Transcript Lipoprotein disorders and cardiovascular disease

Lipoprotein management in
Patients With Cardiometabolic
Risk
Consensus conference report JACC April
2008
Sandra Rodriguez, M.D.
Internal Medicine
Factors Contribuiting to
Cardiometabolic risk
To What Extent Do Lipoproteins
Contribute to CVD?
• Serum levels of lipids and lipoprotein lipids have proven to be
among the most potent and best substantiated risk factors for
atherosclerosis in general and coronary heart disease (CHD) in
particular.
• Lipoproteins, as LDL, interact with the arterial wall, in the intima the
LDL bound to proteoglycans, where it suffers oxidation, macrophage
uptake and foam cell formation, initiating the cascade of
atherosclerosis.
• Small VLDL’s and IDL’s can enter the subendothelial space also,
and they increase prothrombotic factors.
• Small dense LDL have increase endothelial permeability.
• HDL is inversely associated to CV risk.
What Are the Clinically Important
Lipoprotein Parameters?
• LDL Cholesterol: Lowers CVD event rates for primary
and secondary prevention. (HPS, CARDS, SSSS).
Measurement might be underestimated as triglycerides
levels increase.
• LDL Particle number and size: Both are important
predictors of CVD. Found strongly associate to Carotid
intima-media thickness (MESA) and CHD events(VAHIT). Not widely available, and is expensive.
• Lp(a): Is an apoB-LDL, predicts CVD, if high, more
aggressive treatment is recommended.
What Are the Clinically Important
Lipoprotein Parameters?
• Non-HDL Cholesterol: Is a secondary goal after LDL.
Became better predictor of CVR in statin-treated
patients. Can be nonfasting.
• ApoB-100: Represents total atherogenic particles,
nonfasting. Better predictor of CVD risk than LDL, even
more once the LDL is lowered. More value in patientes
with cardiometabolic risk. Associated with obesity,
diabetes, insulin resistance, and Non-HDL.
• Triglycerides: Univariate predictor of CVD but not
independent.
• HDL: Strong inverse predictor of CVD events in diabetics
and nondiabetics.
In the Evaluation and Treatment of Patients with
Lipoprotein Abnormalities, Are There Other Factors That
Should Be Considered?
What Are the Principles and Objectives of Treatment of
Lipoprotein Abnormalities?
• Lipoprotein Goals for
Three Risk Levels:
– RiskLevel/LDL/NonH
DL/ ApoB (mg/dl)
• CVD and CVD risk
equivalent<70/100/80
• Multiple (2+) risk
factors<100/130/90
• 0–1 risk factor<130/160
• Triglycerides <150mg is
fourth goal except if
initial more than
500mg/dl.
• Weight loss of 5-10%
• Diet Cholesterol
<200mg/day
• Saturated and trans
fat to <7% of calories.
• Measure LDL, and
Non-HDL and ApoB in
patients with CMR on
statins.
Types of lipids
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Cholesterol: essential component of cell
membranes, substrate for steroid hormones
and bile acids.
Cholesteryl esters: Circulating from of
cholesterol, in the core of lipoprotein
particles. The enzyme lecithin cholesterol
acyltransferase (LCAT) forms cholesteryl
esters in the blood compartment by
transferring a fatty acyl chain from
phosphatidylcholine to cholesterol.
Triglycerides consist of a three-carbon
glycerol backbone covalently linked to three
fatty acids. Triglyceride molecules are
nonpolar and hydrophobic; they are
transported in the core of the lipoprotein.
Hydrolysis of triglycerides by lipases
generates free fatty acids (FFAs) used for
energy.
Phospholipids, constituents of all cellular
membranes, consist of a glycerol molecule
linked to two fatty acids, soluble than
triglycerides or cholesterol or its esters.
Hydrolysis by phospholipases generates
second messengers such as diacyl
glycerols, lysophospholipids, phosphatidic
acids, and FFAs such as arachidonate that
can regulate many cell functions.
Lipoproteins
Lipid Transport System
Lipoprotein Management
Current Lipid-Lowering Medications
• Statins: Atorvastatin, Fluvastatin, Lovastatin,
Pravastatin, Rosuvastatin,Simvastatin.
• Bile Acid Absorption Inhibitor
– CholestyramineQuestran 4-24 gm
– Colestipol, Colestid5-30 gm
– Colesevelam, WelChol3.8-4.5 gm
• Cholesterol Absorption Inhibitors:
– Ezetimibe: Zetia10
• Fibrates: Lopid600-1200 mg
• Niacin: Niacin1-3 gm, Nicotinic acid1-2 gm
Bile Acid–Binding Resins
• Interrupt the enterohepatic circulation of bile acids by inhibiting their
reabsorption in the intestine (more than 90 percent of bile acids
reabsorbed).
• Adjunctive therapy in patients with severe hypercholesterolemia due
to increased LDL cholesterol.
• Because bile acid–binding resins are not absorbed systemically
(they remain in the intestine and are eliminated in the stool), they
are considered safe in children.
• Cholestyramine (Questran) is used in 4-gm unit doses as powder,
and colestipol (Colestid) is used in 5-gm unit doses. Effective doses
range from 2 to 6 unit doses/day, always taken with meals.
• Side effects: sensation of fullness, gastrointestinal discomfort.
Hypertriglyceridemia can result from the use of these drugs.
Decreased drug absorption.
• Can be used in combination with statins and/or cholesterol
absorption inhibitors in cases of severe hypercholesterolemia.
Hydroxymethylglutaryl–Coenzyme A Reductase
Inhibitors (Statins)
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Statins prevent the formation of mevalonate, the rate-limiting step of sterol
synthesis. To maintain cellular cholesterol homeostasis, expression of the
LDL-R increases and the rate of cholesteryl ester formation declines. These
homeostatic adjustments to HMG-CoA reductase inhibition increase LDL
cholesterol clearance from plasma and decrease hepatic production of
VLDL and LDL.
Statins may increase HDL cholesterol in part by regulating apo AI
transcription.[49] Altered protein prenylation may also mediate some of the
putative effects of statins not related to a reduction in LDL cholesterol levels.
Statins decrease C-reactive protein, induce apoptosis in smooth muscle
cells, alter collagen content of atherosclerotic plaques, alter endothelial
function, and decrease the inflammatory component of plaques. Some
investigators argue that statins possess effects independent of their
inhibition of HMG CoA reductase.
Side effects include reversible elevation in transaminases and myositis, in
less than 1%. Concomitant drugs that interfere with the metabolism of
statins by inhibiting the cytochrome P450 can increase plasma
concentrations of statins. These include antibiotics, antifungal medications,
certain antiviral drugs, grapefruit juice, cyclosporine, amiodarone, and
several others.
Studies
• SSSS: 4444 patients w/ CHD, at 5.4yr showed 30-44% mortality and
CHD events.
• West of Scotland Study: Pravastatin reduce CHD events by 32%
and mortality by 22%.
• HPS: Simvastatin reduced risk of major CV events in 25%.
• CARE: Pravastatin reduce CV event in 24% in patients with average
total cholesterol of 209mg/dl.
• FIELD: Non-fatal MI decreased by 24%.
• Helsinki Heart Study showed no decrease in total mortality.
Cholesterol Absorption Inhibitors
• Ezetimibe is the first such compound. It appears to limit
selective uptake of cholesterol and other sterols by
intestinal epithelial cells, by interfering with the NiemannPick C1-like 1 protein .
• Ezetimibe is indicated for patients with LDL cholesterol
levels above target on a maximally tolerated statin dose.
• Ezetimibe lowers LDL cholesterol by about 18 percent
and adds to the effect of statins.
• It might be the drug of choice in cases of sitosterolemia.
Fibric Acid Derivatives (Fibrates)
• For hypertriglyceridemia when diet and lifestyle changes are not
sufficient. Also prevention of cardiovascular diseases in patients with
elevated plasma triglycerides and low HDL cholesterol, although the
data supporting their use are weaker than those for statins.
• Side effects: cutaneous manifestations; Gl effects (abdominal
discomfort, increased bile lithogenicity); erectile dysfunction;
elevated transaminases; interaction with oral anticoagulants; and
elevated plasma homocysteine, especially with fenofibrate and, to a
lesser extent, with bezafibrate.
• Because fibrates increase LPL activity, LDL cholesterol levels may
rise in patients with hypertriglyceridemia treated with this class of
medications.
• Fibrates, especially gemfibrozil, can inhibit the glucuronidation of
statins and thus retard their elimination. For this reason, combination
of gemfibrozil with statins may increase the risk of myotoxicity.
Nicotinic Acid (Niacin)
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Increases HDL cholesterol and lowering triglyceride levels. The effect of
niacin on LDL cholesterol is more modest.
Effective doses of niacin are in the range of 3000 mg/day, in three separate
doses. Using an escalating dose schedule to reach the full dose in 2 to 3
weeks rather than starting with the full dose is preferable.
Slow-release forms of niacin including Niaspan (1 to 2 gm/day) decrease
the side effect profile of the drug. Niacin decreases the hepatic secretion of
VLDL from the liver and decreased FFA mobilization for the periphery.
Side effects of niacin include flushing, hyperuricemia, hyperglycemia,
hepatotoxicity, acanthosis nigricans, and gastritis. Close laboratory
monitoring of side effects is warranted. Long-acting niacin has the
advantage of a once- or twice-daily dosing schedule, but older preparations
of slow-release niacin were potentially more hepatotoxic.
Niacin effectively raises HDL cholesterol levels and, in combination with
low-dose statin, can retard the angiographic progression of CAD and
decrease adverse cardiac events.
Other
• Fish oils are rich in polyunsaturated fatty acids such as
eicosapentaenoic acid or docosahexaenoic acid, with the
first double bond in the omega-3 position.
• These fatty acids lower plasma triglyceride levels and
have antithrombotic properties at doses >4g/day and as
adyuvant to statin can lower non-HDL cholesterol.
• Fish oils decrease VLDL synthesis and decrease VLDL
apo B.
• Metformin has modest triglyceride lowering properties.
• Pioglitazone raises HDL and lowers triglycerides and
LDL.
• Rosiglitazone increases LDL particle number.
Algorithm for lipid lowering therapy