SKHALILZADEH Lipids are hydrophobic molecules that are insoluble in water They are in cell membranes as a major form of stored nutrients triglycerides as precursors of adrenal and gonadal ID: 332593
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Slide1
DIABETES AND LIPID
S-KHALILZADEHSlide2
Lipids are hydrophobic molecules that are insoluble in water. They are in cell membranes
as a major form of stored nutrients (triglycerides),
as precursors of adrenal and
gonadal
steroids and bile acids
as extracellular and intracellular messengers (e.g., prostaglandins,
phosphatidylinositol
).
Lipoproteins provide a vehicle for transporting the complex lipids in the blood as water-soluble complexes and deliver lipids to cellsSlide3
Fatty acids vary in length and in the number and position of double bonds
Saturated
fatty acids
lack
double
bonds
unsaturated fatty acids have one or more double bonds.
Monounsaturated fatty acids have one double bond, and polyunsaturated fatty acids (PUFAs) have two or more. Slide4
Cholesterol is a four-ring hydrocarbon with an eight-carbon side chain.
It is a major component of cell membranes and as a precursor of steroid hormones (adrenal and
gonadal
hormones) and bile acids
In the blood, about two thirds of the cholesterol is
esterified
Slide5Slide6
Triglycerides consist of three fatty acid molecules
esterified
to a glycerol molecule Triglycerides store fatty acids and form large lipid droplets in adipose tissue. They are also transported as a component of certain lipoproteins. When triglycerides are hydrolyzed in
adipocytes
, free fatty acid (FFA) are released to be used as a source of energySlide7Slide8
Chylomicrons
are the largest of the plasma lipoproteins (>1000 Å in diameter) ,float after ultracentrifugation of plasma.
They are composed of 98% to 99% lipid (85%-90% triglyceride) and 1% to 2% protein
Chylomicrons
are present in postprandial plasma (but are absent after an overnight fast) and contain apo-B48,
apo
-AI,
apo
-AIV,
apo
-E, and the C
apolipoproteins
Slide9
VLDLs are particles 300 to 700 Å
They are composed of 85% to 90% lipid (about 55% triglyceride, 20% cholesterol, and 15%
phospholipid
) and 10% to 15% protein. The distinctive
apolipoprotein
is apo-B100, the hepatic form of
apo
-B. VLDLs also contain
apo
-E and C
apolipoproteins
Slide10
IDLs present in low concentrations in the plasma and are intermediate in size and composition between VLDL and LDL
Their proteins are apo-B100 and apo-E.
The IDLs are precursors of LDLs and represent metabolic products of VLDL catabolism in the plasma by the action of lipases.
IDLs are often considered to be VLDL remnants and to be atherogenic.Slide11
LDLs are about 200 Å in diameter, are the major cholesterol-carrying lipoproteins in the plasma; about 70% of total plasma cholesterol is in LDL. LDLs are composed of approximately 75% lipid (about 35%
cholesteryl
ester, 10% free cholesterol, 10% triglyceride, and 20%
phospholipid
) and 25% protein. Apo-B100 is the principal protein in these particles, with trace amounts of
apo
-ESlide12
The clearance of LDL is mediated by apo-B100. The affinity of apo-B100 for the LDL receptor is lower than that of
apo
-E, and clearance of LDL is much slower (with a half-life of 2 to 3 days).
Compared with apo-B100–containing LDLs,
apo
-E–containing lipoproteins have 20-fold greater affinity for the LDL receptorSlide13
HDLs are small particles (70-120 Å in diameter)
HDLs contain about 50% lipid (25%
phospholipid
, 15%
cholesteryl
ester, 5% free cholesterol, and 5% triglyceride) and 50% protein Their major
apolipoproteins
are
apo
-AI (65%),
apo
-AII (25%), and smaller amounts of the C
apolipoproteins
and
apo
-E Slide14
Apo-E is a minor component of a subclass of HDL referred to as HDL
1
, but about 50% of total plasma
apo
-E is in this HDL fraction. The major classes of HDLs lack
apo
-E and do not interact with the LDL receptorSlide15
Apolipoproteins
—
Understanding the major functions of the different
apolipoproteins
is important clinically, because defects in
apolipoprotein
metabolism lead to abnormalities in lipid handlingSlide16Slide17
Apolipoproteins
A-I — Structural protein for HDL; activator of lecithin-cholesterol
acyltransferase
(LCAT).
A-II — Structural protein for HDL; activator of hepatic lipase.
A-IV — Activator of lipoprotein lipase (LPL) and LCAT.
B-100 — Structural protein for VLDL, IDL, LDL, and
Lp
(a);
ligand
for the LDL receptor; required for assembly and secretion of VLDL.
B-48 — Contains 48 percent of B-100; required for assembly and secretion of
chylomicrons
; does not bind to LDL
receptor. Slide18
C-I — Activator of LCAT.
C-II — Essential cofactor for LPL.
C-III — Interferes with
apo
-E mediated clearance of triglyceride-enriched lipoproteins by cellular receptors ; inhibits triglyceride hydrolysis by lipoprotein lipase and hepatic lipase ,interferes with normal endothelial function . Slide19
D — May be a cofactor for
cholesteryl
ester transfer protein (CETP).
E —
Ligand
for hepatic
chylomicron
and VLDL remnant receptor, leading to clearance of these lipoproteins from the circulation;
ligand
for LDL receptor
. Slide20
Human LPL is synthesized by
adipocytes
, by
myocytes
in skeletal and cardiac muscle, and by macrophages but is not produced by
hepatocytes
.
LPL is transported to the capillary endothelial cells where it interacts with
chylomicrons
and VLDL in the circulation and mediates the hydrolysis of their triglycerides to FFAs.
The fatty acids are stored as triglyceride in
adipocytes
and in the formation of hepatic VLDL.Slide21
Hepatic lipase is primarily a
phospholipase
but also possesses triglyceride
hydrolase
activity
It is synthesized by
hepatocytes
Hepatic lipase is transported from the liver to the capillary endothelium of the adrenals, ovaries, and testes, where it functions in the release of lipids from lipoproteins for use in these organs.
Its activity is increased by androgens and reduced by estrogensSlide22
EXOGENOUS PATHWAY OF LIPID METABOLISM
starts with the intestinal absorption of dietary cholesterol and fatty acids The mechanisms regulating the amount of dietary cholesterol that is absorbed are unknown.
Sitosterolemia
is a rare
autosomal
recessive disorder associated with
hyperabsorption
of cholesterol and plant sterols from the intestine . Slide23
Within the intestinal cell, free fatty acids combine with glycerol to form triglycerides, and cholesterol is
esterified
by
acyl
-coenzyme A:cholesterol
acyltransferase
(ACAT) to form cholesterol esters
Triglycerides and cholesterol are assembled
intracellularly
as
chylomicrons
.
The main
apolipoprotein
is B-48, but C-II and E are acquired as the
chylomicrons
enter the circulation. Apo B-48 permits lipid binding to the
chylomicron
but not to LDL receptor.Slide24
Apo C-II is a cofactor for LPL which makes the
chylomicrons
smaller by hydrolyzing the core triglycerides and releasing free fatty acids. The free fatty acids are then used as an energy source, converted to triglyceride, or stored in adipose tissue. The end-products of
chylomicron
are
chylomicron
remnants that are cleared from the circulation by hepatic
chylomicron
remnant receptors for which
apo
E is a high-affinity
ligand
. Slide25Slide26
ENDOGENOUS PATHWAY OF LIPID METABOLISM
begins with the synthesis of VLDL by the liver
Microsomal
triglyceride transfer protein is essential for the transfer of the bulk of triglycerides
into the
endoplasmic reticulum for VLDL assembly
They include
apo
C-II which acts as a cofactor for LPL,
apo
C-III which inhibits this enzyme, and
apo
B-100 and E which serve as
ligands
for LDL receptor Slide27
The triglyceride core of VLDL particles is hydrolyzed by lipoprotein lipase. During
lipolysis
, the core of the VLDL particle is reduced, generating VLDL remnant particles (also called IDL) that are depleted of triglycerides via a process similar to the generation of
chylomicron
remnants
. Slide28
Some of the excess surface components in the remnant particle, including
phospholipid
,
unesterified
cholesterol, and
apolipoproteins
A, C and E, are transferred to HDL
VLDL remnants can either be cleared from the circulation by the
apo
B/E (LDL) or the remnant receptors or remodeled by hepatic lipase to form LDL particles
. Slide29
Slide30
LDL can be internalized by hepatic and
nonhepatic
tissues. Hepatic LDL cholesterol can be converted to bile acids and secreted into the intestinal lumen.
LDL cholesterol internalized by
nonhepatic
tissues can be used for hormone production, cell membrane synthesis, or stored in the
esterified
formSlide31
Circulating LDL can also enter macrophages and some other tissues through the unregulated scavenger receptor. This pathway can result in excess accumulation of intracellular cholesterol and the formation of foam cells which contribute to the formation of
atheromatous
plaquesSlide32
These cholesterol-enriched cells can rupture, releasing oxidized LDL, intracellular enzymes, and oxygen free radicals that can further damage the vessel wall. Oxidized LDL induces apoptosis of vascular smooth muscle and human endothelial cells via activation of a protease which suggests a mechanism for the response to injury hypothesis of atherosclerosisSlide33Slide34
anti-atherogenic effect of HDL
Apolipoprotein
A-I on the surface of HDL serves as a signal to mobilize cholesterol esters from intracellular pools. After diffusion of cholesterol onto HDL, the cholesterol is
esterified
to cholesterol esters by LCAT, a plasma enzyme that is activated primarily by
apolipoprotein
A-I.
HDL can act as an acceptor for cholesterol released during
lipolysis
of triglyceride-containing lipoproteinsSlide35Slide36Slide37Slide38
Diabetes mellitus
insulin deficiency and poor
glycemic
control lead to increases in the plasma levels of triglycerides and
apo
-B–containing lipoproteins insulin deficiency results in impaired LPL activity and diminished clearance of triglyceride-rich particles.
Insulin deficiency also enhances
lipolysis
, which increases FFA flux to the liver, increased FFA flux drives triglyceride and VLDL synthesis and secretion
. Slide39
Plasma levels of LDL are increased in some but not all subjects. the
hyperlipidemia
in type 2 diabetes is often characterized by an increase in small, dense LDLs which are particularly
atherogenic
a portion of the plasma LDL undergoes
glycosylation
, which can increase binding to arterial wall
proteoglycans
and susceptibility to oxidation.Slide40
(CHD) are common in industrialized societies
There is a direct relation between the plasma levels of total and LDL cholesterol and the risk of CHD and mortality
LDL cholesterol lowering in moderate to high-risk patients leads to a reduction in cardiovascular events
Abnormalities of plasma lipids (
dyslipidemia
) other than LDL cholesterol are common in patients with early onset CHD
HDL cholesterol levels are related to absolute CHD event rates in treated
hypercholesterolemic
subjects with and without baseline clinical CHD
Screening tests for
dyslipidemia
are widely available Slide41
Guidelines developed by the NCEP in 2001 recommend that a complete plasma lipid profile (total cholesterol, LDL-C, HDL-C, and triglycerides) be measured in all adults 20 years of age and older at least once every 5 yearsSlide42
The ATP III recommendations for the treatment of hypercholesterolemia are based on the LDL-cholesterol (LDL-C)and are influenced by the coexistence of CHD and the number of cardiac risk factors.
There are five major steps to determining an individual's risk category, which serves as the basis for the treatment
guidelines Slide43
Step 1 — The first step in determining patient risk is to obtain a fasting lipid profileSlide44
Step 2 — CHD equivalents, that is, risk factors that place the patient at similar risk for CHD events as a history of CHD itself, are identified :
Diabetes mellitus
Symptomatic carotid artery disease
Peripheral arterial disease
Abdominal aortic aneurysm
Multiple risk factors that confer a 10-year risk of CHD >20 percent Slide45
Step 3 — Major CHD factors other than LDL are identified:
Cigarette smoking
Hypertension (BP ≥140/90 or antihypertensive medication)
Low HDL-C (<40 mg/
dL
)
Family history of premature CHD (in male first degree relatives <55 years, in female first degree relative <65 years)
Age (men ≥45 years, women ≥55 years)
HDL-C ≥60 mg/
dL
counts as a "negative" risk factor; its presence removes one risk factor from the total countSlide46
STEP-4
If two or more risk factors other than LDL (as defined in step 3) are present in a patient without CHD or a CHD equivalent (as defined in step 2), the 10-year risk of CHD is assessed using the ATP III modification of the Framingham risk tablesSlide47
Step 5 — The last step in risk assessment is to determine the risk category that establishes the LDL goal, when to initiate therapeutic lifestyle changes, and when to consider drug therapy Slide48
Total-to-HDL-cholesterol ratio
Among men, a ratio of 6.4 or more identified a group at 2 to 14 percent greater risk than predicted from serum total or LDL-C
Among women, a ratio of 5.6 or more identified a group at 25 to 45 percent greater risk than predicted from serum total or LDL-C Slide49
Non-HDL-cholesterol
Non-HDL-C is defined as the difference between the total cholesterol and HDL-C. Non-HDL-C includes all cholesterol present in lipoprotein particles that is considered
atherogenic
, including
LDL,lp
(a),IDL and VLDL .
It has been suggested that the non-HDL-C fraction may be a better tool for risk assessment than LDL-CSlide50
ATP III identifies the
non-HDL-C concentration as a secondary target of therapy in people who have high triglycerides ≥200 mg/dl.
The goal for non-HDL-C in this circumstance is a concentration that is 30 mg/
dL
(0.78
mmol
/L) higher than that
for LDL-CSlide51Slide52
A standard serum lipid profile consists of total cholesterol, triglycerides, and HDL-cholesterol. Lipoprotein analysis should be performed after 9 to 12 hours of fasting to minimize the influence of postprandial
hyperlipidemia
. Either a plasma or serum specimen can be used; the serum cholesterol is approximately 3 percent lower than the plasma valueSlide53Slide54Slide55Slide56
HMG-CoA Reductase Inhibitors
Inhibition of cholesterol biosynthesis up-regulates cellular LDL receptors and enhances clearance of LDL from the plasma into cells.Slide57
Statins
Competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme
A (HMG-
CoA
)
reductase
, which catalyzes an early,
ratelimiting
step in cholesterol biosynthesisSlide58
Chemistry
The
statins
possess a side group that is structurally similar to HMG-
CoA
Mevastatin, lovastatin, simvastatin, and pravaslatin
are fungal metabolites
fluvastatin
,
atorvastatin
, and
rosuvastatin
are entirely synthetic
Lovastatin
and
simvastatin
are
lactone
prodrugs
that are modified in the liver to active
hydroxy
acid forms
Since they are lactones, they are less soluble in water than are the other
statinsSlide59
Mechanism of Action
Statins
exert their major
effectreduction
of LDL levels-through a
mevalonic
acid-like moiety that competitively inhibits HMG-
CoA
reductase
.
By reducing the conversion of HMG-
CoA
to
mevalonate
,
statins
inhibit an early and rate-limiting step in cholesterol biosynthesisSlide60Slide61
Inhibition of hepatic cholesterol synthesis, results in increased expression of the LDL receptor gene
Degradation of LDL receptors also is reduced
The greater number of LDL receptors on the surface of
hepatocytes
results in increased removal of LDL from the blood,
statins
also can reduce LDL levels by enhancing the removal of LDL precursors (VLDL and IDL) and by decreasing hepatic VLDL production Slide62
Triglyceride Reduction by Statins.
Triglyceride levels >250
mgldl
are reduced substantially by
statins
,
If baseline triglyceride levels are below 250 mg/dl. Reductions in triglycerides do not exceed 25% irrespective of the dose or
statin
used
simvastatin
and
atorvastatin
, 80,mg/day;
rosuvastatin
, 40 mg/day experience a 35% to 45% reduction in fasting triglyceride levelsSlide63
Effect of Statins on HDL-C Levels
patients with elevated LDL-C levels and gender- appropriate HDL-C levels (40 to 50
mgldl
for men; 50 to 60 mg/dl for women). an increase in HDL-C of 5% to 10% was observed, irrespective of the dose or
statin
employed
In patients with reduced HDL-C levels (35 mg/dl)
statins
may differ in their effects on HDL-C levels (
Simvastatin
>
Atorvastatin
)Slide64
Effects of Slatins on LDL-C Levels
Statins
lower LDL-C by 20% to 55% depending on the dose and
statin
used
Maximal effects on plasma cholesterol levels are achieved within 7 to 10 days.
The
statins
are effective in almost all patients with high LDL-C levels.
The exception is patients with homozygous familial hypercholesterolemia,
the partial response in these patients is due to a reduction in hepatic VLDL synthesis associated with the inhibition of HMG-
CoA
reductase
-mediated cholesterol synthesisSlide65Slide66Slide67
potency
rosuvastatin > atorvastatin > simvastatin > pravastatin = lovastatin > fluvastatinSlide68
Nonlipid roles of statins
Endothelial Function
Plaque Stability
Inflammation
Lipoprotein Oxidation
CoagulationSlide69
Statins
and Endothelial Function
Statin
therapy enhances endothelial production of the vasodilator nitric oxide, leading to improved endothelial function after a month of therapySlide70
Statins and Plaque Stability.
They reportedly inhibit
monocyte
infiltration into the artery wall in a rabbit model
Inhibit macrophage secretion of matrix
metalloproteinases
in vitro
modulate the
cellularity
of the artery wall by inhibiting proliferation of smooth muscle cells and enhancing apoptotic cell deathSlide71
Statins and Inflammation
Statins
decreased the risk of CHD and levels of C-reactive protein (CRP, an independent marker for inflammation and high CHD risk) independently of cholesterol loweringSlide72
Coagulation
Statins
reduce platelet aggregation
reduce the deposition of platelet thrombi in the porcine aorta model
the different
statins
have variable effects on fibrinogen levelsSlide73
SECONDARY BENEFITS
Bone metabolism
Hypertension
Heart failure
Dementia
Cancer prevention
Renal function
Sepsis and infections Slide74
Hepatotoxicity
Elevation in hepatic
transaminase
to values greater than three times the upper limit of normal
Incidence as great as 1%
The incidence appeared to be dose related
liver failure one case per million person-years of use
measure
alanine
aminotransferase
(ALT) at baseline and thereafter when clinically indicated.Slide75
Patients taking 80-mg doses (or 40 mg of
rosuvastatin
) should have their ALT checked after 3 months. If the ALT values are normal, it is not necessary to repeal the ALT test unless clinically indicatedSlide76
Myopathy
myopathy
as any muscle disease
myalgia
as muscle ache or weakness without increased serum CK levels
myositis
as muscle symptoms with elevated CK levels
rhabdomyolysis
as muscle symptoms with marked CK elevations (>10 times upper limit of normal [ULN]) plus an elevated serum
creatinine
.
(FDA) defines
rhabdomyolysis
as organ damage, typically renal insufficiency, with a CK level greater than 10,000 IU/LSlide77
Myopathy
major adverse effect
The incidence of
myopathy
is quite low (~0.0 1%). but the risk of
myopathy
and
rhabdomyolysis
increases in proportion to plasma
statin
concentrations
Factors inhibiting
statin
catabolism are associated with increased
myopathy
risk, including advanced age (especially >80 years of age), hepatic or renal dysfunction.
perioperative
periods. multisystem disease (especially in association with diabetes mellitus), small body size, and untreated hypothyroidismSlide78
RISK FACTORS FOR STATIN MYOPATHY
conditions that increase
statin
serum and muscle concentration
factors that increase muscle susceptibility to injurySlide79
Asymptomatic patients
Routine surveillance of CK levels is not required except in high-risk patients
If CK measured
CK < 5× ULN: reassurance
CK ≥5 - <10× ULN: monitor for symptoms and periodical CK determination
CK ≥10× ULN: stop
statin
and reconsider risks and benefits of
statin
treatmentSlide80
Factors related to an increase in statin serum level
Statin
dose
Small body frame
Decreased
statin
metabolism and excretion
Drug–drug interactions
Grapefruit juice (possibly also pomegranate &
starfruit
)
Hypothyroidism and diabetes mellitus
Advanced age
Liver disease
Renal diseaseSlide81
Factors related to muscle predisposition
Alcohol consumption
Drug abuse (cocaine, amphetamines, heroin)
Heavy exercise
Baseline muscular disease:
Multisystemic
diseases: diabetes mellitus, hypothyroidism
Inflammatory or inherited metabolic muscle defectsSlide82
Bile acid sequestrants
The bound bile acids are excreted in the
feces.The
increased excretion of bile acids causes increased oxidation of cholesterol to form bile acids in
hepatocytes
, and the resultant up-regulation of hepatic LDL receptors in turn lowers plasma LDL concentrations.
side effects are limited to local effects in the gastrointestinal system (e.g., bloating, gas, constipation)Slide83
these agents can lower plasma cholesterol levels by 15% to 25%.
they can increase plasma triglyceride levels and must be used with caution in patients predisposed to
hypertriglyceridemia
. Slide84
because they bind negatively charged molecules in the intestine, these agents can interfere with the absorption of other medications, including
levothyroxine
,
digoxin
,
warfarin
, and
thiazide
diuretics. Therefore, resins are given at least 4 hours before or 1 hour after other medications.
Colesevelam
does not bind other drugs to the same extent as the resins
cholestyramine
and
colestipol
.Slide85
niacin
typically 2.0 to 6.0 g/day lower both total and LDL cholesterol by 15% to 30%, lower triglyceride levels by 30% to 40%, and raise HDL-C levels by 15% to 25%. Maximum HDL increases usually occur with therapeutic doses of 1.5 to 2.0 g/day. Niacin also lowers plasma
Lp
(a) concentrations by up to 40%.
The mechanism whereby niacin affects plasma lipids is unclear, but it seems to be associated with decreased hepatic VLDL production.Slide86
The most troublesome side effect of niacin is a flushing syndrome that occurs shortly after taking the medicine. Flushing can be minimized by initiating therapy with small doses (e.g., 100 mg) and gradually increasing the dosage to the therapeutic range over weeks to months.
taking an aspirin about 1 hour before the niacin can diminish the flushing, possibly by inhibiting prostaglandin-mediated side effects.Slide87
The most serious complication of niacin
therapy is
hepatotoxicity
, and therapy should be accompanied by monitoring of serum liver function tests
therapy should be discontinued if
transaminases
reach >3 times normal. Because
hepatotoxicity
appears to be more common with sustained-release preparations of niacin, the immediate-release form is preferred.
Other side effects of niacin therapy include impairment or worsening of glucose tolerance and
hyperuricemia
.Slide88
The fibric acid derivatives
clofibrate
,
gemfibrozil
, and
fenofibrate
—lower plasma triglycerides by about 40% and increase HDL-C levels by about 10% but have only minor effects on LDL-C. These agents act by activating the (PPAR) a, a nuclear hormone receptor that is expressed in the liver and other tissues. This results in increased fatty acid oxidation, increased LPL synthesis, and reduced expression of
apo
-CIII, all of which contribute to lowering plasma triglycerides. Slide89
Side effects include gastrointestinal discomfort and possibly an increased incidence of cholesterol gallstones (documented for
clofibrate
).
Fibric
acid derivatives should be used with great caution in the setting of renal insufficiency
Fenofibrate
, which does not interfere with
statin
metabolism and has a much lower risk of causing
myopathy
, is the preferred
fibrate
to use in combination with a
statin
.Slide90
Omacor
is prepared in capsule form containing a gram of oil, which includes a total of 840 mg of EPA plus DHA. At the recommended dosage of four capsules daily given to patients who have triglycerides of 500-2000 mg/
dL
,
Omacor
lowers triglycerides by about 50%, raises HDL-C by about 10%, lowers VLDL-C by about 40%, and raises LDL-C by about 50%. Overall the total cholesterol-to-HDL-C ratio is reduced by about 20% and the non-HDL-C is lowered by about 10%Slide91Slide92
Chylomicronemia Syndrome
Patients with the
chylomicronemia
syndrome often present with acute pancreatitis and severe
hypertriglyceridemia
(triglycerides >22.6 mm/L [2000 mg/
dL
]).
These patients should be treated with total fat restriction until the triglyceride level falls to a safe range
The goal is to maintain the triglyceride level at less than 11.3 mm/L (1000 mg/
dL
) and preferably less than 4.5 mm/L (400 mg/
dL
).
such patients often require a triglyceride-lowering drug, such as a
fibrate
or niacin, to maintain the plasma triglyceride level in a range that prevents subsequent episodes of pancreatitisSlide93