Indian Specialty

↑TG ↑LDL

The Triad

↓HDL

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Prevalence in Young Indian Adults

JAPI 2008; 56: 99-102 2

Prevalence in Young Indian Adults

JAPI 2008; 56: 99-102 3

Clinical 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 risk

Risk of CAD over 4

years of follow-up*
3
2.5
2 HDL-C
1.5 25 mg/dl
1 45 mg/dl
0.5 65 mg/dl
85 mg/dl
0
100 mg/dl 160 mg/dl 220 mg/dl

LDL-C
*Men aged 50–70
Am J Med 1977; 62: 707–714
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Cutaneous Manifestations of Dyslipidemia

Xanthelasmas
& tendon
xanthomata in
patients with
severe ↑LDL

Eruptive xanthomata on
the forearm of a patient
with severe ↑TGs

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Screening & 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 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 Guidelines

Risk Profiling CHD Equivalents:

• Other clinical forms of
• Very High Risk
atherosclerotic disease (PAD,
– CHD + multiple risk factors (diabetes)
– CHD + poorly controlled risk factor (smoking) abdominal aortic aneurysm,
– CHD + metabolic syndrome symptomatic carotid artery disease)
– CHD + ACS • Diabetes
• Multiple risk factors that confer a
• High Risk
– CHD 10-year risk for CHD >20%
– CHD Equivalents
Risk Factors:
• Moderately High Risk • Cigarette smoking
– >2 Risk Factors + Framingham Risk of 10-20% • Hypertension (BP 140/90 mmHg
• Intermediate Risk or on antihypertensive medication)
– >2 Risk Factors + Framingham Risk of < 10% • Low HDL cholesterol (<40 mg/dL)*
• Family history of premature CHD
• Low Risk
– 0-1 Risk Factor • 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. 9
LDL Targets – NCEP ATP III Guidelines

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LDL Targets – NCEP ATP III Guidelines

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LDL Targets – NCEP ATP III Guidelines

LDL Level at Which to LDL Level at Which

Initiate Therapeutic to Consider
LDL Goal Lifestyle Changes Drug Therapy
Risk Category (mg/dL) (TLC) (mg/dL) (mg/dL)

CHD or CHD Risk 130

Equivalents <100 100 (100–129: drug
(10-year risk >20%) optional)

10-year risk 10–20%:

130
2+ Risk Factors
<130 130
(10-year risk 20%)
10-year risk <10%:
160

190
(160–189: LDL-
0–1 Risk Factor <160 160
lowering drug
optional)

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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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Lifestyle Modification (LSM)

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

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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
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
• 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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Statins – Comparative Overview

Comparative efficacy of different Statins

In general, doubling dose = additional 6% reduction in LDL

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Fibrates – MoA & General Properties
• 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

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Fibrates – Key Outcomes Studies

• 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

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Bile Acid Sequestrants – MoA

Bind bile acids in the intestine and promote their excretion in the stool.

To maintain the bile acid pool size, liver diverts cholesterol to bile acid synthesis.
Leading to decreased hepatic intracellular cholesterol content

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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Bile Acid Sequestrants – General Properties

• 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)

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Ezetimibe

• 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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Ezetimibe – Synergism with Statins

60
50 51
50
% LDL Lowering

40
Zetia
30
20 Zetia+Atorv10
20 Atorv80

10

0
Zetia Zetia+Atorv10 Atorv80

Ballantyne CM. Circulation 2003; 107: 2409-2415.

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Niacin – MoA & General Properties

• 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

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Niacin – 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

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