L39&40.Drugs Used to Treat Hyperlipidemia Flashcards Preview

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Flashcards in L39&40.Drugs Used to Treat Hyperlipidemia Deck (71):
1

Define hyperlipidemia

abnormal/elevated (elevated LDL or low HDL) levels of cholesterol/triglycerides in blood

2

Define atherosclerosis

build-up of lipids, cells, and other compounds in the arterial wall (can be over the course of many years)
-hardening of artery and narrowing of the arterial lumen
-increased risk of plaque rupture and clot formation (can lead to MI or stroke)

3

What is the relationship with LDL and atherosclerosis

-an increase in LDL (bad cholesterol) progresses hyperlipidemia
-triglycerides also have some increase on hyperlipidemia (not as strong as LDL)
-at >500mg/dL triglycerides can lead to pancreatitis (painful, deadly)
-in general, elevated serum triglycerides are an INDEPENDENT risk factor for atherosclerosis and cardiovascular dz
-HDL (good cholesterol) can inhibit hyperlipidemia
-decreased levels of HDL=independent risk factor for development of cardiovascular dz

4

What are lipoprotein particles?

-carrier molecules for the transport of cholesterol and triglyceride in the blood (from the liver to the periphery)
-differ in size, lipid content, and associated apolipoproteins

5

What are the THREE main components of lipoprotein particles?

1. lipid membrane-phospholipids/cholesterol
2. hydrophobic core-triglycerides and cholesterol esters
3. apolipoproteins-structural proteins and ligands for particle uptake
-apolipoprotein B100 (structural/LDLR ligand)

6

What is the lipid composition of LDL?

60 cholesterol
25 triglyceride
BAD CHOLESTEROL makes up 65-75% of total plasma cholesterol

7

What is the lipid composition of IDL?

35 cholesterol
25 triglyceride

8

What is the lipid composition of VLDL?

20 cholesterol
55 triglyceride

9

What is the lipid composition of chylomicrons?

85 triglyceride
~3 dietary cholesterol

10

What is the lipid composition of HDL?

35 phospholipid
20 cholesterol
5 triglyceride
GOOD CHOLESTEROL

11

What are the causes of hyperlipoproteinemia?

1. Genetics: monogenic (defective LDL receptor in familial hypercholesterolemia) or polygenic (familial combined hyperlipoproteinemia)
2. lifestyle (high fat diet) and other secondary causes (T2DM, lipodystrophy, and hypothyroidism)
3. combo

12

Type 2a primary Hyperlipoproteinemias

effects on lipoproteins: INCREASE LDL
atherosclerosis:+++
1. familial hypercholesterolemia
-0.2%
-LDL receptor defect
2. familial apoB100 defect
-0.1%
-decreased binding of LDL to LDLR
3. polygenic hypercholesterolemia
-relatively COMMON
-unknown defects result in impaired clearance of LDLs

13

Type 2b primary hyperlipoproteinemias

effects on lipoproteins: INCREASE VLDL+LDL
atherosclerosis:+++ (obesity, insulin resistance often present)
1. familial combined hyperlipidemia
-0.5%
-unknown (polygenic):overproduction of B100 and triglycerides (VLDL) and decreased LDL clearance

14

Type 3 primary hyperlipoproteinemias

effects on lipoproteins:INCREASE IDL
atherosclerosis:+++
1. familial dysbetalipoproteinemia
-0.02%
-mutant ApoE: increased production/decreased clearance of VLDL remnants

15

What are the three main Types of primary hyperlipoproteinemias with the Fredrickson classification?

-Type 2a
-Type 2b
-Type 3

16

What are the secondary causes of hyperlipoproteinemias? [Hypertriglyceridemia]

-obesity and overweight
-physical inactivity
-cigarette smoking
-excess alcohol intake
-high carb diet (>60%)
-stress
-pregnancy
-certain diseases (T2DM, nephrosis, hypopituitarism, lipodystrophy)
-certain drugs (estrogens, corticosteroid excess, OCP, ARV therapy)

17

What are the secondary causes of hyperlipoproteinemias? [Hypercholesterolemia]

-dietary excess: cholesterol and saturated fats
-nephrotic syndrome
-hypothyroidism
-hypopituitarism
-T2DM
-anorexia nervosa
-acute intermittent porphyria
-biliary cirrhosis
-corticosteroid treatment
-ARV therapy

18

What are the treatment option for hypercholesterolemia dependent on?

-dependent on the degree of LDL-cholesterol elevation and the calculated CV risk
a) For moderate hyperlipidemia with low cardiovascular risk factors lifestyle changes maybe sufficient to normalize lipoprotein levels.
(i) Dietary reduction of cholesterol intake
(ii) Exercise- improves lipoprotein metabolism
(iii) Weight reduction- improves lipoprotein metabolism

b) For patients with more severe hypercholesterolemia and/or with a high
cardiovascular risk, drug therapy should be initiated. The initial drug of choice is a STATIN

19

What are the treatment options for hypertriglyceridemia (elevated triglycerides)?

a) Lifestyle change: very low fat diet and exercise
b) If necessary (i.e. TG> 500mg/ml), triglyceride-lowering drugs such as a fibrate or niacin can be initiated

20

What are the HMG-CoA reductase inhibitors ("STATINS")?

Atorvastatin (Lipitor®)
Fluvastatin (Lescol®)
Lovastatin (Mevacor®)
Simvastatin (Zocor®)
Pravastatin (Pravachol®)
Rosuvastatin (Crestor®)

21

STATINS primary clinical effect

x Significant reduction in LDLs (20-60%- dose and drug specific)
x Modest reduction in triglycerides (10-20%)
x Modest 5-10% increase in HDLs

22

STATINS MOA

a) Inhibition of HMG-CoA reductase
-The statins are analogs of 3 hydroxy-3 methylglutarate, a key metabolite of cholesterol biosynthesis and inhibit HMG-CoA reductase- the rate-limiting step in cholesterol biosynthesis, thereby inhibiting endogenous cholesterol synthesis and the production of VLDLs.

b) Increased expression of LDL receptors
x Inhibition of HMG-CoA reductase results in the depletion of intracellular cholesterol, which activates the SREBP transcription factor resulting in the increased transcription of the gene encoding the LDL receptor.
x Increased LDL receptor expression at the plasma membrane results in the uptake of additional LDL from the circulation and the overall reduction of plasma LDL-cholesterol levels

c) Other properties of Statins that contribute towards their beneficial effects in the tx of atherosclerosis:
(i) Inhibit the adhesion of monocytes to the endothelium and migration to the arterial wall
(ii) Inhibit monocyte proliferation
(iii) Inhibit the expression of adhesion molecules expressed on the endothelium
(iv) Inhibit the oxidation of LDL to ox-LDL
(v) Inhibit SMC proliferation
(vi) Inhibit immune and inflammatory responses
(vii) Stabilize the endothelium making atherosclerotic plaques less likely to rupture

23

STATINS Therapeutic Uses

a) Drug of choice for treating patients with increased plasma LDL-C levels in all types of hyperlipidemia
b) The dose response relationship of STATIN drugs is non-linear: Doubling the STATIN dose only results in a 5-6% further decrease in LDL-C, while increasing potential toxicity.
c) Patients with Familial hypercholesterolemia benefit much less because of defect in LDL receptor.
d) Drug of choice for patients with high risk of cardiovascular disease irrespective of plasma cholesterol levels.

Numerous clinical trials have demonstrated that the use of either Atorvastatin (Lipitor®) or Simvastatin (Zocor®) in patients with a high cardiovascular risk (i.e. previous history of coronary heart disease, high blood pressure + smoking or type-2 diabetes) can significantly decrease (25-30%) their risk of future cardiovascular events (i.e. heart attack and stroke) and death due to CHD no matter what their initial baseline serum LDL-cholesterol levels.

24

STATIN PK

a) Statins are directly taken up into the liver by a specific anion transporter OATP2
b) There is extensive 1st pass extraction in the liver- consequently these drugs primarily exhibit their dominant effect in the liver
c) Lovastatin (Mevacor®), Simvastatin (Zocor®) & Atorvastatin (Lipitor®) are metabolized by CYP3A4 mechanisms
d) Fluvastatin (Lescol®) and Rosuvastatin (Crestor®) are metabolized by CYP2C9 mechanisms
e) Pravastatin (Pravachol®) is not metabolized via the cytochrome P450 pathway
f) Half-lives for Lovastatin (Mevacor®), Simvastatin (Zocor®), Pravastatin (Pravachol®) & Fluvastatin (Lescol®) are ~ 1.5- 2hrs
g) Half-life for Atorvastatin (Lipitor®) is 14hrs and for Rosuvastatin (Crestor®) is 19 hrs
h) All Statin drugs are glucoronidated in the liver: enhances metabolism and secretion

25

STATIN AE

a) Generally well tolerated- patients that can tolerate one statin can generally tolerate another- mild GI disturbances, headache or rash may occur
b) Biochemical abnormalities in liver function have also been reported (1-2%)
c) Small risk in type-2 diabetes, although benefit clearly outweighs the risk
d) Myalgia (muscle pain; 2-11%) and Myopathy (muscle weakness) are common and increase with increasing dose of drug
e) Rhabdomyolysis (muscle disintegration), although reported, is rare and occurs
primarily at high doses of drug – can lead to renal failure and even death (8% of cases)
-Symptoms: fever, malaise, diffuse myalgia and/or tenderness, marked elevation of serum creatine kinase and myoglobin present in the urine
--- More common in patients with either acute/chronic renal failure, obstructive liver disease, or hypothyroidism
---Can be observed with drug interaction especially inhibitors of CYP3A4 e.g. cyclosporin, tacrolimus, ketoconazole/itraconazole, HIV Protease inhibitors (see below) and gemfibrozil
---Fewer muscle effects are observed with Pravastatin (Pravachol®)

26

Generalized STATIN Drug Interactions

a) All statins with the exception of Pravastatin (Pravachol®) are metabolized in the liver by the cytochrome P450 system
b) Drugs that inhibit cytochrome P450 enzymes will increase the concentrations of statins leading to increased risk of adverse effects such as myopathy and Rhabdomyolysis

x CYP3A4 inhibitors lead to elevated levels of Lovastatin (Mevacor®), Simvastatin (Zocor®) & Atorvastatin (Lipitor®)
CYP3A4 inhibitors associated with increased risk of Rhabdomyolysis:
--Immunosuppressants: cyclosporin & tacroliminus
--Macrolide antibiotics: erythromycin, clarithromycin
--Calcium channel blockers: diltiazem, verapamil
--Anti-arrhthymia drugs: amiodrone
--Azole anti-fungal agents: itraconazole, ketoconazole
--HIV anti-retrovirals: amprenavir, indinavir, neflinavir & ritonavir
--Anti-coagulants: warfarin

x Inhibitors of CYP2C9 increase the plasma concentration of Fluvastatin (Lescol®) and Rosuvastatin (Crestor®) e.g. ketoconazole, itraconazole, metronidazole, sulfinpyrazone,

c) Grapefruit juice in large amounts (>1 liter/day) may also increase the plasma concentrations of Lovastatin, Simvastatin & Atorvastatin via inhibition of CYP3A

d) Drugs such as phenytoin, griseofulvin, barbiturates, rifampin and thiazolidnediones that increase expression of CYP3A4 can reduce plasma concentrations of Lovastatin (Mevacor®), Simvastatin (Zocor®) & Atorvastatin (Lipitor®).

e) Pravastatin (Pravachol®) is not metabolized by the cytochrome P450 system and is therefore the drug of choice for use with verapamil, the ketoconazole group of fungal agents and macrolide antibiotics.

f) Gemfibrozil (a fibrate -see below) inhibits the metabolism of ALL statin drugs (including pravastatin) by inhibiting statin glucoronidation, which is involved in the metabolism of all Statin drugs, thereby acting to increase statin drug concentrations and increasing the risk of myopathy and rhabdomyolysis. Gemfibrozil also affect Statin drug concentrations by inhibiting the OATP2 transporter-mediated uptake of Statins into the liver.

27

STATIN contraindications

a) Pregnancy and Nursing Mothers- statins have been shown to induce birth defects
b) Patients with Liver disease
c) Patients taking Gemfibrozil have an increased risk of myopathy and rhabdomyolysis.

28

What are the main bile acid-binding resins?

Cholestyramine (Questran®)
Colestipol (Colestid®)
Colesevelam (Welchol®)

29

Bile acid-binding resins-primary clinical effects

x Modest 10-25% reduction in LDLs (less effective than statins)
x can potentially cause a small increase in serum triglycerides

30

Bile acid-binding resins-MOA

a) Bile acid-binding resins are cationic polymers that act as anion exchangers that bind to negatively charged bile acids/salts and prevent their reabsorption in the small intestine

b) Resin/Bile acid complexes are excreted in the feces (~10-fold increase in excretion)

c) The decreased concentration of re-circulating bile acids up regulates the expression of cholesterol 7-D hydroxylase (rate limiting enzyme in the synthesis of bile acids) thereby promoting the enhanced hepatic conversion of cholesterol into additional bile acids, this lowers the concentration of hepatic cholesterol thereby increasing expression of LDL receptors (via activation of SREBP-see
above), which promotes the hepatic uptake of LDL from the plasma, resulting in an overall decrease in the plasma LDL concentration

d) Bile acids normally serve to suppress endogenous triglyceride synthesis (via a
complex pathway involving the FXR transcription factor). Consequently, in the
presence of bile acid resins this suppression is removed leading to increased synthesis of triglycerides. In the setting of type III dyslipoproteinemia this can lead to a significant increase in the production of VLDLs, leading to greatly enhanced levels of serum triglycerides that can potentially lead to the development of pancreatitis.

31

Bile acid-binding resins-Therapeutic Use

a) Because of the clinical efficacy of statins, bile acid-binding resins have largely been relegated to second line drugs that are mainly used for the treatment of primary hyperlipidemias in the young (

32

Bile acid-binding resins-PK

a) Not absorbed or metabolically altered by the intestine
b) Totally excreted in the feces

33

Bile acid-binding resins-AE

a) Since these agents are not absorbed or metabolized they are very safe with few side effects

b) GI disturbances are the most common side effects e.g. constipation, bloating, nausea and flatulence

c) At high concentrations Cholestyramine (Questran®) and colestipol (Colestid®), but not colesevelam (Welchol®) can impair the absorbtion of the fat soluble vitamins A, D, E and K – decreased Vitamin K can result in bleeding.

34

Bile acid-binding resins-Drug Interactions

a) Cholestyramine (Questran®) and colestipol (Colestid®), but not colesevelam (Welchol®), interferes with the intestinal absorption of many drugs e.g. tetracycline, Phenobarbital, digoxin, warfarin, paravatatin, fluvastatin, aspirin and
thiazide diuretics. - These Drugs should be taken either 1-2 hrs before or 4-6 hrs after bile acid-binding resins

35

Bile acid-binding resins-Contraindications

a) Dysbetalipoproteineimia and Raised Triglycerides (>400 mg/dL) due to risk of
further increasing triglyceride levels

36

What are some Inhibitors of intestinal sterol absorption?

Ezetimibe (Zetia®)

37

Ezetimibe (Zetia®)-Primary Clinical Effect

x Reduces LDL levels by ~18%
x Minimal effect on HDL and triglycerides

38

Ezetimibe (Zetia®)-MOA

a) Ezetimibe (Zetia®) inhibits the action of the Niemann-Pick C1-like protein (NPC1L1) involved in the absorption of both dietary and biliary cholesterol in the small intestine

b) This decreases the delivery of dietary cholesterol to the liver, thereby reducing the production of VLDLs. Since VLDLs are the precursors of LDLs, this also leads to a reduction in the serum concentration of LDL-cholesterol.

c) In addition, the reduction in hepatic cholesterol will also result in an increase in
the expression of LDL receptors, thereby promoting increased LDL clearance.

39

Ezetimibe (Zetia®)-Therapeutic uses

a) Reduces LDL levels in patients with primary hypercholesterolemia

b) Significant LDL lowering effects when combined with a STATIN- a further 25%
decrease in LDL versus STATIN-treatment alone.

c) The combination of Ezetimibe (Zetia®) together with a STATIN allows the use of
a lower dose of the STATIN drug, thereby avoiding potential STATIN-associated
adverse effects (e.g. Rhabdomyolysis).

40

Ezetimibe (Zetia®)-PK

a) Rapidly absorbed by the enterocytes

b) Recirculates enterohepatically several time/day. This acts to continuously re-
circulate the drug back to its site of action and limits systemic exposure.

41

Ezetimibe (Zetia®)-AE

a) Generally well tolerated

b) Flatulence is most common effect

c) Diarrhea and myalgia can occur

d) Low incidence of impaired liver function (reversible)

42

Ezetimibe (Zetia®)-Drug Interactions

a) Cyclosporin increases concentration of Ezetimibe (Zetia®)

b) Bile acid resins interfere with the absorption of Ezetimibe (Zetia®), and if used concurrently should be taken several hours apart

43

Ezetimibe (Zetia®)-Contraindications

a) Hypersensitivity to Ezetimibe (Zetia®)

b) Patients with mild to severe hepatitis

c) Pregnant women

44

What are the New anti-cholesterolemia drugs- inhibitors of PCSK9?

Alirocumab (Praluent®) and Evolocumab (Repatha®)

45

New anti-cholesterolemia drugs- inhibitors of PCSK9--Primary Clinical Effect

reduces LDL-C

46

New anti-cholesterolemia drugs- inhibitors of PCSK9-MOA

a) Alirocumab and Evolocumab are human antibodies that bind to the PCSK9 protein and prevent it from binding to the LDLR

b) PCSK9 is a secreted protein implicated in regulating the stability of the LDLR

c) Under normal conditions PCSK9 binds to the LDLR and is internalized with the receptor along with LDL. PCSK9 then helps target the LDLR to the lysosome where it is degraded rather than being recycled back to the plasma membrane

d) By binding to PCKS9 alirocumab and evolocumbab prevent the interaction of PCSK9 with the LDLR, thereby preventing its lysosomal degradation, resulting in higher levels of LDLR expressed on the plasma membrane and corresponding increased levels of LDL clearance.

e) Mutations in the gene encoding PCSK9 have been found to be responsible for a certain subset of patients with Familial Hypercholesterolemia. Those patients with gain-of-function PCSK9 mutations exhibit a greatly increased LDL serum concentration (>350 mg/dL) and a greatly increased risk of experiencing CVD mortality prior to 50 years of age.

f) Individuals with loss-of-function mutations in PCSK9 exhibit greatly reduced levels of LDL (>40%) and a greatly reduced risk of developing CVD.

47

New anti-cholesterolemia drugs- inhibitors of PCSK9-Therapeutic Use

a) Alirocumab and Evolocumab have been approved for treatment of:
--hypercholesterolemia in patients with heterozygous familial hypercholesterolemia
---the control of high LDL levels in patients that have not achieved goals using maximally tolerated doses of a STATIN.
---may also be useful for patients that are intolerant to STATINs.

48

New anti-cholesterolemia drugs- inhibitors of PCSK9-AE

Currently there have been no reports of significant adverse effects or drug interactions associated with the use of these drugs.

49

What are drugs to treat homozygous Familial Hypercholesterolemia?

1. Lomitapide
-an inhibitor of microsomal triglyceride transfer protein (MTP)
-responsible for the assembly to apoB48 and apoB100-containing chylomicrons and
VLDLS in enterocytes and hepatocytes, respectively.
-As a result, lomitapide reduces the endogenous production of both chylomicrons and VLDLs, thereby reducing levels of LDLs.
-Adverse Effects: Hepatotoxicity
-Contraindications: Pregnancy
-Drug Interactions: Many (inhibitor of Cyp3A4 and P-gp)

2. Mipomersen
-an antisense oligonucleotide specific for apoB100.
-administration of Mipomersen inhibits the synthesis of apoB100, thereby diminishing
the production of VLDLs and as a result lowering the serum concentration of LDLs.
-Adverse Effects: Hepatotoxicity
-Contraindications: mild to moderate hepatic impairment
-Drug Interactions: None reported

50

What are the Treatment Options for hypertriglyceridemia?

1. When serum triglyceride levels are borderline high (150-199 mg/dL) a lifestyle change is indicated including a low fat diet, exercise and cessation of smoking/alcohol

2. When serum triglyceride levels are high (200-499 mg/dL) initial emphasis should be on
reducing non-HDL cholesterol (i.e. LDL-C and VLDL) using a LDL-C lowering drug such as a
STATIN or the addition of niacin or a fibrate- ie. To reduce the risk of atherosclerosis

3. When serum triglyceride levels are very high (>500 mg/dL) the initial goal should be to reduce triglyceride levels with either niacin or a fibrate to reduce the risk of pancreatitis. Once triglyceride levels are below 500 mg/dL then LDL-C goals should be addressed

51

Drugs used in the treatment of Hypertriglyceridemia: NIACIN

Niacin (nicotinic acid/vitamin B3) is a water-soluble vitamin that, at physiological concentrations is used in the synthesis of NAD & NADP, both important co-factors in
intermediary metabolism. The pharmacological effects of niacin require large doses
(1,500- 3,000 mg/day) and are independent of conversion to NAD & NADP.

52

Drugs used in the treatment of Hypertriglyceridemia: NIACIN-Primary Clinical Effecct

x 30-80% reduction in triglycerides

x 10-20% reduction in LDLs

x 10-30% increase in HDLs-most effective drug at reducing HDL

53

Drugs used in the treatment of Hypertriglyceridemia: NIACIN-Therapeutic Use

a) Lowers both plasma cholesterol and triglycerides

b) Particularly useful in the treatment of familial combined hyperlipidemias and familial dysbetalipoproteinemia (elevation of both triglycerides and cholesterol)

c) Most effective agent at elevating HDL levels.

d) Often combined with another lipid lowering drug such as a statin or a resin

e) Niacin has been shown to reduce the incidence of myocardial reinfarctions and
overall mortality in patients with a history of previous MI

f) The use of Niacin is often limited by poor tolerability (see below).

54

Drugs used in the treatment of Hypertriglyceridemia: NIACIN-MOA

a) Niacin improves virtually all lipid parameters resulting in decreased free fatty acids (FFA), VLDL & LDL and increased HDL

b) Niacin acts via its Gi-coupled GPCR (GPR109A) expressed in adipose tissue to
inhibit cAMP-induced lipolysis (stimulated via the Gs-coupled beta-adrenergic receptor.

c) The reduced levels of lipolysis reduce the release of free FFA to the liver

d) Decreased FFA to the liver causes a reduction in the synthesis of triglycerides
that in turn reduces production of VLDLs

e) Reduced VLDLs in turn reduce the production of LDL-C

f) Niacin inhibits DGAT2 (Diacylglycerol acyltransferase)- the rate limiting step in
hepatic triglyceride synthesis, thereby decreasing hepatic VLDL production

g) Niacin decreases the expression of apoCIII (secreted inhibitor of Lipoprotein Lipase) resulting in increased LPL activity and a corresponding increase in VLDL clearance

h) Niacin acts to decrease macrophage recruitement to atherosclerotic plaques

i) Niacin also increases the half-life of apoAI, the major apolipoprotein present in HDL, which in turn increases the plasma concentration of HDL and promotes reverse cholesterol transport (the HDL-mediated transport of cholesterol from the peripheral tissues to the liver where it can be excreted).

j) Niacin also significantly reduces the levels of Lp(a) lipoprotein, which is a modified form of LDL that is covalently coupled to the Lp(a) protein. The Lp(a) protein is homologous to plasminogen and is found in atherosclerotic plaques, where it is thought to contribute towards atherosclerosis by antagonizing the
activation of plasminogene thereby inhibiting thrombolysis. Niacin is the only lipid lowering drug to significantly reduce the levels of Lp(a) lipoprotein.

55

Drugs used in the treatment of Hypertriglyceridemia: NIACIN-AE

a) Most patients experience skin flushing, itching (pruritis) and a sensation of warmth – this prostaglandin-mediated effect can be diminished by prior treatment with Aspirin or Ibuprofen

b) Some patients experience GI distress, nausea and abdominal pain.

c) Niacin inhibits tubular secretion of uric acid and therefore predisposes to hyperuricemia and gout (20% of patients)

d) Can cause insulin resistance (generally reversible) and hyperglycemia may be worsened in susceptible patients i.e. Type-2 diabetes

e) Hepatic toxicity has been reported

f) Niacin can exacerbate peptic ulcer and is therefore contraindicated in patients with severe peptic disease

g) Poor tolerability often limits the use of the drug

56

Drugs used in the treatment of Hypertriglyceridemia: NIACIN-Contraindications

a) Peptic Ulcer disease

b) Patients with a history of Gout

c) Caution should be observed in diabetics

d) Caution should be observed in patients with impaired liver function

57

What are the drugs used in the treatment of Hypertriglyceridemia: Fibrates?

Fenofibrate (Tricor®, Lofibra®)
Gemfibrozil (Lopid®)

58

Drugs used in the treatment of Hypertriglyceridemia: Fibrates-Primary clinical effect

x 40-60% reduction in triglycerides

x mild (10-20%) reduction in LDL

x 10-20% increase in HDL

59

Drugs used in the treatment of Hypertriglyceridemia: Fibrates-MOA

a) Fibrates are derivatives of fibric acid and act as ligands for the nuclear hormone transcription factor peroxisome proliferator-activated receptors alpha (PPARD).

b) Fibrates activate PPARD, which then binds to its responsive element in the promoters of numerous genes involved in lipoprotein structure and function

c) PPARalpha activation acts to decrease plasma triglyceride concentrations by:
(i) increasing the expression of lipoprotein lipase in muscle, thereby resulting in increased muscle lipolysis leading to enhanced uptake and catabolism of triglyceride-rich lipoproteins.
(ii) decreasing the hepatic expression of apolipoprotein CIII (a known inhibitor of lipoprotein lipase), which acts to enhance overall lipoprotein lipase activity, thereby increasing the catabolism of triglyceride-rich lipoproteins.)
(iii) increasing the expression of genes involved in fatty acid transport and fatty acid oxidation in hepatocytes, which results in increased fatty
acid catabolism, thereby reducing hepatocyte triglyceride synthesis and decreasing the hepatic production of VLDLs

Overall effect: Increased peripheral VLDL clearance and decreased hepatic TG
production = DECREASED serum [VLDL]

d) PPARD activation increases the plasma concentration of HDLs by increasing the synthesis of apoAI and apoAII, the major apolipoproteins found in HDL. This promotes reverse cholesterol transport.

e) PPARD activation also induces the upregulation of the SR-B1 scavenger receptor in hepatocytes, which binds to HDL and promotes increased transfer of cholesterol from HDLs to hepatocytes, thereby leading to increased secretion of cholesterol into the bile duct. This can lead to increased risk of gallstone formation.

60

Drugs used in the treatment of Hypertriglyceridemia: Fibrates--Therapeutic Uses

a) Effective at decreasing serum triglyceride levels

b) Useful for increasing concentration of serum HDL-C levels

c) Used in the treatment of hypertriglyceridemias, especially in patients with severe hypertriglyceridemia at risk of pancreatitis and in hypertriglyceridemia with low HDL-C

d) Therapy of choice for patients with Familial dysbetaliporoteinemia (Type III hyperlipoproteinemia: increased plasma triglycerides and lipoprotein remnants)

e) Long-term fibrate usage has been clinically proven to reduce the incidence of coronary events (22%), stroke (25%), and transient ischemia events (59%).

61

Drugs used in the treatment of Hypertriglyceridemia: Fibrates--PK

a) Both drugs are completely absorbed after oral administration

b) Drugs are distributed widely and are bound to serum proteins

c) Both drugs undergo extrahepatic circulation

d) Half-life for gemfibrozil is 1.5 hrs and for fenofibrate is 20 hrs

62

Drugs used in the treatment of Hypertriglyceridemia: Fibrates--AE

a) Generally well tolerated

b) most common side effects are mild GI disturbances

c) Predisposition to gallstone formation due to increased cholesterol excretion in the bile. Fibrates inhibit expression of cholesterol 7alpha-hydroxylase (the rate-limiting enzyme in Bile acid production), thereby decreasing Bile acid production resulting in increased secretion of free cholesterol, which can result in the formation of gallstones

d) Myopathy and rhabdomyolysis have been reported (esp. Gemfibrozil: increased risk when given with a STATIN)

e) Hepatitis

63

Drugs used in the treatment of Hypertriglyceridemia: Fibrates--Drug Interactions

a) Both drugs are strong protein binders and can therefore displace other protein-
bound drugs from albumin resulting in an increased serum drug concentration.
x potentiates the effects of oral anti-coagulants (e.g. warfarin) leading to increased risk of bleeding. Anticoagulant drug concentrations should be reduced by 30% when given together with a STATIN
x enhances hypoglycemic effects of sulfonylureas

b) Gemfibrozil increases the serum concentration of STATINS leading to increased risk of STATIN-induced adverse effects such as myopathy and rhabdomyolysis
x Gemfibrozil inhibits the transporter responsible for hepatic uptake of STATINs
x Gemfibrozil inhibits STATIN glucoronidation that is involved in the metabolism and excretion of all STATINs

c) Fenofibrate does not affect STATIN metabolism and is therefore the drug of choice for use with a STATIN in combination therapy.

d) Because both drugs are renally excreted, drug concentrations are elevated in patients with renal insufficiency, thereby increasing the risk of drug interactions.

64

Drugs used in the treatment of Hypertriglyceridemia: Fibrates--Contraindications

a) Pregnant/lactating women

b) Patients with severe hepatic dysfunction-due to increased risk of hepatic damage

c) Patients with severe renal dysfunction-since both drugs renally secreted

d) Patients with pre-existing gallbladder disease

e) Caution should be observed in patients taking a STATIN because of increased risk of Rhabdomyolysis

65

What are the drugs used in the treatment of Hypertriglyceridemia: Fish Oils: Omega-3 long chain polyunsaturated fatty acids?

A mixture of Eicosapentaenoic acid and Docosahexanoic acis (Omacor/Lorvaza)

66

Drugs used in the treatment of Hypertriglyceridemia: Fish Oils: Omega-3 long chain polyunsaturated fatty acids--Primary clinical effects

x Lowers serum triglyceride levels by 50%

x Minor increase in HDL

x Can increase LDLs in some individuals

67

Drugs used in the treatment of Hypertriglyceridemia: Fish Oils: Omega-3 long chain polyunsaturated fatty acids--MOA

Unclear, but appears to involve the inhibition of hepatic triglyceride synthesis and the increased triglyceride clearance

68

Drugs used in the treatment of Hypertriglyceridemia: Fish Oils: Omega-3 long chain polyunsaturated fatty acids--Therapeutic Uses

Currently approved only as an adjunct to diet and lifestyle interventions in the treatment of hypertryglyceridemia in patients with TG levels >500 mg/dl

69

Drugs used in the treatment of Hypertriglyceridemia: Fish Oils: Omega-3 long chain polyunsaturated fatty acids--AE

a) Fishy after taste

b) GI: nausea, bloating, diarrhea, flatulence

c) reduces serum concentrations of vitamin E

70

Drugs used in the treatment of Hypertriglyceridemia: Fish Oils: Omega-3 long chain polyunsaturated fatty acids--Drug Interactions

a) None

b) Unlike fibrates, fish oils are not associate with an increased risk of Rhabdomyolysis when given together with a STATIN

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When is combination drug therapy useful?

a) LDL-cholesterol levels are not sufficiently reduced in high-risk patients even withthe highest dose of STATIN
- A STATIN + either a Resin, Ezetimibe or Niacin
Synergistic reduction of LDL-cholesterol with drug combination

b) Both LDL and VLDL levels are elevated (e.g. combined hyperlipoproteinemia)
- STATIN + Niacin – more effective than either agent alone
- STATIN + fibrate - in cases where TG and LDL are very high- however should be used with caution as increased risk of myopathy especially with Gemfibrozil (Fenofibrate is preferred drug in this case)

c) When LDL or VLDL levels are not normalized with a single drug regime

d) When HDL deficiency co-exists with other hyperlipidemias

e) When VLDL levels are increased during treatment of hypercholesterolemia with a bile acid-binding resin
- Niacin is added to control elevated VLDL levels
- Either Niacin or a fibrate is added to increase HDL