Hyperlipidemia - BeKnowledge

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Hyperlipidemia
 Dr.Hashim Rida Fida




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Objectives
   The story of hyperlipidemia
   Causes of hyperlipidemia
   Screening for hyperlipidemia
   Classification
   Risk factor for CHD
   Goals for lipids
   Treatments

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The story of lipids
   Chylomicrons transport fats from the intestinal
    mucosa to the liver
   In the liver, the chylomicrons release triglycerides
    and some cholesterol and become low-density
    lipoproteins (LDL).
   LDL then carries fat and cholesterol to the body’s
    cells.
   High-density lipoproteins (HDL) carry fat and
    cholesterol back to the liver for excretion.


                                                           4
The story of lipids (cont.)
   When oxidized LDL cholesterol gets high,
    atheroma formation in the walls of arteries
    occurs, which causes atherosclerosis.
   HDL cholesterol is able to go and remove
    cholesterol from the atheroma.
   Atherogenic cholesterol → LDL, VLDL,IDL



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Atherosclerosis




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  ATHEROSCLEROSIS
                                     LDL
LDL from the blood penetrates the
arterial walls and accumulates in
smooth muscle cells in the form of
cholesterol esters.



These smooth muscle cells
along with activated
macrophages are transformed
into lipid-filled foam cells.



These foam cells shear off with
constant blood flow and pull of
parts of the vessel walls along
with them, exposing underlying
tissue


The end result is a plaque with a
center consisting of 
cholesterol deposits and cell
components and  a “cap”                   
consisting of aggregated
platelets and fibrin.                          

                                                   7
                            High Cholesterol      • Formation of atherosclerotic plaques
TYPICAL                                           • No Symptoms
PROGRESSION
OF EVENTS IN
CLASSIC ANGINA
                             Stable Angina        • Partial occlusion of coronary artery
PECTORIS                                          • Symptoms only during exertion




                                                  • Partial occlusion of coronary artery with
                                                    sudden, intermittent vasoconstriction.
                             Unstable Angina
                                                  • Symptoms increase in frequency and
                                                    begin to occur at rest



                           Acute Myocardial       • Complete occlusion of coronary artery
                              Infarction          • Cell death and myocardial damage




     Acute Heart           Congestive Heart                  Cardiac
       Failure                 Failure                     Arrhythmias
                                                                                            8
                   • Consequences of damage to the heart
Causes of Hyperlipidemia
   Diet                    Obstructive liver
   Hypothyroidism           disease
   Nephrotic syndrome      Acute hepatitis
   Anorexia nervosa        Systemic lupus
   Obstructive liver        erythematousus
    disease                 AIDS (protease
   Obesity                  inhibitors)
   Diabetes mellitus
   Pregnancy

                                                 9
Hereditary Causes of Hyperlipidemia
   Familial Hypercholesterolemia
           Co dominant genetic disorder, occurs in heterozygous form
           Occurs in 1 in 500 individuals
           Mutation in LDL receptor, resulting in elevated levels of LDL at birth
            and throughout life
           High risk for atherosclerosis, tendon xanthomas (75% of patients),
            tuberous xanthomas and xanthelasmas of eyes.
   Familial Combined Hyperlipidemia
           Autosomal dominant
           Increased secretions of VLDLs
   Dysbetalipoproteinemia
           Affects 1 in 10,000
           Results in apo E2, a binding-defective form of apoE (which usually
            plays important role in catabolism of chylomicron and VLDL)
           Increased risk for atherosclerosis, peripheral vascular disease
           Tuberous xanthomas, striae palmaris



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Dietary sources of Cholesterol
Type of Fat       Main Source                                   Effect on
                                                                Cholesterol levels
Monounsaturated   Olives, olive oil, canola oil, peanut oil,    Lowers LDL, Raises
                  cashews, almonds, peanuts and most            HDL
                  other nuts; avocados
Polyunsaturated   Corn, soybean, safflower and cottonseed       Lowers LDL, Raises
                  oil; fish                                     HDL

Saturated         Whole milk, butter, cheese, and ice cream;    Raises both LDL and
                  red meat; chocolate; coconuts, coconut        HDL
                  milk, coconut oil , egg yolks, chicken skin

Trans             Most margarines; vegetable shortening;        Raises LDL
                  partially hydrogenated vegetable oil; deep-
                  fried chips; many fast foods; most
                  commercial baked goods


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Checking lipids
   Nonfasting lipid panel
          measures HDL and total cholesterol
   Fasting lipid panel
          Measures HDL, total cholesterol and triglycerides
          LDL cholesterol is calculated:
             LDL cholesterol = total cholesterol – (HDL + triglycerides/5)




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When to check lipid panel
   Two different Recommendations
      Adult Treatment Panel (ATP III) of the National
       Cholesterol Education Program (NCEP)
             Beginning at age 20: obtain a fasting (9 to 12 hour) serum lipid
              profile consisting of total cholesterol, LDL, HDL and triglycerides
             Repeat testing every 5 years for acceptable values
       United States Preventative Services Task Force
             Women aged 45 years and older, and men ages 35 years and
              older undergo screening with a total and HDL cholesterol every 5
              years.
             If total cholesterol > 200 or HDL <40, then a fasting panel should
              be obtained
             Cholesterol screening should begin at 20 years in patients with a
              history of multiple cardiovascular risk factors, diabetes, or family
              history of either elevated cholesterol levels or premature
              cardiovascular disease.



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               Classification
Hyperlipidemias are classified according to the
Fredrickson classification which is based on the
pattern of lipoproteins on electrophoresis or
ultracentrifugation. It was later adopted by the
World Health Organization (WHO). It does not
directly account for HDL, and it does not
distinguish among the different genes that may
be partially responsible for some of these
conditions. It remains a popular system of
classification, but is considered dated by many.

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Fredrickson classification of Hyperlipidemias




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Goals for Lipids
   LDL                             HDL
       < 100 →Optimal                  < 40 → Low
       100-129 → Near optimal          ≥ 60 → High
       130-159 → Borderline        Serum Triglycerides
       160-189→ High                   < 150 → normal
       ≥ 190 → Very High               150-199 → Borderline
   Total Cholesterol                   200-499 → High
       < 200 → Desirable               ≥ 500 → Very High
       200-239 → Borderline
       ≥240 → High


                                                                19
Determining Cholesterol Goal
(LDL!)
   Look at JNC 7 Risk Factors
          Cigarette smoking
          Hypertension (BP ≥140/90 or on anti-
           hypertensive)
          Low HDL cholesterol (< 40 mg/dL)
          Family History of premature coronary heart
           disease (CHD) (CHD in first-degree male relative
           <55 or CHD in first-degree female relative < 65)
          Age (men ≥ 45, women ≥ 55)


                                                              20
Determining Goal LDL
   CHD and CHD Risk Equivalents:
       Peripheral Vascular Disease
       Cerebral Vascular Accident
       Diabetes Mellitus




                                      21
LDL Goals
   0-1 Risk Factors:
          LDL goal is 160
          If LDL ≥ 160: Initiate TLC (therapeutic lifestyle changes)
          If LDL ≥ 190: Initiate pharmaceutical treatment
   2 + Risk Factors
          LDL goal is 130
          If LDL ≥ 130: Initiate TLC
          If LDL ≥ 160: Initiate pharmaceutical treatment
   CHD or CHD Risk Equivalent
          LDL goal is 100 (or 70)
          If LDL ≥ 100: Initiate TLC and pharmaceutical treatment



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     TREATMENT OF HYPERLIPIDEMIA

TWO BASIC STRATEGIES:
1.   DECREASE THE AMOUNT OF LIPID ENTERING THE BLOOD
         Low-fat, low-calorie diets
               First line of defense; should continue through drug treatment
         Drugs that reduce lipoprotein synthesis

2.   IMPROVE THE CLEARANCE OF LIPID FROM THE BLOOD
         For VLDL (triglyceride source) this involves the enzyme
          LIPOPROTEIN LIPASE
         For LDL (cholesterol source) this involves LDL RECEPTORS: the
          less cholesterol in the liver, the more LDL receptors will be
          synthesized
         MORE LDL RECEPTORS = MORE EFFICIENT
          REMOVAL OF LDL FROM THE BLOOD


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Treatment of Hyperlipidemia
   Lifestyle modification
       Low-cholesterol diet
       Exercise




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Medications for Hyperlipidemia
   Drug Class             Agents          Effects (% change)                Side Effects
HMG CoA reductase      Lovastatin       LDL (18-55), HDL (5-15)     Myopathy, increased liver
inhibitors             Pravastatin         Triglycerides (7-30)      enzymes
Cholesterol            Ezetimibe         LDL( 14-18),  HDL (1-3)    Headache, GI distress
absorption inhibitor                        Triglyceride (2)
Nicotinic Acid                          LDL (15-30),  HDL (15-35)   Flushing, Hyperglycemia,
                                           Triglyceride (20-50)      Hyperuricemia, GI distress,
                                                                      hepatotoxicity
Fibric Acids           Gemfibrozil      LDL (5-20), HDL (10-20)     Dyspepsia, gallstones,
                       Fenofibrate        Triglyceride (20-50)       myopathy


Bile Acid              Cholestyramine             LDL                GI distress, constipation,
sequestrants                                      HDL                decreased absorption of
                                         No change in triglycerides   other drugs




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         DRUGS USED FOR TREATING
         HYPERLIPIDEMIA

HYPERTRIGLYCERIDEMIA:
  Niacin
  Fibric acid derivatives

HYPERCHOLESTOLEMIA:
  Bile-acid binding resins
  Statins                                     FYI: LIPITOR (generic
                                               name atorvastatin) = a
  Ezetimibe                                   statin drug
  Combination therapy (e.g., ezetimibe + a statin drug)




                                                                    30
   DRUGS USED TO TREAT HYPERLIPIDEMIA: CHOLESTEROL


• STATIN DRUGS: HMG-CoA Reductase Inhibitors
   • ATORVASTATIN (Lipitor) – most prescribed (Pfizer)
   – HMG-CoA reductase is a key liver enzyme for the synthesis of cholesterol
   – By inhibiting cholesterol synthesis in the liver, cellular concentrations are reduced
     and LDL receptors are up-regulated resulting in increased removal of LDL from the
     blood.



                                                                         STATIN DRUGS
                                             HMG CoA

                                                   HMG CoA Reductase


                                             Cholesterol




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MECHANISM OF ACTION OF STATINS




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         STATINS
   2003: atorvastatin (Lipitor) alone = 65.5 million prescriptions;
    MOST FOR ANY TRADE-NAME DRUG
   All appear to be equally efficacious (20-60% reductions)
   Taken orally before bed (most cholesterol is made when you sleep)
   Marked first-pass metabolism

SIDE EFFECTS:
 Usually safe with mild side effects (GI). Some side effects are more
   severe:
        NOT PRESCRIBED TO CHIDREN AND WOMEN WHO ARE PREGNANT,
         LACTATING, OR MAY BECOME PREGNANT
        LOW INCIDENCE OF LIVER TOXICITY (0.5% PATIENTS). THESE
         AGENTS SHOULD BE USED WITH CAUTION IN PATIENTS WITH
         PARENCHYMAL LIVER DISEASE, ASIANS, AND ELDERLY
        LOW INCIDENCE OF RHABDOMYOLYSIS
             Skeletal muscle cell lysis and release of muscle cell
              contents into the circulation, potentially resulting in kidney
              failure and death.
             SYMPTOMS: muscle pain, muscle atrophy, fatigue, dark
              urine, elevated blood creatine kinase levels (skeletal muscle
              enzyme)


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               STATINS
Statin              FYI: Brand name
Atorvastatin        Lipitor, Torvast

                    Lipobay, Baycol. (Withdrawn from the
Cerivastatin        market in August, 2001 due to risk of
                    rhabdomyolysis)

Fluvastatin         Lescol, Lescol XL
Lovastatin          Mevacor, Altocor
Pitavastatin        Livalo, Pitava

Pravastatin         Pravachol, Selektine, Lipostat

Rosuvastatin        Crestor

Simvastatin         Zocor, Lipex




                                                            34
DRUGS USED TO TREAT HYPERLIPIDEMIA: CHOLESTEROL



EZETIMIBE - newest anti-cholesterol drug
(FYI: Merck)

Inhibitor of intestinal cholesterol absorption:
1.   Selective inhibitor of intestinal cholesterol
     absorption
2.   Reduced re-absorption of cholesterol secreted in
     bile

Reduces LDL levels, synergistic with statins
May induce rhabdomolysis by itself and/or
increase the risk for statin-induced
rhabdomyolysis

                                                        35
 EZETIMIBE




                                    STATINS




BILE ACID
 RESINS



                -
                     NIACIN   +
               FIBRIC ACID AGENTS



Mechanisms of action of lipid-lowering drugs   36
    DRUGS USED TO TREAT HYPERLIPEMIA: TRIGLYCERIDES

   VLDL = PRIMARY CARRIER OF TRIGLYCERIDES
TREATMENT OF HYPERTRIGLYCERIDEMIA INVOLVES DECREASING
  CIRCULATING VLDL LEVELS
DRUGS THAT DECREASE VLDL LEVELS:
   NIACIN (a.k.a., nicotinic acid); NIACIN also increases HDL levels and decreases and
    LDL levels
   FIBRIC ACID DERIVATIVES

MECHANISMS:                                                                  Stimulation of
                     Liver                        Blood
                                                                        lipoprotein lipase also
                 Cholesterol                                            increases LDL – this is
                                                                          offset by decreased
                                                                            VLDL synthesis
                                      VLDL
                     VLDL                                   LDL
                                                                    •   Niacin: net decrease in LDL
              1. Inhibit
        VLDL synthesis in liver
                                       + Lipoprotein Lipase
                                           2. Stimulate breakdown
                                           of VLDL by lipoprotein
                                                    lipase                                    37
    DRUGS USED FOR THE TREATMENT OF
    HYPERTRIGLYCERIDEMIA
   Niacin
        Clinical use
             Hypertriglyceridemia
             Familial hypersholesterolemia (in combination with cholesterol-
              lowering drugs)
             Mixed (multi-factorial) hyperlipidemias
        Adverse effects
             Flushing (cutaneous vasodilation and sensation of warmth) –
              prostaglandin-related effect
             Increase gastric acid secretion – may be taken with antacids or
              inhibitors of gastric acid secretion – is contraindicated in patients
              with peptic ulcer
             Impairment of glucose tolerance – is contraindicated in patients with
              insulin resistance
             Hepatotxicity
             Hyperuricemia – may precipitate gout
                                                                                  38
    DRUGS USED FOR THE TREATMENT OF
    HYPERTRIGLYCERIDEMIA
   Fibric acid derivatives: Gemfibrozil, Fenofibrate
       Mechanism of action
            Ligands of nuclear receptor, peroxisome proliferator-activated
             receptor-alpha (PPAR-α)
            Increase expression of LPL, increase lipolysis of triglycerides
            Intracellular lipolysis in adipose tissue is decreased
            LDL levels may increase, especially in patients with mixed
             hyperlipidemias
       Clinical use
            Hypertriglyceridemia
       Adverse effects
            May promote cholesterol gallstones
            Myopathy
            Liver toxicity
                                                                           39
  DRUGS USED TO TREAT HYPERLIPIDEMIA: CHOLESTEROL


                            BILE ACID-BINDING RESINS:
                             (colestipol cholestyramine,
                             colesevelam; all begin with chol- or
                             col-)
                                 REDUCE LDL (CHOLESTEROL), used for
                                  isolated increase in LDL
                                 Level of VLDL may increase in patients
                                  with hypertriglyceridemia
                                 Large hydrophobic resins taken orally that
                                  bind to bile acids in the intestine and
                                  prevent bile acid re-absorption (usually
                                  95% re-absorbed)
                                 Cholesterol is required for bile acid
                                  synthesis in the liver
                                 Reduced bile acid concentrations in the
                                  liver results in greater conversion of
                                  cholesterol to bile acids and lower liver
                                  cholesterol levels
                                 Lower cholesterol results in an up-
                                  regulation of the number of LDL receptors
                                  on liver cells which increases cholesterol
BINDING RESINS                    uptake from the blood



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American Heart Association Guidelines for
Prescribing Cholesterol Lowering Drugs
    Risk      Risks           Start        Goal
  Category                    Drug
                                                         Risk factors:
                                                         Smoking
 Low          No CHD          >190 mg/dl   < 160 mg/dl   Family history
              1 risk factor                              Hypertension
                                                         Diabetes
                                                         Age (>45 for men an
 Moderate     No CHD          >160 mg/dl   <130 mg/dl    > 55 for women)
              2 or more
              moderate
              risk factors
 Moderate     No CHD          >130 mg/dl   <130 mg/dl
 High         2 or more
              high risk
              factors
 High         CHD             >100 mg/dl   <100 mg/dl


        CHD: coronary heart disease                                            41
Case # 1
   A 55-year-old woman without symptoms of CAD
    seeks assessment and advice for routine health
    maintenance. Her blood pressure is 135/85 mm
    Hg. She does not smoke or have diabetes and
    has been postmenopausal for 3 years. Her BMI is
    24. Lipoprotein analysis shows a total cholesterol
    level of 240 mg/dL, an HDL level of 55 mg/dL, a
    triglyceride level of 85 mg/dL and a LDL level is
    180 mg/dL. The patient has no family history of
    premature CAD.


                                                     42
Case # 1 (cont.)
   What is the goal LDL in this woman?
   What would you do if exercise/diet change
    do not improve cholesterol after 3 months?
   How would your management change if
    she complained of claudication with
    walking?



                                                 43
Case # 2
   A 40- year-old man without significant past
    medical history comes in for a routine annual
    exam. He has no complaints but is worried
    because his father had a “heart attack” at the age
    of 45. He is a current smoker and has a 23-pack
    year history of tobacco use. A fasting lipid panel
    reveals a LDL 170 mg/dL and an HDL of 35
    mg/dL. Serum Triglycerides were 140 mg/dL.
    Serum chemistries including liver panel are all
    normal.


                                                         44
Case # 2 (cont.)
   What is this patient’s goal LDL?
   Would you start medication, and if so,
    what?




                                             45
Case # 3
   A 65 year-old woman with medical history of Type
    II diabetes, obesity, and hypertension comes to
    your office for the first time. She has been told
    her cholesterol was elevated in the past and
    states that she has been following a “low
    cholesterol diet” for the past 6 months after seeing
    a dietician. She had a normal exercise stress test
    last year prior to knee replacement surgery and
    has never had symptoms of CHD. A fasting lipid
    profile was performed and revealed a LDL 130,
    HDL 30 and a total triglyceride of 300. Her
    Hgba1c is 6.5%.

                                                       46
Case # 3 (cont.)
   What is this patient’s goal LDL?
   What medication would you consider
    starting in this patient?
   What labs would you want to monitor in this
    patient?




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