Dyslipidemia: Updated Guidelines

DyslipidemDyslipidemia: ia: Updated Updated Guidelines Guidelines

CCatalino L. De La Cruz, Jr., atalino L. De La Cruz, Jr., MD, FACCMD, FACC

DisclosuresDisclosures

Nothing to discloseNothing to disclose

DefinitionDefinitionCholesterol is Cholesterol is

a fatty a fatty substance substance manufactured manufactured in the liver and in the liver and is carried is carried throughout the throughout the body in the body in the bloodstream.bloodstream.

SynthesisSynthesis Primary synthetic sites are extrahepatic, but Primary synthetic sites are extrahepatic, but

liver is key regulator of homeostasisliver is key regulator of homeostasis AbsorptionAbsorption

Largest source is biliary secretion, not diet.Largest source is biliary secretion, not diet. Normal absorption: 50%Normal absorption: 50% For cholesterol to be absorbed it must:For cholesterol to be absorbed it must:

undergo hydrolysis (de-esterification by undergo hydrolysis (de-esterification by esterases)esterases)

be incorporated into micellesbe incorporated into micelles be taken up by cholesterol transporterbe taken up by cholesterol transporter be re-esterified and incorporated into be re-esterified and incorporated into

chylomicronschylomicrons

NORMAL CHOLESTEROL METABOLISM

400 mg/day

1,300 mg/day

17,400 mg/day

850 mg/day

NORMAL CHOLESTEROL ABSORPTION

Defect in ABCG5/G8transporter causesphytosterolemia

Oil phase

17 GBA*

NORMAL CHOLESTEROL METABOLISMNORMAL CHOLESTEROL METABOLISM

Tissuepools70G

0.8 GSYN CHOL

17.35 GBA*

0.85 GABS CHOL

0.35 G BA*

.35 G

.65 G

.20 G

1.20 GCHOL + BA

50% 95%

0.4 G CHOL

1.3 GCHOL

* BA = BILE ACIDS

.20 G CHOL 0.65 G CHOL

Why High Cholesterol Why High Cholesterol MattersMatters

High cholesterol is one of the major risk High cholesterol is one of the major risk factors for coronary artery disease, heart factors for coronary artery disease, heart attacks, and strokes. It also appears to attacks, and strokes. It also appears to boost the risk of Alzheimer's disease. boost the risk of Alzheimer's disease.

High cholesterol leads to a buildup of High cholesterol leads to a buildup of plaque that narrows the arteries. The plaque that narrows the arteries. The most dangerous or rupture-prone most dangerous or rupture-prone plaques are caused by lesions that were plaques are caused by lesions that were less than 70% stenotic and not by those less than 70% stenotic and not by those with the most severe narrowing.with the most severe narrowing.

PrevalencePrevalence

About 50% of U.S. adults have an About 50% of U.S. adults have an elevated total cholesterol levelelevated total cholesterol level

Majority of patients with atherosclerosis Majority of patients with atherosclerosis have some form of dyslipidemiahave some form of dyslipidemia

70-80% of individuals with dyslipidemia 70-80% of individuals with dyslipidemia do not meet LDL cholesterol targets do not meet LDL cholesterol targets despite lipid therapydespite lipid therapy

SymptomsSymptoms

High cholesterol does High cholesterol does not cause any not cause any symptoms.symptoms.

Too much cholesterol Too much cholesterol may lead to a buildup may lead to a buildup of plaque inside the of plaque inside the arteries.arteries.

This is known as This is known as atherosclerosisatherosclerosis, a , a condition that causes condition that causes narrowing of the space narrowing of the space available for blood flow available for blood flow

Development of Development of AtherosclerosisAtherosclerosis

AtherosclerosisAtherosclerosis

Leading cause of morbidity and mortality in Leading cause of morbidity and mortality in the U.S.the U.S.

Accounts for more than 1/3 of all deaths each Accounts for more than 1/3 of all deaths each yearyear

About 13 million Americans have coronary About 13 million Americans have coronary heart disease (CHD)heart disease (CHD)

Dyslipidemia is the most prevalent and Dyslipidemia is the most prevalent and important modifiable risk factor for important modifiable risk factor for atherosclerosisatherosclerosis

Total CholesterolTotal Cholesterol

Total cholesterol measures the Total cholesterol measures the combination of LDL, HDL, and VLDL combination of LDL, HDL, and VLDL (very low density lipoprotein) in your (very low density lipoprotein) in your bloodstream. VLDL is a precursor of bloodstream. VLDL is a precursor of LDL, the bad cholesterol.LDL, the bad cholesterol.

A total cholesterol score of under A total cholesterol score of under 200 is considered healthy in most 200 is considered healthy in most cases. cases.

Low Density LipoproteinsLow Density Lipoproteins

Most of the cholesterol in the blood is carried by Most of the cholesterol in the blood is carried by proteins called proteins called low density lipoproteinslow density lipoproteins or LDL or or LDL or the the bad cholesterol bad cholesterol

LDL combines with other substances to clog the LDL combines with other substances to clog the arteries. arteries.

A diet high in saturated fats and trans fats tends A diet high in saturated fats and trans fats tends to raise the level of LDL cholesterol.to raise the level of LDL cholesterol.

For most people, an LDL score below 100 is For most people, an LDL score below 100 is healthy, but people with heart disease may need healthy, but people with heart disease may need to aim even lowerto aim even lower

Consistent relationship Consistent relationship betweenbetweenLDL-C reduction and CHD relative risk for LDL-C reduction and CHD relative risk for all all

LDL-lowering treatmentsLDL-lowering treatments

Robinson JG et al. J Am Coll Cardiol. 2005;46:1855–1862.

15 20 25 30 35 40

–20

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20

40

60

80

100

LDL-C reduction, %

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4S CARDSPOSCH ASCOT-LLANHLBI PROSPERLRC ALERTUpjohn HPSLos Angeles AF/TexCAPSMRC LIPIDOslo CARELondon WOSCOPS

Cholestyramine

Colestipol

High-Density High-Density LipoproteinsLipoproteins

Up to a third of blood cholesterol is carried by Up to a third of blood cholesterol is carried by high-density lipoproteinshigh-density lipoproteins or HDL or the good or HDL or the good cholesterol.cholesterol.

HDL helps remove bad cholesterol, preventing HDL helps remove bad cholesterol, preventing it from building up inside the arteries.it from building up inside the arteries.

The higher the level of HDL cholesterol, the The higher the level of HDL cholesterol, the better. People with too little are more likely to better. People with too little are more likely to develop heart disease. develop heart disease.

TriglyceridesTriglycerides The body converts excess calories, sugar, and The body converts excess calories, sugar, and

alcohol into alcohol into triglyceridestriglycerides, a type of fat that is , a type of fat that is carried in the blood and stored in fat cells carried in the blood and stored in fat cells throughout the body. throughout the body.

People who are overweight, inactive, smokers, People who are overweight, inactive, smokers, or heavy drinkers and those who eat a very or heavy drinkers and those who eat a very high carbohydrate diet tend to have high high carbohydrate diet tend to have high triglyceridestriglycerides

A triglycerides score of 150 or higher puts you A triglycerides score of 150 or higher puts you at risk for metabolic syndrome, which is linked at risk for metabolic syndrome, which is linked to heart disease and diabetes.to heart disease and diabetes.

PlasmaTriglyceride

(VLDL)

Dietary Carbohydrate Increases VLDL Production

DietaryCarbohydrate

Causes of high triglycerides in the general population•Overweight and obesity•Physical inactivity•Cigarette smoking•Excess alcohol intake•Very high carbohydrate diets (>60% of

energy)•Other disease (diabetes, renal failure,

nephrosis)•Drugs: steroids, protease inhibitors,

estrogen, etc•Genetic factors

NCEP JAMA 2001;285:2486 Final Report Circulation 2002;106:3143-3421

TriglyceridesTriglycerides

Risk Classification of Serum TriglyceridesRisk Classification of Serum Triglycerides

Normal Normal <150 mg/dL<150 mg/dLBorderline highBorderline high 150–199 mg/dL150–199 mg/dL

HighHigh 200–499 mg/dL200–499 mg/dLVery highVery high 500 mg/dL500 mg/dL



• Publication of meta-analyses have shown Publication of meta-analyses have shown that elevated triglycerides are in fact an that elevated triglycerides are in fact an independent risk factorindependent risk factor for CHDfor CHD • This suggests that This suggests that some triglyceride-rich some triglyceride-rich lipoproteinslipoproteins (TGRLP) are atherogenic. (TGRLP) are atherogenic.



NCEP ATP III Chapter II Circulation December 2002 pp3169


When When triglyceride levels are ≥200 mg/dLtriglyceride levels are ≥200 mg/dL, , the presence of increased quantities of the presence of increased quantities of atherogenic remnant lipoproteinsatherogenic remnant lipoproteins can can heighten CHD risk heighten CHD risk substantiallysubstantially beyond that beyond that predicted by LDL cholesterol alone. predicted by LDL cholesterol alone.

For these reasons, For these reasons, ATP III modified the ATP III modified the triglyceride classificationtriglyceride classification to give to give more more attentionattention to moderate elevations. to moderate elevations.

NCEP ATPIII. Chapter IV Circulation December 2002 pp 3247


• If triglycerides are If triglycerides are very highvery high (≥500 mg/dL),(≥500 mg/dL), attention turns attention turns first to prevention of acute pancreatitis, which is more likely first to prevention of acute pancreatitis, which is more likely to occur when triglycerides are >1000 mg/dL. to occur when triglycerides are >1000 mg/dL.

• Triglyceride-lowering drugsTriglyceride-lowering drugs (fibrate or nicotinic acid) (fibrate or nicotinic acid) become become first line therapyfirst line therapy; although statins can be used to lower LDL ; although statins can be used to lower LDL cholesterol to reach the LDL goal, in these patientscholesterol to reach the LDL goal, in these patients

Statin Therapy Does Not Statin Therapy Does Not Eliminate CV Eliminate CV

Risk Associated With Risk Associated With High High TG LevelTG Level

HPS Collaborative Group. Lancet. 2002;360:7-22 Sacks FM et al. Circulation. 2000;102:1893-1900

Low TG + statin

High TG + statin

CVD

Even

t Rat

e, %

HPS = Heart Protection Study: High TG > 354 mg/dL

CARE = Cholesterol & recurrent Events High TG > 207 mg/dl

LIPID = Long Term Intervention with Pravastatin in Ischemic Disease High TG > 207 mg/dL

Metabolic SyndromeMetabolic Syndrome

Clinical diagnosis requires more than 3 of the Clinical diagnosis requires more than 3 of the following risk factors:following risk factors: Abdominal Obesity (waist circumference): Abdominal Obesity (waist circumference):

men men > > 102 cm (40 in) women 102 cm (40 in) women >> 88 cm (35 in) 88 cm (35 in) Elevated Triglycerides Elevated Triglycerides >> 150 mg/dL 150 mg/dL Reduced HDL cholesterol: men < 40 mg/dL Reduced HDL cholesterol: men < 40 mg/dL

women < 50 mg/dLwomen < 50 mg/dL Hypertension Hypertension >> 130/85 130/85 Impaired fasting glucose Impaired fasting glucose >> 100 mg/dL 100 mg/dL

EEnlarged nlarged WWaist Combined With aist Combined With EElevated levated TTriglyceride (riglyceride (EWETEWET) )

EditorialEditorial• There is a growing consensus about the There is a growing consensus about the

importance of triglycerides, particularly in importance of triglycerides, particularly in women, and it has been shown in the same women, and it has been shown in the same national US sample that triglyceride level was national US sample that triglyceride level was the single most predictive component of the the single most predictive component of the MS-NCEP for CVD in multivariate analysis.MS-NCEP for CVD in multivariate analysis.

Conclusions: Conclusions: The combined presence of EWET The combined presence of EWET may be the best indicator of cardiovascular may be the best indicator of cardiovascular risk in postmenopausal women. risk in postmenopausal women. The TG value of concern is 128 mg/dLThe TG value of concern is 128 mg/dL

Michael Criqui Editorial Circulation.2005;111:1869-1870

What Increases Your Risk?What Increases Your Risk?

Several factors can make you more Several factors can make you more likely to develop high cholesterol:likely to develop high cholesterol:A diet high in saturated fats and A diet high in saturated fats and

cholesterolcholesterolA family history of high cholesterolA family history of high cholesterolBeing overweight or obeseBeing overweight or obeseGetting olderGetting older

Ways to Lower Ways to Lower CholesterolCholesterol

Dietary ModificationsDietary ModificationsLifestyle ModificationsLifestyle ModificationsMedications/DrugsMedications/Drugs

StatinsStatinsNon-StatinsNon-Statins

Dietary ModificationsDietary Modifications

Eat more fiberEat more fiberKnow your fatsKnow your fatsSmart proteinSmart proteinLow-carb dietLow-carb diet

Eat More FiberEat More Fiber

Good sources of Good sources of soluble fiber soluble fiber include whole-grain include whole-grain breads and cereals, breads and cereals, oatmeal, fruits, oatmeal, fruits, dried fruits, dried fruits, vegetables, and vegetables, and legumes such as legumes such as kidney beans.kidney beans.


Eat more fiberEat more fiberKnow your fatsKnow your fats

Know Your FatsKnow Your Fats

No more than 35% of your daily No more than 35% of your daily calories should come from fat. calories should come from fat.

But not all fats are equalBut not all fats are equalSaturated FatsSaturated FatsTrans FatsTrans FatsUnsaturated FatsUnsaturated Fats


Saturated fats -- from animal products Saturated fats -- from animal products and tropical oils -- raise LDL cholesterol.and tropical oils -- raise LDL cholesterol.

Trans fats increase bad cholesterol and Trans fats increase bad cholesterol and lowers the good cholesterollowers the good cholesterol

These two bad fats are found in many These two bad fats are found in many baked goods, fried foods (doughnuts, baked goods, fried foods (doughnuts, french fries, chips), stick margarine, french fries, chips), stick margarine, and cookies. and cookies.


Unsaturated fats Unsaturated fats may lower LDL may lower LDL when combined when combined with other healthy with other healthy diet changes. diet changes. They're found in They're found in avocados, olive avocados, olive oil, and peanut oil, and peanut oil. oil.


Eat more fiberEat more fiberKnow your fatsKnow your fatsSmart proteinSmart protein

Smart ProteinSmart Protein Meat and full-fat milk Meat and full-fat milk

are protein but they are protein but they are also major sources are also major sources of cholesterol. of cholesterol.

Switch to soy protein, Switch to soy protein, such as tofu.such as tofu.

Fish is rich in omega-Fish is rich in omega-3 fatty acids, which 3 fatty acids, which can improve can improve cholesterol levels.cholesterol levels.

The AHA recommends The AHA recommends eating fish at least eating fish at least twice a week.twice a week.


Eat more fiberEat more fiberKnow your fatsKnow your fatsSmart proteinSmart proteinLow-carb dietLow-carb diet

Low-Carb DietLow-Carb Diet

There's growing There's growing evidence that low-carb evidence that low-carb diets may be better diets may be better than low-fat diets for than low-fat diets for improving cholesterol improving cholesterol levels.levels.

In a two-year study In a two-year study funded by the National funded by the National Institutes of Health, Institutes of Health, people who followed a people who followed a low-carb plan had low-carb plan had significantly better HDL significantly better HDL (good cholesterol) (good cholesterol) levels than those who levels than those who followed a low-fat plan.followed a low-fat plan.

Lifestyle ModificationsLifestyle Modifications

Lose weightLose weightQuit smokingQuit smokingExerciseExercise

Lose WeightLose Weight

If you're overweight, If you're overweight, talk to your doctor talk to your doctor about beginning a about beginning a weight loss program.weight loss program.

Losing weight can Losing weight can help you reduce your help you reduce your levels of levels of triglycerides, LDL, triglycerides, LDL, and total and total cholesterol. cholesterol.

Good cholesterol Good cholesterol level tends to go up level tends to go up 1 point for every 6 1 point for every 6 pounds you lose.pounds you lose.

A couple were talking, and the wife says, “It’s my birthday tomorrow.”

Her husband responds with, “What do you want for your birthday?”

The wife says, “I want something that goes very fast.”

The next day, the husband comes home and says, “I have a gift for you, which goes from 0 to 300 in 3 seconds.”

The wife asks, “Is it a Ferrari? Or a Lamborghini?”

The husband says, “No, it’s a weighing scale!!!”

…The husband’s funeral is tomorrow.


Lose weightLose weightQuit smokingQuit smoking

Quit SmokingQuit Smoking

Tobacco use is one of Tobacco use is one of the most important the most important risk factors for CHDrisk factors for CHD

It is the most It is the most preventable cause of preventable cause of death in the USdeath in the US

440,000 deaths each 440,000 deaths each year are attributable year are attributable to tobacco useto tobacco use

When you stop When you stop smoking, your good smoking, your good cholesterol is likely to cholesterol is likely to improve improve


Lose weightLose weightQuit smokingQuit smokingExerciseExercise

ExerciseExercise

If you're healthy but not If you're healthy but not very active, starting an very active, starting an aerobic exercise program aerobic exercise program could increase your good could increase your good cholesterol by 5% in the cholesterol by 5% in the first two months.first two months.

Regular exercise also Regular exercise also lowers bad cholesterol. lowers bad cholesterol. Choose an activity that Choose an activity that boosts your heart rate, boosts your heart rate, such as running, such as running, swimming, or walking swimming, or walking brisklybriskly

Aim for at least 30 minutes Aim for at least 30 minutes on most days of the week. on most days of the week. It doesn't have to be 30 It doesn't have to be 30 continuous minutes; two continuous minutes; two 15-minute walks works just 15-minute walks works just as well.as well.

MedicationsMedications

StatinsStatinsNon-StatinsNon-Statins

Cholesterol Absorption Inhibitor Cholesterol Absorption Inhibitor (Ezetimibe)(Ezetimibe)

Nicotinic Acid (Niacin)Nicotinic Acid (Niacin)Bile Acid SequestrantsBile Acid SequestrantsFibric Acid DerivativesFibric Acid DerivativesOmega-3 Fatty Acids Omega-3 Fatty Acids

StatinsStatins

AtorvastatinAtorvastatinFluvastatinFluvastatinLovastatinLovastatinPravastatinPravastatinRosuvastatinRosuvastatinSimvastatinSimvastatin

StatinsStatins

Decrease LDL by 18 – 55 %Decrease LDL by 18 – 55 %

Increase HDL by 5 – 15 %Increase HDL by 5 – 15 %Decrease TG by 7 – 30 %Decrease TG by 7 – 30 %

StatinsStatins

The drug of choice for elevated LDL The drug of choice for elevated LDL levelslevels

Prevents cardiovascular and Prevents cardiovascular and cerebrovascular eventscerebrovascular events

Contraindicated in active or chronic liver Contraindicated in active or chronic liver disease, pregnancy and lactationdisease, pregnancy and lactation

Adverse effects include myopathy and Adverse effects include myopathy and increase in liver transaminasesincrease in liver transaminases

Statin Safety: Key Conclusions and Statin Safety: Key Conclusions and Recommendations Recommendations

of the NLAof the NLA

Conclusions of the NLA Conclusions of the NLA Safety Task Force for Muscle Safety Task Force for Muscle

SafetySafety Myopathy and rhabdomyolysis are associated with Myopathy and rhabdomyolysis are associated with statin therapy, as a class effectstatin therapy, as a class effect Elevated creatine kinase (CK) levels may indicate Elevated creatine kinase (CK) levels may indicate statin-induced muscle damagestatin-induced muscle damage Muscle weakness or pain without CK elevation may Muscle weakness or pain without CK elevation may indicate statin-induced muscle damage indicate statin-induced muscle damage Myopathy and rhabdomyolysis risk increases with Myopathy and rhabdomyolysis risk increases with increased statin dose and serum levelsincreased statin dose and serum levels Myopathy and rhabdomyolysis risk increases with Myopathy and rhabdomyolysis risk increases with drug-drug interactions that retard statin drug-drug interactions that retard statin metabolismmetabolism Drugs that can interact to amplify statin related Drugs that can interact to amplify statin related myopathy include gemfibrozil and CYP-3A4 myopathy include gemfibrozil and CYP-3A4 inhibitorsinhibitors

Thompson PD et al. Am J Cardiol. 2006;97:69C-76C

Conclusions of the NLA Conclusions of the NLA Safety Task Force on Liver Safety Task Force on Liver

FunctionFunction Statin use is associated with elevated serum Statin use is associated with elevated serum

aminotransferase levels, but it is unclear whether aminotransferase levels, but it is unclear whether this is a causal linkthis is a causal link

Statin-associated serum aminotransferase Statin-associated serum aminotransferase elevation is not predictive of liver damageelevation is not predictive of liver damage

Very rare case reports of liver failure have Very rare case reports of liver failure have occurred in patients receiving statin therapyoccurred in patients receiving statin therapy

Patients on statin therapy do not require routine Patients on statin therapy do not require routine liver function testingliver function testing

Statin therapy is not contraindicated in any Statin therapy is not contraindicated in any hepatic conditions, with the exception of hepatic conditions, with the exception of decompensated cirrhosis and acute liver failuredecompensated cirrhosis and acute liver failure

Cohen DE et al. Am J Cardiol. 2006;97:77C-81C

Conclusions of the NLA Conclusions of the NLA Safety Task Force on Renal Safety Task Force on Renal

IssuesIssuesMarketed doses of statins do not Marketed doses of statins do not produce clinically meaningful produce clinically meaningful proteinuriaproteinuriaThere is no association between There is no association between statin use and renal tubular damagestatin use and renal tubular damageThere is no evidence that statin use There is no evidence that statin use leads to renal glomerular damage leads to renal glomerular damage There is no convincing link between There is no convincing link between statin use and hematuriastatin use and hematuriaSome evidence indicates statins may Some evidence indicates statins may provide some kidney protectionprovide some kidney protection

Kasiske BL et al. Am J Cardiol. 2006;97:82C-85C

Conclusions of the NLA Conclusions of the NLA Safety Task Force on Safety Task Force on

NeurologyNeurologyThere is no association between statin use There is no association between statin use

and clinically meaningful peripheral and clinically meaningful peripheral neuropathyneuropathy

There is no convincing evidence that There is no convincing evidence that statins cause impaired memory or statins cause impaired memory or cognitive dysfunctioncognitive dysfunction

Clinical trial data indicate that lowering Clinical trial data indicate that lowering lipids with statins does not increase risk of lipids with statins does not increase risk of cerebral hemorrhagecerebral hemorrhageBrass LM et al. Am J Cardiol. 2006;97:86C-88C

Recommendations Recommendations Regarding Patient Regarding Patient

MonitoringMonitoringMonitoring CK levels is recommended Monitoring CK levels is recommended

only for symptomatic patientsonly for symptomatic patientsPatients on statin therapy do not Patients on statin therapy do not

require routine monitoring of liver require routine monitoring of liver function, renal function, or cognitive function, renal function, or cognitive functionfunction

Messages for PatientsMessages for PatientsStatins can produce muscle pain and Statins can produce muscle pain and

weakness, which can very rarely become weakness, which can very rarely become an important medical probleman important medical problem

Serious liver damage due to statins is Serious liver damage due to statins is extremely rareextremely rare

Marketed doses of statins do not have Marketed doses of statins do not have any direct adverse effects on the kidneyany direct adverse effects on the kidney

Statins do not cause peripheral Statins do not cause peripheral neuropathy and do not impair memory or neuropathy and do not impair memory or cognitioncognition

Non-Statins: Non-Statins: Cholesterol Absorption Cholesterol Absorption

InhibitorInhibitorDecrease LDL by 18 – 20%Decrease LDL by 18 – 20%Increase HDL by 1 – 5%Increase HDL by 1 – 5%Decrease TG by 5 – 11%Decrease TG by 5 – 11%

Non-Statins:Non-Statins:Cholesterol Absorption Cholesterol Absorption

InhibitorInhibitorEzetimibe Ezetimibe Safe and effective adjunct to statins Safe and effective adjunct to statins

when further LDL lowering is when further LDL lowering is requiredrequired

Contraindicated in patients with Contraindicated in patients with active liver disease or unexplained active liver disease or unexplained persistent transaminase elevationspersistent transaminase elevations

Adverse effects include GI complaintsAdverse effects include GI complaints

Non-Statins: NiacinNon-Statins: Niacin

Decrease LDL by 5 – 25 %Decrease LDL by 5 – 25 %Increase HDL by 15 – 35 %Increase HDL by 15 – 35 %Decrease TG by 20 – 50%Decrease TG by 20 – 50%

Non-Statins: NiacinNon-Statins: Niacin

Uniquely effective in atherogenic Uniquely effective in atherogenic dyslipidemiadyslipidemia

Useful in nearly all dyslipidemias and Useful in nearly all dyslipidemias and adjunctive therapy for mixed dyslipidemiasadjunctive therapy for mixed dyslipidemias

Contraindicated in chronic liver disease, Contraindicated in chronic liver disease, severe gout, active peptic ulcer diseasesevere gout, active peptic ulcer disease

Adverse effects include flushing, Adverse effects include flushing, hyperglycemia, hyperuricemia, hyperglycemia, hyperuricemia, hepatotoxicityhepatotoxicity

Safety Considerations with Niacin TherapySafety Considerations with Niacin Therapy

Recommendations to healthcare professionals Recommendations to healthcare professionals regarding niacin safetyregarding niacin safety

Healthcare professionals may expect that Healthcare professionals may expect that 5%–10% of patients will not tolerate niacin 5%–10% of patients will not tolerate niacin in long-term use because of flushing. in long-term use because of flushing.

Skin rashes associated with niacin therapy Skin rashes associated with niacin therapy are generally not allergic but are likely are generally not allergic but are likely related to dermal prostaglandin release and related to dermal prostaglandin release and to dry skin. to dry skin.

Serious hepatic toxicity can occur with Serious hepatic toxicity can occur with niacin therapy, but it is almost entirely niacin therapy, but it is almost entirely associated with the use of slow-release associated with the use of slow-release formulations. IR (regular or crystalline) formulations. IR (regular or crystalline) niacin or ER niacin generally should be used niacin or ER niacin generally should be used rather than SR niacin. rather than SR niacin.

CK creatine kinase; ER extended release; HDL high-density lipoprotein; IR immediate release; PCP phencyclidine; SR sustained release; ULN upper limit of normal


Hepatic transaminase levels should be Hepatic transaminase levels should be monitored every 6–12 week during the first 6–monitored every 6–12 week during the first 6–12 month of treatment with niacin and 12 month of treatment with niacin and periodically thereafter (eg, at 6-mo intervals). periodically thereafter (eg, at 6-mo intervals).

Niacin is useful for the treatment of the Niacin is useful for the treatment of the dyslipidemia of diabetes mellitus, especially dyslipidemia of diabetes mellitus, especially low HDL cholesterol. Minor increases (4%–5% low HDL cholesterol. Minor increases (4%–5% on average) in glucose levels result from on average) in glucose levels result from niacin-induced insulin resistance, but these niacin-induced insulin resistance, but these increases are often clinically insignificant.increases are often clinically insignificant.

The onset of type 2 diabetes (multiple fasting The onset of type 2 diabetes (multiple fasting glucose levels 125 mg/dL or postprandial glucose levels 125 mg/dL or postprandial glucose levels 200 mg/dL) in a patient taking glucose levels 200 mg/dL) in a patient taking niacin should prompt consideration of niacin niacin should prompt consideration of niacin withdrawal or dosage reduction. withdrawal or dosage reduction.


On the basis of almost 2 decades of On the basis of almost 2 decades of clinical evidence, niacin clinical evidence, niacin coadministration with a statin does coadministration with a statin does not potentiate statin-related not potentiate statin-related myopathic reactions.myopathic reactions.

Niacin should not be used in the Niacin should not be used in the presence of active peptic ulcer presence of active peptic ulcer disease, but a remote history of disease, but a remote history of peptic ulcer is not a contraindication peptic ulcer is not a contraindication to niacin use. Gastroesophageal reflux to niacin use. Gastroesophageal reflux disease is generally not affected by disease is generally not affected by niacin.niacin.


Palpitations and tachycardia are Palpitations and tachycardia are potential adverse experiences with potential adverse experiences with niacin. In rare cases, this may relate to niacin. In rare cases, this may relate to the increased incidence of “definite or the increased incidence of “definite or suspected” atrial fibrillation.suspected” atrial fibrillation.

Active gout is a relative contraindication Active gout is a relative contraindication to niacin use, because niacin (nicotinic to niacin use, because niacin (nicotinic acid) competes with uric acid for acid) competes with uric acid for secretion by kidney tubules and raises secretion by kidney tubules and raises serum uric acid levels by 5%–15%.serum uric acid levels by 5%–15%.Guyton G, Bays H. Report of the National Lipid Association’s Safety Task Force: The Nonstatins. Am J Cardiol 2007;99(suppl):22C-31C

Non-Statins: Non-Statins: Bile Acid SequestrantsBile Acid Sequestrants

Decrease LDL by 15 – 30 %Decrease LDL by 15 – 30 %Increase HDL by 3 -5 %Increase HDL by 3 -5 %TG is usually not affected but may TG is usually not affected but may

increaseincrease

Non-Statins: Non-Statins: Bile Acid SequestrantsBile Acid Sequestrants

Include Colesevelam, Cholestyramine , Include Colesevelam, Cholestyramine , ColestipolColestipol

Indicated for moderate Indicated for moderate hypercholesterolemia, in younger patients hypercholesterolemia, in younger patients with elevated LDL and women with elevated with elevated LDL and women with elevated LDL who are considering pregnancy LDL who are considering pregnancy

Adverse effects include constipation, Adverse effects include constipation, flatulence and decreased absorption of flatulence and decreased absorption of other drugs like digoxin, warfarin, HCTZ, other drugs like digoxin, warfarin, HCTZ, beta blockers, thyroxine and penicillin Gbeta blockers, thyroxine and penicillin G

Non-Statins: FibratesNon-Statins: Fibrates

Decrease LDL by 5 – 20 %Decrease LDL by 5 – 20 %Increase HDL by 10 – 35 %Increase HDL by 10 – 35 %Decrease TG by 20 – 50 %Decrease TG by 20 – 50 %

Non-Statins: FibratesNon-Statins: Fibrates Includes Gemfibrozil, Fenofibrate and Includes Gemfibrozil, Fenofibrate and

ClofibrateClofibrate Indicated in hypertriglyceridemia and Indicated in hypertriglyceridemia and

atherogenic dyslipidemiaatherogenic dyslipidemia Contraindicated in severe hepatic or renal Contraindicated in severe hepatic or renal

dysfunction, primary biliary cirrhosis and dysfunction, primary biliary cirrhosis and gall bladder diseasegall bladder disease

Adverse effects include dyspepsia, upper GI Adverse effects include dyspepsia, upper GI complaints, cholesterol gallstones, complaints, cholesterol gallstones, myopathymyopathy

Recommendations to healthcare professionals Recommendations to healthcare professionals regarding fibrate safetyregarding fibrate safety

Before the initiation of fibrate therapy, a Before the initiation of fibrate therapy, a measurement of serum creatinine should be measurement of serum creatinine should be determined. If impaired renal function is present, determined. If impaired renal function is present, the patient should be prescribed gemfibrozil the patient should be prescribed gemfibrozil (unless taking a statin), or a lower starting dose (unless taking a statin), or a lower starting dose of fenofibrate (48 mg is most commonly of fenofibrate (48 mg is most commonly available) should be considered. available) should be considered.

Routine monitoring of creatinine is not required.Routine monitoring of creatinine is not required. Creatinine monitoring may be advisable if a Creatinine monitoring may be advisable if a

patient is taking another medication, such as patient is taking another medication, such as metformin, which may need to be discontinued metformin, which may need to be discontinued for creatinine elevations 1.4 mg/dL in women and for creatinine elevations 1.4 mg/dL in women and 1.5 mg/dL in men, or a statin, which may require 1.5 mg/dL in men, or a statin, which may require downward dosage adjustment.downward dosage adjustment.

CK creatine kinase; HDL high-density lipoprotein; INR international normalized ratio; IV intravenous; PT prothrombin time; ULN upper limit of normal

Recommendations to healthcare Recommendations to healthcare professionals regarding fibrate safetyprofessionals regarding fibrate safety

Clinicians should still use caution when Clinicians should still use caution when prescribing the highest doses of statins used prescribing the highest doses of statins used in combination with fibrate therapy, because in combination with fibrate therapy, because both classes of drugs are independently both classes of drugs are independently associated with an increased risk for associated with an increased risk for myopathy. In combination with a statin, myopathy. In combination with a statin, fenofibrate is the preferred option, and fenofibrate is the preferred option, and gemfibrozil should be avoided.gemfibrozil should be avoided.

Gemfibrozil has less effect than fenofibrate on Gemfibrozil has less effect than fenofibrate on creatinine and therefore is the National Kidney creatinine and therefore is the National Kidney Foundation’s (NKF) fibrate of choice for renal Foundation’s (NKF) fibrate of choice for renal insufficiency. It does seem reasonable to insufficiency. It does seem reasonable to discourage the administration of fenofibrate discourage the administration of fenofibrate to kidney transplant patients and those on to kidney transplant patients and those on dialysis, because fenofibrate is nondialysable.dialysis, because fenofibrate is nondialysable.


Clinicians should warn patients about Clinicians should warn patients about the possibility of myopathy on fibrate the possibility of myopathy on fibrate therapy and advise the reporting of therapy and advise the reporting of side effects of diffuse muscle pain or side effects of diffuse muscle pain or weakness as soon as possible.weakness as soon as possible.

It is not necessary to measure CK It is not necessary to measure CK levels in asymptomatic patients during levels in asymptomatic patients during the course of fibrate therapy, because the course of fibrate therapy, because marked, clinically important CK marked, clinically important CK elevations are relatively rare. elevations are relatively rare.


Clinicians should be aware that Clinicians should be aware that fibrates have not been demonstrated fibrates have not been demonstrated to significantly reduce total and to significantly reduce total and cardiovascular mortality. cardiovascular mortality.

Fibrate therapy elevates Fibrate therapy elevates homocysteine, however, routine homocysteine, however, routine monitoring of plasma homocysteine monitoring of plasma homocysteine levels on fibrate is not necesary levels on fibrate is not necesary unless further research ascertains unless further research ascertains that this elevation is clinically that this elevation is clinically relevant.relevant.


Caution should be exercised when Caution should be exercised when anticoagulants are given in conjunction with anticoagulants are given in conjunction with both fenofibrate and gemfibrozil because of both fenofibrate and gemfibrozil because of the potentiation of coumarin-type the potentiation of coumarin-type anticoagulants in prolonging PT and the INR.anticoagulants in prolonging PT and the INR.

All fibrates have the potential to increase the All fibrates have the potential to increase the cholesterol saturation index and increase the cholesterol saturation index and increase the risk for cholelithiasis; however, cases of risk for cholelithiasis; however, cases of gallbladder disease and cholecystectomies gallbladder disease and cholecystectomies appear to be uncommon with gemfibrozil and appear to be uncommon with gemfibrozil and fenofibrate.fenofibrate.

Davidson M, Armani A, McKenney JM, Jacobson T. Report of the National Lipid Association’s Safety Task Force: The Nonstatins. Am J Cardiol 2007;99(suppl):3C-18C

Non-Statins: Non-Statins: Omega-3 Fatty AcidsOmega-3 Fatty Acids

Decrease TG by 45 %Decrease TG by 45 %Increase HDL by 9 %Increase HDL by 9 %Increase LDL by 44 %Increase LDL by 44 %

Non-Statins: Non-Statins: Omega-3 Fatty AcidsOmega-3 Fatty Acids

Fish OilsFish Oils Its major use is in hypertriglyceridemia Its major use is in hypertriglyceridemia

greater than 500mg/dLgreater than 500mg/dLContraindicated in patients with known Contraindicated in patients with known

hypersensitivity to fish and in women hypersensitivity to fish and in women who are pregnant or breastfeedingwho are pregnant or breastfeeding

Adverse effects include eructation, Adverse effects include eructation, dyspepsia, and taste perversiondyspepsia, and taste perversion

Safety Considerations with Omega-3 Safety Considerations with Omega-3 Fatty Acid TherapyFatty Acid Therapy

Recommendations to healthcare professionals regarding fish Recommendations to healthcare professionals regarding fish oil therapy safetyoil therapy safety

The clinical trial evidence does not support The clinical trial evidence does not support an increased bleeding risk with fish oil an increased bleeding risk with fish oil therapy, even when used in combination therapy, even when used in combination with other agents that may increase with other agents that may increase bleeding (such as aspirin and warfarin).bleeding (such as aspirin and warfarin).

It is reasonable to monitor patients It is reasonable to monitor patients treated with fish oils and anticoagulants treated with fish oils and anticoagulants for potential bleeding adverse for potential bleeding adverse experiences.experiences.

Fish oils should probably be discontinued Fish oils should probably be discontinued during acute bleeding episodes, such as during acute bleeding episodes, such as hemorrhagic stroke.hemorrhagic stroke.

Recommendations to healthcare professionals Recommendations to healthcare professionals regarding fish oil therapy safetyregarding fish oil therapy safety

The decision to discontinue fish oils days before The decision to discontinue fish oils days before an invasive procedure at high risk for bleeding an invasive procedure at high risk for bleeding complications should be based on weighing the complications should be based on weighing the unproved potential increase in bleeding risk unproved potential increase in bleeding risk versus the potential reduction in atrial fibrillation versus the potential reduction in atrial fibrillation before certain procedures, such as coronary before certain procedures, such as coronary artery bypass surgery.artery bypass surgery.

Rigorous purification processes involved in fish Rigorous purification processes involved in fish oil manufacturing reduce the risk of fatty acid oil manufacturing reduce the risk of fatty acid oxidation, hypervitaminosis, and exposure to oxidation, hypervitaminosis, and exposure to environmental toxins.environmental toxins.


Clinicians and patients should be aware of the Clinicians and patients should be aware of the variance in the purification processes among variance in the purification processes among different fish oil manufacturers.different fish oil manufacturers.

Because fish oil supplements are generally regarded Because fish oil supplements are generally regarded as safe, they are not subject to FDA premarket and as safe, they are not subject to FDA premarket and approval requirements.approval requirements.

If a product has the “USP-Verified” mark on its label, If a product has the “USP-Verified” mark on its label, the manufacturer has met voluntary USP standards, the manufacturer has met voluntary USP standards, which include initial and ongoing determinations to which include initial and ongoing determinations to ensure that (1) what is on the label is in fact in the ensure that (1) what is on the label is in fact in the bottle (all the listed ingredients in the declared bottle (all the listed ingredients in the declared amounts), (2) the supplement does not contain amounts), (2) the supplement does not contain harmful levels of contaminants, (3) the supplement harmful levels of contaminants, (3) the supplement will break down and release ingredients in the body, will break down and release ingredients in the body, and (4) the supplement has been made under current and (4) the supplement has been made under current good manufacturing practices.good manufacturing practices.


Claims of a fish oil supplement being Claims of a fish oil supplement being “pharmaceutical grade” have little “pharmaceutical grade” have little meaning regarding safety and have meaning regarding safety and have even less meaning with regard to even less meaning with regard to efficacy, unless the fish oil preparation efficacy, unless the fish oil preparation has been approved by the FDA as a has been approved by the FDA as a prescription pharmaceutical.prescription pharmaceutical.

Prescription fish oil preparations Prescription fish oil preparations undergo the same rigorous FDA undergo the same rigorous FDA regulatory requirements as other regulatory requirements as other prescription pharmaceuticals, with prescription pharmaceuticals, with regard to both efficacy and safety.regard to both efficacy and safety.


One of the most common pitfalls in the day-to-day, One of the most common pitfalls in the day-to-day, clinical use of fish oil therapy is the sense among clinical use of fish oil therapy is the sense among patients that all fish oil therapies are the same. patients that all fish oil therapies are the same. Clinicians need to educate patients of the wide Clinicians need to educate patients of the wide variance in fish oil therapies regarding efficacy, variance in fish oil therapies regarding efficacy, tolerability, and perhaps even safety. For example, tolerability, and perhaps even safety. For example, the efficacy of fish oil therapy is most dependent on the efficacy of fish oil therapy is most dependent on the amount of omega-3 fatty acids (such as EPA and the amount of omega-3 fatty acids (such as EPA and DHA) in each capsule, not the total amount of fish oil DHA) in each capsule, not the total amount of fish oil concentrate. Thus, to achieve the same level of concentrate. Thus, to achieve the same level of omega-3 fatty acid intake, patients may have to take omega-3 fatty acid intake, patients may have to take as many as 11 capsules of some fish oil supplements as many as 11 capsules of some fish oil supplements to match the same amount of omega-3 fatty acid to match the same amount of omega-3 fatty acid intake as 4 fish oil capsules of prescription fish oil.intake as 4 fish oil capsules of prescription fish oil.

Bays H. Report of the National Lipid Association’s Safety Task Force: The Nonstatins. Am J Cardiol 2007;99(suppl):35C-43C

Add-on to statin therapy Add-on to statin therapy Drug options to ↓LDL & ↓Non-Drug options to ↓LDL & ↓Non-

HDL-CHDL-CDrug LDL-C Non-HDL-C Trigs HDL-C

Double statin dose -6% -6% -2 to -12% -2 to +2%

Ezetimibe 10 mg -15% -12% -9% NS

Niacin 2 gr -14% -31%* -24% +18%

Bile acid binding agent Colestipol 2 scoops (6 gr) Cholestyramine 2 scoops (8 gr) Coleselvalam 6 tabs (3.75 gr)

-12% -5-8% 0 to +23% +1-7%

Fenofibrate 145 mg -6% to +4% -3% to -18%* -15 to -20% +13%

Gemfibrozil 600 mg BID +7% +2% -18% 0%

Jones PH, et al. Am J Cardiol 2003; 92: 152-60.Robinson JG, Davidson MH. Expert Rev Cardiovasc Ther. 2006: 4: 461-76Kos Niaspan® prescribing information 2005Sankyo Welchol® prescribing information 2005Athyros VG et al. Diabetes Care 2002; 25: 1198-1202; Durrington PN et al. Diab Res Clin Pract 2004; 64: 137-51.Wagner AM, et al. J Clin Endocrinol Metab 2003; 88: 3212-17.*Estimated Total cholesterol-HDL

Take Home PointsTake Home Points In the treatment of dyslipidemia:In the treatment of dyslipidemia:

Statins are the most effective and safe first Statins are the most effective and safe first line of treatment.line of treatment.

Non-statins, which include cholesterol Non-statins, which include cholesterol absorption inhibitors, niacin, bile acid absorption inhibitors, niacin, bile acid sequestrants, fibrates, and omega-3 fatty sequestrants, fibrates, and omega-3 fatty acids, probably help improve the outcomes of acids, probably help improve the outcomes of patients with CHD, although strong evidence patients with CHD, although strong evidence remains lacking. remains lacking.

Triglycerides are now considered as an Triglycerides are now considered as an independent risk factor for CHD.independent risk factor for CHD.

Documents

Dyslipidemia: Updated Guidelines