Managing Hypertriglycerdemia

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Done by: Rola Awad Presented to : Dr. Etwal bouraad January 2013

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Abbreviations   

    

CVD: cardiovascular diseases LDL: low density lipoprotein VLDL: very low density lipoprotein HDL: high density lipoprotein TG: triglycerides NCEP ATPIII DM: diabetes mellitus Lpl : lipoprotein lipase

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Outline   



Introduction Pathophysiology Guidelines recommendations Treatment  Non-pharmacologic  Pharmacologic ○ Omega 3 fatty acids ○ Niacin ○ Fibrates

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Introduction 

To date, treatment of hyperlipidemia has centered on the management LDL



There’s a robust evidence between LDL and CVD



However, between TG and CVD uncertain

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Introduction (Cnt’d)

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Introduction (Cnt’d) 

Severe and very severe  increase risk of pancreatitis



Mild or moderate  maybe a risk factor for CVD

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Introduction (Cnt’d) 

Causes of secondary high triglycerides:  Overweight and obesity  Physical inactivity

 Cigarette smoking  Excess alcohol intake  Very high carbohydrate diet  Diseases : Type II DM, chronic renal failure,

nephrotic syndrome  Drugs: CS, estrogens, beta blockers

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Introduction (Cnt’d) 

Causes of primary high triglycerides:  Familial combined hyperlipidemia (FCHL)

 Familial hypertriglyceridemia (FHTG)  Familial dysbetalipoprotenemia  FHA

 Familial chylomicronemia and related disorders

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Pathophysiology 

TG  The most dense form of calories  Serve as an important source of energy



Dietary TG assembled in the gut into chylomicrons



Their interaction with LpL leads to liberation of free fatty acids from TG

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Pathophysiology (Cnt’d) 

The remainder of the lipoprotein,(chylomicron remnant),contains  Cholesteryl esters  Retinyl esters  apoB-48

 

VLDL particles  produced by the liver VLDL contains TG ,deriving from:  Lipoprotein triglyceride  Free fatty acids  De novo fatty acids 10

Pathophysiology (Cnt’d) 

VLDL IDL LDL

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The concentration of VLDL cholesterol and apoB is 10X > than the corresponding chylomicron

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VLDL cholesterol is at least as much as LDL cholesterol

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Pathophysiology (Cnt’d) 

In hypertriglyceridemia:  More VLDL particles, as measured by apoB  Larger and more triglyceride- and apoC-III

enriched lipoproteins  Clearance of VLDL ↓ (due to saturation of TG clearance) 

Hepatic insulin resistance  ↑ production rate of VLDL (Insulin ↓ apoB synthesis and VLDL secretion in the liver)

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Pathophysiology (Cnt’d)

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Update 

In september 2012 , the endocrine society released an updated guideline about the evaluation and treatment of hypertriglyceridemia

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Guidelines recommendations 

For severe and very severe hypertriglyceridemia(> 1000 mg/dl)  combining reduction of dietary fat and simple

carbohydrate intake with drug treatment to reduce the risk of pancreatitis 

The treatment goal for patients with moderate hypertriglyceridemia be a non-HDL cholesterol level in agreement with NCEP ATP guidelines

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Guidelines recommendations 

A fibrate be used as a first line agent for reduction of triglycerides in patients at risk for triglyceride-induced pancreatitis

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Three drug classes (fibrates, niacin, n-3 fatty acids) alone or in combination with statins options in patients with moderate to severe triglyceride levels

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Statins not be used as monotherapy for severe or very severe hypertriglyceridemia

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However, statins may be useful for the treatment of moderate hypertriglyceridemia

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Non-HDL cholesterol 

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Treatment goal is according to the non-HDL cholesterol rather than TG level (when the TG is above 250 mg/dl) Non-HDL chol is the product of TC minus the LDL level  Non-HDL=TC - LDL Normal non-HDL level is 30 mg/dl above the LDL level  Individualized for each patient according to CV

risk

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Treatment 

Non pharmacologic  Diet  Exercise

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Pharmacologic

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Diet 

Factors that might increase TG  Weight gain  Diet rich in simple carbohydrates and sugar

sweetened beverages 

Diet quality should be:  Low in carbs

 High in fat

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Diet (Cnt’d) 

Carbs  Fructose may have stronger triglyceride-raising

effects than glucose 

Fats  Saturated, monounsaturated, and n-6

polyunsaturated fatty acids all lower serum triglycerides  However, the effects of fats go beyond lowering TG i.e. increasing LDL levels

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Diet (Cnt’d)

Effect on LDL

Effect on TG

Saturated

↑↑↑

↓

Monounsaturated

↓

↓↓

N3-polyunsaturated

↓↓

↓↓

N6-polyunsaturated

↓↓↓

↓↓↓

Table : Effects of fat on LDL and TG

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Pharmacological treatment 

Three classes:  Omega 3 fatty acids  Niacin

 Fibrates

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Statins

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Omega 3 fatty acids 

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)



OTC preparations have variable quantities of EPA and DHA (20-50%)

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The nutritional label should be examined to calculate how many capsules/day should be taken Dose:3-5 g /day



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Omega 3 fatty acids (Cnt’d) 

Lovaza, (85% )  4 g/day  ↓ TG levels by 45 %

 but ↑ LDL-C levels by 31 % 

Vascepa, (>95%)  4 g/day

 also ↓ TG levels by up to 45%  but did not significantly affect LDL-C levels

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Omega 3 fatty acids (Cnt’d) 

Side effects :  fishy taste  CNS ( headache, dizziness)

 GI ( abdominal pain, diarrhea, nausea, vomiting,

acid regurgitation)  Back pain , weakness  URI, cough

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Niacin 

Aka nicotinic acid, vitamin B3 Water- soluble, member of the vitamin B family

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Dose :

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 Regular release: 1.5-2 g in 2-3 divided doses. ↑ every 4-7

days  Extended release: 500 mg at bedtime for 4 weeks then 1g 

Primarily used to increase HDL

Ref: Goodman and Gilamn’s ; the pharmacological basis of therapeutics; 11th edition ; chapter 35;page 955

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Niacin(Cnt’d) 

Mechanism of action  Liver: ○ ↑ HDL  ↓ fractional clearance of apoA-I in HDL ○ ↓ TG synthesis Inhibit the synthesis and esterification of

fatty acids  ↓ VLDL production  ↓LDL ○ ↑LPL activity  ↑ clearance of chylomicrons and VLDL TG  Adipose tissue: ○ Reduces transport of free fatty acids to the liver ○ May also inhibit the rate-limiting enzyme of TG synthesis, diacylglycerol acetyltransferase 2

Ref: Goodman and Gilamn’s ; the pharmacological basis of therapeutics; 11th edition ; chapter 35;page 955

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Fig. 2: Mechanism of niacin action.

Fung M A , Frohlich J J CMAJ 2002;167:1261-1266

©2002 by Canadian Medical Association

Niacin (Cnt’d) Side Effects

Comments

Flushing, pruritus, skin rashes

-aspirin 325-650 mg 30 mins prior Ibuprofen 200 mg 60 mns prior

Dyspepsia

CI in active peptic ulcer disease

May worsen glucose tolerance in diabetic patient Hyperuricemia

precipitating acute gouty arthritis

Hypotension in subjects treated with vasodilators Can exacerbate unstable angina pectoris Dose-dependent ↑in plasma homocysteine levels

Ref: lipid lowering drugs other than statins, uptodate

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Niacin (Cnt’d) 

Clinical trials  AIM-HIGH ○ Randomized 3414 patients with heart disease, low HDL, and raised TG. ○ Niacin (1500-2000mg/day) ○ All patients also received simvastatin plus ezetimibe if needed to maintain LDL levels below 80 mg/dL

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Niacin (Cnt’d) 

Clinical trials (Cnt’d):  AIM-HIGH- outcomes

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Niacin (Cnt’d) 

Clinical trials (Cnt’d)  HPS2-THRIVE ○ Niacin/laropiprant + simvastatin (or + simvastatin/ezetimibe) Vs. Placebo+simvastatin (or + simvastatin/ezetimibe) ○ Four years of follow-up, the combination did not significantly reduce the primary outcome ○ It significantly increased the risk of nonfatal but serious side effects

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Fibrates 

Five fibrates are currently used by human therapy:  Clofibrate

 Gemfibrozil  Fenofibrate  Bezafibrate

 Ciprofibrate

Ref: Cardiovascular therapeutics: A companion to braunwald’s heart disease; 2007;chapter 26; page 520

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Fibrates (Cnt’d) 

Mechanism of action:  Synthetic ligands for PPARα  Located in the liver, skeletal muscle, heart

muscle, and cells in the arterial wall  PPARα play a key role in the development of atherosclerosis

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Fibrates (Cnt’d)

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Fibrates (Cnt’d) 

Effects on LDL and HDL subtypes particles:  The raised TG-low HDL-C dyslipidemia have

LDL particles that are smaller and contain less cholesterol than average  As a result, the number of atherogenic LDL particles is frequently elevated, even though LDL-C levels are not

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Fibrates (Cnt’d)

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Fibrates (Cnt’d) 

Adverse effects and precautions:  Common: GI (epigastric distress, flatulence,

nausea, diarrhea, constipation) and dermatologic (pruritus, urticaria, or erythema)  Less common : musculoskeletal (muscular

weakness, pain, and muscle cramps) and neurological (headache, dizziness) systems

Ref: Update on the use of fibrates: focus on bezafibrate-Vasc Health Risk Manag. 2008 February; 4(1): 131–141. 40

Fibrates (Cnt’d) 

Adverse effects and precautions (Cnt’d):  Hematologic  Liver function first monitor every 3-6 months,

then yearly  Cholelithiasis  Hepatobiliary  contraindicated in liver and gallbladder disease  Skeletal muscle Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness/weakness, or marked elevations in CPK levels. Ref: Update on the use of fibrates: focus on bezafibrate-Vasc Health Risk Manag. 2008 February; 4(1): 131–141. 41

Fibrates (Cnt’d) 

Drug interactions:  Myopathy  gemfibrozil and fenofibrate  Gemfibrozil inhibits glucuronidation of statins↑

level of statins  Plus  competitive inhibition of CYP3A4↓ statin metabolism  Risk of rhabdomyolysis with Gemfibrozil+statin 10-15X more than Fenofibrate+statin

Ref: clinical neurotoxicology: Syndromes,Substances,environments; Micheal R. Dobbs;1st edition 2009; section 4 part B; page 387

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Clinical trials

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Thank you , Questions/comments

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