Lipids

Macromolecular complex that transports lipids in the blood

Lipoprotein

Proteins on the surface of lipoproteins; regulate lipoprotein metabolism and cellular uptake; act as ligands for lipoprotein receptors.

Apoproteins

Largest lipoprotein; transport triglycerides and cholesterol from gastrointestinal tract to extra-hepatic tissues

Chylomicron

secreted by the liver; initial transporter of

triglycerides and cholesterol from liver to periphery

Very Low Density Lipoproteins

contributes to plaque build-up in arteries;

formed from VLDL in plasma

Low Density Lipoproteins

Transport cholesterol to Liver

High Density Lipoproteins

Major form of fat storage

Triglycerides

Enzyme found primarily on the surface of endothelial cells that releases

free fatty acids from triglycerides in lipoproteins

Lipoprotein Lipase (LPL)

enzyme that

catalyzes the rate-limiting step in cholesterol biosynthesis

HMG-CoA Reductase

Precursor for steroid hormones, vit D, signaling molec.

Used to synthesize bile salts

Lipids

Adverse effects if there are High [LDL] or Low [HDL]

Atherosclerosis → CVD

Rank high to low protein content

HDL

LDL

IDL

VLDL

CM

Rank high to low Lipid size

CM

VLDL

IDL

LDL

HDL

Liver synthesized endogenous TG are assembled into ___ and secreted into plasma

VLDL

Formed in the small intestines and transport dietary TG throughout body

CM

Hydrolyzes TG → fatty acids and glycerol

LPL

Clears high amounts of LDL from plasma and mostly in hepatocytes

LDL-Receptor

Major constituent of atherosclerotic lesion

Foam cell

Used for reverse cholesterol transport

HDL

Increased risks from Hypercholesterolemia and Hypertriglyceridemia

Atherosclerosis

MI

Mortality

Genetics that can cause Dyslipidemia

Lack of functional LDL-R

Defective apoB100

Secondary causes of Dyslipidemia

DM

Alcohol intake

Hypothyroidism

Competitive inhib of HMG CoA reductase and rate-limiting step in cholesterol synthesis → increase LDL uptake to decrease plasma levels

Statins

What enzyme does statins inhibit

HMG CoA reductase

Statin pleiotropic effects

Decrease inflammation

Reverse endothelial dysfunction and response to NO

Decrease prothrombin activation

Increase plaque stability

First line for elevated LDL

Statins

Primary and secondary prevention for CVD (MI, stroke, angina) in those w/ Coronary Heart Disease risk factors

Statins

Primary Tx of Hypercholesterolemia and mixed dyslipidemia

Statins

What statins are metabolized by CYP3A4

Atorvastatin

Lovastatin

Simvastatin

What statins are metabolized by CYP2C9

Fluvastatin

Rosuvastatin

What food product inhibits CYP3A4 and increase statin levels

Grapefruit juice

The combination of statins + niacin or statins + fibrates (gemfibrozil) increases risk of what

Myopathy

Statin AEs

Myopathy (rhabdomyolysis)

• high dose, SNP in SLCO1B1 gene

• Monitor creatine kinase

Metabolism risk of new onset DM

Liver toxicity

CYP3A4 interactions

Statins CI

Nursing mothers

Decompensated hepatic dysfunction

Cationic polymer resins that bind noncovalently to negative acids in small intestines → complex excreted in stool

Bile acids sequestrants (resins)

Bile acids sequestrants effects

Interrupt enterohepatic bile acid circulation

Up-regulation of 7 α-hydroxylase in hepatocyte (bile acid synthesis)

Increase the conversion of cholesterol to bile

Decreased hepatocyte cholesterol concentration

Increased LDL receptor expression

Increased LDL clearance from plasma

Bile sequestrants should be used w caution in those w ___ due to its partial offset to increase VLDL synthesis

Hypertriglyceridemia

List of Bile Sequestrants

Cholestyramine

Colesevelam

colestipol

Bile acids use

Second line in Hypercholesterolemia

Which bile acid is used for pruritis due to increased bile acids

Cholestyramine

Which bile acid is used for T2DM

colesevelam

Bile acids AEs

Bloating & Dyspepsia

Decrease vitamin absorption → vitamin K deficiency → bleeding

Bile acids DDI and should give 1 hr before or 4 hrs after

Digoxin

Warfarin

Decrease cholesterol absorption (CM & VLDL) via NPC1L1 in small intestines

Inhibitors of Cholesterol absorption (Ezetimibe, Plant sterols)

Which agent is used for Hypercholesterolemia and can be combined with statins to prevent compensatory increase

Ezetimibe

Ezetimibe AE

Diarrhea

Arthralgia

Increased transaminases w/ statins

activates PPAR-Alpha nuclear receptor in hepatocyte and brown adipocytes

Fibrates

Fibrates effects when modulating protein transcription

Decreased TG

Increased HDL (increased apoA-I)

Anti-inflammatory → decreased athersclerotic plaque rupture

List of fibrates

Gemfibrozil

Fenofibrate

statins can be combo with __ when LDL & TG are elevated or HDL is decreased

Fibrates

Fibrates AEs

GI, Dyspepsia, N

Myopathy ( with gemfibrozile + lovastatin)

Gallstone

Arrhythmia

Increased liver transaminases

Fibrates DDI

Warfarin

activates its receptor on adipocytes to decrease LDL and apoA-I clearance to increase HDL

Niacin (vit B3)

Most effective agent to increase HDL; given in grams

Niacin

Niacin AEs

Cutaneous flushing and itching (prevent w NSAIDs)

Hyperuricemia

Impaired insulin sensitivity (NO DM)

Hepatotoxicity

GI bleed

Myopathy w statins

List of fish oils

Eicosapentaenoic acid (EPA)

Docosahexaenoic acid (DHA)

Fish oil MOA to decrease TG levels

decrease hepatic TG synthesis

regulation of transcription factors (SREBP-1c, PPARα)

increase fatty acid oxidation in the liver

increase plasma lipoprotein lipase activity.

Prescription fish oil for those w CAD risk and Hypertriglyceridemia

Lovaza

Lovaza AEs

N/D/ abdominal pain

Bleeding risk w anti-plat/coag

Prescription fish oil that has AE of Afib

Vascepa

Inhibitor of MTP in ER lumen to prevent apo-B, reduce VLDL and CM

Lomitapide

Adjunct for diet and other lipid lowering drugs in homozygous familial hypercholesterolemia

Lomitapide

Lomitapide AEs

N/V/D

Chest pain

Hepatotox

Back pain

Inhibits regulator of LDL-R expression

PCSK9 inhibitors

List of PCSK9i

Alirocumab

Evolocumab

Adjunct to diet, alone or in combo w statins/ezetimibe for additional LDL-C lowering

PCSK9 inhibitors

Target population for PCSK9

Heterozygous familial hypercholesterolemia (HeFH)

Athersclerotic CVD as secondary

PCSK9 AE

Inj. Site rxn

Diarrhea

Influenza

Myalgia

Small interfering RNA against PCSK9 mRNA → increase LDL-R → increase LDL uptake

Inclisiran

Inclisiran use

adjunct to diet and/or maximally tolerated statin therapy, for the

additional lowering of LDL-C, in patients with:

• heterozygous familial hypercholesterolemia (HeFH)

• administration –injection SQ, every 6 months

Inclisiran AE

Inject site rxn

Arthalgia

UTI

To reduce the risk of MI and coronary revascularization in adults who are

unable to take recommended statin therapy (including those not taking a statin)

with:

• established cardiovascular disease (CVD), or

• a high risk for a CVD event but without established CVD.

Bempedoic acid

Bempedoic acid AE

endocrine & metabolic (gout), atrial fibrillation, tendon rupture

first-in-class human monoclonal antibody against angiopoietin-

like protein 3 (ANGPTL3) [inhibit the ability of ANGTPL3 to inhibit LPL] → decrease VLDL and CM clearance

ANGPTL3 inhibitor (Evinacumab)

evinacumab use

homozygous familial hypercholesterolemia (HoFH) as an

adjunct to other lipid-lowering therapies - for adults and pediatric patients

(> 12 years-old) IV infusion q 4 wks

Evinacumab AE

influenza-like illness, dizziness, rhinorrhea, nausea;

teratogen

Antisense Oligonucleotide (ASO-Ga1NAc3) conjugate - binds to apoC-III

mRNA → reduces serum apoC-III protein → increases clearance of

triglycerides and VLDL

Olezarsen

Olezarsen use

Familial chylomicronemia syndrome- adjunct to diet to reduce triglycerides

in adults with familial chylomicronemia syndrome. - subQ

Olezarsen AE

Inj site reaction

Hyperglycemia, decreased platelet count. antibody development