1. Statins, Fibrates, Niacin,
Cardio-Vascular
Anti-lipidemics
Statins, Fibrates, Niacin,
Omega3, ezetimide…
8/2010
NUR 7755

2. HYPERLIPIDEMICS Total Chol Trigs Fats…not water soluble…. LIPOPROTEINS
HDL
LDL
IDL
VLDL
Chylo-microns
PEOPLE don’t clog interstate…
Chol. and Trigs don’t clog arteries…

3. lipids LIPOPROTEINS HDL LDL IDL VLDL Chylo-microns
vehicles..not people clog highway
Lipid panels count cholesterol…
Each vehicle carries lots of Chol and Trigs (people)

4. LIPOPROTEINS Chylo-microns VLDL IDL LDL HDL ligand lipophilic
Lipids: molecules which includes fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, phospholipids, and others.
Functions: energy storage, structural components of cell membranes, signaling molecules.
Chol. Ester: ester of cholesterol. The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol. Cholesteryl Esters have a lower solubility in water than Cholesterol
Chole-sterol : alcohol form
Phospholipid: lipid w phospherous group.. Neg charge
lipophilic
Hydrophilic..water soluble

5. “Cholesterol” Stored in gb as bile Requires transport protein Sources:
Substrates for
cell membranes formation
hormone synthesis
needed for ADEK vit absorption
Stored in gb as bile
Requires transport protein
Sources:
liver synthesis (20-25%)
intestines
adrenal glands
reproductive organs
animal foods

6. Cholesterol synthesis
starts w/ 1 molecule of acetyl CoA and 1 molecule of acetoacetyl-CoA => dehydrated to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA).
=> reduced to mevalonate by the enzyme HMG-CoA reductase.
This is the regulated, rate-limiting and irreversible step in cholesterol synthesis and is the site of action for the statin drugs (HMG-CoA reductase competitive inhibitors).

7. HMG pathway

8. “Triglycerides” Most dietary fats are “tri” glycerides.
Glycerol molecule PLUS 3 fatty acid molecules.
triglyceride form not absorbable in duodenum
“pancreatic lipase” enzyme releases the fatty acids
Mono-glycerides & di-glycerides are absorbable
Used as energy source
Require a transport protein

9. Triglycerides
XANTHOMAS
SERUM
XANTHELASMA

10. lipoproteins
Total Chol
Trigs
HDL
LDL
IDL
VLDL
Chylo-microns

11. Chylomicrons
Replete w/ dietary trigs ->deliver trigs to skeletal muscle and adipose tissue
Large.
Contain:
apo B 48 (SI)
apo B100(liver)
apo E
90% trigs
Source: dietary fat
Life: 12-14hr
Catabolized by lipoprotein lipase ->
to Chylomicron remnants ->
return to liver
Free cholesterol liberated
Trigs converted to FFA

12. VLDL/IDL VLDL Synthesized in liver->
contain excess Triglyceride (& Cholesterol) not used by the liver for synthesis of bile acids.
contain apolipoprotein B100 and apo E in shell.
=>Secreted by liver-> vessels cleave and absorb trigs -> leave IDL molecules (w/ even more chol) >
Half are taken up by the liver for metabolism into other biomolecules then to LDL
other half continue to lose triacylglycerols in the bloodstream until they form LDL molecules, w/ highest % of cholesterol
Regulated by diet, hormones
Inhibited by chylomicron remnants in liver

13. LDL Only 1 Lots of Chol Few Trigs ApoB=bad!
LDL carries chol to end organs.
Receptors recognize Apo B.
Remaining LDL-Chol is taken back to liver & degraded
Unless: over production, reduced receptors, fat in diet
Increased intracellular Chol (from LDL catabolism) inhibits HMG-CoA

14. HDL Reverse Cholesterol Transport (RCT )
Synth. in liver
Lots of Chol
Few Trigs
Apo A=good
Reverse Cholesterol Transport (RCT )
transport cholesterol back to the liver for excretion
or to other tissues that need cholesterol to synthesize hormones
photo

15. Lipoprotein separation
Apo B
Apo B
Apo A
Lipoprotein separation
Chol amount is by weight or volume… not counted particles… may be VWs… may be buses..
Not the Chol that counts… but the Lipoproteins
..not counted cholesterol..

17. LIPID Classes

18. Lipid cycle LDL enters endothelium…oxidized
..macrophage attack..foam cell..plaque..
Lipid cycle
If no LDL… chol can’t cross cell wall anyway.
LDL.. Oxidized.. Acted on by macrophage… becomes foam cell.. Becomes plaque

19. Atherosclerosis
Nl……mild……severe……..rupture

20. Fredrickson-Levy-Lees Classification of Hyperlipoproteinemia
Phenotype
Occurrence
Present in
Chol
Trig
Excess
VLDL I
Rare
Chylomicrons
>2500 V
Chylomicrons,
IIA
Common
LDL
>250
<150
IIB
Most common
LDL,VLDL
>250
III
Rare
VLDL remnants
content IV
Common
VLDL

21. ADVANCED TESTING LDL-S3GGEｮ HDL-S10GGEｮ ApoB (part #) GENETIC: Lp(a)
ApoE
LPA-Aspirin response
KIF6-Statin response
9p21-EarlyMI
CYP2C19: plavix response
’s coag. ->CVD risk x3.
phptp
DIET RESPONSE

22. ADVANCED TESTING INFLAMMATORY MARKERS Lp-PLA2 hsCRP
Homocysteine by-product of methionine
Vascular inflammation
Gen. inflammation
OTHER:
Insulin
Fibrinogen
NT-proBNP
Q-LDL
VIT D
phptp
Cardiac stress
Response to lipid rx

23. GOALS Lower the LDL (<70-<160)
“National Cholesterol Education Program (NCEP)
Adult Treatment Panel III (ATP III)”
Risk stratification and treatment guidelines
Framingham risk stratification
LDL:
NO risk factors<160
1-2 RF <130
High risk <100
Lower the LDL (<70-<160)
Lower the non-HDL (30 pt > LDL)
Raise the HDL (>40/50)
Lower the Trigs (<150)

24. OPTIONS: Statins Fenofibrates Niacin Omega 3 Fish Oil
Bile Acid Sequestrants
Ezetimide

25. STATINS: best LDL reduction
MOA: inhibits enzyme HMG-CoA reductase
Thus:  cholesterol synthesis
Thus: synthesis of LDL receptors
Thus: LDL clearance
USE: LDL
SE: LFTs, myalgias/ rhabdomyositis
CI: antifungals, erythro’s, grapefruit / grapefruit juice inhibit the P450 3A4, (lova-, simva-, less w/atorva)
Most Chol produced at night, thus PM dosing

26. % LDL reduction:6% rule Dosage 10mg 20mg 40mg 80mg Crestor 46 52 55
Lipitor
Zocor
Pravachol
Lescol
Mevacor
Livalo

27. Statins: examples Potency: $$ Metab./SE T1/2 Prot. Bind.
Crestor H2O sol 2C9/2C hr %
Lipitor fat sol 3A hr %
Zocor gen. H2O sol 3A hr %
Pravachol $4 fat sol %
Lescol fat sol 2C >90%
Mevacor $4 fat sol 3A hr >95%
??Livalo fat sol 2C9

28. Red Yeast Rice & Statins
bright reddish-purple fermented rice, which acquires its color from being cultivated w/ the mold Monascus
1970's researchers in US & Japan were isolating lovastatin from Aspergillus and monacolins from Monascus, (same yeast used to make red yeast rice, but cultured under carefully controlled conditions.)
lovastatin (Mevacor) & monacolin K chemically identical.

29. Red Yeast rice 1998: FDA banned Cholestin
2001: decision reversed on appeal; FDA sent Warning Letters to companies selling red yeast rice; disappeared x yrs
2003: began to reappear
2007: FDA :consumers should not buy or eat red yeast rice products, may contain an unauthorized harmful drug
2010: 30+ brands available. Many avoid FDA restriction by not having any appreciable moncolin content.
Labels / websites say no more than "fermented according to traditional Asian methods" or "similar to that used in culinary applications.” (no mention of cholesterol)
If they do not contain/claim to contain lovastatin, and do not make a claim to  cholesterol-> not subject to FDA action.
monacolin content of red yeast rice dietary supplements can vary widely.

30. Fenofibrates: MOA
Activates “Peroxisome Proliferator Activated Receptor type alpha” (PPARα).
 lipolysis & elimination of trig-rich particles
by activating lipoprotein lipase and  apo CIII production
PPARα also  synthesis of apoproteins AI & AII
 VLDL & LDL  HDL
photo

31. Fibrate MOA
Activate peroxisome proliferator activated receptor a (PPAR a)
 hepatic lipogenesis and VLDL secretion
 fatty acid oxidation in liver and muscle
 lipoprotein lipase activity
 transcription of Apo AI and AII
 transfer of phospholipid and chol to HDL
Remodel LDL particles

32. Fenofibrates… Generic fenofibric acid 105
Gen. fenofibrate, micronized 200 w/ meals
Gen. fenofibrate/Triglide/Lofibra 160
Antara
Fenoglide w/ meals
Fibricor
Lipofen ($25 cash) w/meals
Tricor
Trilipix
Lopid/generic gemfibrozil bid, 30” ac, *caution w/ statin

33. FENOFIBRATES USE to :TG (LDL, VLDL, HDL)
SE: GI, rashes, pruritus, urticaria, photosensitivity, myopathy
CI: liver insufficiency, gallstones, RI
gall stones:  lithogenicity of bile b/c  chol to phosphoipids & bile salts
Feno:  creatinine w/o  in cr cl
Feno may prevent albuminuria, may induce regression of albuminuria
Hi protein binding ‘s INR w/ coumadin ( coumadin dose 25-35%)
May  homocysteine b/c p-par-a
Met: 3A4

34. PK OF FIBRATES Fenofibrate: Gemfibrozil Absorbed in intestine
hydrolyzed by esterases in intestine to form active metabolite fenofibric acid
then hepatic glucuronidation
T 1/2 fenofibric acid 20hr ( qd)
60%excreted in urine
25% in feces
Gemfibrozil
Absorbed from GI tract
Extensive hepatic conjugation
T !/2 1.5hr
(600 bid ac)
Metabolites excreted in urine

35. Remember 2 phase metab… Fibrates… Phase 2: involves conjugation -
Phase 1:oxidation.
May involve reduction or hydrolysis of drug
Oxidation is catalysed by CYP450 enzymes and results in the loss of electrons from the drug
resulting drug metabolite is still often chemically active.
Fibrates…
Phase 2: involves conjugation -
attachment of an ionized group to the drug.
Ionized groups include glutathione, methyl or acetyl
Conjugated w/ hydrophylic substance such as glucuronic acid
…glucuronidation
makes substances more water-soluble,thus, easier elimination through urine or faeces (via bile from the liver).
allows easier transport around the body.
Sometimes less toxic after glucuronidation.

36. Gemfibrozil inhibits glucuronidation and cyp450 metab of statins
“Changes in CYP enzyme activity may affect the metabolism and clearance of various drugs.
if one drug inhibits the CYP-mediated metabolism of another drug, the second drug may accumulate within the body to toxic levels.”
Thus ’s AUC & Cmax of all statins (except fluvastatin)
Toxicity
Thus  rhabdomyolysis w/ statin
33x higher risk w/ cerivaststin/ Baycol
15x higher risk w/ other statins
Trilipix only one approved for combo use.

37. Niacin vitamin B3, nicotinic acid
Other forms of vit B3 : nicotinamide ("niacinamide")
Niacin is converted to nicotinamide
Although identical in vitamin activity, nicotinamide does not have the same pharmacological effects as niacin
Nicotinamide does not reduce cholesterol or cause flushing.
Nicotinamide may be toxic to the liver at doses exceeding 3 g/day for adults.

38. Niacin Blocks breakdown of fats in adipose tissue
thus ’s FFA’s-> ’s secretion of VLDL and cholesterol by the liver.
By ’ing VLDL levels, niacin also ’s HDL
’sTC, TG (38%), VLDL, LDL(16%)
HDL (22%)
May  lipoprotein(a)

39. Niacin Pharmacological doses :1.5 - 6 g/d
SE:flushing, itching,rash, acanthosis nigricans, hyperuricemia (hi dose, exac. gout)
GI: dyspepsia, liver toxicity (>2gm/d, slow release)
Hyperglycemia (hi dose), cardiac arrhythmias
Flush duration ”, itching sensation
mediated by prostaglandin
blocked by 325mg ASA 30”before or ibuprofen
take w/meals, 8oz liquid
resolves w/2wk, slow titrate
slow- or "sustained"-release forms lessen flush

40. inositol dietary supplement, esterified with niacin
sold as "flush-free" or "no-flush" niacin
often marketed and labeled as niacin
misleading consumers into thinking they are getting the active form of the medication.
this form does not cause the flushing
lipid-modifying evidence is contradictory, at best.

41. Niacin/ Niaspan
AHA & NCEP state: only prescription niacin should be used to treat dyslipidemias
and only under the management of a physician.
Because: niacin at effective intakes of  mg/day can also potentially have severe AE.
Monitoring of liver enzymes is necessary.

42. Niacin options: Niaspan (Tier 2) 1-2g qhs Slo-Niacin Nicotinic acid
start 500 x1mo,  by 500 qmo; max 2g/d cyp450
Slo-Niacin
Nicotinic acid
vit B3
niacin
Make sure it’s nicotinic acid!!

43. OMEGA 3 MOA:Nutritionally important n−3 fatty acids:
α-linolenic acid (ALA)
eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA)
All polyunsaturated
OMEGA 3
EPA & DHA
stimulate circulation
 breakdown of fibrin
 blood pressure
 trigs
regular intake ‘s Mi risk
Body cannot synthesize n−3 fatty acids
Converts α-linolenic acid to ALA, EPA, DHA
conversions slows if high levels of n−6 fatty acids,
(closely related, derived from linoleic acid)

44. Omega 3: n−3 & n-6 fatty acids
1979: “eicosanoids” discovered: thromboxanes (platelet function), prostacyclins, leukotriene
N6 & N3 compete to be converted to eicosanoids; so ratio of 3:6 affects type eicosanoids produced.
(n−6 converted to pro-inflammatory prostaglandins)
(N-3: ALA, DHA, EPA)
To control the synthesis of n−6 eicosanoids, consume more n−3
n−6:n−3 fatty acids in oils:
canola 2:1
soybean 7:1
Olive :1
sunfl(no n−3)
flax :3
cottonseed (almost no n−3)
peanut (no n−3)
grapeseed oil (almost no n−3)
corn oil :1

45. Omega 3: OTC
OTC products claim to contain health promoting 'omega 3', but contain only α-linolenic acid (ALA), not EPA or DHA.
They contain plant oils that must be converted to DHA -> less efficient.
DHA & EPA are made by microalgae in seawater, consumed by fish, accumulate in internal organs.

46. Daily values Foods: cold water oily fish 7x n3:n6 Salmon Herring
Mackerel
Anchovies
sardines
tuna (less n−3)
Daily values
Acceptable intake for n−3 is 1.6 grams/day for men and 1.1 grams/day for women
Higher intakes : protection against CAD
3 g of total EPA/DHA qd safe, no increased risk of bleeding
Perceived risk heavy metal poisoning
Heavy metals selectively bind with protein in the fish flesh rather than accumulate in the oil.

47. Omega 3: rx Lovaza Highly purified, more effective
Combination E-EPA / E-DHA
4gm /d
TG 14-30%
HDL 10%
DI: anticoagulants
SE: fish burp (freeze)
Monitor: LFTs

48. OTC:Krill relatively new source of n−3 fatty acids.
Various claims are made in support of krill oil as a superior source of n−3 fatty acids
B/c less contamination, contain a special antioxidant called astaxanthin.
However, numerous studies have found krill is often contaminated by pollution and astaxanthin hasn't been demonstrated to have a very potent antioxidant capacity

49. EZETIMIDE MOA: localizes at brush border of SI
 cholesterol absorption
Specifically, binds to a critical mediator of cholesterol absorption, the Niemann-Pick C1-Like 1 (NPC1L1) protein on the GI epithelial cells and hepatocytes
 cholesterol absorption leads to an upregulation of LDL-receptors thus  LDL-c uptake into cells, thus decreasing plasma levels

50. Zetia
LDL 18%
2 major, high-quality clinical trials (2008,2009) showed that it did not improve clinically significant outcomes
panel of experts concluded in 2008 that it should "only be used as a last resort".
Formulations: Zetia10mg, Vytorin (Simva+Zetia)
SE:
HA, diarrhea
Rare: myalgia,  LFTs, rash, angioedema, myopathy

51. Bile Acid sequestrants
Bile Function:
-made in liver
-stored in gb
-released in to duodenum
Where it emulsifies fats:
-hydrophilic & hydrophobic side, thus aggregate around fat (trigs & phospholipids)
to form micelles
Then absorbed by intestinal villi
TG’s
P’s
photo

52. BILE ACID SEQUESTRANTS: MOA
BAS exchange
Cl- ions for bile
acids.
bind bile acids
->remove from
enterohepatic circ.
->excrete in feces
With in bile acids, cholesterol is converted to bile acid to normalize bile acid levels.
Thus, ’ing plasma cholesterol concentrations.

53. Bile acid sequestrants
hypercholesterolemia
prevention of pruritus w/ chronic liver dz
Post chole dumping syndrome
USES
No systemic side effects.
GI: constipation, diarrhea, flatulence.
CI: bind other drugs, preventing absorption.
spaced several hours apart from other drugs.
bind fat-soluble vitamins, ADEK-> deficiency SE

54. Bile Acid Sequestrant
Cholestyramine Tier 1 4g/scoop qd-bid, by 4g/d qmo Max 24g.d; pre-meals 1-6x/d
Colestid Tier 3 1gm tab/ 5g/pkt or scoop g qd-bid; max 16/g/d;
give other meds >1hr pre or 4hr post
Colestipol Tier 1
Prevalite Tier 1 sugar free 4gm/scoop
Questran Tier 3 4g/scoop
Questran Light Tier 3 4g/scoop sugar free
Welchol Tier mg/tab or powder
6 tab qd; w/meals; other drugs >4hr pre

55. the end! Get those buses off the road!!
Questions?