Focus on triglycerides

Focus on Focus on TriglyceridesTriglycerides

Dr. Sachin Verma MD, FICM, FCCS, ICFCDr. Sachin Verma MD, FICM, FCCS, ICFCFellowship in Intensive Care MedicineFellowship in Intensive Care Medicine

Infection Control Fellows Course Infection Control Fellows Course Consultant Internal Medicine and Critical CareConsultant Internal Medicine and Critical Care

Ivy Hospital Sector 71 MohaliIvy Hospital Sector 71 MohaliWeb:- Web:- http://www.medicinedoctorinchandigarh.com

Mob:- +91-7508677495Mob:- +91-7508677495

Lipoprotein Classes and InflammationLipoprotein Classes and Inflammation

Doi H, et al. Circulation. 2000;102:670-676; Colome C, et al. Atherosclerosis. 2000;49:295-302; Cockerill GW, et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994.

HDLHDLLDLLDLChylomicrons, VLDL, Chylomicrons, VLDL, and their catabolic and their catabolic

remnantsremnants

> 30 nm> 30 nm 20–22 nm20–22 nm

Potentially proinflammatoryPotentially proinflammatory

9–15 nm9–15 nm

Potentially anti- Potentially anti- inflammatoryinflammatory

Classification of Lipids and LipoproteinsClassification of Lipids and Lipoproteins

Chacteristics of LipoproteinsChacteristics of Lipoproteins

Triglyceride rich LipoproteinsTriglyceride rich Lipoproteins

Structure of LDL and HDLStructure of LDL and HDL

Hydrophobic CoreHydrophobic Coreof Triglyceride and of Triglyceride and Cholesteryl EstersCholesteryl Esters

LDL

Hydrophobic Core of TriglycerideHydrophobic Core of Triglycerideand Cholesteryl Estersand Cholesteryl Esters

Surface Monolayer of Phospholipids Surface Monolayer of Phospholipids and Free Cholesteroland Free Cholesterol

Apo A-IIApo A-II

Apo A-IApo A-I

Surface Monolayer of Phospholipids Surface Monolayer of Phospholipids and Free Cholesteroland Free Cholesterol

HDL

Digestion and Metabolism of Digestion and Metabolism of Dietary FatDietary Fat

Reverse Cholesterol TransportReverse Cholesterol Transport

BloodBloodBloodBloodPeripheralPeripheralTissuesTissues

PeripheralPeripheralTissuesTissues

LiverLiverLiverLiver

BileBileExcessExcessCholesterolCholesterol

Reverse Cholesterol TransportReverse Cholesterol Transport

Cholesterol Catabolism into Bile SaltsCholesterol Catabolism into Bile Salts

CholateCholateCholateCholateCholesterolCholesterolCholesterolCholesterol

CholesterolCholesterol77-hydroxylase-hydroxylase

CholesterolCholesterol77-hydroxylase-hydroxylase

HOHOHOHO

OHOH

COO -COO -

OHOH

Bile salts are the breakdown products of cholesterol. Their function is to transport cholesterol in the digestive system

LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyte IntestinalIntestinalLumenLumen

IntestinalIntestinalLumenLumen

Cholesterol AbsorptionCholesterol Absorption

Cholesterol

NPC1L1

CholesterylEster

ABCG5/G8

ACAT



Triglyceride AbsorptionTriglyceride Absorption

2 Fatty Acid

+Monoglyceride

DGAT

Triglyceride



Chylomicron FormationChylomicron Formation

CholesterylEster

CMapoB48

Triglyceride

Intestinal Cholesterol AbsorptionIntestinal Cholesterol Absorption

IntestinalIntestinalepithelial cellepithelial cell

LuminalLuminalcholesterolcholesterol

MicellarMicellarcholesterolcholesterol

BileBileacidacid

uptakeuptake

ABCG5ABCG8

Cholesteryl esters

ACAT

MTP

CM

(esterification)

excretion

Freecholesterol

CholesterolCholesterolTransporterTransporter

DietaryDietarycholesterolcholesterol

DietaryDietarycholesterolcholesterol

BiliaryBiliarycholesterolcholesterol

ThroughThroughlymphaticlymphatic

systemsystemto theto the liver liver

Lipoprotein MetabolismLipoprotein Metabolism

HDL is assembled through the combination of cholesterol, phospholipids, and apo A I, produced in the liver and gut. Cholesterol is incorporated in part by the action of the adenosine triphosphate-binding cassette-1 and is then esterified by lecithin CE transfer protein (LCAT) allowing HDL to enlarge into spherical HDL3 and HDL2. VLDL is secreted by the liver and processed on the vascular endothelium by LPL. LPL is activated by apo C II and inhibited by apo C III. CMs are secreted by the gut. Phospholipids released by lipolysis of both CM and VLDL contribute to the formation of small dense pre |[beta]| or discoidal HDL and the VLDL remnant particle is either taken up directly by the liver through the lipoprotein-like receptor or is transformed into LDL by action of CE transfer protein, exchanging the CE-rich core of HDL with VLDL TGs. CM remnants are taken up by the liver. TG-rich HDL is then processed by HL into smaller dense HDL. Mature HDL2 either transfers CEs to the liver by interaction with the scavenger receptor B-1 or transfers its CE-rich core to VLDL remnants creating LDL. Small dense pre |[beta]| or discoidal HDL is subject to accelerated degradation in part by the kidney.

The exogenous, endogenous, and reverse The exogenous, endogenous, and reverse cholesterol pathways.cholesterol pathways.

The exogenous pathway transports dietary fat from the small intestine as chylomicrons to the periphery and the liver. The endogenous pathway denotes the secretion of very low density lipoprotein (VLDL) from the liver and its catabolism to intermediate density lipoprotein (IDL) and low-density lipoprotein (LDL). Triglycerides are hydrolyzed from the VLDL particle by the action of lipoprotein lipase (LPL) in the vascular bed, yielding free fatty acids (FFAs) for utilization and storage in muscle and adipose tissue. High-density lipoprotein (HDL) metabolism is responsible for the transport of excess cholesterol from the peripheral tissues back to the liver for excretion in the bile. Nascent HDL-3 particles derived from the liver and small intestine are esterified to more mature HDL-2 particles by enzyme-mediated movement of chylomicron and VLDL into the HDL core, which is removed from the circulation by endocytosis.

Endogenous Lipid MetabolismEndogenous Lipid Metabolism

• In the liver, triglycerides (TGs), cholesteryl esters (CEs), and apolipoprotein B100 are packaged as very low density lipoprotein (VLDL) particles.

• TG is hydrolyzed by lipoprotein lipase (LPL) to generate intermediate density lipoprotein (IDL), which is further metabolized to generate low density lipoprotein (LDL).

• This particle can be removed by the liver or by peripheral cells. Cholesterol derived from LDL regulates several processes and can be used for the synthesis of bile acids, steroid hormones, and cell membranes.

Chylomicron Remnant MetabolismChylomicron Remnant Metabolism

Atherogenicity of TG-rich particlesAtherogenicity of TG-rich particles

Modulation of VLDLModulation of VLDL

Specific Dyslipidemias: Elevated Specific Dyslipidemias: Elevated TriglyceridesTriglycerides

Classification of Serum Classification of Serum TriglyceridesTriglycerides

Normal Normal <150 mg/dL<150 mg/dL Borderline highBorderline high 150–199 mg/dL150–199 mg/dL HighHigh 200–499 mg/dL200–499 mg/dL Very highVery high 500 mg/dL500 mg/dL

Causes of Elevated TriglyceridesCauses of Elevated Triglycerides

Obesity and overweightObesity and overweight Physical inactivityPhysical inactivity Cigarette smokingCigarette smoking Excess alcohol intakeExcess alcohol intake High carbohydrate diets (>60% of energy intake)High carbohydrate diets (>60% of energy intake) Several diseases (type 2 diabetes, chronic renal failure, Several diseases (type 2 diabetes, chronic renal failure,

nephrotic syndrome)nephrotic syndrome) Certain drugs (corticosteroids, estrogens, retinoids, Certain drugs (corticosteroids, estrogens, retinoids,

higher doses of beta-blockers)higher doses of beta-blockers) Various genetic dyslipidemiasVarious genetic dyslipidemias

Hypertriglyceridemia Increases CHD Hypertriglyceridemia Increases CHD Risk in Patients with Low HDL-C Risk in Patients with Low HDL-C LevelsLevels

* Bar represents 5% of subjects in which 25% of CHD events occurred. Assmann G, Schulte H. Am J Cardiol 1992;70:733–737.

24 31

116

245

0

50

100

150

200

250

5.0 > 5.0

*

LDL-C/HDL-C ratio

Inci

den

cep

er

1,0

00 (

in 6

years

) TG < 200 mg/dL

TG 200 mg/dL

Triglycerides as a risk factor for CHD Triglycerides as a risk factor for CHD Copenhagen Male StudyCopenhagen Male Study

4.6%

7.7%

11.5%

0

2

4

6

8

10

12

14

39-97mg/dl (n=982) 98-140 (n=973) >140 (n=951)

Am J Cardiol 1999; 83: 13F-16F

Triglyceride level(mg/dL)

Cum

ulat

ive

inci

denc

e of

CH

Dan

d al

l-cau

se m

orta

lity

N=2906; 8years

Triglycerides as a risk factor for CHDTriglycerides as a risk factor for CHD

Cumulative Incidence of MI

Cumulative Incidence of IHD

Triglycerides as a risk factor for CHDTriglycerides as a risk factor for CHD

Cumulative Incidence of Total Death

<130LDL-C

300

250

200

150

100

50

0

18

4338

4756

112 107

255

Elevated triglycerides: A synergistic risk Elevated triglycerides: A synergistic risk factorfactor

TG < 200 mg/dl

TG > 200 mg/dl

130-159 160-189 >190

CH

D c

ases

/ 10

00 in

8 y

ears

PROCAM Study: Incidence of coronary heart disease events according to serum LDL-C and triglyceride concentration

Global Cardiometabolic RiskGlobal Cardiometabolic Risk

TG and Metabolic SyndromeTG and Metabolic Syndrome

InsulinInsulin

ResistanceResistance

Hyper-Hyper-

insulinaemiainsulinaemia

HypertensionMicroalbuminuria

Centralobesity

Triglycerides

HDLcholesterol

Small dense LDL

Hyperuricemia

Prothrombotic state (fibrinogen,Factor VIIa,

fibrinolytic activity)

Impaired Glucose Tolerance

Type 2 DiabetesDiabetes Care 1998;21(2):310–314. Williams G, Pickup JC. Handbook of Diabetes. 2nd Edition, Blackwell Science. 1999.

Ethnic Variations in Lipid Parameters Ethnic Variations in Lipid Parameters

African-African- Non-HispanicNon-HispanicAmericansAmericans Hispanics Hispanics Whites Whites PP value value

N=N= 462 (27%)462 (27%) 546 (34%)546 (34%) 612 (38%) 612 (38%) < 0.001< 0.001

Total-C (mg/dL)Total-C (mg/dL) 212.5212.5 211.1211.1 213.2213.2 0.7820.782

LDL-C (mg/dL)LDL-C (mg/dL) 143.8143.8 139.4139.4 140.7140.7 0.4100.410

HDL-C (mg/dL)HDL-C (mg/dL) 47.047.0 42.342.3 44.044.0 < 0.001< 0.001

TG (mg/dL)TG (mg/dL) 102.1102.1 147.7147.7 134.0134.0 < 0.001< 0.001

LDL size (Å)LDL size (Å) 262.1262.1 257.6257.6 259.2259.2 < 0.001< 0.001

Haffner SM et al. Arterioscler Thromb Vasc Biol 1999;19:2234–2240.

Plasma Insulin and Triglycerides Predict Plasma Insulin and Triglycerides Predict Ischemic Heart DiseaseIschemic Heart Disease

Despres JP, et al. N Engl J Med. 1996;334:952-957.

>150 mg/dl

Triglycerides

0.0

2.0

4.0

6.0

8.0

Od

ds

Rati

o

<12 12-15 >15

F-Insulin (U/ml)

4.6

p=0.005

<150 mg/dl

1.0

1.5

5.3

p=0.001

p<0.001

6.7

5.4

p=0.002

Mechanisms Relating Insulin Resistance Mechanisms Relating Insulin Resistance and Dyslipidemiaand Dyslipidemia

Fat CellsFat Cells LiverLiver

InsulinInsulin

IRIR XX

FFAFFA



InsulinInsulin

IRIR XX

TGTG Apo BApo B VLDLVLDL

VLDLVLDL

FFAFFA

(hepatic(hepaticlipase)lipase)



KidneyKidney

InsulinInsulin

IRIR XX

(CETP)(CETP)

CECE


HDLHDL

TGTG

Apo A-1Apo A-1

FFAFFA

VLDLVLDL

(hepatic(hepaticlipase)lipase)



KidneyKidney

InsulinInsulin

IRIR XX

(CETP)(CETP)

CECE


(CETP)(CETP)

HDLHDL

(lipoprotein or hepatic lipase)(lipoprotein or hepatic lipase)

SDSDLDLLDLLDLLDL

TGTG

Apo A-1Apo A-1

TGTGCECE

FFAFFA

VLDLVLDL

Schematic SummarySchematic Summary

Schematic summary relating insulin resistance (IR) to the characteristic dyslipidemia of type 2 diabetes mellitus.

Schematic SummarySchematic Summary

The suppression of lipoprotein lipase and very-low-density lipoprotein (VLDL) production by insulin is defective in insulin resistance, leading to increased free fatty acid (FFA) flux to the liver and increased VLDL production, which results in increased circulating triglyceride concentrations. The triglycerides are transferred to low-density lipoprotein (LDL) and high-density lipoprotein (HDL), and the VLDL particle gains cholesterol esters by the action of the cholesterol ester transfer protein (CETP). This leads to increased catabolism of HDL particles by the liver and loss of apolipoprotein (Apo) A, resulting in low HDL concentrations. The triglyceride-rich LDL particle is stripped of the triglycerides, resulting in the accumulation of atherogenic small, dense LDL particles.

IncreasedIncreased

Dyslipidemia in DiabetesDyslipidemia in Diabetes

DecreasedDecreased

Triglycerides

VLDL

LDL and small dense LDL

Apo B

HDL

Apo A-I

Increased susceptibility to oxidation

Increased vascular permeability

Conformational change in apo B

Decreased affinity for LDL receptor

Association with insulin resistance syndrome

Association with high TG and low HDL

Small Dense LDL and CHD: Small Dense LDL and CHD: Potential Atherogenic MechanismsPotential Atherogenic Mechanisms

Austin MA et al. Curr Opin Lipidol 1996;7:167-171.

Accumulation of chylomicron remnants

Accumulation of VLDL remnants

Generation of small, dense LDL-C

Association with low HDL-C

Increased coagulability

- plasminogen activator inhibitor (PAI-1)

- factor VIIc

- Activation of prothrombin to thrombin

Hypertriglyceridemia and CHD Risk: Hypertriglyceridemia and CHD Risk: Associated AbnormalitiesAssociated Abnormalities

ATP III Lipid and Lipoprotein ATP III Lipid and Lipoprotein ClassificationClassification

LDL Cholesterol (mg/dl) HDL Cholesterol LDL Cholesterol (mg/dl) HDL Cholesterol (mg/dl)(mg/dl)

<100<100 Optimal Optimal < 40 Low < 40 Low

100-129 Near/Above Optimal100-129 Near/Above Optimal >> 60 High 60 High (Desirable)(Desirable)

130-159 Borderline High130-159 Borderline High

160-189 High160-189 High

>>190190 Very High Very High

Categories of Risk that Modify LDL GoalsCategories of Risk that Modify LDL Goals

CHD and CHD risk equivalentsCHD and CHD risk equivalents <100<100

Multiple (2+) risk factorsMultiple (2+) risk factors <130<130

Zero to one risk factorZero to one risk factor <160<160

Treating Elevated TriglyceridesTreating Elevated Triglycerides

Non-HDL Cholesterol: Secondary TargetNon-HDL Cholesterol: Secondary Target

Primary target of therapy: LDL cholesterolPrimary target of therapy: LDL cholesterol Achieve LDL goal before treating non-HDL Achieve LDL goal before treating non-HDL

cholesterolcholesterol Therapeutic approaches to elevated non-HDL Therapeutic approaches to elevated non-HDL

cholesterolcholesterol– Intensify therapeutic lifestyle changesIntensify therapeutic lifestyle changes– Intensify LDL-lowering drug therapyIntensify LDL-lowering drug therapy– Nicotinic acid or fibrate therapy to lower VLDLNicotinic acid or fibrate therapy to lower VLDL

Management of dyslipidemiaManagement of dyslipidemia

Primary aim is to achieve LDL goalPrimary aim is to achieve LDL goal For high TG (200-499 mg/dl), non-HDL is the For high TG (200-499 mg/dl), non-HDL is the

secondary target of therapysecondary target of therapy– Increase statin doseIncrease statin dose

OROR– Add fibrates/nicotinic acidAdd fibrates/nicotinic acid

For HDL < 40 mg/dl drugs such as nicotinic For HDL < 40 mg/dl drugs such as nicotinic acid or fibrates have to be consideredacid or fibrates have to be considered

NCEP guidelines, May 2001

Managing Very High Triglycerides (≥500 Managing Very High Triglycerides (≥500 mg/dL)mg/dL)

Goal of therapy: prevent acute pancreatitisGoal of therapy: prevent acute pancreatitis Very low fat diets (Very low fat diets (15% of caloric intake)15% of caloric intake) Triglyceride-lowering drug usually required (statins, Triglyceride-lowering drug usually required (statins,

fibrate or nicotinic acid)fibrate or nicotinic acid) Reduce triglycerides Reduce triglycerides before before LDL lowering LDL lowering

First-line agentsFirst-line agents

HMG CoA reductase HMG CoA reductase inhibitorinhibitor

Fibric acid derivativeFibric acid derivative

Second-line agentsSecond-line agents

Bile acid binding resinsBile acid binding resins

Nicotinic acidNicotinic acid

Pharmacologic Agents for Pharmacologic Agents for Treatment of DyslipidemiaTreatment of Dyslipidemia

American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.

In diabetic patients, nicotinic acid should be restricted to <2g/day. Short-acting nicotinic acid is preferred.

Effect on lipoprotein

LDL HDL Triglyceride

LDL cholesterol lowering*LDL cholesterol lowering* First choice: HMG CoA reductase inhibitor (statin) Second choice: Bile acid binding resin or fenofibrate

HDL cholesterol raisingHDL cholesterol raising Behavior interventions such as weight loss, increased

physical activity and smoking cessation Glycemic control Difficult except with nicotinic acid, which is relatively

contraindicated or fibrates

Triglyceride loweringTriglyceride lowering Glycemic control first priority Fibric acid derivative (gemfibrozil, fenofibrate) Statins are moderately effective at high dose in

hypertriglyceridemic subjects who also have high LDL cholesterol

* Decision for treatment of high LDL before elevated triglyceride is based on clinical trial data indicating safety as well as efficacy of the available agents.

Order of Priorities for Treatment of Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults*Diabetic Dyslipidemia in Adults*

LDLLDLReceptorReceptor

LDLLDLReceptorReceptor

Statins: Mechanism of ActionStatins: Mechanism of Action

Acetate

LDLLDLLDLLDL

HMG-CoAReductase

Cholesterol

Statins

Statins: Mechanism of ActionStatins: Mechanism of Action

LDL receptor–mediated hepatic LDL receptor–mediated hepatic uptake of LDL and VLDL uptake of LDL and VLDL remnantsremnants

Serum VLDL remnantsSerum VLDL remnants

Serum LDL-CSerum LDL-C

Cholesterol Cholesterol synthesissynthesis

LDL receptor LDL receptor (B–E receptor) (B–E receptor) synthesissynthesis

Intracellular Intracellular CholesterolCholesterol

Apo BApo B

Apo EApo E

Apo BApo B

Systemic CirculationSystemic CirculationHepatocyteHepatocyteReduce hepatic cholesterol synthesis, lowering intracellular cholesterol, which stimulates Reduce hepatic cholesterol synthesis, lowering intracellular cholesterol, which stimulates upregulation of LDL receptor and increases the uptake of non-HDL particles from the systemic upregulation of LDL receptor and increases the uptake of non-HDL particles from the systemic circulation.circulation.

LDLLDL

Serum IDLSerum IDL

VLDLVLDLRRVLDLVLDLRR

VLDLVLDL

Statins: Beyond LDLStatins: Beyond LDL

Trial Statin dose (mg)Triglyceride Lowering

Effect

4s Simvastatin 10-40 10%

WOSCOPS Pravastatin 40 12%

CARE Pravastatin 40 14%

LIPID Pravastatin 40 11%

PROSPER Pravastatin 40 13%

AFCAPS Lovastatin 20-40 13%

ASCOT Atorvastatin 10 14%

CARDS Atorvastatin 10 19%

HPS Simvastatin 40 14%

JUPITER Rosuvastatin 20 17%

Statins reduce TG levels in the range of 10% to 20%

Rosuvastatin: The Switch Over Rosuvastatin: The Switch Over AdvantageAdvantage

0

10

20

30

40

Percentage

reduction

Lipid Parameters

Rosuvastatin Naïve 39.9 28.8 9.2

Switch Over to

Rosuvastatin

24.5 16.6 3.8

LDL-C TC TG

Reduction in LDL-C,

TC and TG in both

rosuvastatin naïve and

switch over patients.

Improvement in LDL-C

targets from 29% to

72.9% in switch over

group.

Fibric Acid derivates: Mechanism of Fibric Acid derivates: Mechanism of ActionAction

Interaction of Interaction of Fibrates with PPAR Fibrates with PPAR αα


Fibrates lower small dense Fibrates lower small dense LDLLDL


PPAR PPAR αα activated by fibrates activated by fibrates negatively regulates fibrinogen- negatively regulates fibrinogen- ββ expressionexpression

Nicotinic Acid: Mechanism of ActionNicotinic Acid: Mechanism of Action

LiverLiver CirculationCirculation

HDLHDL

Serum VLDL results in Serum VLDL results in reduced lipolysis to LDL reduced lipolysis to LDL

Serum LDLSerum LDL

VLDL

Decreases hepatic production of VLDL and of apo BDecreases hepatic production of VLDL and of apo B

VLDL VLDL secretionsecretion

Apo BApo B

HepatocyteHepatocyte Systemic CirculationSystemic Circulation

Mobilization of FFAMobilization of FFA

TG synthesisTG synthesis

VLDL

LDL

Acyl-CoA synthase

FA Uptake

FA

Glycerol-3-P Lyso PA PA

DAGDGAT

TG

Phospholipids

Acyl-CoA Acetyl CoA

Glucose Uptake

Lipogenesis

Acetyl-CoA carboxylaseFA synthase

VLDL

Apo B-100

NEFA Hormone-Sensitive Lipase

Adipose TG

Degradation

PAP

Cell membrane

Triglyceride-Lowering Mechanisms of Omega-3 Triglyceride-Lowering Mechanisms of Omega-3 FAFA

MitochondriaCPT-I, -IIAcyl-CoA

dehydrogenase

MitochondriaCPT-I, -IIAcyl-CoA

dehydrogenase

PeroxisomeAcyl-CoA oxidase

(rodents only?)

+

+

+

+

Β-oxidation

–

–

–

––

В-oxidation

Harris WS and Bulchandani D. Curr Opin Lipidol 2006; 17:387-393.

Dyslipidemia Treatment SummaryDyslipidemia Treatment Summary

Focus on triglycerides

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