Metabolism of lipoproteins Dyslipidemias - III. SZ. · PDF file · 2013-02-25 Hyperlipidemias secondary 95% (other causes) primary 5% (familial & genetic) Secondary dyslipidemias

Metabolism of lipoproteins

Dyslipidemias

Covered topics:

• Lipoproteins and atherosclerosis

• Pathways of lipoprotein-metabolism

• Primary dyslipidemias

• Secondary dyslipidemias

• Treatment of dyslipidemias

• Dyslipidemias and cardiovascular risk

CHD mortality

Atherosclerosis

Libby P, Circulation. 1995;91:2844-2850.

– T-lymphocyte

– macrophage-derived foam cell (tissue factor+)

– activated SMC in the intima (HLA-DR+)

– normal SMC in the media Stable plaque

Vulnerable plaque

Atherosclerotic plaques

6

Convetional risk factors:

• atherogenic dyslipidemia

• hypertension

• smoking

• diabetes mellitus and insulin resistance

• obesity, leptin

• homocysteine

• genetical factors (familial/inherited diseases)

Atherosclerosis

25 year CHD risk in different countries

Cholesterol and CHD

Cholesterol and CHD

Lipoprotein-metabolism

Lipoprotein-metabolism

Cholesterol:

• structural component of cell membranes

• synthesis of colic acid and steroid hormones

• sorms cholesterol esters with fatty acids

Triglycerides:

• glicerine and 3 fatty acid chains

• main molecule for energy storage

Phospholipids:

• phosphoric acid instead of the third fatty acid chain

• structural component of cell membranes

Lipoproteins

Lipoprotein subclasses

Exogenic pathway of lipoprotein-metabolism

Endogenic pathway of lipoprotein-metabolism

HDL and reverse

cholesterol

transport

Metabolism

of LDL

Lipoproteins and atherosclerosis

hydrophobic

core

ApolipoproteinAI

hydrophylic

surface

human

paraoxonase-1

LCAT,

CETP,

PAFAH

Antioxidant enzymes of HDL

High density lipoprotein and

atherosclerosis

• Reverse cholesterol transport

• Maintenance of endothelial function

• Protection against thrombosis (Apo A-I inhibits generation of calcium-induced procoagulant activity on erythrocytes by stabilizing cell membrane)

• Low blood viscosity via permitting red cell deformability

• Anti-oxidant properties (human paraoxonase)

Key enzymes and cofactors in lipid metabolism

• HMG-CoA reductase: reduces HMG-CoA to mevalonic acid in the rate-limiting step of cholesterol biosynthesis (mainly liver and intestine)

• LPL (lipoprotein lipase): digests TG core of chylomicron and VLDL

• HL (hepatic lipase): conversion of IDL to LDL

• CETP (cholesterol-ester transfer protein): transfers cholesteryl esters from HDL to other lipoproteins in exchange for TG

• LCAT (lecithin:cholesterol acyl transferase): conversion of cholesterol to cholesterol esters

http://content.onlinejacc.org

Key enzymes and cofactors in lipid metabolism

• Apolipoprotein A: major protein of HDL activating many reactions (e.g. reverse cholesterol transport)

• Apolipoprotein B: major structural protein of VLDL, IDL, and LDL, binds to hepatic LDL-R

• Apolipoprotein CII and Apolipoprotein E: obtained from HDL by CMC and VLDL for activation of LPL and receptor recognition respectively

Primary dyslipidemias

Frederickson’s classification of dyslipidemias (fasting sample, 12 h at 4 °C, Chol- and Tg-content)

N I IIa IIb III IV V

Etiological classification of dyslipidemias

Dyslipidemia type I (exogenic hypertriglyceridemia, familial hyperchylomicronemia,

Bürger-Grütz syndrome)

• Et: decreased activity of lipoprotein lipase, or decreased ApoCII (activator of LPL)

• Symptoms: – abdominal cramps after meals

– enlarged liver and spleen

– eruptive xanthomas

– retinal lipemia (shiny, white retinal vessels)

– pancreatitis

• Dg: – lipemic serum

– high serum triglyceride (Tg>10 mmol/L) with normal or moderately elevated serum cholesterol

– intensive chylomicron line in lipid elfo

• Treatment: – diet with lipid restriction (10-20 g/day)

– moderate-length chain triglycerides (MCT)

– plasmapheresis (danger of pancreatitis)

– substitution of ApoCII with FFP

Lipemic serum • store for 24 hs at 4 °C • chylomicron layer

appears on top • clear infranatant

Lipemic serum • at room temperature

• opalescent

Normal serum • at room temperature

• clear

Symptoms of

hyper-

triglyceridemia:

eruptive

xanthomas

Type IIa dyslipidemia

(essential/familial hypercholesterolemia, familial xanthomatosis)

• Et: lack or abnormality (Goldstein) of ApoB/E-binding LDL-receptor (LDL-R) resulting in increased hepatic cholesterol-synthesis – homozygous (1/1 million births, Chol:12-25 mmol/l) or

– heterozygous (1-2/1 thousand births, Chol:9-11 mmol/l)

• Symptoms: – tendon xanthomas, xanthelasmas

– corneal arcs (in young patients)

– early myocardial infarcts, sudden cardiac deaths

– aortic and supravalvular stenosis

– often die before the age of 20

– family history is usually + for premature CHD

• Dg: isolated elevation of LDL, genetic or cellular confirmation

• Th: – homoz.: combined therapy, liver transplantation, weekly LDL-

apheresis

– heteroz.: statins, resins, ezetimibe

• Et: the normal LDL-R cannot recognize

the defective ApoB

• Dg:

– Normal elimination of IDL result in

less severe hypercholesterolemia

– tendon xanthoma is less common

Type IIa dyslipidemia (familial defect of ApoB)

Symptoms of

hyper-

cholesterolemia:

palpebral

xanthelasma

Symptoms of

hyper-

cholesterolemia:

tendon

xanthoma

tuberous

xanthoma

Type IIa dyslipidemia (primary polygenic increase of LDL)

• Etiology: heterogenous: VLDL or LDL metabolism: • elevated TG and Chol

• elevated LDL

• isolated hypertriglyderidemia (rise in VLDL)

• overproduction of ApoB100/decreased LDL-R activity

– prevalence: 1-2%

– only 10% of 1st degree relatives are involved

– association with metabolic syndrome (LDL phenotype B, increased Tg, decreased HDL-C=atherogenic dyslipidemia)

– diet rich in saturated fat and cholesterol and

– lack of physical activity is common

• Symptoms: – xanthomas are less common

– xanthelasmas can appear

– lower risk of coronary heart disease

• Dg: Chol: 6.5-9 mmol/L

R K 13 years old

• Complaints: xellow papules appear in the corner of both

eyes and the insides of knees and elbows xanthelasma!

• Lab: – Chol:12.88 mmol/L

– LDL-C:10.83 mmol/L

– Tg:0.51 mmol/L

– VLDL:0.23 mmol/L

– TSH:norm., CK:norm

• Dg: Heterozygous dyslipidemia type II/a

• Family screening: – mother and younger sister have normal lipids

– father is not available

• Treatment: – diet

– cholestyramine 12 g/day

– later simvastatin (10-20-40 mg/day)

• Control lab: – Chol:8.62 mmol/L

– LDL-C:6.94 mmol/L

– Tg:0.89 mmol/L

– VLDL:0.4 mmol/l

• Further treatment: ezetimibe instead of cholestyramine?

Familial combined dyslipidemia

(type IIa, IIb, IV, and V) • Et: – genetical defect is

not known

– prevalence: <2% (in the USA)

• Dg: – usually manifests in

the adulthood

– Chol<9 mmol/L – no tendon xanthoma

– xanthelasmas, and corneal arcs can be present

– increased risk of early CHD

– Tg: 2,3-12 mmol/L – low HDL-C

– accompanied by hypertension, obesity, or diabetes mellitus

• Th: – change of lifestyle is important

Type III dyslipidemia (remnant particle disease, familial dysbetalipoproteinemia, broad

beta disease, floating beta disease)

• Et: Structural defect of ApoE (ApoE2)

– prevalence: 0.25-2% of primary dyslipidemias

– homozygous: 1%

– heterozygous: 8%

– manifests when another metabolic defect is present (obesity, diabetes, hypothyreosis) → phenotype: 0,02%

• Dg: – Derfective ApoE → decreased binding to hepatic receptors →

Chylomicron- and VLDL-remnants are increased

– flat palmar xanthomsa (xanthoma striatum palmare)

– tuberous xanthoma

– tuboeruptive xanthoma

– Chol and Tg: 9-14 mmol/L – early atherosclerosis

• Th: – good reaction to diet and fibrates

palmar xanthoma

Type IV dyslipidemia (familial hypertriglyceridemia, carbohydrate-induced

hyperlipoproteinemia, endogenous hypertriglyceridemia)

• Dg:

– increased Tg with normal Chol

– large, Tg-rich VLDL

– xanthomas are rare

– opalescent serum without chylomicron-layer

– risk of CHD is usually not increased

– diabetes, obesity, goiter

– female with Tg>3.4 mmol/L → estrogen th/pregnacy → Tg-increase

→ acute pancreatitis

• Th:

• in case of normal LDL-C and HDL-C, family history without early

atherosclerosis, medical treatment is not necessary

• change of lifestyle (physical activity, weight loss, native sugar-

free diet) is useful

Type V dyslipidemia

(familial hypertriglyceridemia)

• Et: – fat- and carbohydrate-induced, endogenous and

exogenous hypertriglyceridaemia – decreased activity of LPL with type IV genetical

defect, or defective ApoCII/ApoCIII

– normal production of ApoB100, Tg-righ VLDL → large, loose VLDL

• Dg:

– increased Tg – combination of type I and IV: opalescent serum and

chylomicron layer

– manifests when another metabolic defect is present (obesity, diabetes, decreased physical activity)

– risk of acute pancreatitis is lower than in type I

– risk of CHD is usually not increased

• Th: change of lifestyle is useful

eruptive xanthoma

Small, dense LDL (LDL phenotype B) • Dg: ELFO with LDL-subclassifcation

• Pg: direct association: – longer residence time in plasma than normal sized LDL

(decreased recognition by receptors in liver)

– more susceptible to oxidation due to decreased antioxidants in the core→increased modification (e.g. glycation, oxidation, homocysteinylation)

– normal LDL-C can mean many sdLDL-particles and high atherogenity → ApoB100 measurement is important (but non-HDL is cheaper)

– enter and attach more easily to arterial wall

– endothelial cell dysfunction

– enhanced interaction with scavenger receptor promoting foam cell formation

indirect association: – inverse relationship with HDL

– marker for atherogenic Tg-remnant accumulation

– insulin resistance and postprandial hyperlipidemia can accompany

– sdLDL can be present in secondary dyslipidemias (type 2 diabetes, chronic renal disease)

Increased risk of CVD!

Familial hypoalphalipoproteinemia

• Et:

– more common in males, manifests after menopause in

females

• Dg:

– low HDL

– decreased alpha-lipoprotein in ELFO

– increased risk of CHD (in most cases)

• Th:

– change of lifestyle (physical activity, weight loss,

cessation of smoking) is useful

– limited increase with currently available medication

(fibrates, nicotinic acid)

Increased Lp(a) Pg: – specialized LDL (Apolipoprotein(a) bound to ApoB)

– structural similarity to plasminogen→ interferes with fibrinolysis

– induces macrophage binding and cholesterol deposition

Dg: ELISA – most common inherited abnormality in

patients who survived a myocardial infarct

– association with premature CHD, complex coronary lesions and unstable angina

– possible role in target organ damage in HT

– independent risk is difficut to determine (recurrent MI is less frequent after LDL-C lowering; conflicting results)

Indications for screening: – CHD and no other identifiable dyslipidemia

– strong CHD family history and no other dyslipidemia

– HT and early premature target organ damage

– hypercholesterolemia refractory to statins and bile acid sequestrants

Th: – limited decrease with currently available medication

(nicotinic acid (38%), estrogen, apheresis), primary goal is LDL

www.drsarma.in

Hyperlipidemias

secondary 95%

(other causes)

primary 5%

(familial & genetic)

Secondary dyslipidemias

• Type 1 diabetes mellitus

– poor CH-control: increased VLDL-C and LDL-C,

decreased HDL-C (caused by increased lipolysis

in adipose tissue and increased FFA)

– good CH-control: no change

• Type 2 diabetes mellitus and metabolic

syndrome

– insulin-resistance

– decreased HDL, increased Tg, normal/elevated

LDL-C, sdLDL

K.A. • Complaints:

– polyuria, polydipsia, weight loss

– current weight: 85 kg, height: 165 cm

• Dg: – serum: lipemic, many parameters cannot be measured, glu 20

mmol/L, urine: glu:+, ket:-

• Th: diet (CH and fat restriction), human insulin 4x/day

• Control labs: – after 1 week: Chol:42 mmol/L, Tg:29 mmol/L, other lipid parameters

cannot be measured, GGT:1805 U/mL, normal lipase, glu:15.8 mmol/L, HbA1c:13.8%, urine: glu:+, ket:-

– after 2 weeks: Chol:18 mmol/L, Tg:8.3 mmol/L, LDL-C 12.4 mmol/L, VLDL-C:4,7 mmol/L, GGT:655 U/mL, glu: 11.9 mmol/L, urine: glu:-, ket:-

• One more week later: – Chol:6.2 mmol/L, Tg:0.85 mmol/L, HDL-C:1.2 mmol/L, LDL-C: 4.6

mmol/L, VLDL-C:0.4 mmol/L, GGT:73 U/mL, glu:8.72 mmol/L, urine: glu:-, ket:-

• Th: statin is started

• Currently: – Chol:4.8 mmol/L, Tg:0.7 mmol/L, LDL-C:3.1 mmol/L, VLDL-C 0.5

mmol/L, HDL-C 1.2 mmol/L, HbA1c:6.7%


• Hypothyreosis:

– type IIa dyslipidemia: increased LDL-C and Chol

– decreased synthesis and activity of LDL-R

• Alcoholism:

– increased Tg and HDL(!), high GGT

– increased etanol- and FA-oxidation→increased

Tg-synthesis

– increased activity of LPL

• Zieve-sy.:

– icterus

– hemolytic anemia

– dyslipidemia

Mrs Cs. S. (55 y)

• Complaints 9 years ago: weight gain

• Dg: hypothyreosis

• Th: 50 µg L-thyroxin, stopped taking it 5 years ago

• This year: hypercholesterolemia diagnosed during routine screening, took statins

• ECG: sinusbradycardia

• Current labs: Chol:10.2 mmol/L, Tg:2 mmol/L, HDL-C:2.3 mmol/L, CPK 1098 U/l

• TSH:100 mU/L, FT4:1.4 pmol/L, FT3:0.2 pmol/L

• Th: L-thyroxin

Medications:

• Thiazides: increase Chol and Tg

• Beta-blockers (without ISA): increase Tg and

decrease HDL-C

• Alpha-blockers: decreace Chol

Liver disease:

• PBC and other obstructive liver diseases: high Chol (high

LpX)

Pregnancy:

• high Chol and Tg

• estrogen increases VLDL-C (decreased hepatic lipase

activity)

• diet is necessary when primary hypertriglyceridemia is

also present


Chronic renal failure:

• nephrosis-syndrome: proteinuria → hypalbuminemia → increased synthesis/decreased breakdown of lipoproteins

(including ApoB) → hyperlipoproteinemia (OR 5.5 for MI and 2.8 for coronary death) → can increase progression of glomerular disease!

• other causes of CRD:

– type IV dyslipidemia is the most common

– LPL-, and HL-activity is decreased, ApoCIII increased

– decline in HDL

– elevated lipoprotein(a )

– increased oxLDL

• dialyzed patients: Lp(a) increases after hemodialysis


54

healthy chronic renal

disease

LDL

HDL

VLDL

Lp(a)

sdLDL

piHDL

VLDL

Lp(a)

oxLDL

Diagnosis of dyslipidemias:

measurement of serum lipids

• 12 h fasting+48 h abstinence is necessary (postprandial

increase of chylomicron and IDL interferes)

• in case of normal/near normal Tg, LDL can be calculated

(Tg:Chol ratio in VLDL~2.2:1)

• the Friedewald equation:

LDL-C=Chol–HDL-C–(Tg/2.2) (mmol/L)

• can be used if Tg<4.5 mmol/L

• direct determination of LDL-C is more precise (e.g.

immunological determination)

• acute phase response (i.e. MI, surgical trauma or infection)

can reduce levels of Chol, HDL-C, LDL-C, ApoA+B through

impairment of hepatic lipoprotein production and

metabolism, and raise Lp(a), Tg

• lipoprotein analysis should be done one month after event

Diagnosis of dyslipidemias: screening

• To exclude/confirm primary dyslipidemias lipid profile around 20 years is useful

• Adult Treatment Panel III (NCEP): repeat at least once in 5 years – if non-fasting obtained and Chol is higher or HDL is lower:

fasting profile is recommended

– if no known CHD and serum LDL is normal re-screen in 5 years

– borderline high cholesterol and <2 risk factors: re-screen in 1-2 years

• Differential diagnosis: – primary or secondary dyslipidemia?

– background?

Treatment of dyslipidemias

Treatment of

dyslipidemias:

lifestyle changes

• nutrition

• cessation of

smoking is also

important!

• fat intake<30% of kcal

• cholesterol<300 mg/day

• kcal<needed to maintain current weight (usually 1500 kcal) until ideal weight is reached

• soy, garlic, margarine, green tea, nuts: modest LDL-C-decrease

Effect of LDL-C lowering in 6-12 months!

Treatment of dyslipidemias:

physical activity (until loss of breath/sweating)

Adverse CV effects of increased body weight

Source: ESC guirelines

Decrease in VLDL, Tg, and increase in LDL size (reduction in CETP, elevation in LCAT, reduced hepatic lipase and elevated LPL activity, effect on LDL particle size)


medication • Statins (HMG-CoA-reductase inhibitors – rate limiting

enzyme in Chol biosynthesis): decrease Chol-synthesis in the liver→expression of LDL-R→serum LDL-C decreases

• most powerful for lowering LDL cholesterol

• modest effect on raising HDL

• reduction of Tg due to decreased VLDL synthesis and clearance of VLDL remnants by ApoB/E-(LDL-)receptors

• reduction of oxidized and small dense LDL-subfractions and reduction of remnants (reduction of CE -transfer from LDL to VLDL)

Comparable efficacy of statins

Special considerations:

• no renal dosing: atorvastatin and fluvastatin

• chronic liver disease: pravastatin and rosuvastatin

• less drug interactions: pravastatin, fluvastatin, rosuvastatin

(not metabolized via CYP3A4)

• less muscle toxicity: pravastatin and fluvastatin

• cost-effectiveness: rosuvastatin, atorvastatin, fluvastatin

Number of patients needed to treat

4S secondary prevention

simvastatin 20/40 mg

CHD event and death:

10

CARE secondary prevention

pravastatin 40 mg

fatal and non-fatal CHD events:

33

WOSCOPS primary prevention

pravastatin 40 mg

fatal and non-fatal CHD events:

48

AFCAPS/TexCAPS primary prevention

lovastatin 40 mg

first major CHD event:

58

FIELD primary prevention

fenofibrate 200 mg

total of CHD events:

50

• regression of atherosclerosis

• plaque stabilization

• reduced inflammation

• decreased thrombogenity

• reversal of endothelial dysfunction

• reduced monocyte adhesion to endothelium

• reduced oxidative modification of LDL

• increased mobilization and differentiation of endothelial progenitor cells leading to new vessel formation

Time course of statin effects

days years

LDL-C lowered

inflammation reduced

vulnerable plaques

stabilized

endothelial function restored

ischemic episodes reduced

cardiac events reduced

Side effectgs of statins: generally well tolerated

• Main side effect of statins: myalgias (2-11%), myositis (0,5%), rhabdomyolysis (<0,1%) after <4 months (shold normalize in days-1 month) → Monitor CPK!

– hypothyreosis may cause hypercholesterolemia and increase CPK! → If the underlying cause of hypercholesterolemia is not diagnosed and statin is adminstered, increased CPK may be mistaken for statin-induced myopathy!

– some drugs increase the risk of statin-induced myopathy (Cyp3a4 inhibition/ other mechanism)

– increased risk in ARF/CRF, obstructive liver disease


Side effects of statins:

• liver enzymes – 0.5 to 3% persistent elevations in amino-transferases in first 3

months (dose-dependent?)

– randomized trials: no difference compared with placebo

– clinically significant liver disease is extremely rare

– routine control of liver enzymes is currently not advised

• CNS – case reports of memory loss (lipophilic statins)

– not reported with hydrophilic statins (prava/rosuva)

– no significant difference with placebo in trials

• statins’ ability to decrease CVD-risk exceeds the benefit of LDL-lowering – decreases endothelial

dysfunction

– decreased vascular pleiotropic effects inflammation

– antithrombotic effect


Treatment of dyslipidemias: medication

• Statins (HMG-CoA-reductase inhibitors): decrease Chol-synthesis in the liver→expression of LDL-R→serum LDL-C decreases

• Fibrates:

– increase LPL-activity, PPAR-alpha agonist→secretion of VLDL is decreased, clearence is increased, Tg decreases (35-50%);

– stimulation of ApoAI,II-synthesis, increased transfer of apo AI with diminished cholesterol transfer from HDL to VLDL→HDL-C increases (15-25%)

– increases LDL buoyancy

– improve endothelial function pleiotropic effects?

– favorable effect on macrophage responses

Agents:

– gemfibrozil (11% raise in HDL, modest LDL- reduction, can increase LDL in pure hypertriglyderidemia)

– fenofibrate (better for LDL-lowering)



• Fibrates: side effects:

– gallstone-formation

– dyspepsia, diarrhea, nausea, vomiting, abdominal pain, eczema, rash, vertigo and myalgias

– adverse drug interaction • gemfibrozil: inhibits glucuronidation of

lipophilic statins and increases levels→ increased risk of myopathy

• gemfibrosil decreases warfarin by 30%

• fenofibrate: decreases cyclosporin levels PPAR: peroxisome proliferator activator receptor



• Fibrates: increase LPL-activity, PPAR-alpha agonist→Tg decreases , HDL-C increases

• Resins (bile acid sequestrants): binds colic acids in the small intestine→enterohepatic circulation is interrupted→Chol-synthesis decreases→increased Chol-uptake into cells→decreased serum LDL-C (10-30%) + intestinal formation of nascent HDL

Available agents: cholestyramine, colestipol, colesevelam

Adverse effects usually limit use: – GI (nausea, bloating, cramping: least with colesevelam)

– increased liver enzymes

– drug interactions (impair absorption of digoxin, warfarin, fat soluble vitamins)

– contraindications: pts with elevated TG

Bile acid resins: mechanism of action

net effect: LDL-C

gallbladder

LDL-receptors

VLDL -and LDL- removal

Chol-7- hydroxylase

conversion of Chol to BA

BA secretion

liver

BA excretion

terminal ileum

bile acid

enterohepatic

recirculation

reabsorption of

bile acids

Treatment of dyslipidemias: medication • Statins (HMG-CoA-reductase inhibitors): decrease Chol-

synthesis in the liver→expression of LDL-R→serum LDL-C decreases


• Resins: binds colic acids→enterohepatic circulation is interrupted→Chol-synthesis decreases→increased Chol-uptake into cells→decreased serum LDL-C

• Nicotinic acid: decreases lipolysis and VLDL-synthesis, decreases Chol-transfer from HDL to VLDL→serum Tg and VLDL decreases, HDL-C increases, LDL-size increases, fibrinogen decreases Immediate, or sustained release (Niacor, Niaspan) Side effects usually limit use: +outcomes didn’t improve!

– flushing (less common with controlled release, less with ASA)

– nausea, paresthesias, pruritis (20% each)

– elevation of liver enzymes, possible hepatotoxicityi

– insulin resistance, worsening hyperglycemia

– hyperuricemia

– hypotension in combination with other vasodialtors (increases unstable angina)

Nicotinic acid: mechanism of action

liver circulation HDL

serum VLDL

results in

reduced lipolysis

to LDL

serum LDL

VLDL

NA decreases hepatic production of VLDL and of ApoB

VLDL-

secretion

ApoB

hepatocyte systemic circulation

mobilization of FFA

Tg-

synthesis

VLDL

LDL


• Ezetimibe: selective inhibitor of Chol-uptake from the small intestine (Niemann-Pick C1 like protein involved) →enterohepatic circulation is interrupted→Chol-synthesis decreases→increased Chol-uptake into cells→decreased serum LDL-C (15-20%), little effect on HDL and TG Adverse effects are rare, higher incidence of myopathy and elevated liver enzymes when given with a statins No definite clinical outcome studies available




• Resins: binds colic acids in the small intestine→enterohepatic circulation is interrupted→Chol-synthesis decreases→increased Chol-uptake into cells→decreased serum LDL-C

• Nicotinic acid: decreases lipolysis and VLDL-synthesis→serum triglyceride and VLDL decreases, HDL-C increases

• Ezetimibe: selective inhibitor of Chol-uptake from the small intestine→enterohepatic circulation is interrupted→Chol-synthesis decreases→increased Chol-uptake into cells→decreased serum LDL-C

• Fish oil (rich in omega-3 FA): promote intracellular breakdown of Apo-B100→decreased secretion of VLDL→plasma VLDL decreases, (possibly decreases small LDL by inhibiting CETP), lower risk of coronary events, GI side effects)

• Up to 70% decrease in LCL-C and Chol can be achieved with the initial statin dose

• Further 6-6% decrease can be achieved with the doubling of the dose, but side effects increase

• Addition of ezetimibe can achieve further 25% decrease (3x dobuling the statin can achieve only 18%!)

• Dual inhibition (statin + ezetimibe) can total to 60% LDL-C lowering

• LDL-apheresis can be an option in very severe cases (e.g. homozygous FH)


Cs.M. 50 year old male

• Family history: – father: type 2 diabetes

– mother: hyperlipoproteinemia, multiple times acute pancreatitis, diabetes treated with insulin

• Previous diseases: – 14 years ago: hyperlipoproteinaemia

– 8 years ago: acute necrotizing pancreatitis, partial pancreatectomy, inzulin dependent diabetes

• Currently: – weight:110 kg

– height=176 cm

– BMI=35.5 kg/m2

– WHR=124 cm/116 cm=1.07

Treatment: acipimox + gemfibrozil/ciprofibrate/fenofibrate +

simvastatin/atorvastatin + ezetimibe

ICT (Actrapid/Insulatard→Humalog/HumulinN→Humalog/Lantus)

2002.

03.

2002.

03.

2004.

06.

2004.

10.

2005.

02.

2005.

11.

2005.

12.

2006.

03.

2006.

05.

hbA1c 10.19 9.48 9.05 9.24 9.61 9.16 9.01 9.1

Chol

12.58 6.09 15.45 7.57 8.52 8.17 4.42 4.87 4.49

Tg 39.77 10.75 34.15 10.8 8.55 8.67 9.27 7.83 5.44

HDL-C

1.64 1.05 2.65 0.83 0.93 0.97 0.87 1.04 0.89

LDL-C - - - 3.22 4.04 4.09 2.1 1.9 1.83

VLDL-C - - - 3.52 3.4 3.45 3.6 2.9 2.6

Cs.M. 50 year old male

Cardiovascular risk assessment (influencable+non-influencable)

• CHD equivalents:

– carotid artery disease

– peripheral arterial disease

– abdominal aortic aneurysm

– diabetes mellitus/metabolic syndrome

– multiple risk factors that confer a 10-year risk of CHD > 20%

• Identify major risk factors other than LDL:

– smoking (OR 3.6-6.7, with DM OR 2.64)

– HT (BP>140/90 or on anti-hypertensive medication) (OR 2.69)

– low HDL <40 mg/dL

– family history of premature CHD (CHD in men 1st degree relative <55; women <65 years old)

– age (men >45; women >55)

• Other potential risk factors

– chronic renal insufficiency (GFR <60)

– obesity (OR 1.62), physical inactivity, impaired fasting glucose, CRP

• HDL >1,5 mmol/l is protective

• if patient without CHD or equivalent has 2 or more major risk factors, then calculate the Framingham risk (age, Chol, HDL-C, smoking, HT)

Pais P: Lancet, 1996, 348, 358-363.

Framingham CHD

predictor:

• good in white and

black population

• overestimates

risk in asian,

hispanic, and

native American

population

SCORE: 10 year risk of

fatal CVD in contries at

high CV risk

Number of risk factors and CHD

Dyslipdemia in CHD

Lipid markers of

atherosclerosis

Decrease in deaths from CHD attributed to treatments and risk factor changes

Guideline recommendations vs. achievements in patients with established CHD

Low risk

• isolated hypercholesterolemia alone, or with 1 more risk factor

• coronary risk<10%/10 years

• fatal cardiovascular risk<3%/10 years

• after lifestyle changes, initiation of medical treatment is advisable:

– Chol>=6.5 mmol/L

– LDL-C>=4.0 mmol/L

– Tg>=4.5 mmol/L

Medium risk

• hypercholesterolemia with two or more risk factors

• coronary risk:10-20%/10 years

• fatal cardiovascular risk:3-4%/10 years

• after lifestyle changes, initiation of medical treatment is advisable:



– Tg>=2.3 mmol/L

High risk

• cerebrovascular, cardiovascular, or

peripheral vessel-disease (>50% decrease

is necessary to see plaque regression)

• diabetes mellitus (type 2, or type 1 with

micro/macroalbuminuria), (or metabolic syndrome)

• other high risk condition: (a) one serious risk factor

+ Chol>8 mmol/L, RR>80/110 Hgmm, BMI>40 kg/mm2,

ankle/brachial index=<0.9, GFR<60 ml/min,

microalbuminuria (30-300 mg/l), arterial plaque; (b) two

or more of the following risk factors: Lp(a)>= 30 mg/dL,

RP>=3 mg/L, homocysteine>=12 μmol/L, familiarity and

presence of atherogenic genes; (c) SCORE mortality

risk>=5%/10 years, or Framingham risk of CHD>20%/10

years

High risk

• after lifestyle changes,

initiation of medical treatment is advisable:



– Tg>=1.7 mmol/L

Very high risk (CVD+diabetes mellitus/

smoking/metabolic

syndrome/ACS/CRD/PVD)

• after lifestyle changes,

initiation of medical treatment is advisable:



– Tg>=1.7 mmol/L


Source: ESC guirelines

Elderly patients: underutilization of lipid-lowering drugs due to: • concern for safety (hepatic/renal impairment)

• time-course to benefit

• evidence-bases studies showed benefits!

• Primary aim: LDL-C(+ApoB) lowering (in DM as well)

– statins are first choice, ezetimibe can be added (variable drug response depending on endogenous v. exogenous hypercholesterolemia)

• Secondary aim: non-HDL-C (LDL-C+0.8 mmol/l) lowering if Tg is still high

– statins and ezetimibe, fish oil may be an option

• Tertiary aim: HDL-C increase, Tg lowering (limited medication for HDL) (important in DM and MS)

– fibrates, nicotinic acid may be an option


- DM: diet, metformin,TZD (insulin senzitizers), insulin

- CRF: hydrophylic statins (atorva/rosuva)+low protein-diet, ACEI/ARB

(decrease protein excretion), EPO

- HT: ACEI, indapamide

Intervention strategies as a function of CV risk and LDL-C

The dyslipidemic triad

isolated High LDL 32.90%

isolated low HDL 21.35%

isolated high TG 10.45%

Hypertriglyceridemia • evidence-based studies (Helsinki

Heart Study,VA-HIT ): elevated Tg is an independent risk factor for CHD

• normal<1,7 mmol/L very high>6 mmol/L

• dentify those with hyperchylomicronemia: Tg>100 mmol/L, eruptive xanthomas, pancreatitis

• familial hypertriglyceridemia: 1.7-6 mmol/l, or combined hyperlipidemia

• find+treat secondary causes:

– obesity

– DM

– nephrotic syndrome

– hypothyroidism

– estrogen replacement

– beta blockers

– glucocorticoids, cyclosporin

• Treatment :

after achievement of LDL-C goal:

– 1.7-2.3: weight reduction and physical activity

– 2.3-6: non-HDL second target, pharmacologic Th for those with CHD or at high risk

– >6: prevention of pancreatitis with non-pharmacologic and pharmacologic therapy (fibrates can be started before statins)

– isolated Tg-elevation: Th indications:

• overt CHD

• strong family history of CHD

• multiple cardiac risk factors

– statins (atorva/rosuva) if LDL-C is elevated

– fibrates or nicotinic acid

– add fish oil (refractory cases)

Treatment of isolated low HDL-C Evidence-based studies:

• Framingham Heart Study: MI risk increases when HDL decreases

• LIPID and CARE trials: increase in HDL-C, can decrease event rate more in case of low LDL-C than in case of high LDL-C

• VA-HIT trial: reduction in MI and CHD death with serum HDL achieved with gemfibrozil simvastatin+niacin: higher reduction in events achieved than statin-only trial

Expolre:

• familial history of premature CHD is helpful in differentiating high from low risk patients with low HDL

• Differentiate causes!

– familial forms

– elevated CETP-activity (decreased CHD-risk!)

– LPL-deficiency

– elevated HL-activity

– LCAT-deficiency

– insulin-deficiency

– drugs (beta blockers, benzodiazepines, anabolic steroids)

Treatment:

• Weight management, exercise, smoking cessation

• Medical treatment indications of isolated low HDL:

– CHD OR CHD equivalent

– first-degree relative with early onset CHD and similar lipid profile

• fibrates+/-niacine

• CETP-inhibitors (i.e. torcetrapib) (some: worse outcomes!)

Evolving Methods of Risk Assessment • Chol/HDL-C ratio:

– ratio <4.0 advocated by some guidelines

– aggressive lowering of LDL-C vs. raising HDL-C

– better epidemiologic predictor of CV events than LDL-C, but no

trials based on this ratio

• non-HDL-C=Chol-HDL-C

– includes all atherogenic Chol (LDL, Lp(a), IDL, VLDL)

– stronger predictor of CVD than LDL-C

– secondary target in patientes with high triglycerides (ATP III)

– goal 0,8 mmol/L LDL-C goal

• apolipoprotein measurement

– ApoB/ApoAI: better predictor of CV-events than LDL-C, Chol/HDL-C

– most useful in hypertriglyceridemic patients (elevated ApoB)

– not universally available, much more expensive

• hsCRP

– intensity of atherosclerotic process

– useful in patients with intermediate risk (10-20%)

– questionable correlation with LDL-C

• Can risk assessment be improved by novel risk measures to indicate

patients at higher risk who benefit from more aggressive intervention?

•To what extent should plasma levels of LDL-C be lowered to reach

optimal risk reduction?

Thank You for Your attention!

Documents

Metabolism of lipoproteins Dyslipidemias - III. SZ. · PDF file · 2013-02-25 Hyperlipidemias secondary 95% (other causes) primary 5% (familial & genetic) Secondary dyslipidemias