Update on Dyslipidemias

Kristopher Maday, MS, PA-C, CNSCUniversity of Alabama at Birmingham

Pegasus Emergency Group

Objectives• Review the different types of lipids that are

important for clinical practice• Discuss the cardiovascular risk scores• Describe current lifestyle modification

recommendations in the treatment of hyperlipidemia

• Evaluate the 2013 AHA/ACC guidelines for dyslipidemia management

• Appraise the pharmacologic treatment options for dyslipidemias

What are lipids?• Carbon and hydrogen containing compounds

that are insoluble in water, but are soluble in organic solvents

• Functions– Sources of energy– Formation of cell membrane– Constitute bile acids

• Derived from both dietary sources and internal body processes

Types of Plasma Lipids• Sterols

– Cholesterol• Neutral Fats

– Triglycerides– Free Fatty Acids

• Conjugated Lipids– Phospholipids– Lipoproteins

Cholesterol• Necessary for the formation of cell

membranes, bile salts, adrenocorticosteroids, estrogens, and androgens

• 75% is bound to LDL• Levels can fluctuate as much as 8%

during one day and 15% from day to day

Free Fatty Acids• Travel through

bloodstream combined with albumin

• Blood levels are never high unless stimulated to release fat– Same stimulus will also

elevate triglycerides• Utilized for energy in

muscle tissue

Triglycerides• Combination of 3 FFA and 1 glycerol

molecule• Main form of lipid storage• Used in the body to provide energy:

– Directly as a energy source– Indirectly for gluconeogenesis

• Transported by VLDL and LDL

Phospholipids• 3 main types

– Lecithins• Involved in pulmonary gas exchange

– Cephalins• Major constituent of thromboplastin

– Sphingomyelins• Involved with formation of myelin sheath in CNS

• Important for the formation of cell membrane and transportation of fatty acids through the intestinal mucosa into lymph

• Lecithin:Sphingomyelin ratio– Fetal lung maturation

Lipoproteins• Main function is to transport cholesterol and

triglycerides

• Grouped by density– Chylomicrons

• Primarily triglycerides– Very-Low Density Lipoprotein (VLDL)

• Mainly triglycerides– Low Density Lipoprotein (LDL)

• Primarily cholesterol– High Density Lipoprotein (HDL)

• Mainly protein with small amount of cholesterol

Very-Low Density Lipoprotein

• Predominant carrier of blood triglycerides

• High concentrations cause alterations of appearance of serum (ie. hazy, turbid)

• Associated with increased risk of CAD

Low Density Lipoprotein

• Very cholesterol rich• High association with CAD• ***Main focus of pharmacotherapy***• Friedewald Formula

– LDL = TC – (HDL + (triglycerides/5))

Lipoprotein CharacteristicsLipoprotein Size Density Major

Apolipoprotein Origins Comments

Chylomicron Largest Least ApoB-48 Intestines Primarily triglycerides

Very Low-Density

Lipoprotein(VLDL)

ApoB-100 Liver and Intestines Primarily triglycerides

Intermediate-density

Lipoprotein(IDL)

ApoB-100 Chylomicrons and VLDL

Transitional forms

Low-density Lipoprotein

(LDL)ApoB-100 End-product of VLDL Major carrier

of cholesterol

High-density Lipoproteins

(HDL)Smallest Most ApoA-1 Intestines and liver Removes

cholesterol

Lipoprotein Phenotyping• 6 different phenotypes of lipoproteins• Each phenotype has correlated with

genetically determined abnormalities as well as a variety of acquired conditions

• Useful in diagnosing and treating specific hyperlipoproteinemias

Physical Exam Findings• Majority of hypercholesterolemia

patients are diagnosed by laboratory abnormalities

• Extremely elevated LDL and triglycerides– Eruptive xanthomas

• Red-yellow papules– Tendinous xanthomas– Lipemia retinalis

• Cream-colored blood vessels in fundus

Eruptive Xanthomas

Tendinous Xanthoma

Lipemia Retinalis

Treatment

Lifestyle Modifications • Diet

– Decrease:• Total fat to 25-30% of calories

– Saturated fat < 7% of calories• Total cholesterol < 200 mg/dl

• Physical Activity– 150 minutes a week

• Weight loss– > 10% for overweight patients

Who Needs Pharmacotherapy?

• Clinical Atherosclerotic Cardiovascular Disease (ASCVD)– Acute Coronary Syndrome– Myocardial Infarction– Stable or Unstable Angina– Revascularization Procedures– Cerebrovascular Disease– Peripheral Arterial Disease

• LDL ≥ 190 mg/dL• Type I or II Diabetes AND age 40-75• 10-year ASCVD risk ≥ 7.5% AND age 40-75

Cardiovascular Risk Scores• Calculates a patient’s 10 year risk for a

major cardiovascular event– Framingham Score

• Age, Gender, Total cholesterol, HDL, SBP, Smoking

– Reynolds Score• Age, Smoking, SBP, Total Cholesterol, CRP, Family

History– PROCAM Score

• Age, Gender, DM, Smoking, Family History, SBP, BMI, Antihypertensive therapy

Statins: Mechanism of Action

LDL receptor–mediated hepatic uptake of LDL and VLDL remnants

Serum VLDL remnantsSerum LDL-C

Cholesterol synthesis

LDL receptor (B–E receptor) synthesis

Intracellular Cholesterol

Apo BApo E

Apo B

Systemic CirculationHepatocyteReduce hepatic cholesterol synthesis, lowering intracellular

cholesterol, which stimulates upregulation of LDL receptor and increases the uptake of non-HDL particles from the systemic

circulation.

LDL

Serum IDL

VLDLR

VLDL

Risk Reduction with Statin Therapy

Endpoints +20 –35–30–250 –5 –10–15–20Relative Risk Reduction (%)

–40–45–50

Major coronary eventsCoronary deathsCardiovascular deathsNoncardiovascular events

Total mortalityStrokesIntermittent claudicationAngina

Statin Adverse Events• Common side effects

- Headache – Myalgia – Fatigue- GI intolerance – Flu-like symptoms

• Increase in liver enzymes– Occurs in 0.5 to 2.5% of cases in dose-dependent manner– Serious liver problems are exceedingly rare– Manage by reducing statin dose or discontinue until levels return to

normal• Myopathy

– Occurs in 0.2 to 0.4% of patients– Rare cases of rhabdomyolysis– Reduce by

• Cautiously using statins in patients with impaired renal function• Using the lowest effective dose• Cautiously combining statins with fibrates• Avoiding drug interactions• Careful monitoring of symptoms

– Presence of muscle toxicity requires the discontinuation of the statin

Nicotinic Acid: Mechanism of Action

Liver CirculationHDL

Serum VLDL results in reduced lipolysis to LDL

Serum LDL

VLDL

Decreases hepatic production of VLDL and ApoB

VLDL secretion

Apo B

Hepatocyte Systemic Circulation

Mobilization of FFA

TG synthesis

VLDL

LDL

Nicotinic Acid• Products available (daily dose)

• Immediate-release, 2–4 g/d• Extended-release (Niaspan®), 1–2 g/d• OTC products, sustained-release, 2 g/d

• Best agent to raise HDL-C• Adverse effects

• Flushing, itching, headache (immediate-release, Niaspan®)

• Hepatotoxicity, GI (sustained-release)• Activation of peptic ulcer• Hyperglycemia and reduced insulin sensitivity

• Contraindications• Active liver disease or unexplained LFT elevations• Peptic ulcer disease

Bile Acid Resins: Mechanism of Action

Net Effect: LDL-C

Gall Bladder

­ LDL Receptors­ VLDL and LDL removal

­ Cholesterol 7- hydroxylase­ Conversion of cholesterol to BA­ BA Secretion

Liver

­ BA Excretion

Terminal Ileum

Bile AcidEnterohepatic Recirculation

Reabsorption of bile acids

Bile Acid Binding Resins• Products available:

• Cholestyramine (Questran), 4–16 g/d• Colestipol (Colestid), 5–20 g/d• Colesevelam (WelChol) 625 mg tablets, 6–7 tablets/d

• Reduce coronary events (LRC-CPPT)• Adverse effects

• GI intolerance: constipation, bloating, abdominal pain, flatulence

• Lack systemic toxicity• Drug interactions (colestipol and cholestyramine)

• Bind other negatively charged drugs• Impede the absorption of drugs and/or fat-soluble vitamins• Must give other drugs 1 hour before or 4–6 hours after

Fibric Acid Derivatives: Mechanism of Action

Fibric Acid Derivitives• Products available:

• Fenofibrate 48-160mg • Fenofibric acid 35-105mg• Gemfibrozil 600mg

• Adverse effects• GI side effects• Myositis• Abnormal liver function

• Contraindications• Hepatic or renal dysfunction• Pre-existing gall bladder disease

Duodenum

Jejunum

Ileum

CMapoB48

Liver

CM RemnantapoB48

VLDLapoB100

EzetimibeX

LDLapoB100

XStatin

Colon

Ezitimibe: Mechanism of Action

Omega-3 Fatty Acids• Lipid effect

– Reduced hepatic VLDL production• EPA (eicosapentaenoic acid) and DHA

(docosahexaenoic acid) in fish oils are more effective than alpha-linolenic acid in vegetable sources

• Doses >7g/day – decreased TG 25% and increased TC 2% in normal patients; – 28% and 7%, respectively, in HTG patients

• Omacor (85% omega-3 fatty acid ethyl esters) at 4g/day = 27-45% TG reduction

• Side Effects: fishy aftertaste

Conclusion• Encourage lifestyle modifications• Start statin pharmacotherapy if:

– (+) ASCVD– LDL > 190 mg/dL– 40-75yo AND:

• DM type I or II or • > 7.5% 10-year CV risk

• Tailor additional pharmacotherapy based on lipid panel