Hyperlipidemia/Dyslipidemia

1
Hyperlipidemia/Dyslipidemia

• J.B. Handler, M.D.
• Physician Assistant Program
• University of New England

2
Abbreviations

• LDL- low density lipoprotein
• HDL- high density lipoprotein
• IDL- intermediate density lipprotein
• VLDL- very low density lipoprotein
• Lp(a)- lipoprotein a
• CAD- coronary artery disease
• CHDCAD coronary heart disease
• CVD- cerebrovascular disease
• LFT- liver function test
• GI- gastrointestinal
• ETOH- alcohol
• D.M.- diabetes mellitus
• CK- creatine kinase

• NNT- number needed to treat
• ARR- absolute risk reduction
• IVUS- intravascular ultrasound
• RRR- relative risk reduction
• PAD- peripheral arterial disease
• PVD- peripheral vascular disease
• CVD- cerebrovascular disease
• ACS- acute coronary syndrome
• HTN- hypertension
• TLC- therapeutic lifestyle changes
• UAP- unstable angina pectoris
• PE- physical exam
• ACC- American College of Cardiology

3
Lipids and Atherosclerosis

• Thickened and hardened lesions of the medium and
  large muscular and elastic arteries lipid rich.
  Lesions occur in the innermost layer of the
  artery (intima) and are largely confined to this
  region of the vessel.
• Deposition of lipid within the artery is
  dependent on 2 major factors
• LDL carries lipid to the arteries (LDL must be
  oxidized)
• HDL removes lipid from the arteries
• The role triglycerides play is not as well
  understood, but considered a risk factor. See
  below.

4
Lipoproteins

• Lipoproteins carry lipids - Cholesterol,
  Triglyceride, Phospholipids.
• Lipoproteins of importance VLDL, (IDL), LDL,
  chylomicrons.
• Apolipoproteins- Protein constituents of
  lipoproteins that add structural stability may
  help mediate catabolism. Apolipoprotein B (LDL)
  increases coronary risk.
• Lipid catabolism - 70 LDL removed in liver by
  LDL receptors.

5
Cholesterol Biosynthesis

• Liver and intestines - major sources of
  endogenously derived cholesterol.
• Diet - exogenously derived cholesterol.
• In liver- rate limiting step is converting HMG
  CoA to mevalonic acid by HMG CoA Reductase (role
  of STATINS).
• Increase intake in dietary cholesterol - down
  regulation of LDL receptors ? subsequent
  elevation of serum LDL cholesterol.

6
Hypercholesterolemia

• Diet and drug induced reductions of total and LDL
  Cholesterol can significantly reduce mortality
  and morbidity from Coronary Heart Disease.
• Cholesterol reduction can slow progression of
  atherosclerosis, and in some cases, halt or
  reverse (isolated cases) its course.

7
Lipids and Atherogenesis

• Vascular injury from any source (smoking, HTN,
  DM) can lead to uptake of lipoproteins.
• Elevation of LDL (oxidized) can lead to vascular
  injury resulting in premature atherosclerosis.

8
Lipids and Atherogenesis

• LDL oxidation necessary for endothelial damage.
• HDL- Inverse correlation between serum HDL and
  atherosclerosis reverse cholesterol transport
  and prevents oxidation of LDL- cardioprotective.
• A low HDL level (dyslipidemia) is a strong risk
  factor for CHD even when LDL and total
  cholesterol are normal.
• Next major advance safe drugs that substantially
  increase HDL levels, while reducing cardiac
  events (MI, Death).

9
Hyperlipidemia- Clinical Findings

• Often asymptomatic.
• Atherosclerosis and disease- CHD, PVD, etc.
• Eruptive xanthomas- red papules on buttocks seen
  with extremely high levels of chylomicrons or
  VLDL (triglycerides).
• Tendinous xanthomas- Very high LDL- nodules on
  tendons (achilles, back of hand, patella).
• Xanthelasma- yellow placques in skin around the
  eyes.

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Xanthelasma
Images.google.com
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Dyslipidemias in Adults

• Most cases are multifactorial
• Influenced by diet, lifestyle and genes
• Often detected in asymptomatic adults during
  routine blood screening
• In patients with atherosclerosis involving the
  coronary arteries, carotids, aorta or periperal
  vessels, a high percentage will be found to have
  a dyslipidemia.

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Secondary Dyslipidemia

• Diabetes Mellitus (discussed in Endocrine
  section)
• Nephrotic Syndrome (Renal system)
• Chronic Renal Failure
• Hypothyroidism - high TG, low HDL

13
Familial Dyslipidemia

• At least six documented disorders all with
  accelerated atherosclerosis.
• Example Familial hypercholesterolemia?LDL
  receptor defect heterozygous -total cholesterol
  at birthgt 350 mg/dlHomozygous - total
  cholesterol gt 700mg/dl
• PE Tendon xanthomas, xanthelasma, cutaneous
  xanthomas
• Most patients with lipid disorders carry genes
  that can predispose them to develop dyslipidemia
  when additional factors (diet, obesity, etc.) are
  present. Likely multiple genes involved.

14
Rationale for Treatment

• Primary prevention- Lowering cholesterol/LDL will
  prevent new onset CHD. Every 1 drop in
  cholesterol produces a 2-3 decrease in CHD risk.
  
• Secondary prevention - Lowering cholesterol/LDL
  will prevent recurrent coronary events and
  decrease coronary and total mortality in the
  presence of existing CHD or equivalent(s).
• Angiographic/IVUS trials? retarded progression of
  of coronary lesions regression in some.

15
Primary Prevention

• ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial)
• 10,305 patients with HTN but without heart
  disease randomized to Placebo vs. Atorvastatin
  10 mg/daily
• Baseline LDL-133 mg/dL, treated LDL- 103mg/dL
• Primary endpoints Nonfatal MI and fatal CHD
• Study ended prematurely at 3.3 years
• Results 36 ? in primary endpoint (100 vs 154
  events)

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Secondary Prevention

• High risk prevention
• Patients with known CHD have a 5-7x risk of
  recurrent MI.
• Patients with known PAD, Carotid or Aortic
  disease have a 4-6x incidence of developing CHD
  and its consequences.
• Other high risk subsets DM, others (see below)
• Goal lower LDL to lt100 mg/dl or less (below).

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Heart Protection Study

• Patients with documented CHD or equivalent (DM,
  PAD).
• gt20,000 patients placebo vs 40mg Simvastatin
  daily.
• Baseline LDL 131-155 mg/dL. Rx with simvastatin
  resulted in
• ? all cause mortality by 13
• ? coronary death by 18
• ? non fatal MI coronary death by 27
• ? coronary revascularization procedures by 24.
• ? stroke by 25 .
• ? major vascular events by 24

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Risk Stratification (NCEP)

• Determine number of major risk factors besides
  elevated lipids. Excludes patients with
  documented CHD/PAD/CVD or diabetes (coronary risk
  equivalent).
• Age/gender mengt45, women gt55
• FH of premature CHD ?MI or SD in 1st degree
  relative malelt55, female lt 65
• Hypertension whether treated or not
• Current cigarette smoker
• Low HDL lt 40 mg/dL
• 2 or more risk factors? calculate statistical
  risk for subsequent MI/death in next 10 years.

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Risk Stratification (NCEP)

• For patients with 2 or more risk factors and no
  evidence yet of CHD Determine 10 year CHD risk
  (for hard CHD outcomes- MI or coronary death)
  assessment using Framingham risk assessment tool.
• Newest guidelines and options NCEP ATP III,
  7/04 amended in 2007.

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Risk Assessment Tool

• Estimates 10 yr risk () of developing hard CHD
  (MI or coronary death) outcomes in patients
  without CHD.
• Gender and age
• Total or LDL cholesterol
• HDL cholesterol
• Smoker
• Systolic blood pressure on meds for HTN?
• Tables based on Framingham Heart Study

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High Risk

• Presence of CHD, PAD, CVD or DM (coronary risk
  equivalent even if no CHD yet documented).
• Absence of clinical atherosclerosis with 2 or
  more risk factors (such as smoking or HTN) that
  give a greater than 20 chance of having an MI or
  coronary death within 10 years (risk factor
  tool). Remember IS case Lenny L.
• Goal LDLlt 100 mg/dL initiate meds if gt
  100mg/dL.
• Initiate TLC simultaneously.
• Some High Risk patients will fall into the Very
  High Risk subset (see below).

22
Very High Risk

• Established CHD with DM, multiple and poorly
  controlled risk factors (such as smoking),
  metabolic syndrome, or recent ACS (MI or UAP).
• Goal LDL lt 70mg/dL is a therapeutic option- a
  reasonable therapeutic strategy, on the basis of
  available clinical trial evidence.
• This will require drug therapy, possibly 2 drugs
  (see below).
• Initiate TLC if not already done.
• Evidence PROVE-IT trial (see below).

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Metabolic Syndrome (3 of 5 Factors)

• Central obesity waist circumferencegt88cm in
  women, gt102 cm in men.
• Hyperglycemia FBS ?110 mg/dL.
• Hypertension BP ? 135/85.
• ?trig ? 150 mg/dL.
• ?HDL ?40 for men, ?50 for women (any 3 of 5
  meets criterion).
• 3x ?risk of atherosclerosis.
• Metabolic syndrome often associated with insulin
  resistance- to be discussed in Endocrine system.

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Is Greater Lowering Better?

• PROVE IT-TIMI 22 Atorvastatin 80 mgs/d vs
  Pravastatin 40 mgs/d in patients with ACS (AMI or
  UAP). Prospective, randomized, double blind
  study of 4162 patients 2 yr follow-up.
• End-points All cause mortality, MI, UAP,
  coronary revascularization, stroke.
• Pravastatin group mean LDL- 95mg/dL, 26.3 had
  primary end-point.
• Atorvastatin group mean LDL- 62mg/dL, 22.4 had
  primary end point.
• ARR with Atorvastatin 3.9, NNT 25
• RRR 16

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Moderately High Risk

• Absence of clinical atherosclerosis
• 2 or more risk factors for CHD and a 10-20 risk
  of MI/Coronary Death within 10 years (risk factor
  tool).
• Goal LDLlt130mg/dL
• Therapeutic option LDLlt100mg/dL
• Initiate TLC if not already started.
• Initiate drug therapy for LDLgt130 mg/dL.

26
Moderate Risk

• Absence of clinical atherosclerosis
• 2 or more risk factors for CHD and a lt 10 risk
  for MI/coronary death within 10 years (risk
  factor tool).
• Goal LDLlt130mg/dL
• Initiate TLC
• Initiate drug therapy if LDL?160 mg/dL

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Lower Risk

• 0-1 risk factors
• Do not need to calculate risk score as will be
  lt10.
• Goal LDLlt 160 mg/dL
• TLC
• Initiate drug therapy if LDL?190mg/dL
• Option Initiate drug therapy if LDL ?160mg/dL

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Other Goals

• Total Cholesterol lt 200mg/dL
• HDL ? 40 (45) mg/dL in men ? 50 (55) mg/dL in
  pre-menopausal women.
• Bloodwork Fasting Lipoprotein AnalysisTotal
  chol, Triglycerides, HDL, LDL LDL TC - HDL -
  (Trig /5).
• Can now measure direct LDL- does not require
  fasting values usually lower (?10) than
  calculated LDL levels.

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Treatment Considerations

• Age, weight and sex of patient
• Presence or absence of CAD risk factors
• Socioeconomic factors
• Patient compliance
• Availability of support personnel
  dietary,educational, administrative

30
Hypertryglyceridemia

• Risk for developing CAD/CHD from elevated
  triglycerides alone is controversial likely
  contributes when LDL-C is ? or HDL-C is ?.
• Pure hypertriglyceridemia associated with VLDL
  elevations is often accompanied by mild
  elevations of total and LDL-C (small dense LDL).
• Inverse relationship between VLDL (triglycerides)
  and HDL.
• ?Tryglycerides (gt500 mg/dL) ?s risk of
  pancreatitis
• Consensus treat hypertriglyceridemia but
  lowering LDL-C much more important.

31
Hypertriglyceridemia

• Often associated with obesity, type 2 diabetes
  metabolic syndrome mildly ? with some drugs
  estrogen, corticosteroids, ß-Blockers
  (Non-selective) and thiazides. Increased by
  alcohol.
• Very sensitive to diet, weight reduction and
  exercise.
• Triglycerides gt 200mg/dL may warrant additional
  Rx. Important to consider Rx if HDL is very low.
• Rx with fibric acid agents or niacin.

32
HDL

• Cardioprotective facilitates removal of
  cholesterol in tissues also has direct
  protective effects.
• Reduced in presence of obesity, smoking,
  inactivity.
• Modest increase with weight reduction, regular
  exercise, smoking cessation, estrogen therapy in
  post menopausal women (avoid where
  possible?risks), alcohol in low quantities.
• Increased with some meds fibric acid derivatives
  and niacin. Off label indication in patients
  with CHD and very low HDL levels

33
Therapeutic Lifestyle Changes (TLC)

• Smoking cessation
• Decrease intake of saturated fats (details below)
• Decrease total calories if overweight
• Increase physical activity
• Decrease sodium intake
• Treat other risk factors if applicable

34
Treatment of Dyslipidemia Diet

• The typical American diet is a major
  contributor to lipoproten disorders.
• Dietary Cholesterol - Raises LDL - Egg yolks,
  animal fat, red meat, etc.
• Dietary Fat- Saturated fat, saturated fatty acids
  and animal fat.
• Ideal Diet lt 30 fat, lt7 saturated fat, lt200
  mgs/day cholesterol. Fat replaced with
  carbohydrates.
• Obesity - Minimum 10 weight reduction.
• Result ?10 lowering of LDL, but varies.

35
Drug Therapy - Hyperlipidemia

• HMG CoA reductase inhibitors (statins)
• Bile Acid sequestrants (resins)
• Nicotinic Acid (niacin)
• Fibric Acid derivatives (fibrates)
• Cholesterol absorption inhibitor- Ezetimibe

36
HMG CoA Reductase Inhibitors

• Atorvastatin (Lipitor) 10-80 mg/D
• Simvastatin (Zocor/generic) 10-80 mg/D
• Rousuvastatin (Crestor) 5-40 mg/D
• Lovastatin (Mevacor/generic) 10-80 mg/D
• Pravastatin (Pravachol/generic) 10-80 mg/D
• Fluvastatin (Lescol) 20-40 mg/D
• Inhibit rate limiting step in cholesterol
  synthesis in liver up regulate synthesis of LDL
  receptors - further reduction LDL cholesterol
  LDL and TC lowered by 30-55.
• Some statins ?triglycerides and ?HDL but mildly.

37
Statins - Side Effects

• Increase in serum transaminase levels- must be
  monitored closely initial year.
• GI disturbance infrequent
• Myopathy Dose related skeletal muscle
  complaints are most commonly reported adverse
  effects.
• Myalgia is most common (1-5) and benign.
• Myositis with rhabdomyolysis is rare but can be
  life threatening CK confirmation is essential to
  decision making gt10 ULN with myositis or rhabdo

38
Statin Induced Myopathy

• Mechanism unknown but dose related. Evaluate
  patients with muscle Sx ASAP? hold drug and
  obtain CK. It may be as simple as lowering the
  dose.
• Signs and symptoms myalgia, muscle weakness,
  ?CK, rarely progressing to rhabdomyolysis,
  myoglobinemia, renal failure and death.
• Cerivistatin (Baycol) was taken off market
  because of 31 reported deaths from
  rhabdomyolysis.
• Risk of myopathy increased with a variety of
  drugs that inhibit statin metabolism niacin,
  fibrates, bile acid sequestrants, ketoconazole,
  erythromycin, clarithromycin, cyclosporin and
  others.

39
Statins Pleiotropic Effects

• Statins have beneficial effects independent of
  lipid lowering
• Placque stabilization
• Anti-inflammatory effects
• Reduce C-reactive protein levels
• Protection of vessels subject to invasive
  coronary interventions

40
Ezetimibe

• Relatively new- released in 2003 inhibits
  intestinal absorption of dietary and biliary
  cholesterol
• As monotherapy (randomized double blind study of
  893 patients), 10 mg daily lowered LDL by up to
  17, triglycerides by 6 and increased HDL by 1.3
  (minimal) .
• Very well tolerated but avoid in patients with
  hepatic insufficiency.

41
Ezetimibe

• When added to a statin there was additional LDL
  cholesterol lowering of up to 25? likely a
  synergistic effect.
• Ezetimibe plus low/moderate dose statin is more
  effective in lowering LDL cholesterol than
  doubling the dose of the statin. Butsee
  controversies below.
• Ezetimibe very low incidence of myopathy

42
Ezetimibe- Recent Concerns

• 1/14/08- Enhance Trial (Merck/Schering Plough),
  simvastatin vs simvastatin ezetimibe.
• Patients with familial hyperlipidemia marked ?
  in LDL-C. Simvastatin ? LDL-C by 41 (2 yrs),
  simvastatin ezetimibe ? LDL-C by 58. No
  difference in outcomes (MI or stroke), but study
  not powered for outcomes.
• But Carotid intima media wall thickness (IMT)
  increased faster in group treated with combined
  therapy compared with simvastatin alone.
  ?Significance.
• More trials needed. Opinion (ACC) Continue to
  use if LDL goal not reached with statin (hi dose)
  alone.

IMT- surrogate end point for clinical coronary
events
43
Bile Acid Sequestrants (Resins)

• Bind bile in the intestine and stimulate
  conversion of cholesterol to bile acids in the
  liver up regulate LDL receptors- result is
  decrease in LDL cholesterol.
• Cholestyramine and Cholestipol- up to 12 scoops
  of powder in water daily. Colesevelam (Welchol)
  tablet form. Expensive.
• Side effects - Constipation, GI Distress
  (flatulence, constipation, dyspepsia) less
  common with colesevelam
• These drugs can also cause myopathy.

44
Nicotinic Acid

• Mechanism of action unclear (hepatic).
• Lowers Triglycerides and to a lesser degree LDL
  cholesterol.
• Modest (20-30 increase) elevation HDL.
• Side effects GI distress flushing/itching,
  small elevations of LFTs.
• Pre-treat with ASA for itching/flushing
• Caution use in uncontrolled diabetes?? blood
  sugar.
• Start with very low doses and work upwards
• Increases the likelihood of myopathy when added
  to statins or bile acid sequestrants.

45
Fibric Acid Derivatives

• Gemfibrozil 600 mgs. 2x/dayPrimary effect -
  lower triglycerides
• Fenofibrate Once daily, may be more effective
  than gemfibrozil in lowering LDL and
  triglycerides.
• Rx of low HDL (off label indication). ?HDL by
  15-20Consider fibrates in patients with CHD and
  very low (lt30 mg/dL) HDL levels. Variable
  reduction in LDL.
• Side effects GI, myopathy, gallstones.

46
Guidelines for Drug Therapy

• Elevations of total and LDL cholesterolStatin
  (TC and LDL decreased up to 50) Goal based on
  degree of risk statin dose increased to maximum
  as necessary (see below).
• If goal not achieved, the addition of other
  agents (cholestyramine, niacin, ezetimibe, etc)
  will need to be determined on a case by case
  basis as supported by clinical trials, weighing
  the pros/cons, cost, side-effects, compliance and
  more.
• Most experts recommend adding additional drugs to
  max dose statins to lower LDL to goals if
  necessary.

47
Guidelines for Drug Therapy

• ?? Triglycerides mild ?hypercholesterolemia
  Gemfribrozil, Fenofibrate or Niacin. Must
  control Diabetes, reduce smoking, reduce ETOH and
  lose weight if indicated. Add statin if LDL
  remains above goal.
• Combination drugs (Advicor- extended release
  niacin plus lovastatin in fixed combination
  Vytorin- simvastatin ezetimibe) may play a role
  for some patients.
• Very low HDL with CHD consider fibric acid agent
  or niacin.

48
References

• Grundy, SM, et. Al., Implications of Recent
  Trials for National Cholesterol Education Program
  Adult Treatment Panel III Guidelines.
  Circulation, 2004 110 227-239
• Canon, CP, et. al., PROVE IT TIMI trial NEJM,
  2004 3501495-1504