Hyperlipidemia Chapter 23

1
Hyperlipidemia Chapter 23
Pharmacotherapy A Pathophysiologic Approach
The McGraw-Hill Companies
2
Abbreviations
3
Overview

• Definition
• Background pathophysiology
• Classification
• Goals of therapy
• Risk factors
• Lifestyle modifications
• Treatment
• Hyperlipidemia in children pregnancy
• Monitoring
• Pharmacoeconomic considerations

4
Hyperlipidemia

• Elevated blood levels of lipoproteins
  (cholesterol, triglycerides, phospholipids)
• Lipoprotein abnormalities gt 1 of the following
• elevated total cholesterol (TC)
• elevated low-density lipoprotein (LDL)
• elevated triglycerides (TG)
• reduced high-density lipoprotein (HDL)
• National Guideline
• The National Education Program (NCEP) Adult
  Treatment Panel III (ATP III)
• ?TC, ? LDL, ?HDL reduces mortality/CHD events

Expert Panel on Detection E, and Treatment of
High Blood Cholesterol in Adults. Executive
summary of the third report of the National
Cholesterol Education Program (NCEP) Expert Panel
on Detection, Evaluation and Treatment of High
Blood Cholesterol in Adults (Adult Treatment
Panel III). JAMA 200128524862497.
5
Hyperlipidemia

• CHD risk directly correlates with TC LDL levels
  in graded, continuous fashion
• gt 50 of American adults total cholesterol gt 200
  mg/dL
• lt 50 of patients with established CHD are
  receiving lipid lowering treatment
• Lipid lowering drug therapy reduces risk of
  cardiovascular/cerebrovascular events, death

5
Rosamond W, Flegal K, Friday G, et al. Heart
disease and stroke statistics2007 update A
report from the American Heart Association
Statistics Committee and Stroke Statistics
Subcommittee. Circulation 20071156.
6
Hyperlipidemia

• Hypercholesterolemia additive to nonlipid CHD
  risk factors cigarette smoking, HTN, DM, low
  HDL, electrocardiographic abnormalities
• Presence of CHD, prior MI increases MI risk 5 to
  7 times
• LDL level significant predictor of
  morbidity/mortality
• 50 of MIs and gt 70 of CHD deaths occur in
  patients with known CHD

Menotti A, Lanti M, Nedeljkovic S, Nissinen A,
Kafatos A, Kromhout D. The relationship of age,
blood pressure, serum cholesterol and smoking
habits with the risk of typical and atypical
coronary heart disease death in the European
cohorts of the Seven Countries Study. Int J
Cardiol 2006106157163.
Kannel WB. Range of serum cholesterol values in
the population developing coronary artery
disease. Am J Cardiol 19957669C77C.
7
Background Pathophysiology

• Cholesterol essential for cell membrane
  formation hormone synthesis
• Lipids not present in free form in plasma
  circulate as lipoproteins
• 3 major plasma lipoproteins
• VLDL carries 10 to 15 of total serum
  cholesterol carried in circulation as TG VLDL
  TG/5
• LDL carries 60 to 70 of total serum cholesterol
  IDL is also included in this group
• HDL carries 20 to 30 of total serum cholesterol
  reverse transportation of cholesterol

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Background Pathophysiology

• VLDL secreted from the liver
• converted to IDL then LDL
• Plasma LDL taken up by receptors on liver,
  adrenal, peripheral cells
• recognize LDL apolipoprotein B-100

10
Background Pathophysiology

• LDL internalized degraded by these cells
• Increased intracellular cholesterol levels
  inhibits HMG-CoA reductase decreases LDL
  receptor synthesis
• Decreases in LDL receptors plasma LDL not as
  readily taken up broken down by cells
• LDL also excreted in bile
• joins enterohepatic pool
• eliminated in stool
• can be oxidized in subendothelial space of
  arteries

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Background Pathophysiology

• Oxidized LDL in artery walls provokes
  inflammatory response
• Monocytes recruited transformed into
  macrophages
• results in cholesterol laden foam cell
  accumulation
• Foam cells beginning of arterial fatty streak
• If processes continue angina, stroke, MI,
  peripheral artery disease, arrhythmias, death

14
Etiology

• Lipoprotein disorders 6 categories based on
  phenotype
• Specific genetic defects with disrupted protein,
  cell, and organ function give rise to several
  disorders within each family of lipoproteins
• Elevated cholesterol not necessarily familial
  hypercholesterolemia (type IIa)
• cholesterol may be elevated in other lipoprotein
  disorders
• lipoprotein pattern does not describe underlying
  genetic defect

15
Hyperlipoproteinemia Classification
Fredrickson-Levy-Lees Classification
IDL, intermediate-density lipoprotein LDL,
low-density lipoprotein VLDL, very-low-density
lipoprotein
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
16
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
17
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
18
Etiology

• Many genetic abnormalities environmental
  factors lead to lipoprotein abnormalities
• Current laboratory values can not define
  underlying abnormality
• 2 hyperlipidemia should be initially managed by
  correcting underlying abnormality when possible

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19
Lipoprotein Abnormalities 2 Causes

• Hypercholesterolemia
• hypothyroidism
• obstructive liver disease
• nephrotic syndrome
• anorexia nervosa
• acute intermittent porphyria

19
20
Lipoprotein Abnormalities 2 Causes

• Hypercholesterolemia
• medications

• protease inhibitors
• cyclosporine
• mirtazipine
• sirolimus

• progestins
• thiazide diuretics
• glucocorticoids
• ß-blockers
• isotretinoin

21
Lipoprotein Abnormalities 2 Causes

• monocolonal gammopathy multiple myeloma,
  lymphoma
• acute hepatitis
• systemic lupus erythematous

• Hypertriglyceridemia
• obesity
• DM
• lipodystrophy
• glycogen storage disease
• ileal bypass surgery
• sepsis
• pregnancy

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22
Lipoprotein Abnormalities 2 Causes

• Hypertriglyceridemia
• medications

• asparaginase
• interferons
• azole antifungals
• mirtazipine
• anabolic steroids
• sirolimus

• alcohol
• estrogens
• isotretinoin
• ß-blockers
• glucocorticoids
• bile acid resins
• thiazides

23
Lipoprotein Abnormalities 2 Causes

• Hypocholesterolemia
• malnutrition
• malabsorption
• myeloproliferative diseases
• chronic infectious diseases
• acquired immune deficiency syndrome
• tuberculosis
• monoclonal gammopathy
• chronic liver disease

23
24
Lipoprotein Abnormalities 2 Causes

• Low high-density lipoprotein
• malnutrition
• obesity
• medications

• isotretinoin
• progestins

• non-ISA ß-blockers
• anabolic steroids

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Clinical Presentation

• Most patients asymptomatic for years before
  disease is clinically evident
• Metabolic syndrome gt 3 of the following
• abdominal obesity
• atherogenic dyslipidemia
• increased BP
• insulin resistance glucose intolerance
• prothrombotic state
• proinflammatory state

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Clinical Presentation

• Symptoms
• none
• severe chest pain, palpitations
• sweating
• anxiety
• SOB
• loss of consciousness
• speech or movement difficulty
• abdominal pain
• sudden death

27
Clinical Presentation

• Signs
• none
• severe abdominal pain
• pancreatitis
• eruptive xanthomas
• peripheral polyneuropathy
• HTN
• BMI gt 30 kg/m2
• waist size gt 40 in (men), gt 35 in (women)

28
Clinical Presentation

• Lab Tests
• ? TC
• ? LDL
• ? TG
• ? apolipoprotein B
• ? C-reactive protein
• ? HDL

29
Patient Evaluation

• Fasting lipid panel every 5 yrs adults gt 20 years
  
• if patient not fasting only TC HDL are reliable
• TC gt 200 or HDL lt 40 obtain follow-up fasting
  lipid panel
• Once lipoprotein abnormality confirmed assess
  health CV risk factors
• Initiate individualized LDL goals treatment

30
Clinical Controversy

• CHD events occur in healthy patients lt LDL goal
• hsCRP inflammatory biomarker, predicts future
  vascular events independent of LDL
• not currently recommended as a screening tool
• JUPITER study (Justification for the Use of
  Statins in Prevention An Intervention Trial
  Evaluating Rosuvastatin)

Ridker PM, Danielson E, Fonseca FA, et al.
Rosuvastatin to prevent vascular events in men
and women with elevated C-reactive protein. N
Engl J Med 20083592195-2207.
31
Clinical Controversy

• JUPITER
• rosuvastatin 20 mg vs placebo (n17,802)
• healthy patients with LDL lt 130 mg/dL, hsCRP gt
  2.0 mg/dL
• average LDL hsCRP reduction by 50 in
  rosuvastatin group
• Patients in this study would not have qualified
  for lipid-lowering therapy according to NCEP
  ATPIII
• Long-term safety unknown

Glynn RJ, Danielson E, Fonseca FA, et al. A
randomized trial of rosuvastatin in the
prevention of venous thromboembolism. N Engl J
Med 20093601851-61.
Ridker PM, Danielson E, Fonseca FA, et al.
Rosuvastatin to prevent vascular events in men
and women with elevated C-reactive protein. N
Engl J Med 20083592195-2207.
32
Clinical Controversy

• JUPITER combined 1 endpoint MI, stroke, CV
  death, arterial revascularization, unstable
  angina hospitalization
• combined 1 endpoint met early (1.9 years
  planned to last 5 years)
• substudy evaluated incidence of venous
  thromboembolism
• patients treated with rosuvastatin had
  significantly lower incidence of CV events
  symptomatic venous thromboembolism

Glynn RJ, Danielson E, Fonseca FA, et al. A
randomized trial of rosuvastatin in the
prevention of venous thromboembolism. N Engl J
Med 20093601851-61.
Ridker PM, Danielson E, Fonseca FA, et al.
Rosuvastatin to prevent vascular events in men
and women with elevated C-reactive protein. N
Engl J Med 20083592195-2207.
33
Classification
All values are mg/dL
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
34
Risk Factorsa
aDiabetes regarded as coronary heart disease
(CHD) risk equivalent. bHDL cholesterol gt60 mg/dL
counts as "negative" risk factor its presence
removes one risk factor from the total count.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
35
Treatment Goals

• LDL predicts morbidity, mortality
• 1 treatment target
• More CHD risk factors or higher Framingham Global
  Risk Score more stringent LDL goal

36
Goals Cutpoints
aSome authorities recommend use of LDL-lowering
drugs in this category if LDL cholesterol lt100
mg/dL cannot be achieved by therapeutic lifestyle
changes (TLC). Others prefer to use drugs that
primarily modify triglycerides and high-density
lipoprotein, e.g., nicotinic acid or fibrates.
Clinical judgment also may call for deferring
drug therapy in this subcategory. bAlmost all
people with 01 risk factor have a 10-year risk
lt10 thus,10-year risk assessment in people with
01 risk factor is not necessary.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
37
Hyperlipidemia in Children

• Guidelines/goals of therapy different from adults
• NCEP does not provide cut points for TGs or HDL
  in children adolescents
• American Heart Association considers TG gt 150
  HDL lt 35 abnormal for children/adolescents
• Children should receive fasting lipid profile
  after age 2 but no later than 10 years if
• family history of dyslipidemia or premature CVD
• unknown family history
• overweight, DM, HTN, smoker

Daniels SR, Greer FR and the Committee on
Nutrition. Lipid Screening and Cardiovascular
Health in Childhood. Pediatrics
2008122198208.
38
Lipid Level Classification

• Children adolescents (age lt 20 yrs)
• acceptable
• TC lt 170 mg/dL
• LDL lt 110 mg/dL
• borderline
• TC 170-199 mg/dL
• LDL 110-129 mg/dL
• elevated
• TC gt 200 mg/dL
• LDL gt 130 mg/dL

American Academy of Pediatrics. National
Cholesterol Education Program report of the
expert panel on blood cholesterol levels in
children and adolescents. Pediatrics. 199289(3
pt 2)525-584
Daniels SR, Greer FR and the Committee on
Nutrition. Lipid Screening and Cardiovascular
Health in Childhood. Pediatrics
2008122198208.
39
Hyperlipidemia in Children

• Implement healthy lifestyle/diet in all children
  gt 2 yrs
• low-fat dairy products in children gt 1 year who
  are overweight or family history of obesity,
  dyslipidemia, CVD
• Drug therapy not recommended age lt 8 years
• exception LDL gt 500 mg/dL such as seen in
  homozygous familial hypercholesterolemia
• Statins safe effective in children BARs,
  absorption inhibitors may also be used

Daniels SR, Greer FR and the Committee on
Nutrition. Lipid Screening and Cardiovascular
Health in Childhood. Pediatrics
2008122198208.
40
Hyperlipidemia in Children

• Pharmacologic intervention considered in patients
  age gt 8 years after failure of dietary therapy
  when
• LDL gt 190 mg/dL if no additional risk factors
• LDL gt 160 mg/dL if family history or gt 2
  additional risk factors
• LDL gt 130 mg/dL if patient has diabetes mellitus

Daniels SR, Greer FR and the Committee on
Nutrition. Lipid Screening and Cardiovascular
Health in Childhood. Pediatrics
2008122198208.
41
Lifestyle Modification

• Initial treatment for any lipoprotein disorder is
  TLC (Therapeutic Lifestyle Changes)
• restricted total fats, saturated fats,
  cholesterol intake
• modest increase in polyunsaturated fat
• increased soluble fiber intake
• exercise moderate intensity 30 min/day most days
  
• caution in high risk patients or those with CAD
• weight reduction (initial goal of 10) if needed
• smoking cessation
• treat HTN

42
TLC Dietary Recommendations
aCalories from alcohol not included. bComplex
carbohydrates (whole grains, fruits, vegetables).
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
43
Treatment

• Most patients should receive 3 month TLC trial
  before initiating pharmacologic therapy unless
  very high risk
• If patient unable to reach goals with TLC alone
  choose lipid-lowering drugs based on lipoprotein
  disorder
• Combination therapy may be necessary
• monitor closely increased risk of drug
  interactions, adverse effects

44
Kastelein JJ, Akdim F, Stroes ES, et al.
Simvastatin with or without ezetimibe in familial
hypercholesterolemia. N Eng J Med
20083581431-1443.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
45
Recommended Drug Treatment
aBile acid resins (BARs) not 1st line if TGs are
elevated at baseline hypertriglyceridemia may
worsen with BAR monotherapy. bFibrates
gemfibrozil, fenofibrate
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
46
HMG-CoA Reductase Inhibitors

• Lovastatin, pravastatin, simvastatin,
  fluvastatin, atorvastatin, rosuvastatin
• Inhibit HMG-CoA conversion to mevalonate
• rate limiting step in cholesterol synthesis
• Most potent TC/LDL lowering agents
• Dose dependent decrease in TC/LDL
• averages gt 30 when used with dietary therapy
• Short t½ except atorvastatin, rosuvastatin
• may account for higher atorvastatin
  rosuvastatin potency

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HMG-CoA Reductase Inhibitors

• Dosed once daily in evening
• hepatic cholesterol production peaks at night
• exceptions atorvastatin, rosuvastatin
• Rosuvastatin requires dosage adjustment in severe
  renal impairment hepatic disease
• Good compliance rate, low incidence of adverse
  effects
• Adverse effects
• elevated serum transaminases, myalgia, myopathy,
  rhabdomyolysis, flu-like symptoms, mild GI
  disturbance

50
Statin Pharmacokinetics
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
51
Bile Acid Resins

• Colestipol, cholestyramine, colesevelam
• Bind intestinal bile acid
• increase fecal bile excretion
• stimulate bile acid synthesis from cholesterol
• upregulate LDL receptors
• Normally 2nd-line agents when statins not
  sufficient or not tolerated
• May aggravate hypertriglyceridemia
• caution if TG gt 200 mg/dL
• contraindicated if TG gt 400 mg/dL

52
Bile Acid Resins

• Adverse effects
• GI distress, constipation
• titrate slowly, increase fluid intake, increase
  dietary bulk, add stool softeners
• hypernatremia, hyperchloremia
• impair fat soluble vitamin absorption
• A, D, E, K
• reduce bioavailability of other medications
• warfarin, levothyroxine, digoxin
• dose 6 hrs from other medications to avoid
  interactions

53
Bile Acid Resins

• Low doses well-tolerated
• Often used in combination with other drugs
• With proper counseling dose titration many
  patients tolerate higher doses
• Tablet formulation may increase palatability
  however, tablets are large
• Mix powder with liquids or food such as orange
  juice, oatmeal, applesauce
• Colestipol odorless, tasteless

54
Nicotinic Acid/Niacin

• IR, SR, ER formulations
• OTC Rx (Niaspan)
• Decreases LDL TG
• Increases HDL
• May exacerbate gout DM
• monitor closely
• slow dose titration
• Contraindications active liver disease, severe
  gout
• Combination with statin or gemfibrozil therapy
  increases myopathy risk

55
Nicotinic Acid/Niacin

• Adverse effects
• cutaneous flushing, itching
• ASA 325mg 30 min prior
• titrate dose slowly, avoid spicy foods/hot
  beverages
• GI intolerance
• acanthosis nigricans (marker for insulin
  resistance)
• elevated LFTs, hyperuricemia, hyperglycemia
• niacin associated hepatitis
• more common with SR

56
Clinical Controversy

• CETP (cholesterol ester transfer protein)
  inhibition leads to elevation in HDL levels
• The CETP inhibitor torcetrapib substantially
  increased HDL decreased LDL
• Torcetrapib resulted in increased BP CHD events
• Unknown whether lack of efficacy due to mechanism
  of action or chemical specific events
• Other means of raising HDL are being researched
  tested

57
Fibric Acids

• Gemfibrozil, fenofibrate, clofibrate
• Reduce TG
• May result in concurrent increase in LDL
• TC remains fairly unchanged
• May increase HDL gt 10 to 15
• 20 to 25 LDL reduction in patients with
  heterozygous familial hypercholesterolemia
• Efficacy depends on lipoprotein type, baseline TG

58
Fibric Acids

• Gemfibrozil dosed BID 30 min before meals
• Fenofibrate can be taken without regards to food
• CI in renal failure
• Combination therapy with niacin or statins
  increases risk of muscle toxicity

59
Fibric Acids

• Adverse effects
• GI complaints, rash, myalgia, headache, fatigue
• transient increase in transaminase alkaline
  phosphatase
• gallstones (clofibrate)
• enhanced hypoglycemic effects in patients on
  sulfonylureas
• may potentiate effects of oral anticoagulants
• monitor PT/INR closely in patients on
  anticoagulants

60
Absorption Inhibitor

• Ezetimibe
• Inhibits cholesterol absorption across the gut by
  23 to 50 hepatic LDL synthesis upregulation
  partially offsets impaired absorption
• Often used in combination with statins, other
  drugs
• Dosed once daily without regard to meals
• 18 LDL reduction
• Effect of ezetimibe on CV morbidity mortality
  unknown

61
Clinical Controversy

• ENHANCE trial (Ezetimibe and Simvastatin in
  Hypercholesterolemia Enhances Atherosclerosis
  Regression)
• Familial hypercholesterolemia patients
• autosomal dominant LDL receptor mutation
• severely elevated LDL
• premature atherosclerosis
• 2 groups (n720)
• simvastatin 80 mg placebo
• simvastatin 80 mg ezetimibe 10 mg

Kastelein JJ, Akdim F, Stroes ES, et al.
Simvastatin with or without ezetimibe in familial
hypercholesterolemia. N Eng J Med
20083581431-1443.
62
Clinical Controversy

• ENHANCE 1 outcome change in carotid
  intima-media thickness (CIMT) after 24 months
• no significant difference in CIMT between groups
• simvastatin ezetimibe group greater decreases
  in LDL C-reactive protein
• No differences in elevated liver enzymes,
  myopathy
• Limitations prior lipid-lowering therapy (many
  patients had near normal CIMT at initiation) not
  designed to evaluate differences in incidence of
  vascular events

Kastelein JJ, Akdim F, Stroes ES, et al.
Simvastatin with or without ezetimibe in familial
hypercholesterolemia. N Eng J Med
20083581431-1443.
63
Clinical Controversy

• SEAS (Simvastatin and Ezetimibe in Aortic
  Stenosis)
• Simvastatin 40 mg ezetimibe 10 mg vs placebo
  (n1873)
• No change in clinical course of aortic stenosis
• Simvastatin ezetimibe increased incidence of
  cancer
• SHARP IMPROVE-IT trials in progress
• evaluating ezetimibe for vascular risk reduction
• interm analyses do not show increased cancer risk

Peto R, Emberson J, Landray M, et al. Analyses of
cancer data from three ezetimibe trials. N Eng J
Med 20083591357-1366.  
Rosseb? AB, Pedersen TR, Boman K, et al.
Intensive lipid lowering with simvastatin and
ezetimibe in aortic stenosis. N Eng J Med
20083591343-1356.
64
Omega 3 Fatty Acids

• Diets rich in omega 3 fatty acids from oily fish
  decrease TC, TG, LDL, increase HDL decrease CV
  events
• Rx fish oil Lovaza
• lowers TG 14 to 30
• raises HDL 10
• FDA approved as dietary adjunct for very high TG
  levels (gt 500 mg/dL)
• Thrombocytopenia, bleeding disorders potential
  complication of high doses

65
Omega 3 Fatty Acids

• lt 3 g/day generally recognized as safe
• Until further research is done on nutraceuticals
  it is recommended that patients get dietary EPA
  DHA
• 2 to 4 g of EPA DHA may be used for very high
  TG
• Adverse effects
• GI disturbance
• fishy aftertaste
• increased bleeding risk
• worsening glycemic control
• increased LDL
• abnormal LFTs

66
Hypertriglyceridemia

• Lipoprotein types I, III, IV, V associated with
  hypertriglyceridemia
• Exclude 1lipoprotein disorders underlying
  diseases prior to implementing therapy
• TLC
• achieve desirable body weight
• diet low in saturated fat, cholesterol
• regular exercise
• smoking cessation
• alcohol restriction

67
Hypertriglyceridemia

• Non-HDL total cholesterol HDL
• LDL VLDL
• 2 target when TG gt 200 mg/dL
• goal
• 30 mg/dL higher than LDL
• normal VLDL 30 mg/dL

Expert Panel on Detection E, and Treatment of
High Blood Cholesterol in Adults. Executive
summary of the third report of the National
Cholesterol Education Program (NCEP) Expert Panel
on Detection, Evaluation and Treatment of High
Blood Cholesterol in Adults (Adult Treatment
Panel III). JAMA 200128524862497.
68
Hypertriglyceridemia

• Borderline-high TGs CHD risk factors
• family history of premature CHD
• concomitant LDL elevation or low HDL
• genetic forms of hypertriglyceridemia associated
  with CHD
• familial dysbetalipoproteinemia
• familial combined hyperlipidemia
• consider initiation of niacin
• caution in DM patients

69
Hypertriglyceridemia

• Alternatives therapies
• gemfibrozil
• statins
• modest TG reduction HDL elevation
• higher doses may reduce HDL, LDL, TGs
• related to baseline concentration, dose
• fish oil
• fibrates
• may increase LDL
• monitor carefully with borderline-high
  triglyceridemia

70
Hypertriglyceridemia

• Very high TGs (gt 500 mg/dL) associated with
  pancreatitis
• TG gt 500 mg/dL genetic form of
  hypertriglyceridemia often coexists with other
  causes (e.g. DM)
• dietary fat restriction (10 to 20 of calories)
• weight loss
• alcohol restriction
• treat coexisting disorders

71
Hypertriglyceridemia

• Medications for TG gt 500 mg/dL
• gemfibrozil preferred in diabetics
• niacin
• higher-potency statins atorvastatin,
  rosuvastatin, simvastatin
• fenofibrate may be preferred in combination with
  statins
• does not impair glucuronidation
• minimizes potential drug interactions
• Successful treatment TG lt 500 mg/dL

Expert Panel on Detection E, and Treatment of
High Blood Cholesterol in Adults. Executive
summary of the third report of the National
Cholesterol Education Program (NCEP) Expert Panel
on Detection, Evaluation and Treatment of High
Blood Cholesterol in Adults (Adult Treatment
Panel III). JAMA 200128524862497.
72
Low HDL-C

• Low HDL strong independent CHD risk predictor
• ATP III low HDL-C lt 40 mg/dL
• No specific goal for HDL-C raising
• Causes of low HDL
• insulin resistance
• physical inactivity
• type 2 diabetes mellitus
• cigarette smoking
• very high carbohydrate intake
• certain drugs

73
Low HDL-C

• LDL remains ATP III 1 target
• ATP III recommendations
• weight reduction
• increased physical activity
• smoking cessation
• drug therapy
• fibric acid derivatives
• niacin
• potential for greatest HDL increase
• effect more pronounced with regular or IR forms
  than SR

Expert Panel on Detection E, and Treatment of
High Blood Cholesterol in Adults. Executive
summary of the third report of the National
Cholesterol Education Program (NCEP) Expert Panel
on Detection, Evaluation and Treatment of High
Blood Cholesterol in Adults (Adult Treatment
Panel III). JAMA 200128524862497.
74
Diabetic Dyslipidemia

• Characterized by hypertriglyceridemia, low HDL,
  minimally elevated LDL
• DM ATP III CHD risk equivalent
• Small, dense LDL (pattern B) in DM patients is
  more atherogenic than larger, more buoyant LDL
  (pattern A)
• 1target LDL
• Goal of treatment LDL-C lt 100 mg/dL
• LDL gt 130 mg/dL TLC drug therapy often
  required
• Statins often considered initial drugs of choice

Expert Panel on Detection E, and Treatment of
High Blood Cholesterol in Adults. Executive
summary of the third report of the National
Cholesterol Education Program (NCEP) Expert Panel
on Detection, Evaluation and Treatment of High
Blood Cholesterol in Adults (Adult Treatment
Panel III). JAMA 200128524862497.
75
Diabetic Dyslipidemia

• Collaborative Atorvastatin Diabetes Study (CARDS)
  
• LDL lowering for 1 CHD prevention in type 2 DM
• Randomized, double-blinded placebo controlled
• Atorvastatin 10 mg/day versus placebo (n2,838)
  diabetes to reduce first CHD events
• Baseline LDL 118 mg/dL LDL ? 46 mg/dL with
  atorvastatin

Colhoun HM, Betteridge DJ, Durrington PN, et al.
Primary prevention of cardiovascular disease with
atorvastatin in type 2 diabetes in the
Collaborative Atorvastatin Diabetes Study
(CARDS) Multicentre randomised
placebo-controlled trial. Lancet
2004364685696.
76
Diabetic Dyslipidemia

• CARDS trial 37 reduction in composite 1end
  point
• 1 endpoint acute CHD death, nonfatal MI,
  hospitalized unstable angina, resuscitated
  cardiac arrest, coronary revascularization, or
  stroke
• Suggests diabetics should have target LDL much
  lower than 100 mg/dL

Colhoun HM, Betteridge DJ, Durrington PN, et al.
Primary prevention of cardiovascular disease with
atorvastatin in type 2 diabetes in the
Collaborative Atorvastatin Diabetes Study
(CARDS) Multicentre randomised
placebo-controlled trial. Lancet
2004364685696.
77
Elderly Patients

• More susceptible to adverse effects of
  lipid-lowering drug therapy
• Start with lower doses, titrate slowly to
  minimize adverse effects
• Risks or benefits from cholesterol reduction not
  well defined

78
Women

• Cholesterol important CHD determinant
• relationship not as strong as for women as men
• HDL may be more important predictor of disease in
  women
• No apparent difference between men women in
  LDL/HDL genetic regulation

79
Hyperlipidemia in Pregnancy

• TC TG levels increase throughout pregnancy
• average cholesterol increase 30 to 40 mg/dL
  around weeks 36 to 39
• TGs may increase as much as 150 mg/dL
• Drug therapy typically not initiated/continued
  during pregnancy
• TLC is the mainstay but BARs absorption
  inhibitors may be considered in high risk
  patients
• ezetimibe category C
• Statins category X

80
Children

• Drug therapy not recommended age lt 8 yrs
• Different guidelines, goals
• Bile acid sequestrants 1st-line in the past
• GI adverse effects limit use
• New evidence shows statins are safe effective
  in children
• greater lipid lowering than BAR
• severe forms may require more aggressive
  treatment
• e.g., familial hypercholesterolemia

Daniels SR, Greer FR and the Committee on
Nutrition. Lipid Screening and Cardiovascular
Health in Childhood. Pediatrics
2008122198208.
81
Concurrent Disease States

• Nephrotic syndrome, end-stage renal disease,
  nephrotic syndrome, HTN compound dyslipidemia
  risks
• may be difficult-to-treat
• Nephrotic syndrome lipoprotein metabolism
  abnormalities
• elevated TC, LDL-C, lipoprotein(a), VLDL, TGs
• Statins reduce TC LDL-C in nephrotic syndrome
• levels do not usually return to normal
• may slow declining renal function

82
Concurrent Disease States

• Renal insufficiency without proteinuria
  hypertriglyceridemia, slightly elevated TC
  LDL-C, low HDL
• Polyunsaturated fatty acids may slow pregression
  of renal disease CV complications
• Bile acid sequestrants do not correct lipid
  abnormalities seen in renal insufficiency

83
Concurrent Disease States

• Lovastatin or its active metabolite may
  accumulate in renal insufficiency, use lower
  doses to avoid adverse effects
• Treat CKD patients to LDL goal lt 100 mg/dL
• lowering LDL to lt 70 in high risk patients not
  supported by clinical trials

84
Clinical Controversy

• Atorvastatin 20 mg/day vs placebo (n1,200) in
  diabetic patients on hemodialysis
• No significant difference in 1 endpoints
  (cardiovascular death, non-fatal MI, stroke)
• Significantly greater risk of fatal stroke in
  atorvastatin group
• Treatment with statins not supported in this
  patient population
• Unknown how results would compare in non-diabetic
  hemodialysis patients

84
Wanner C, Krane V, Marz W, et al. Atorvastatin in
patients with type 2 diabetes mellitus undergoing
hemodialysis. N Engl J Med 2005353238248.
85
Dyslipidemia in CKD Patients
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
86
Concurrent Disease States

• Use gemfibrozil with caution
• pharmacokinetics unchanged
• lowers TGs
• increases HDL
• Combination statins fibric acid derivatives
  increases risk of severe myopathy
• monitor for myositis
• Niacin may be useful in nondiabetic patients with
  renal insufficiency

87
Concurrent Disease States

• Hypertensive patients greater-than-expected
  prevalence of hypercholesterolemia
• Patients with hypercholesterolemia have a higher
  than expected prevalence of HTN
• caused by metabolic syndrome
• HTN management
• avoid drugs that elevate cholesterol
• diuretics
• a-blockers
• niacin may magnify vasodilator hypotensive
  effects

88
Monitoring
89
Pharmacoeconomic Considerations

• Statin therapy cost-effective in patients with
  CHD, CHD risk equivalents, or 10 year risk 10 to
  20
• Depending on lipoprotein phenotype, compliance,
  efficacy other drug therapies may also be cost
  effective
• Specialty lipid clinics more expensive than
  usual care
• project ImPACT (Improve Persistence And
  Compliance with Therapy) showed pharmacist run
  clinics result in improved persistence/compliance
• nearly 2/3 patients achieved NCEP lipid goal
• other programs show similar benefits

Bluml BM, McKenney JM, Cziraky MJ. Pharmaceutical
care services and results in project ImPACT
Hyperlipidemia. J Am Pharm Assoc 200040157165.
90
Acknowledgements

• Writer Andrea Bourgoin, Pharm.D.
• Series Editor April Casselman, Pharm.D.
• Editor-in-Chief Robert L. Talbert, Pharm.D.,
  FCCP, BCPS, FAHA
• Chapter Author/Section Editor
• Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA