Dyslipidemia Drugs Flashcards
A 56- year old retired school teacher with treated blood
pressure of 125/82 mmHg comes in for a semi annual
exam.Blood chemistry is showed LDL is 230 and HDL
is 54. You placed him on a drug and asked him to
return after one month. Usually, in managing patients
with dyslipidemia, we advise follow up after a month to
assess the response to treatment as well as the
adverse effect. On his return, his LDL is reduced to 189
but complains of cramping pain in the gastrocnemius
on both legs
The drug that will most likely have this adverse effect is which drug? a. Ezetimibe b. Rosuvastatin c. Hydrochlorothiazide d. Niacin e. Gemfibrozi
LDL is elevated. The ideal level of LDL should be <100.
So which among these drugs used in managing
dyslipidemia may cause myopathy or myositis?
It is the statins as well as Gemfibrozil.
But for this case, the most common drug that is being
used is the statins because they are the first line drugs
in managing dyslipidemia so the answer for this case
is Rosuvastatin
LIPOPROTEIN
Lipoproteins are macromolecular assemblies that contain
lipids and proteins
LIPID (Core)
- Contains Cholesteryl ester, Triglycerides
and Fatty Acids - Water insoluble
- Surrounded by unesterified cholesterol,
phospholipids, and apolipoproteins
PROTEIN (outer surface)
Contains Apolipoproteins namely: § Apo A (seen in HDL) § Apo B (Apo B-48 in Chylomicrons, Apo B-100 in VLDL, LDL, IDL) - They have polar surface and are water soluble
Density and Size are inversely related
As you increase the amount of lipid, it
becomes less dense than water.
- Chylomicrons: more lipid, least dense
• The higher amount of lipid, the larger the
structure. The lower amount of lipid, the smaller
the structure
HDL
most dense, smallest
Chylomicrons:
least dense, largest.
APO LIPOPROTEINS
Responsible for the structural integrity
- Functions as a ligand and bind to different
receptors
- Activates enzymes important in lipoprotein
metabolism
Any lipoprotein that contains Apo B-48 and Apo B-100
can cause
Atherosclerosis
Clinical Sequela: Atherosclerosis and Acute pancreatitis
Main goal of management: lower LDL
CIGARETTE SMOKING
Can increase the risk of developing Atherosclerosis - Effects of cigarette smoking: (DICIS) • Decrease in HDL • Impairment of cholesterol retrieval • Cytotoxic effects on the endothelium • Increased oxidation of lipoproteins • Stimulation of thrombogenesis
CHYLOMICRONS
- Largest lipoprotein
- Contains Apo B-48
- Synthesized from the dietary triglyceride and
cholesterol that comes from the diet.
Chylomicrons are formed in the intestine and carry
triglycerides of dietary origin, unesterified cholesterol,
and cholesteryl esters
Pathway for Cholesterol Transport
- Ingestion of dietary fat
- The cholesterol and the triglyceride present in the diet would be esterified by Type II Acyl Coenzyme Cholesterol Transferase
Esterification: elongation and addition of fatty acid to TAG and Cholesterol.
The esterification is with the effect of Microsomal Triglyceride Transfer Protein (MTP) - Cholesteryl Ester + long chain FA with TAG + apo B48 absorbed in the intestine via Niemann Pick C1L1 = CHYLOMICRON
- Once absorbed, the chylomicron enters the thoracic lymph where in it will be used by the peripheral tissue
before it goes to the liver - Chylomicron will become chylomicron remnants when it is acted upon Lipoprotein Lipase (remove the TAG within the chylomicron) LPL needs a cofactor ApoC2 to be activated
- Chylomicron remnants (less TAG, more cholesterol) would then be endocytosed in the liver (apoE mediated)
- It will then be acted upon by Hepatic lipase
- Degraded
Exogenous pathway
transport dietary lipids to the
periphery and the liver
Endogenous pathway
transports hepatic lipid from the
liver to the peripher
• Chylomicrons are converted to chylomicron
remnants by the hydrolysis of their triglycerides
by LPL.
“Remnant receptors”
nclude the LDL receptorrelated protein (LRP), LDL receptors, and other
receptors.
• Free Fatty acid (FFA) released by LPL is used by
muscle tissue or taken up and stored by adipose
tissue.
The TAG is removed from the Chylomicron by
LPL,
the FA will be stored in the adipose tissue
VLDL will then be hydrolyzed by LPL releasing free FA
producing
IDL
Intermediate Density Lipoprotein (IDL
will be
endocytosed to the liver which is ApoE mediated.
- Further hydrolysis of IDL by LPL and Hepatic Lipase
will release more TAG would produce LDL
Low Density Lipoptotein
would then be endocytosed to the liver which is ApoB mediated - LDL binds to the LDL receptor - Liver would have more cholesterol. - Increased Cholesterol level à LDL receptor down regulated
Decreased Cholesterol level
LDL receptor up
regulated
Chylomicron remnants
can indirectly increase
LDL level but do not serve as a precursor for LDL
synthesis.
LOW DENSITY LIPOPROTEIN
LDL are catabolized chiefly in hepatocytes and other cells
after receptor-mediated endocytosis.
- Clearance is mediated by LDL receptor
- Apo B100 is the ligand that binds LDL to its receptors (that is why it is called “BAD
CHOLESTEROL)
- Become atherogenic when they are modified by oxidation à FOAM CELL formation
- Increased LDL receptor à decreased LDL level
HIGH DENSITY LIPOPROTEIN
APO A1 is the major HDL apoprotein
1. The membrane transporter ABCA I facilitates the transfer of free cholesterol from cells to HDL
- As Cholesteryl ester of HDL increases à Cholesteryl ester begin to be exchanged for TAG
derived from any TAG containing Lipoprotein mediated by Cholesteryl Ester Transfer Protein (CETP) - HDL cholesterol selectively taken up by the liver via SR-BI (scavenger receptor class B1
Good cholesterol results from participation of HDL in Reverse Cholesterol Transport =
excess cholesterol is acquired from cells and transferred to the liver for excretion
Chylomicron vs VLDL
Chylo- apob-48
VLDL- apob-100
• High-density lipoproteins (HDL) exert several
antiatherogenic effects.
• They participate in retrieval of cholesterol from
the artery wall and inhibit the oxidation of
atherogenic lipoproteins.
• Low levels of HDL (hypoalphalipoproteinemia)
are an independent risk factor for atherosclerotic
disease and thus are a potential target for
intervention.
ATP binding cassette transporter A1 (ABCA1)
helps in the acquisition of phospholipids and
cholesterol from cells to HDL
Cholesterol will then be esterified by
Lecithin
Cholesterol Acyl Transferase (LCAT)
The cholesteryl ester present in the HDL would be exchanged with the TAG present in the TAG rich lipoprotein (VLDL, IDL, LDL) mediated by
CETP (Cholesteryl Ester Transfer Protein)
CE will be acted upon by lipoprotein lipase and
hepatic lipase incorporating it in the LDL It will
then bind in the LDL receptor, degraded in the
liver therefore
reducing LDL level
DIRECT PATHWAY
HDL interacts with receptor
SR-B1 on the liver, allowing the direct delivery of
cholesterol.
INDIRECT PATHWAY
o Via Cholesterol Ester Transfer Protein
(CETP Mediated).
o CETP facilitates the exchange of cholesterol in HDL for the triglycerides.
o With the triglyceride rich particles such as VLDL and LDL.
o In this one to one exchange, HDL now
becomes enriched with triglycerides and LDL becomes enriched with cholesterol.
o LDL particles interact with LDL receptors in the liver.
o Where LDL deposit the LDL ester content at the LDL receptor
VERY LOW DENSITY LIPOPROTEIN
VLDL are secreted by liver and export
triglycerides to peripheral tissues.
VLDL triglycerides are hydrolyzed by LPL, yielding free fatty acids for storage in adipose tissue and for
oxidation in tissues such as cardiac and skeletal muscle.
“beta shift”
phenomenon, the increase of LDL
(beta-lipoprotein) in serum as hypertriglyceridemia subsides.
• Increased levels of LDL can also result from
increased secretion of VLDL and from decreased
LDL catabolism.
Lp(a) LIPOPROTEIN
- Lp(a) lipoprotein is formed from LDL and the (a) protein, linked by a disulfide bridge.
- The (a) protein is highly homologous with plasminogen but is not activated by tissue plasminogen activator.
- Lp(a) is found in atherosclerotic plaques and contributes to coronary disease by inhibiting thrombolysis.
- It is also associated with aortic stenosis.
- A common variant (I4399M) in the coding region is associated with elevated levels.
Triglycerides
Normal : <150
High : 200-499
Goal : < 120
LIPOPROTEIN DISORDERS
- Primary Hypertriglyceridemias
a. Primary chylomicronemia
b. Familia hypertriglyceridemia
c. Familial combined
hyperlipoproteinemia
d. Familial dyslipoproteinemia - Primary Hypercholesterolemias
- Secondary Hyperipoproteinemia
Before giving drug therapy, identify
first if it is Primary or
Secondary.
Secondary dyslipidemia means
there are other disease entities that cause the increase in LDL
cholesterol levels or reduced in HDL. An example would be Metabolic Syndrome manifested as insulin
resistance, abdominal obesity, high LDL, low HDL, and hyperuricemia. Once you manage DM, dyslipidemia
would also normalize.
Chylomicrons can be seen in the plasma after
3-4 Hours
after a fatty meal.
DIETARY MANAGEMENT OF LIPOPROTEINEMIA
In managing dyslipidemia, Pharmacotherapy is
not the first line. The first line is Lifestyle
modification
LIFESTYLE MODIFICATION:
- 20-25% lipid intake/day
- 8% saturated fat
- <200 mg cholesterol/ day
- Use of complex carbohydrates and fibers
- Cis-monounsaturated fats should predominate
- Weight reduction
- Caloric restriction
- Avoidance of alcohol
- Intake of fish oils
WHOM AND WHEN TO TREAT
• Sex: Both gender • Age: Men >45 yo, Women >55 yo • Cerebrovascular disease patients: because of elevated plasma cholesterol • Peripheral vascular diseases: Statins • Hypertensive patients and smokers • TYPE 2 DM (high TAG, total chole, LDL, and low HDL) • Post myocardial infarction or Revascularization patients.
AGE ASCVD
Male: >45 y/o
Female: >55 y/o
FAMILY HISTORY OF
PREMATURE CHD
a 1st degree relative (male
<55y/o, female <65y/o when
the first CHD clinical event
occurs)
CURRENT CIGARETTE
SMOKING
Defined as smoking within
the preceding 30 days
HYPERTENSION
Systolic BP: ≥ 140 Diastolic BP: ≥ 90 Or use of antihypertensive medication, irrespective of blood pressure
LOW HDL-C
<40 mg/dL (consider 50
mg/dL as “low” for women
OBESITY
T2 DM
BMI: 25 kg/mg2
Waist circumference
Men : > 40 inches
Women : > 35 inches
“STATINS
Competitive Inhibitors of HMG-COA Reductase
- Structural Analogs of HMG-CoA (3-hydroxy3methylglutaryl-coenzyme A)
- Lovastatin
- Atorvastatin
- Fluvastatin
- Pravastatin
- Simvastatin
- Rosuvastatin
- Pitavastatin
MECHANISM OF ACTION of Statins
HMG-CoA reductase inhibition
- Inhibits the important step in cholesterol
synthesis which then decreases cholesterol level therefore decreasing LDL level because of the upregulation of LDL receptor (increased clearance of LDL)
- mediates the first committed step in sterol biosynthesis
- Decreased cholesterol within the cell, LDL, IDL, VLDL
- Increase in the LDL receptor synthesis- more LDL will bind to the receptor decreasing the level of
LDL; increasing the CLEARANCE of LDL
- Increased in HDL
- Given per orem wherein 40% to 75% are absorbed except for fluvastatin (98%)
All undergo first pass hepatic metabolism.
- Adverse effect: Hepatotoxicity
- Half-life ranges from 1-3 hours except for PAR
(Pitav- 12hrs, Ator- 14hrs, Rosu- 19hrs)
- All are excreted in the bile and the remaining will
be excreted in the urine.
- Contraindications:
• Pregnant women
• Nursing mothers
• Children
*Most of the drugs used for managing dyslipidemia are
contraindicated in pregnancy, lactating mothers, and
children EXCEPT for RESINS. In some literatures, they
can give statins for children above 7-8 y/o depending on
the LDL level
Upregulation
> more LDL binds to receptor > LDL levels
in plasma are reduced
LDL level reduction
first drug of choice are STATINS
TAG level reduction:
FIBRATES
Increase HDL levels:
NIACIN
Rosuvastatin
- longest half-life
§ Absorption is enhanced by food except for PRAVASTATIN
Most of the statins are given at night
t (cholesterol
synthesis is usually at night) except for PAR
(Pitavastatin, Atorvastatin, Rosuvastatin)
Statins are classified based on their LDL lowering effect:
High intensity
- Atorvastatin (40-80 mg/day)
- Rosuvastatin (20-40 mg/day)
Moderate intensity
(lowers LDL by approx. 30-
less than 50%) Lova, Pita,Prava, Atro
Low intensity
y (lowers LDL by approx. <30%)
The latest recommendation is to start the patient,
especially those at risk for CHD, on HIGH intensity statins
Fluva
A patient with LDL level of 150 mg/dl came to
your clinic. Our goal is to lower the LDL (100mg/dL). Only
fluvastatin is available. At what dose would you prescribe
fluvastatin
GIVE THE PATIENT FLUVASTATIN
80mg/day (to reduce the LDL level by 33%)
Baseline LDL is 200mg/dL. Goal is 100 mg/dL.
What dosage of Atorvastatin would you give?
GIVE ATORVASTATIN 40 mg/day (50% reduction) interact with gemfibrozil, it would increase the incidence
of myopathy
Hepatotoxic
LFT baseline, 1-2 months then q 6-12 months - Goodmann 13th ed • 2012, FDA no longer recommend routine monitoring of ALT or other liver enzymes
Myopathy
- Elderly
- Hepatic or Renal dysfunction
- Small body size
- Untreated hypothyroidism
- Drugs that diminish statin catabolism
(macrolide, antifungal, fibrates)
CYP3A4 metabolizes
Atorvastain, Lovastatin,
Simvastatin (SAL)
• CYP2C9 metabolizes
Pitavastatin, Rosuvastatin,
Fluvastatin (PiRF)
CYP2C8
metabolizes Fluvastatin and Pitavastatin
All statins would undergo glycosylation
interact with gemfibrozil, it would increase the incidence
of myopathy
NIACIN (Nicotinic Acid)
Adipose tissue
o inhibits lipolysis of TAG by hormone
sensitive lipase
LIVER o reduces TAG synthesis by inhibiting synthesis and esterification of FFA → increase Apo B degradation o reduced TAG → decreased VLDL secretion → decreased production of LDL
Enhanced lipoprotein lipase activity
clearance
of chylomicron and VLDL triglycerides
Decreased fractional clearance of Apo A1 in HDL
→ increase HDL
Net Effects of Niacin
o decreased VLDL, IDL, LDL, as well as
triglycerides and Lipoprotein A
o increased HDL (by decreasing Apo A1
clearance)
Niacin [NYE-uh-sin] reduces LDL-C by 10% to 20% and is the most effective agent for increasing HDL-C. It also
lowers triglycerides by 20% to 35% at typical doses of 1.5 to 3 g/day
Niacin can be used in combination with
statins, and fixed-dose combinations of long-acting niacin with lovastatin and simvastatin are available. [Note: the
addition of niacin to statin therapy has not been shown to reduce the risk of ASCVD events.]
MECHANISM OF ACTION of Niacin
Niacin inhibits the lipolysis and mobilization of FFA
Decreases mobilization of FFA → decrease TAG
synthesis → decrease VLDL secretion → decreased LDL
At gram doses, niacin strongly inhibits lipolysis in adipose tissue, thereby reducing production of free fatty acids
(Figure 22.8). The liver normally uses circulating free fatty acids as a major precursor for triglyceride synthesis.
Reduced liver triglyceride levels decrease hepatic VLDL production, which in turn reduces LDL-C plasma
concentrations.
→ decrease serum VLDL
→ decrease serum LDL
→ increase HDL
due to reduced clearance
increase HDL
15- 30%
decrease TAG
35 – 45%
decrease LDL
20-25%
Absorption/Distribution/Elimination of Niacin
Given orally, excreted in the urine
Clinical use of Niacin
As an adjunct to dyslipidemia, or when a statin is contraindicated
Because niacin lowers plasma levels of both cholesterol and triglycerides, it is useful in the treatment of familial hyperlipidemias. It is also used to treat other severe hypercholesterolemias, often in combination with other agents.
Pharmacokinetics of Niacin
Niacin is administered orally. It is converted in the body to nicotinamide, which is incorporated into the cofactor
nicotinamide adenine dinucleotide (NAD+
). Niacin, its nicotinamide derivative, and other metabolites are excreted
in the urine. [Note: Administration of nicotinamide alone does not decrease plasma lipid levels.]
Adverse effects of niacin
The most common adverse effects of niacin are an intense cutaneous flush accompanied by an uncomfortable
feeling of warmth and pruritus.
Administration of aspirin prior to taking niacin decreases the flush, which is
prostaglandin-mediated.
Some patients also experience nausea and abdominal pain.
Slow titration of the dosage or use of the sustained-release formulation of niacin reduces bothersome initial adverse effects.
Niacin inhibits tubular
secretion of uric acid and, thus, predisposes patients to hyperuricemia and gout.
Impaired glucose tolerance and
hepatotoxicity have also been reported.
The drug should be avoided in active hepatic disease or in patients with an
active peptic ulcer.
Administration of aspirin prior to taking niacin
decreases the flush, which is
prostaglandin-mediated.
) FIBRIC ACID DERIVATIVES (FIBRATES
- Gemfibrozil
- Fenofibrates
- Fibrates function primarily as ligands for the nuclear transcription receptor, PPAR α
- Fish oil activates PPAR α
- Transcriptionally upregulate LPL, apo A-1 and apo A-2
- A major effect is an increase in oxidation of fatty acids in liver and striated muscle
- Increased lipolysis of lipoprotein TG, LPL
MECHANISM OF ACTION of Fibrates
Peroxisome proliferator-activated receptor alpha (PPAR-α) agonist
Apo A-I
Apo A-II
ABCA1
Fenofibrate is more effective than Gemfibrozil
increased HDL
- Increased HDL cholesterol
due to lower TG in
plasma → reduction in the exchange of TG into
HDL in place of cholesteryl ester
Effect on lipid profile by Fibrates
● Upregulation of apo A-1, apo A-2 and ABCA1 →
Increase HDL
- ABCA1: facilitates uptake of cholesterol to HDL
● Decrease apo C-3 (necessary for TAG synthesis and
VLDL synthesis) → Decrease VLDL → Increase action of
LP → Decrease LDL (decrease in substrate)
● Increasing clearance → Decrease LDL and VLDL
Clinical Application of Fibrates
Hypertriglyceridemia, Low HDL
Toxicity of Fibrates
- Rashes
- Gastrointestinal symptoms
- Myopathy (Gemfibrozil + Statin)
- Arrhythmia
- Hypokalemia
- High blood levels of aminotransferases or alkaline phosphatase
- Decrease in white blood count or hematocrit
- Both agents potentiates the action of coumarin and indanedione anticoagulants and doses of these agents should be adjusted
Avoided in patients with:
- Hepatic dysfunction
- Renal dysfunction’
- Biliary tract disease- Gallstones
- Pregnant women
- Children
. Adverse effects of Fibrates
The most common adverse effects are mild gastrointestinal (GI) disturbances. These lessen as the therapy
progresses.
drugs increase biliary cholesterol excretion, there is a predisposition to form gallstones.
Myositis (inflammation of a voluntary muscle) can occur, and muscle weakness or tenderness should be evaluated.
Patients with renal insufficiency may be at risk. Myopathy and rhabdomyolysis have been reported in patients taking
gemfibrozil and statins together.
The use of gemfibrozil is contraindicated with
simvastatin, and, in general, the use
of gemfibrozil with any statin should be avoided. Both fibrates may increase the effects of warfarin
Fibrates should not be used in patients with
severe
hepatic or renal dysfunction, in patients with preexisting gallbladder disease or biliary cirrhosis
BILE ACID – BINDING RESINS
- Enhance conversion of cholesterol to bile acids in
liver via 7-alpha- hydroxylation, which is normally
controlled by negative feedback by bile acids. - Decreased bile acid pool in liver leads to:
o increase hepatic bile acid synthesis
o decreased hepatic cholesterol (because
cholesterol would be used for bile acid
synthesis)
o Low hepatic cholesterol stimulates LDL
receptor synthesis
o Increase LDL clearance - Effect is not in the liver, but in the INTESTINE
Therapeutic uses of BABR
The bile acid sequestrants are useful (often in combination with diet or niacin) for treating type IIA and type IIB
hyperlipidemias. [Note: In those rare individuals who are homozygous for type IIA and functional LDL receptors
are totally lacking, these drugs have little effect on plasma LDL levels.]
Cholestyramine
can also relieve pruritus
caused by accumulation of bile acids in patients with biliary stasis
Colesevelam
also indicated for type 2 diabetes
due to its glucose-lowering effects
has fewer GI side effects than other bile acid sequestrants
Pharmacokinetics
Bile acid sequestrants are insoluble in water and have large molecular weights. After oral administration, they are
neither absorbed nor metabolically altered by the intestine. Instead, they are totally excreted in feces
Adverse effects
The most common adverse effects are GI disturbances, such as constipation, nausea, and flatulence.
BABR agents may impair the
absorption of the fat-soluble
vitamins (A, D, E, and K), and they interfere with the absorption of many drugs (for example, digoxin, warfarin, and
thyroid hormone).
BABR agents may raise triglyceride levels and are contraindicated in patients
hypertriglyceridemia (greater than 400 mg/dL)
only drug given to pregannt
BABR
EZETIMIBE
- A transport protein, NPCILI, is the target of
the drug - Selective inhibitor of intestinal absorption of
cholesterol and phytosterol - decreasing cholesterol in liver → increasing
LDL receptor → it decreases the LDL by 15- 20% - it is effective even in the absence of dietary
cholesterol because it inhibits reabsorption
of cholesterol excreted in the bile
Other effects of Ezetimbe
- Creates a pharmacologic ileal bypass blocking
about 55% of cholesterol absorption in the gut
and losing the return of cholesterol from the gut
to the liver. - Low incidence of reversible impaired hepatic
function with a small increase in incidence when
given with a reductase inhibitor - Myositis has been reported rarely
MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN INHIBITOR (MTTP) –
LOMITAPIDE
• Essential role in addition of TAG to VLDL in liver
and CM in intestine
• Inhibits VLDL secretion and accumulation of TAG
in liver
PCSK9 INHIBITORS
• Alirocumab
• Evolocumab
- Proprotein convertase subtilisin kexin type 9
- PCSK9 binds to the LDL receptor and degrade
the receptor → leads to increase in the level of
LDL in plasma
- PCSK9 inhibitor (antibodies) binds to the PCSK9
→ decreasing/preventing binding of PCSK to LDL
receptor → more LDL receptor present to
facilitate clearance of LDL
Alirocumab
[al-i-ROK-ue-mab] and evolocumab [e-voe-LOK-ue-mab] are PCSK9 inhibitors, which are
fully-humanized
monoclonal antibodies. These agents are used in addition to maximally tolerated statin therapy in patients with
heterozygous or homozygous familial hypercholesterolemia, or in patients with clinical ASCVD who require
additional LDL-C lowering
When combined with statin therapy, PCSK9 inhibitors
provide potent LDL-C lowering
(50% to 70%). They may also be considered for patients with high ASCVD risk and statin intolerance.
PCSK9
inhibitors are only available as
subcutaneous injections and are administered every two to four weeks. Monoclonal
antibodies are not eliminated by the kidneys and have been used in dialysis patients or those with severe renal
impairment. PCSK9 inhibitors are generally well tolerated. The most common adverse drug reactions are injection
site reactions, immunologic or allergic reactions, nasopharyngitis, and upper respiratory tract infections.
CHOLESTEROL ESTER TRANSFER PROTEIN
INHIBITOR (CETP INHIBITOR)
- The first drug in this class, Torcetrapib, aroused great interest because they it
- markedly increased HDL and reduced LDL
- However, it was withdrawn from the clinical trial because it increased cardiovascular event and death in the treatment group
- Anacetrapib and Dalcetrapib are analogs currently in clinical trials
CETP in HDL
facilitate exchange of triglyceride and
cholesterol ester from HDL and VLDL
Treatment with Drug Combination
- When VLDL are significantly increased during
treatment of hyperchole with resin - LDL and VLDL elevated initially
- LDL or VLDL normalized with single agent
- Elevated lp(a) or HDL deficiency coexist with
other hyperlipidemia
Omega-3 fatty acids
Omega-3 polyunsaturated fatty acids (PUFAs) are essential fatty acids that are predominately used for triglyceride
lowering. Essential fatty acids inhibit VLDL and triglyceride synthesis in the liver
The omega-3 PUFAs
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in marine sources such as tuna, halibut,
and salmon. Approximately 4 g of marine-derived omega-3 PUFAs daily decreases serum triglyceride
concentrations by 25% to 30%, with small increases in LDL-C and HDL-C
Icosapent [eye-KOE-sa-pent] ethyl
prescription product that contains only EPA and,
unlike other fish oil supplements, does not significantly raise LDL-C. Omega-3 PUFAs can be considered as an
adjunct to other lipid-lowering therapies for individuals with elevated triglycerides (≥500 mg/dL).
The most common side effects of omega-3 PUFAs include
GI effects (abdominal pain,
nausea, diarrhea) and a fishy aftertaste. Bleeding risk can be increased in those who are concomitantly taking
anticoagulants or antiplatelet agents.
Ezetimibe and PCSK9 inhibitors
can be
considered for add-on therapy, since there is evidence that these combinations further reduce ASCVD events in
patients already taking statin therapy
Liver and muscle toxicity
occur more frequently with
lipid-lowering drug combinations
statins
Lower LDL strongly
Increase HDL moderately
Lower Triglycerides- moderately
Fibrates
Mild effect on LDL lowering
high effect inn HDL increase
Strong lowering effect on Trigluycerides
Niacin
mild lowerinf of LDL
High increase in HDL
Moderate effects in lowering Triglycerides
BABR
Mild effect in LDL decrease
Mild increase in HDL and Triglycerides
CABI
mild lowering of LDL and Triglycerides
Mild increase in HDL
PCSK9 inhib
High lowering of LDL
Moderate incrwase in HDL
low effect on Triglycerides
R.L., a 42-year-old man with moderately severe coronary
artery disease, has a body mass index (BMI) of 29,
increased abdominal girth, and hypertension that is well
controlled. In addition to medicine for hypertension, he is
taking 40 mg atorvastatin.
Current lipid panel (mg/dL)
• Cholesterol: 184
• Triglycerides: 200
• Cholesterol (LDL-C): 110
• HDL-C: 34
• non-HDL-C: 150
• Lipoprotein(a) (Lp[a]) is twice normal.
• Fasting glucose is 102 mg/dL, and fasting insulin
is 38 microunits/mL.
• Liver enzymes are normal.
• Creatinine kinase level is mildly elevated.
The patient is referred for help with management of his
dyslipidemia. You advise dietary measures, exercise and
weight loss.
Which additional drugs would help him achieve his
lipoprotein treatment goals. LDL-C: 60-70 mg/dL,
Triglycerides: <120 mg/dL, HDL-C: >45 mg/ dL and
reduced level of Lp(a)?
NIACIN to markedly increase the HDL level. You
can give STATIN but Creatinine Kinase is mildly elevated
since an adverse effect of using STATIN is myopathy.
STATIN cannot markedly increase the HDL level.
Would this patient also benefit from a drug to manage
insulin resistance? If so, which drug?
• Best drug for patients suffering from metabolic syndrome: STATIN because patients with Metabolic Syndrome have increased LDL, decreased HDL, increased TG • Would cause pruritus? NIACIN • Myopathy? Niacin • Bloating? BA-BR • Contraindicated in pregnancy- Statins • Would increase the risk for gallstones? BA-BR
