Objectives website/09... · 2018. 4. 10. · (AACE) 2017-LDL target European Society of Cardiology...

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By

Susan George, DNP, APRN- CNP, CCNS, CCRN, CHFN

�� Briefly discuss about association between

hyperlipidemia/dyslipidemia and atherosclerotic cardiovascular diseased (ASCVD).

� Review classes of lipoproteins

� Review current evidence-based guideline for hyperlipidemia management

� Discuss various pharmacologic agents used to treat hyperlipidemia

Objectives

�� 94.6 million, or 39.7 percent, of American adults have

total cholesterol of 200 mg/dL or higher

� 28.5 million, or 11.9 percent, of American adults have total cholesterol of 240 mg/dL or higher

� 7% of U.S. children and adolescents ages 6 to 19 have high total cholesterol.

� Nearly 1 of every 3 American adults have high levels of LDL cholesterol.

� About 18.7 percent of American adults have low levels of HDL cholesterol.

Epidemiology of Hyperlipidemia

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�� Accounts for 39% of CAD

� WHO estimates that 80% of ASCVD is preventable

� Effective lipid management slows the progression of ASCVD and lowers morbidity and mortality of CVD

� Early diagnosis and management of hyperlipidemia has become a public health priority in the primary and the secondary prevention of ASCVD.

Hyperlipidemia/Dyslipidemia

�� CVD, listed as the underlying cause of death, accounts for

nearly 801,000 deaths in the US. That’s about 1 of every 3 deaths in the US.

� About 2,200 Americans die of CVD each day, an average of 1 death every 40 seconds.

� More death from CVD each year than all forms of cancer and chronic lower respiratory disease combined.

� About 92.1 million American adults are living with some form of cardiovascular disease or the after-effects of stroke.

� Direct and indirect costs of cardiovascular diseases and stroke are estimated to total more than $316 billion; that includes both health expenditures and lost productivity.

Cardio Vascular Disease

(CVD)

�Primary� Genetic defect in lipoprotein metabolismSecondary� Diet high in cholesterol, saturated fat, and total calories� Obesity� Diabetes� Alcohol Abuse� Chronic kidney disease� Drug induced (estrogen therapy, atypical antipsychotics, corticosteroids, and

selective beta-blockers like propranolol and atenolol, and cyclosporine)Disorders such as:� Hypothyroidism� Primary biliary cirrhosis� Obstructive liver disease� Nephrotic syndrome� Growth hormone deficiency

Causes and Types of Hyperlipidemia

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�� Chylomicrons: Large lipoproteins rich in lipids and

lowest in protein content of all lipoproteins. Synthesized in the intestine. Transport fats from the intestinal mucosa to the liver. In the liver, the chylomicrons release triglycerides and some cholesterol and become LDL.

� Very-Low-Density Lipoproteins (VLDL): Smaller than chylomicrons, has a very high cholesterol and triglyceride content (15-20% of the total blood cholesterol and most of the circulating triglycerides) .

� Intermediate-Density Lipoproteins (IDL): Created when VLDL is depleted in triglycerides as a result of the hydrolysis by the enzyme lipoprotein lipase. IDL is known as the VLDL remnants. It has a short half life

Classes of Lipoprotein

�LDL (bad cholesterol)� Product of VLDL and IDL metabolism by lipoprotein lipase.

� LDL is oxidized in the arterial subendothelium, thus it plays a central role in atherogenesis.

� Remains the cornerstone of dyslipidemia therapy.

� Strongly associated with atherosclerosis and CHD.

� 10% LDL increase results in a 20% increase in CHD risk.

� Atherogenic cholesterol → LDL, VLDL, IDL


�HDL (good cholesterol) � Smallest but densest lipoprotein, 33% protein content.

� Removes cholesterol from the periphery and transports to the liver.

� HDL concentration in the plasma is inversely related to the risk of CVD.

� Low HDL is a strong independent predictor of CHD.

� HDL tends to be low when triglycerides are high.


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�� Chylomicrons transport fats from the intestinal

mucosa to the liver.

� In the liver, the chylomicrons release triglycerides and some cholesterol and become LDL.

� LDL then carries fat and cholesterol to the body’s cells. It is atherogenic.

� HDL carry fat and cholesterol back to the liver for excretion.

� HDL cholesterol is able to go and remove cholesterol from the atheroma.

Lipoproteins

�Exogenous pathway: Dietary source

Endogenous pathway: Hepatic synthesis, major source of cholesterol in the body. Circulating fatty acids are oxidized and transformed in to acetyl-coenzyme A (acetyl-CoA). Major step in the hepatic synthesis of cholesterol from acetyl-CoA is the transformation of hydroxymethylglutaryl-coenzyme A (HMG-CoA) to mevalonic acid with the participation of enzyme HMG-CoA reductase

Pathophysiology

�� Obtain complete and fasting lipid profile.

� A standard lipid profile consist of total cholesterol (TC), HDL, and TG. Laboratory also reports LDL that may have been calculated by Friedewaldformula or directly measured.

� Friedewald formula: LDL-C = TC-HDL-TG/5

� In fasting, total cholesterol in serum is carried primarily in VLDL, LDL, and HDL; so total cholesterol is the sum of VLDL, LDL, and HDL.

Lipid Profile

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�� Non-HDL-C reflects sum of serum cholesterol carried by

all the potentially atherogenic lipoproteins, LDL, VLDL, IDL, and remnant lipoproteins

� Non–HDL-C = TC – HDL� Secondary Target of Therapy in Patients With High TG� LDL is not the only potentially atherogenic lipoprotein.� Other apoprotein-B containing particles such as VLDL,

VLDL remnant, chylomicron remnants, and IDL are also atherogenic. A better summary measure of overall atherogenicity of patient’s serum is needed. Apo-B protein is such a measure but is not widely available in commercial labs

Non-HDL Cholesterol

�

ASCVD

��Primary prevention: Long term management of

individuals at increased risk for atherosclerotic cardiovascular disease (ASCVD).

�Secondary prevention: Patients with known history of ASCVD. They are high risk for cardiovascular events.

Management of Hyperlipidemia

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�� Assess risk- which patient at risk

� Set goals

� Treat

� Primary target LDL cholesterol

� Secondary target nonHDL cholesterol

� Primary treatment statin therapy

Management Steps

�Major risk factors Additional risk factors Nontraditional risk

factors

Advancing age

Elevated TC level

Elevated Non–HDL-C

Elevated LDL-C

Low HDL-C

Diabetes mellitus

Hypertension

Chronic kidney

disease Cigarette

smoking

Family history of

ASCVD

Obesity, abdominal obesityF/H of HyperlipidemiaElevated Small, dense LDL-CElevated Apo BElevated LDL particle concentrationFasting/post-prandial hypertriglyceridemiaPolycystic ovary syndrome (PCOS)Dyslipidemic triad

Elevated Lipoprotein Elevated Clotting factorsElevated Inflammation markers (hsCRP; Lp-PLA)Elevated Homocysteine levels Elevated Uric acidElevated TG-rich remnants

Major ASCVD Risk Factors

American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease (2017).

�� The risk of ASCVD and ASCVD-related mortality is

substantially greater in the presence of multiple risk factors.

� Since epidemiologic evidence indicates that ASCVD risk factors frequently cluster, it should be expected that many individuals have multiple risk factors.

� Identify risk factors that enable personalized and optimal therapy for dyslipidemia.

What are risk factors for ASCVD?

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�� The 10-year risk of a coronary event (high,

intermediate, or low) should be determined by detailed assessment using one or more of the following tools.� Framingham Risk Assessment Tool� Multi-Ethnic Study of Atherosclerosis (MESA) 10-year ASCVD Risk with

Coronary Artery Calcification Calculator� Reynolds Risk Score, which includes hsCRP and family history of premature

ASCVD� United Kingdom Prospective Diabetes Study (UKPDS) risk engine to calculate

ASCVD risk in individuals with T2DM

� When the HDL-C concentration is greater than 60 mg/dL, one risk factor should be subtracted from an individual’s overall risk profile

Assessment of Risk Factor

�

Framingham Risk Assessment Tool

�

UKPDS Risk Engine

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�� American College of Cardiology/American Heart

Association (ACC/AHA) 2103 – No LDL target

� ACC/AHA 2016 Update – LDL target

� American Association of Clinical Endocrinology (AACE) 2017 - LDL target

� European Society of Cardiology (ESC) – LDL target

� Canadian – LDL target

� British/National Institute for Health and Care Excellence (NICE) – No LDL target

Guidelines for Lipid Management

�

ACC/AHA Guideline 2013

2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults

�� 2013 ACC/AHA guidelines have focused on high

intensity statin therapy for specific groups of patients, while abandoning long established LDL-C goals, a strategy which no longer seems valid.

� PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors have emerged as the add-on therapy on top of statins and/or ezetimibe for the treatment of hypercholesterolemia and ASCVD prevention.

� In several clinical trials, PCSK9 inhibitors have demonstrated their safety and robust LDL-C-lowering power.

ACC 2016 Update

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�Treatment goals should be personalized according to levels of risk.

Total Cholesterol goal <200

Lipid Treatment Goals


�� Meta-analysis of randomized controlled trials of major

vascular events (coronary death, myocardial infarction, coronary revascularization, and ischemic stroke) with at least 1,000 patients and ≥2 years of more vs. less intense statin dosage (N=169,138) � Individuals with baseline LDL-C <77 mg/dL had a 29% further

reduction in major vascular events (P=0.007)

� Those with baseline LDL-C <70 mg/dL had a 37% further reduction in major vascular events (P=0.004)

Cholesterol Treatment Trialists’ Collaboration. Lancet 2010

Efficacy of Intensive LDL-C Lowering in Patients

With Low Baseline LDL-C

�Lifestyle changes

� Physical activity

� Medical nutrition therapy

� Smoking cessation

Pharmacologic therapy

Treatment categories for Hyperlipidemia

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�� HMG-CoA reductase inhibitors/Statins

� Cholesterol absorption inhibitors(Ezetimibe)

� PCSK9 (Proprotein convertase subtilisin/kexin type 9) inhibitors

� Fibrates/ Fibric acid derivatives

� Nicotinic Acid

� Bile acid –binding resins/ Bile acid sequestrants

� Microsomal triglyceride transfer protein (MTP) inhibitor

� Antisense apolipoprotein B oligonucleotide

� Omega-3 fatty acids

Pharmacologic Agents

�� Most effective and most prescribed class of lipid

lowering agents.

� Statin therapy is recommended as the primary pharmacologic agent to achieve target LDL-C goals on the basis of morbidity and mortality outcome trials

� For clinical decision making, mild elevations in blood glucose levels and/or an increased risk of new-onset T2DM associated with intensive statin therapy do not outweigh the benefits of statin therapy for ASCVD risk reduction.

Statins/ HMG-CoA reductase inhibitors

�� HMG-CoA reductase, the enzyme responsible for the

conversion of HMG-CoA to mevalonate, the rate-limiting step in the cholesterol synthesis.

� Inhibition of HMG-CoA reductase initiates a series of events that leads to decreased synthesis of cholesterol, decreased hepatic release of VLDL, and activation of a protease, which in turn cleaves sterol regulatory element-binding proteins (SREBPs) from the endoplasmic reticulum, which upregulates the LDL receptor and consequently increases LDL clearance

Mechanism of Action

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�� 60-70% of serum cholesterol is synthesized in the liver by

HMG-CoA reductase and inhibition of this enzyme with statin leads to significant LDL reduction

� LDL reduction is dose dependent (25-60%)� Lowers TG 15-45% when TG >250� Raise HDL-C 5–15%� The lowest recommended starting dose for all statins is set with

goal to decrease LDL by 20-30%� Reduce major coronary events� Reduce CHD mortality� Reduce coronary procedures (PTCA/CABG)� Reduce stroke� Reduce total mortality

Effects of Statin

�� Modulation of endothelial function (NO regulation)� Inhibition of LDL-C oxidation� Atherosclerotic plaque stabilization� Reduced inflammatory infiltrate (macrocytes, T lymphocytes)� Effects on circulating inflammatory markers (CRP, TNF, IL1,

IL6)� Platelet inhibition and antithrombosis� Reduced leukocyte adhesiveness� Effects on circulatory clotting factors� Effects on blood viscosity and flow� Reduced ischemia-reperfusion injury (cardiac and cerebral)� Enhanced angiogenesis

Additional effects of statin

�� Lovastatin was the first approved statin, it was isolated from

mold Aspergillus terreus.� Pravastatin and Simvastatin are chemically modified

derivatives of original molecule� Atorvastatin, fluvastatin, and rosuvastatin are synthetic

compounds with specific molecular structure� Rosuvastatin, atorvastatin, and simvastatin has the same drug

efficacy� All statins are well absorbed through the GI tract and

metabolized in the liver through cytochrome P450� All statin should be taken in the evening because of the

synthesis of cholesterol in the liver is maximal between midnight and 2am except the one with long half life; atorvastatin (13-16hrs) and rosuvastatin (19hrs)

HMG-CoA reductase inhibitors (Statins)

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�Interactions

� CYP3A4 inhibitors such as azole antifungals, erythromycin, protease inhibitors, amiodarone, and grape fruit.

� CYP2c9 inhibitors such as NSAIDS, phenytoin, and warfarin

� Fenofibrates are preferred when the two classes are combined as gemfibrosil can increase the risk of rhabdomyolysis

� Lovastatin, atorvastatin, rosuvastatin, and simvastatin potentiate effect of warfarin; this interaction is not seen with pravastatin or fluvastatin. Most statins can also affect digoxin metabolism and levels.

Contraindications

� Active liver disease

Statins

�

Statins


�

Comparison of the percent reduction in LDL with various statin drugs

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�

Comparison of Statin Effects


�

Cholesterol absorption inhibitors

Ezetimibe (Zetia)� Blocks the intestinal absorption

of cholesterol of dietary and biliary origin as well as plant sterols.

� Ezetimibe selectively inhibits intestinal cholesterol absorption

� Blocks about 55% of cholesterol absorption in the intestine and reducing the return of cholesterol from the intestine to the liver

�� Primarily ↓ LDL-C 10%-18% by inhibiting intestinal absorption of

cholesterol and decreasing delivery to the liver, leading to upregulation of hepatic LDL receptors

� ↓ Apo B 11%-16% � In combination with statins, additional ↓ LDL-C 25%, total ↓ LDL-C

34%-61% � In combination with fenofibrate, ↓ LDL-C 20%-22% and ↓ apo B 25%-

26% without reducing ↑ HDL-C



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�� Primarily ↓ LDL-C 10%-18% by inhibiting intestinal absorption of

cholesterol and decreasing delivery to the liver, leading to upregulation of hepatic LDL receptors

� ↓ Apo B 11%-16% � In combination with statins, additional ↓ LDL-C 25%, total ↓ LDL-C

34%-61% � In combination with fenofibrate, ↓ LDL-C 20%-22% and ↓ apo B 25%-

26% without reducing ↑ HDL-C


�Side effects� Upper respiratory tract infections, sinusitis, diarrhea, arthralgia,

and back painDrug Interactions� Cholestyramine: Ezetimibe should be administered 2 hours

before or 4 hours after � Fibrates: Not currently recommended in combination with

ezetimibe, as safety and efficacy has not yet been established by clinical trials.

� Cyclosporin: May substantially increase ezetimibe levelsContraindication� Combination with statin is contraindicated in patients with

active liver disease or persistent elevation in liver enzymes

Ezetimibe

�Patients with recent ACS were randomized 1:1 to either ezetimibe 10 mg + simvastatin 40 mg or simvastatin 40 mg and followed for a median of 6 years. � Primary endpoint (CV death/MI/UA/coronary revasc/stroke/moderate/severe

bleeding) for ezetimibe/simvastatin vs. simvastatin: 32.7% vs. 34.7% (HR 0.94, 95% CI 0.89-0.99; P=0.016).

� MI: 13.1% vs. 14.8%, P=0.002; stroke: 4.2% vs. 4.8%, P=0.05; CVD/MI/stroke: 20.4% vs. 22.2%, P=0.003

� Median LDL follow-up average: 53.7 vs. 69.5 mg/dL� In patients with high-risk ACS, ezetimibe 10 mg/simvastatin 40 mg was superior to

simvastatin 40 mg alone in reducing adverse CV events � This is the first study powered for clinical outcomes to show a benefit with a non-

statin agent� Reaffirms the “lower is better” hypothesis with LDL-C

IMPROVE-IT: Improved Reduction of Outcomes, Vytorin Efficacy International Trial

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�� Inhibit PCSK9 binding with LDLRs, increasing the number of

LDLRs available to clear LDL, and lowering LDL-C levels

� PCSK9 binds to low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes to promote LDLR degradation within the liver1

� LDLR is the primary receptor that clears circulating low-density lipoprotein (LDL), therefore the decrease in LDLR levels by PCSK9 results in higher blood levels of LDL-C1

� By inhibiting the binding of PCSK9 to LDLR, PCSK9 increases the number of LDLRs available to clear LDL, thereby lowering LDL-C levels.

PCSK9 (Proproteinconvertasesubtilisin/kexin type 9) inhibitors

�� GLAGOV: Global Assessment of Plaque Regression

With a PCSK9 Antibody.

� FOURIER Trial: Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects with Elevated Risk.

PCSK9 (Proproteinconvertasesubtilisin/kexin type 9) Studies

�Patients with angiographic CAD were randomized to receive monthly evolocumab (420 mg) (n=484) or placebo (n=484) SQ for 76 weeks, in addition to statins� Plaque regression measure by intravascular ultrasound� Nominal change in percent atheroma volume at 78 weeks: -0.95% in the

evolocumab group vs. 0.05% in the placebo group (P<0.001 for between-group comparison)

� Patients with plaque regression: 64.3% with evolocumab vs. 47.3% with placebo (P<0.001)

� Major adverse cardiac events: 12.2% with evolocumab vs. 15.3% with placebo

� Among patients with angiographic evidence of CAD on chronic statin therapy, the PCSK9 inhibitor evolocumab resulted in a greater change in percent atheroma volume and a greater proportion of patients with plaque regression

GLAGOV Trial

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�� Randomized, double-blind, placebo-controlled trial

investigated the effects of adding evolocumab to high-intensity statin therapy compared with high-intensity statins alone.

� Sample: 27,500 individuals with clinically evident atherosclerotic disease and baseline LDL-C levels ≥70 mg/dLand non-HDL-C levels ≥100 mg/dL

� All study participants were receiving statin therapy with or without ezetimibe, and the evolocumab and placebo groups had the same baseline LDL-C (92 mg/dL).

� At 26 months, extremely tight lipid control with evolocumabled to a 15% decrease in risk for the primary composite endpoint and 20% decrease in risk for a secondary composite endpoint

FOURIER Trial

�Inhibit PCSK9 binding with LDLRs, increasing the number of LDLRs available to clear LDL, and lowering LDL-C levels.

� Decrease LDL-C 48-71%

� Decrease non-HDL-C 49- 58%

� Decrease total-C 36-42%

� Decrease Apo B 42- 55%

PCSK9 inhibitors

�� Require subcutaneous self-injection; refrigeration

generally needed

� Overall levels of adverse reactions and discontinuation very low

Side Effects

� Alirocumab (Praluent): nasopharyngitis, influenza, urinary tract infections, diarrhea, bronchitis, and myalgia

� Evolocumab (Rapatha): nasopharyngitis, back pain, and upper respiratory tract infection

Main Consideration

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�� Fibrates are agonists at peroxisome proliferator-activated

receptors (PPARα), these nuclear receptors are primarily expressed in hepatocytes and muscle cells. Fibrates stimulates PPARα which results in activation specific genes and subsequent changes in lipid metabolism.

� Activates lipoprotein lipase which lowers TG and VLDL

� Increases HDL by inhibiting synthesis of Apolipoprotein CIII in the liver and stimulation of Apolipoprotein A-I and Apolipoprotein A-II

� Indicated in the prevention of pancreatitis in patients with severely elevated TG (>1000mg/dL)

Fibric Acid Derivatives

�� Increased synthesis of lipoprotein lipase – hydrolyse

triglycerides – decrease circulating TG’s

� Increased expression of LDL receptor in liver –mainly with 2nd generation fibrates

� Increased fatty acid oxidation

� Decrease TG synthesis in liver

� Reduce circulating free fatty acids


�Effects� Decreases TG level by 20-35%� Increases HDL by 6-18%� May lower, TC and LDL 20-25%� Reduces fatal and non-fatal CVD by about 20%� Decreases inflammation



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�Side effects

� GI side effects: diarrhea, nausea, dyspepsia, cholelithiasis, and abdominal pain

� Less common: Skin rash, myalgia, headache, and impotence

Contraindications: Severe renal or hepatic disease

Drug Interactions

� When fibrates are taken with statins myositis can occur in approximately 5% of patients.

� When combined with statin fenofibrate/ fenofibric acid are the preferred drug of choice because it has less risk of rhabdomyolysis compared with gemfibrosil.

� Can potentiate the effects of oral anticoagulants


�

Triglyceride Level

�� The lipid lowering and vasodilatory effect of niacin are

not related to its vitamin properties.

� The metabolic and vascular effects is the results from its binding to a G-protein coupled receptor (GPCR 109A) expressed in blood vessels

� Lipid lowering effects results from niacin binding to another GPCR on adipocytes that inhibits lipoprotein lipase and prevent triglyceride release from chylomicrons.

� Vasodilatory effect is associated with the release of prostaglandin D2 and E2.

Nicotinic Acid (Niacin/Vitamin B3)

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�Effects

• ↓ LDL-C 10%-25%, ↓ TG 20%-30%, ↑ HDL-C 10%-35% by decreasing hepatic synthesis of LDL-C and VLDL-C

• ↓ Lipoprotein (a)

• Transforms LDL-C to less atherogenic form by increasing average particle size and also decreases LDL particle concentration

Nicotinic Acid

�Side effects

� Flushing is the most common side effect, approximately 60% of patients experiences it. This can reduced by slowly increasing the dose, administration with meals, or treatment with NSAIDS. Often disappears after chronic administration of the drug. Flushing is less with extended release.

� Other side effects: Vasodilation, pruritus, rash, headache, dizziness, GI events such as diarrhea, nausea, vomiting, and activation of pre-existing gastric ulcer.

� Hepatotoxicity is a rare but serious side effect and is associated with extended release.

Contraindications: Active liver disease, severe gout, peptic ulcer

Nicotinic Acid

�May be considered for:

� Reducing LDL-C

� Reducing apo B

� Modestly increasing HDL-C

Caution: May increase TG

Bile acid–binding resins

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�Mechanism of Action: � Bile acid–binding resins are positively charged polymers that

bind to the negatively charged bile acids in the lumen of the intestine. The bile acid complex can not be absorbed by the intestinal mucosa and is subsequently eliminated in the feces.

� Bile acids are the source of 75% cholesterol in the intestine, and inhibition of their reabsorption disrupts chylomicron formation and reduces the availability of cholesterol and TG in the liver

� LDL lowering benefit of these drugs is offset in the long-term by the up-regulation of cholesterol and TG synthesis and a possible increase in VLDL synthesis, so cautious in patients with hypertriglyceridemia


�


Effects• Reduce LDL-C 15–30%• Raise HDL-C 3–5%• Reduce major coronary events


�


Side effects� Constipation� Dyspepsia and bloating� Decreased absorption of other drugs including fat soluble

vitamins, corticosteroids, estrogen, progestins, thyroid preparations, warfarin, NSAIDS, furosemide, thiazide diuretics, digoxin, and many oral hypoglycemic agents.

Contraindications� Dysbetalipoproteinemia� Raised TG (especially >400 mg/dL)

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�

Microsomal Triglyceride Transfer Protein (MTP) Inhibitor

• Mechanism of Action: Binds and inhibits Microsomal triglyceride transfer protein (MTP) which inhibits synthesis of chylomicrons and VLDL

• Effects:↓ Up to LDL-C 40%, TC 36%, apo B 39%, TG 45%, and non-HDL-C 40% (depending on dose) in individuals with homozygous familial hypercholesterolemia (HoFH)


�� Can cause increases in transminases (ALT,

AST); monitoring of ALT, AST, alkaline phosphatase, and total bilirubin prior to initiation, and of ALT and AST during treatment.

� Causes increases in hepatic fat (steatosis) with or without concomitant elevated transminases, which may be a risk for progressive liver diseases

� Also causes steatosis of the small intestine with resulting abdominal pain and steatorrhea unless a very-low-fat diet is followed; may also cause fat-soluble vitamin deficiency unless vitamin supplements are taken

� Caution should be exercised when used with other drugs with potential hepatoxicity; because of hepatoxicity risk.

MTP Inhibitor- Main Considerations

�� It acts by decreasing the production of apo-B, which

provides the structural core for all atherogeniclipids, including LDL-C

� ↓ LDL-C 21%, TC 19%, apo B 24%, and non-HDL-C 22% in individuals with HoFH .

Antisense apolipoprotein B oligonucleotide


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�� Can cause increases in transminases (ALT,

AST); monitoring of ALT, AST, alkaline phosphatase, and total bilirubin before initiation, and of ALT and AST during treatment is recommended

� Causes increases in hepatic fat (steatosis) with or without concomitant elevated transminases, which may be a risk for progressive liver diseases

� Caution should be exercised when used with other drugs with potential hepatoxicity; because of hepatoxicity risk.

Main Considerations

�� 2 classes of essential fatty acids (FA), the omega-3 and 6.� Omega-3 FA, found primarily in fatty fish with high oil content

such as salmon, mackrel, sardines, trout, and herring, and other seafood sources, as well as in walnuts, canola, flaxseed, linseed oils.

� They consists of both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derived from alpha-linolenic acid (ALA)

� Prescription omega-3 oil, 2 to 4 g daily, should be used to treat severe hypertriglyceridemia (TG >500 mg/dL). Dietary supplements are not FDA-approved for treatment of hypertriglyceridemia and generally are not recommended for this purpose

� Prescription strength (Lovaza) consists of 900mg of ethyl esters of omega-3 FA (Approximately 500mg of EPA and 400mg of DHA).

Essential Fatty Acids

�� Mechanism of Action: EPA and DHA both reduce the synthesis

and secretion of VLDL and increase triglyceride removal from VLDL and chylomicrons through the up-regulation of lipoprotein lipase.

� Effects: ↓ TG 27%-45%, TC 7%-10%, VLDL-C 20%-42%, apo B 4%, and non-HDL-C 8%-14% in individuals with severe hypertriglyceridemia most likely by reducing hepatic VLDL-TG synthesis and/or secretion and enhancing TG clearance from circulating VLDL particles.

Omega-3 Fatty Acids

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�

Omega-3 Fatty Acids

�� Administered alone or in combination with other lipid

lowering drugs

� Minor GI symptoms like fishy taste, eructation, or diarrhea may occur in dose related manner

� Effect on LDL seem to vary among studies from moderate dose dependent increase to decrease in LDL. In general it can raise LDL by 5-10%

� Due to their antiplatelet activity it may increase bleeding time in a dose dependent manner, so for patients who are anticoagulants initially bleeding time need to be monitored

Omega-3 Fatty Acids

�� Plant sterols and stanols are also known as phytosterols are a

group of naturally occurring compounds found in plant cell membrane. Structurally they are similar to body’s cholesterol.

� When consumed they compete with cholesterol for absorption in the digestive system, thus cholesterol absorption is blocked and decreases the blood cholesterol level.

� Naturally present in small quanties (<500mg) in vegetable oil, nuts, legumes, whole grains, fruits, and vegetables.

� To lower cholesterol at least 2gm/day is needed, so many manufactures fortify foods with phytosterols.

� Consuming 2gm/day has been shown to reduce total cholesterol up to 10% and LDL up to 14%

Sterols and Stanols

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�Drug class

Serum LDL cholesterol(% change)

Serum HDL cholesterol(% change)

Serum triglycerides(% change)

Bile acid sequestrants

↓ 15 to 30 0 to slight increaseNo change or increase


↓ 17 ↑ 1 ↓ 7 to 8

Fenofibrate(micronized form)

↓ 6 to 20 ↑ 5 to 20¶

↓ 41 to 53

Gemfibrozil◊ ↓ 10 to 15 ↑ 5 to 20¶

↓ 35 to 50

Neomycin ↓ 20 to 25 No change No change

Nicotinic acid (niacin)

↓ 10 to 25 ↑ 15 to 35 ↓ 25 to 30

Omega 3 fatty acids∆

↑ 4 to 49 ↑ 5 to 9 ↓ 23 to 45

PCSK9 inhibitors ↓ 38 to 72 ↑ 4 to 9 ↓ 2 to 23

Statins ↓ 20 to 60 ↑ 5 to 10 ↓ 10 to 33

Average effects of different classes of lipid lowering drugs on serum lipids

UpToDate (2017)

�Indicated for patients with severe familial hypercholesterolemia

� LDL-C >200 mg/dL with history of CHD� LDL-C >300 mg/dL without CHD

� Administered every 2 weeks and lasts approximately 2 to 4 hours per treatment session

� Treatment costs approximately $2500.00, most insurance carriers will cover this procedure.

� Only available in selected centers across US

Effects� Removes approximately 60% to 70% of LDL-C.� Improves endothelial function, inhibit the coagulation system, reduce

adhesion molecules, inhibit cytokine production, reduce LDL-C oxidation. These effects can acutely improve the microcirculation.

� Suppression of atherosclerotic plaque progression, and regression in atherosclerotic lesions.

LDL Apheresis

�Indicated for patients with severe familial hypercholesterolemia

� LDL-C >200 mg/dL with history of CHD� LDL-C >300 mg/dL without CHD

� Administered every 2 weeks and lasts approximately 2 to 4 hours per treatment session

� Treatment costs approximately $2500.00, most insurance carriers will cover this procedure.

� Only available in selected centers across USEffects� Removes approximately 60% to 70% of LDL-C.� Improves endothelial function, inhibit the coagulation system, reduce

adhesion molecules, inhibit cytokine production, reduce LDL-C oxidation. These effects can acutely improve the microcirculation.

� Suppression of atherosclerotic plaque progression, and regression in atherosclerotic lesions.

LDL Apheresis

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�

ACC/AHA Guideline- 2016 Focused Update

�

ACC/AHA Guideline- 2016 Update

2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management ofAtherosclerotic Cardiovascular Disease Risk

�

ACC/AHA Guideline- 2016 Focused Update

2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management ofAtherosclerotic Cardiovascular Disease Risk

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�� ASCVD is the leading cause of death in US and

around the world

� Effective lipid management decreases the incidence of ASCVD morbidity and mortality.

� Statin should be the preferred agent for primary and secondary prevention.

� If patients cannot achieve a goal LDL-C with a statin alone, then add a second lipid-lowering agent such as Ezetimibe or PCSK9.

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Objectives website/09... · 2018. 4. 10. · (AACE) 2017-LDL target European Society of Cardiology...

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Transcript of Objectives website/09... · 2018. 4. 10. · (AACE) 2017-LDL target European Society of Cardiology...