Treatment of Dyslipidemia Flashcards
-Hypercholesterolemia is most commonly, but not exclusively, defined as elevated levels of — or —
An alternative term is — , which encompasses elevated — , — levels of HDL-C, and — abnormalities.
-Dyslipidemia isdiagnosed by measuring —
-Routine measurements (lipid profile) include:
total cholesterol (TC),
low-density lipoprotein cholesterol (LDL-C);
high-density lipoprotein cholesterol (HDL-C),
triglycerides (TG)
-Dyslipidemia promotes — .
It is a — disease and is a major risk factor for adverse — events.
low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (HDL-C);
dyslipdemia
triglecrides
low
qualitative lipid
serum lipids
atherscelrosis
complex
cardiovascular
Cholesterol can be obtained from the — or can be synthesised —
Cholesterol is transported in various —
Cholesterol is a component of — .
Cholesterol is a precursor for other important — as
diet or de novo
lipoproteins
cellular membranes
steroid molecules as: Bile salts
Steroid Hormones
Vitamin D
the framingham heart study:
TheFramingham Heart Studyis a long-term, longitudinal ongoingcardiovascularcohort studyof residents of the city ofFramingham,Massachusetts, aiming to assess if cardiac health can be influenced by lifestyle, environmental factors, and by inheritance.
The study began in 1948 with 5,209 adult subjects
Much of the now-common knowledge concerning heartdisease, such as the effects ofdiet,exercise, and commonmedications such asaspirin, and differences in cardiovascular (CV) riskbetween men and women, is based on thisstudy
Over 3,000 peer-reviewed papers published
Showed thathealthy diet, not beingoverweightorobese,and regularexerciseare all important in maintaining goodhealth
The Framingham Heart Study is the source of the term”risk factor”.
major findings from framingham heart study;
1960
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1970
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1980
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1990
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2000
Cigarette smoking is associated with increased risk of heart disease.
Increased cholesterol and elevated blood pressure is associated with increased risk of heart disease.
Exercise is associated with decreased risk of heart disease, and obesity with increased risk.
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Elevated blood pressure is associated with increased risk of stroke.
In women who are postmenopausal, risk of heart disease is increased, compared with women who are premenopausal.
Psychosocialfactors affect risk of heart disease.
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High levels ofHDL cholesterolis associated with lower risk of heart disease.
No empirical evidence found to confirm the rumour that filtered cigarettes lower the risk of heart disease as opposed to non-filters.
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Having an enlarged left ventricle of the heart (left ventricular hypertrophy) is associated with increased risk of stroke. Elevated blood pressure can progress to heart failure.
Framingham Risk Score is published, and correctly predicts 10-year risk of future coronary heart disease (CHD) events.
At 40 years of age, the lifetime risk for CHD is 50% (men) & 33% (women).
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So called “high normal blood pressure” is associated with increased risk of cardiovascular disease (high normal blood pressure is calledprehypertensionin medicine; it is defined as a systolic pressure of 120–139mm Hg and/or a diastolic pressure of 80–89mm Hg).
— mg of cholesterol in a day is made and —- from food
1000
200-500
classification of lipoprotein:
There are – major classes of lipoproteins based on their — .
The degree to which lipoproteins cause atherosclerosis depends to some extent on their – , and thus their ability to enter and form deposits within the —
Thus, – VLDL, IDL and LDL are all — , whereas – VLDL and chylomicrons are not.
HDL carries cholesterol – from the arterial wall and is protective
1-Chylomicrons (is — )
2-Very low-density lipoprotein (VLDL)
3-Intermediate-density lipoprotein (IDL)
4-Low-density lipoprotein (LDL)
Oxidised LDL most –
5-High-density lipoprotein (HDL)
Protective, takes cholesterol away from arterial wall
5
density
size
arterial wall
smaller
atherogenic
large
away
non atherogenic
atherogenic
LDLs ( aka bad cholesterol ) are the — carriers of — in the —
LDLdelivers cholesterol to both — and — cells where it is used in membranes or for the synthesis of —
Too-high levels of LDL are strongly associated with — and – events (10% increase in LDL results in a 20% increase in CHD risk)
Excess LDL is removed from the blood by — receptors
LDL receptors expression on hepatocytes are strictly regulated by — mechanisms
Modified by other risk factors:
— HDL cholesterol
- —
- —-
- —
primary
cholesterol
blood
peripheral
liver cells
steroid hormones
atherscolorsis and CHD events
hepatocyte LDL receptors
homeostatic
low
smoking
hypertension
diabetes
check graph in slide 11 pls
HDL good cholesterol:
High density lipoproteins (HDL) picks up — in the— or – or from – cells, & returns it to the –
This is called — cholesterol transport (RCT)
Plasma HDL has a – correlation with coronary artery disease
Ideally, > 1.0mmol/L
Elevated HDL levels (>1.0 or 1.2 mmol/L)— the risk of CAD
HDL transfers cholesterol to the – for excretion in the bile
HDL receptors are constitutively expressed on —
cholesterol
blood
tissues
dying cells
liver
reverse
-ve
decreases
liver
hepatic cells
CHECK SLIDE 13 PLS
Dyslipidemia and atherosclerotic cardiovascular disease:
-Dyslipidemia is an important risk factor for — cardiovascular disease, including cerebrovascular disease, coronary heart disease, and peripheral arterial disease;
-It is usually symptomatically — until significant atherosclerosis has developed.
-It manifests as – , silent — , – angina, — , — , — , and sudden — :
Cardiovascular Disease
Cerebrovascular disease
Peripheral Vascular Disease
atherosclerotic
quiescent
angina
silent ischemia
unstable angina
myocardial infraction
arrhythmias
heart failure
sudden death
progression of CAD:
Coronary artery disease (CAD) is almost always due to atheromatous — and subsequent — ( — ) of the vessel.
The degree of stenosis is detected using —
Dyslipidemia is treated with:
lifestyle modifications such as dietary changes, exercise, and smoking cessation,
And /or pharmacologic intervention see slides # 25 -> end
narrowing
susbeuqnet occlusion
stasis
angiography
Dyslipidemias are divided into — and — subtypes.
Primary dyslipidemia is usually due to — causes (such as a — in a receptor protein; often but not always –),
Primary dyslipidemia can be due to a combination of — and — .
Secondary dyslipidemia arises due to other underlying causes such as:
Diabetes mellitus
Hypothyroidism
Obesity
Alcohol ingestion
Renal disease
Liver disease
Drugs (OCP, thiazides, steroids)
Secondary dyslipidemia accounts for approximately — of all dyslipidemia.
primary and 2ndary
genetic causes
mutations
polygenic
diet and genetic
30-40%
ethology of 1 degree dyslipidemia:
-Primary dyslipidemias are due to – or — gene — resulting in a disturbance of — and — production or —
-At least 18 separate entities have been described
-Primary dyslipidemias are most commonly seen in — and — and cause only a small percentage of new cases in—.
-Those with primary dyslipidemias are at higher risk of getting complications of dyslipidemias , such as— disease, at a — age
single or multiple
gene mutation
low-density lipoprotein (LDL) and triglyceride
clearance
children and young adults
adults
atherosclerotic cardiovascular
younger
ethology of 2 dyslipidemia:
-In modern world, — lifestyle and excessive consumption of — and– are the most important causes of Secondary Dyslipidemia
-Dyslipidemia can also be secondary to certain — , including chronic renal insufficiency, abdominal obesity, diabetes mellitus, hypothyroidism, cholestatic liver disease, and alcohol dependency.
-Certain drugs, including — -dose thiazide diuretics, oral — , — , anabolic — , — agents, and atypical antipsychotics such as olanzapine and clozapine have also been implicated in causing mild-to-moderate degrees of dyslipidemia.
- Most adult cases of dyslipidemia are due to a combination of the effects of — and –
- dyslipidemias are classified into – phenotypes( check slide 23)
sedentary lifestyle
saturated fats and trans fatty acids
medical conditions
high dose
oestrogen’s
glucoroticodes
steriods
anti hiv
polygenes and unhealthy lifestyle
6
type lla - Familial Hypercholesterolaemia(FH) :
-An especially great risk of — heart disease occurs in a subset of primary type IIa Frederickson’s hyperlipoproteinaemia caused by – -gene defects of – receptors
-This is known asfamilial hypercholesterolaemia(FH),
-In FH, the plasma total cholesterol concentration, normally <– mmol/L, in affected adults is typically >– mmol/L in heterozygotes and — mmol/L in homozygotes.
-Brown and Goldstein (1986) shared a Nobel Prize for defining the LDL receptor pathway of cholesterol homeostasis
-People with very low, or very high, circulating LDL cholesterol concentrationsled to the discovery of inactivating and gain-of-function variants ofthe—
ishcemic
single
LDL
5
8
12-25
PCSK9gene
management of dsyslipidemia:
- Except for familial causes of hypercholesterolemia, of which there are >18 different genetic contributors, acting alone or in combination, the disease is largely related to the — and—.
-The adoption of a — diet, – cessation and a reasonable amount of – exercise, will have a large impact on the prevalence of hypercholesterolemia, as well as of obesity and coronary heart disease.
-Several pharmacological treatment options exist for people with persistent hypercholesterolemia, which may be used individually or in combination with each other or lifestyle modification.
-Pharmacologic treatment to reduce cholesterol are based on the risk of — events.
lifestyle and diet
low fat
smoking
aerobic
cardiovascular
lipid lowering drugs:
-Several drugs decrease plasma lipoprotein concentrations.
1- — : 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors
2- —
3- —
4- Cholesterol absorption inhibitors eg —
5- Bile acid —
6- — or its derivatives
- The guidelines are unanimous in recommending intensive pharmacologic treatment and robust cholesterol reduction with — in high-risk patients mainly those with atherosclerotic cardiovascular disease (ASCVD).
statins
PCSK9
vibrates
ezetimibe
sequestrate
nicotinic acid
statins
-Hepatocytes synthesise ~—- Cholesterol per day
- — is the rate limiting step in the biosynthesis of Cholesterol in the liver.
-Normally this enzyme is competitively supressed by — (derived from internalization of LDL via the LDL Receptor in hepatic cells).
1000mg
HMG- CoA reductase
cholesterol
statins:
-These drugs are – inhibitors of — the rate-limiting step in the biosynthesis of cholesterol in hepatocytes
-The statins are the — effective and —-tolerated agents for treating dyslipidemia
-Statin treatment results in— Cholesterol synthesis in hepatocytes. This triggers an increase in synthesis of the — which removal of LDL from circulation by — , and its degradation in cellular— , — the cholesterol balance in the hepatocyte
competitive
hmm CoA
most effective and best tolerable
decreased
LDL receptor
endoenablescytosis
lysosomes
restoring
— are one of the best-studied classes of medications and the most commonly used drugs for lowering LDL cholesterol.
They are the most effective drugs for prevention of— disease, heart attack,—, and— .
- There are 4 Statin Benefit groups in which the potential for risk reduction benefit clearly exceeds the potential for adverse effects:
- —
- —-
- LDL ≥—mg/dL (4.9mmol/L),
- and ASCVD risk ≥ –%.
- The absolute benefit of statin therapy depends on the individual’s —
- Risk can be calculated using an algorithm that takes Age, Sex, Ethnicity, Smoking status, Diabetes status, Blood pressure, Cholesterol levels, Body mass index (BMI), Family history of CVD &Socioeconomic status into account
-Lowering LDL by 2 mmol/L for 5 years in 10,000 patients would typically prevent major vascular events from occurring in about 1000 patients (10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention).
A similar lowering of LDL by 2 mmol/L for 5 years in 10,000 patients would prevent major vascular events from occurring in 500 patients (5% absolute benefit) who are at increased risk but have not yet had a vascular event (primary prevention)
statins
coronary heart
heart attack
stroke
death
clinical ASCVD ( = AtheroSclerotic CardioVascular Disease)
dieabetes mellitus
190
7.5%
side effects of statins :
1- established side effects :
Note: Statins are generally– tolerated
- — :
— pain and — combined with large increases of— (CK). 10–15% of people who take statins experience — problems
- —- : (ALT>3 x normal limit)
placebo-controlled outcome trials where 10-40 mg doses of simvastatin, lovastatin, fluvastatin, atorvastatin, and pravastatin were compared with placebo, the incidence of ALT elevation was found to be 1.3% with test drugs and 1.1% with placebo with no case of liver failure. Serious hepatotoxicity is rare (< 1 case per million person-years of use)
- —-
Researchers have found associations between statins and decreased — sensitivity, which can lead to —
- ↑Risk of –
2- less established/ nocebo effects:
Behavior, Cognition, Memory loss
Dementia
Cataracts
Liver disease
Sleep disturbance
Erectile dysfunction
well
myopathy
muscle pain and weakness
creatine kinase
muscle problems
hepatoxoticty
diabetes
decreased insulin sensitivity
type 2 diabetes
haemorragic stroke
drug interaction:
Most statins, except Pravastatin, are metabolized/ degraded by the — enzyme — in the —.
-Drugs that are also metabolised by CYP3A4 can interfere with — and include:
- — antibiotics (erythromycin) and —
- Other drugs that can do this include — , — agents, — protease inhibitors and amiodarone
-These pharmacokinetic interactions are associated with — concentration of statins and their metabolites
- — can inhibit CYP34A; and thereby – the effective concentration of statins
-Gemfibrozil, a — type drug, can exacerbate statin drug-induced – .
1- all statins share the common suffix statin:
Atorvastatin (Lipitor)
Simvastatin (Z0cor)
Rosuvastatin (Crestor)
Fluvastatin (Lescol)
Pravastatin (Pravachol)
Pitavastatin (Livalo)
2- medical uses of stains include treatment of:
Clinical Atherosclerosic Vascular Disease (ASCVD)
primary elevations of LDL-C > 4.9 mmol/L (Familial Hypercholesteremia)
with diabetes and LDL-C 1.8-4.8 mmol/L (Usually 40-75 years of age)
without clinical ASCVD or diabetes 40-75 with an estimated 10-year ASCVD risk of 7.5% or greater
3- side effects of satitns nclude:
1- —/—
2—- /—
4- – effects (diarrhea, flatulence)
5- — increase
Avoid in — ( memnominc HMGCOA )
cyt-450
cyp34a
statin oxidation
macrolid antibiotics
azole anti fungal
cyclosporin , ani platelet , hiv protease
increased
grapefruit juice
increase
vibrate
myopathy
heptoatoxity/headchae
mylagia / myopathy
gi effects
cpk
pregnancy
( info :Lowering LDL by 2 mmol/L for 5 years in 10,000 patients would typically prevent major vascular events from occurring in about 1000 patients (10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention).
PCSK9 related Drugs for the treatment of Familial Hypercholesterolaemia(FH):
Further investigation of people with very low or very high circulating LDL cholesterol concentrations led to the discovery of inactivating and gain-of-function* variants aPCSK9gene which affects LDL receptor expression (LDLR; Hall, 2013).
Proprotein convertase subtilisin/kexin type 9(PCSK9) is anenzyme that binds to the — on the surface of the — , leading to the — and — of the LDLR in the— .
*Loss-of-Function (inactivating) mutations in PCSK9 result in — levels of circulating LDL in affected people.
Gain-of-function mutations cause more efficient — of LDL receptors from hepatocytes. People with such mutations present with excessively high levels of —
Understanding the — basis underlying these effects led to the development of a new class of lipid lowering drugs: the PCSK9 inhibitors.
LDL receptor
hepatocyte
internalization and degradation
lysosomes
lower
removal
serum LDL
biochemicals
PCSK9 related Drugs reduce LDL levels:
PCSK9 binds to the— on hepatocyte surfaces to promote LDLR — within the – (A).
If PCSK9 is blocked, LDL – proceeds as normal BUT — of the LDL receptor is prevented in lysosomes.
This means that more LDLRs are – to the surface of cells , where they aid in the removal of LDL-particles from the extracellular fluid.
PCSK9i can reduce — by 50-60% above that achieved by statin therapy alone
low density liporprotein receptors
degradation
liver
uptake
degradation
recycled
plasma LDL-C
-The first two PCSK9 inhibitors (PCSK9i), alirocumabandevolocumab, were approved as once every two week — injections,
= — antibodies that bind to pro protein convertase subtilisin kexin type 9 (PCSK9)
-Administration approved in 2015 for lowering LDL-particle concentrations whenstatinsand other drugs were not sufficiently effective or poorly tolerated.
-The cost of these new medications was $14,000 per year at full retail price in 2015; & was judged not to be cost effective by some. $5850 pa in 2019; 2024 $2,177
-Are used as an adjunct to Statin therapy.
A second therapeutic approach for lowering PCSK9 uses a —
-INCLISIRAN
-These molecules offer profound lowering of (intra- and extracellular) PCSK9 at a —-dose frequency.
-“We await clinical endpoint data showing cardiovascular risk reduction before suggesting broader use ofinclisiranfor—-risk cardiovascular disease patients”.
subcutenaus
human monoclonal
small interfering rna ( sirna)
lower
high risk
Fibrates stimulate — activated receptor (PPAR) alpha, which controls the expression of – products that mediate the metabolism of — and–
As a result, synthesis of TG and VLDL fatty acids is — , whilst that of lipoprotein lipase, which catabolises – , is –
No longer recommended as — treatment for cardiovascular prevention, but may be an option for those unable to take– .
Fibrates slightly reduce the risk of — compared to placebo.
No evidence of additional benefit from adding a fibrate to a statin formost primary prevention patients
They may have a role in those with — or familial —, usually under specialist supervision.
We do not use fibrate therapy to lower LDL-C or to raise high-density lipoprotein cholesterol (HDL-C) in patients without —.
They include:
Gemfibrozil,
Clofibrate,
Fenofibrate,
Bezafibrate
peroxisome proliferator
gene
triglycerides TG
high density lipoprotein HDL
reduced
tg
enhanced
first line
statins
non fatal mi
hypertriglyceridaemia or familial hyperlipidaemia
hypertriglyceridemia
adverse effects and drug interactions:
Fibrate therapy requires close monitoring of — tests throughout.
Gemfibrozil is not administered to patients with – or — dysfunction.
When used with statins, it can increase muscle cramping and myopathy. This combination is contraindicated.
The side effects of gemfibrozil include:
— reactions,
— pain,
increased risk for — ,
Elevated – enzymes
and – .
1-All Fibrates contain the common ‘fibr’ in their name
Gemfibrozil,
Clofibrate,
Fenofibrate,
Bezafibrate
2- Medical Uses of Fibrates include treatment of
patients with moderate to severe hypertriglyceridemia (5.65 to 11.3 mmol/L)
3- Side Effects of Fibrates include
gastrointestinal reactions,
muscle pain,
increased risk for gallstones,
Elevated liver enzymes
and atrial fibrillation
liver function
livr and kidney
gastrointestinal
muscle
gallstones
liver
artiel fibrliation
Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors:
-Ezetimibe—a — inhibitor that impairs dietary and biliary cholesterol absorption at the — of the—
-Bempedoic acidis an inhibitor of – an enzyme upstream of 3-hydroxy-3methylglutarly-CoA reductase (the target of statins) in the cholesterol biosynthesis pathway. Works alone or in combination with a statin orezetimibe;lowers – as well as other atherogenic proteins
cholesterol absorpption
brush boarders
intestine
adenosine triphosphate citrate lyase
LDL-C
cholesterol absorption inhibitor:
Ezetimibe inhibits the— of – , and can be used alone or with – .
Normally, cholesterol from food is absorbed in the — and then enters the – .
Ezetimibe blocks a specific protein (Niemann-Pick C1-Like 1 or NPC1L1) that is responsible for this — process.
By inhibiting this protein, less cholesterol is — , leading to lower levels of cholesterol in the – .
-Ezetimibe is quite effective in reducing — levels. . When used alone, ezetimibe can lower LDL-C levels by approximately 15-22%
-Adding ezetimibe to a statin regimen can lead to — reductions in cholesterol levels compared to simply increasing the statin dose.
-This combination therapy has also been associated with a reduced risk of major– events, such as heart attacks and strokes
intestinal absorption
cholesterol
statins
small intestine
bloodstream
absorption
absorbed
blood
low-density lipoprotein cholesterol (LDL-C)
greater
cardiovascular
side effects of ezetimibe:
Common Side Effects
- Diarrhea
- Cold symptoms (stuffy nose, sneezing, sore throat)
- Pain in an arm or leg
- Joint pain
- Muscle pain (especially when taken with a statin)
Serious Side Effects:
- — muscle damage (rhabdomyolysis, myopathy)
- — damage or – liver enzyme levels
serve
liver damage
increased liver enzymes
bile acid sequestrat resins:
Resins are bile acid sequestrants that work by preventing the intestinal re-uptake of — , thus — their fecal loss.
-Cholestyramine,
-Colestipol,
-“Plant Stanol Esters”
-they — LDL-C while — HDL-C levels slightly
-These are amongst the – of the hypolipidemic drugs, — bc as not absorbed from the – .
-By binding to bile acids, they preventing – and – of bile acids (which enable absorbtion of cholesterol from dietary sources)
-Normally, –% of bile acids are reabsorbed, these drugs deplete the pool of bile acids thus hepatic cholesterol declines, stimulating an increase in LDL receptor- to withdraw LDL from the plasma
They cause the liver to use — (from LDL) for the synthesis of new bile acids
bile acids
increasing
decreases
increasing
oldest
safest
gut
reabsorption and reuse
95%
cholesterol
side effects of bile acid sequestrate / resins:
-Not — . — and — are common side effects
-In addition to bile acids, bile acid sequestrants may also bind drugs in the – , preventing their absorption into the — . For this reason, it is generally advised that bile acid sequestrants be spaced several— apart from other drugs.
-They can also bind— vitamins, such asvitamin A,vitamin D,vitamin E, andvitamin K. This effect could result in a – deficiency, and so checking — levels and possible supplementation has been suggested.
not absorbed
bloating and dyspesia
gi tract
bloodstream
hours
fat soluble
vitamin
blood
nicotinic acid:
- Niacin, also known asnicotinic acid, is a form of— , anessential human nutrient
Converted into –
-Gram levels will—triglyceridesandLDL, and— HDL
-A major side effect is — , – and– disturbance
-Despite the proven– changes, there is no real success decreasing the risk ofcardiovascular diseasein those already on astatin
-However, HPS2-THRIVE trial showed increased side effects
–>Particularly – in Chinese patients
-Prescription niacin was shown to cause –
-It has essentially been de-prioritized for treatment of — (Probably because of the introduction of newer drugs such as PCSK9 inhibitors)
vitamin B3
nicotinamide
lower
raise
lipid
myopathy
heptaotxity
hyperlipidemia
