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

3

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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20

50 51

0

10

20

30

40

50

60

% L

DL

Low

erin

g

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