cholesterol Absorption Inhibitor – Ezetimibe
• Niacin (Nicotinic Acid)
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Statins – MoA Statins – MoA
Competitive inhibitor of Hydroxy Methyl Glutaryl Co-enzyme A Reductase, an enzyme that catalyses the rate limiting step in cholesterol synthesis pathway
Decrease in cholesterol synthesis
Increased expression of LDL receptor on liver cells
Increased LDL cholesterol uptake & clearance by liver cells
Reduces amount of LDL-C in blood
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Statins – General Properties Statins – General Properties
• Reduces LDL by up to 60% & TGs by up to 30%
• Effect on HDL elevation not marked (up to 15%)
• Demonstrated Therapeutic Benefits
• Reduces incidence of major coronary events & Stroke
• Reduce coronary procedures (PTCA/CABG)
• Reduces CHD mortality & all-cause mortality
• Major side effects
• Myopathy
• Increased liver enzymes
• Contraindications
• Absolute: liver disease
• Relative: use with certain drugs
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Comparative efficacy of different Statins
Statins – Comparative Overview Statins – Comparative Overview
In general, doubling dose = additional 6% reduction in LDL
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• Activate PPARα which leads to increased lipolysis
– May increase size of LDL particles and enhance removal
– May increase HDL-mediated reverse cholesterol transport
• Major actions
– Most effective class of drugs for lowering triglycerides, lowers by 20–50%
– Lower LDL-C by 5–20% (with normal TG)
– May raise LDL-C (with high TG)
– Raise HDL-C 10–20%
• Demonstrated Therapeutic Benefits
– Reduce progression of coronary lesions
– Reduce major coronary events
• Side effects: dyspepsia, gallstones, myopathy
• Contraindications: Severe renal or hepatic disease
Fibrates – MoA & General PropertiesFibrates – MoA & General Properties
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• Helsinki Heart Study
– Primary prevention trial
– 4,081 dyslipidemic (non-HDL > 200 mg/dL) men, age 40 to 55
– Gemfibrozil 600 mg bid vs Placebo for 5 years
– Primary endpoint – CHD death or nonfatal MI
• VA-HIT
– Secondary prevention trial
– 2,531 men with documented CAD
– HDL < 40 mg/dL and LDL < 140 mg/dL
– Gemfibrozil 600 mg bid vs Placebo for 5.1 years
– Primary endpoint – CHD death or nonfatal MI
Fibrates – Key Outcomes StudiesFibrates – Key Outcomes Studies
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Bind bile acids in the intestine and promote their excretion in the stool.
Bile Acid Sequestrants – MoA Bile Acid Sequestrants – MoA
Increased expression of LDL receptor on liver cells
Increased LDL cholesterol uptake & clearance by liver cells
Reduces amount of LDL-C in blood
To maintain the bile acid pool size, liver diverts cholesterol to bile acid synthesis. Leading to decreased hepatic intracellular cholesterol content
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• Major actions
– Reduce LDL-C 15–30%
– Raise HDL-C 3–5%
– May increase TG
• Safe in pregnancy
• Side effects
– GI distress/constipation
– Decreased absorption of other drugs
• Contra-indications
– Dysbetalipoproteinemia
– Raised TG (especially >400 mg/dL)
Bile Acid Sequestrants – General PropertiesBile Acid Sequestrants – General Properties
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EzetimibeEzetimibe
• 1st in new class of cholesterol absorption inhibitors
• Works by binding to & blocking sterol transporter on intestinal brush border
• Results in increased LDL-R activity and LDL clearance
– Reduces LDL C by around 18%
– No effect on HDL C or TGs
• Drug & its metabolites circulate enterohepatically with little systemic penetration
• Potential toxicities essentially limited to liver
• Does not induce or inhibit cytochrome P450 system
• Single dosing option of 10 mg once daily
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Zetia Zetia+Atorv10 Atorv80
ZetiaZetia+Atorv10Atorv80
Ballantyne CM. Circulation 2003; 107: 2409-2415.
Ezetimibe – Synergism with StatinsEzetimibe – Synergism with Statins
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• Same as Vitamin B4
• Has hypolipidemic properties in very large doses - 1st reported in 1955
• MOA: Inhibit release of VLDL release in liver, decrease catabolism of HDL
• Most effective drug available currently for raising HDL (15-35%)
• Also effective for reducing LDL (5-25%) & reducing triglycerides (25-50%)
• Reduces Lp (a) by 30% & converts small, dense LDL to large, buoyant LDL
• Reduces major coronary events & with possible reduction in total mortality
Niacin – MoA & General PropertiesNiacin – MoA & General Properties
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Niacin – PitfallsNiacin – Pitfalls
• Cutaneous flushing:
• Very common AE
• PG D2 mediated
• Dose related, do not disappear completely with time
• Reduced if administration with Aspirin
• Least with ER formulation as compared to IR or SR formulations
• Gastro-Intestinal AEs – nausea, abdominal pain, hepatotoxicity
• Metabolic AEs – Glucose intolerance & Hyperuricemia
• Increase risk of myositis if used with statin
• Minimal hard endpoint outcome data