Treatment: Hyperlipidemia

• Dietary Management

  • Preferred initial approach except for conditions in which drug and diet management should begin simultaneously:

    •   familial hypercholesterolemia

    •   familial combined hyperlipidemia

  • Major dietary factors influencing plasma LDL levels:

    •   cholesterol intake

    •  saturated fat intake

  • Major dietary factor influencing plasma triglycerides (hypertriglyceridemia)

    • total fat intake

  • Cholesterol & saturated fats increase ­ LDL concentration independently

  • For patients with elevated LDL:

    •   total fat calories: 20-25% (saturated fats < 8% of total calories); monounsaturated fats predominate within fat allowance

    •   cholesterol < 200 mg/dL

    •   expectable serum cholesterol reduction (with this diet): 10%-20%

    •   weight reduction

    •   caloric restriction (especially for patients with increased VLDL & IDL)

  • For patients with elevated triglycerides:

    •  Omega-3 fatty acids (fish oils): significant serum triglyceride level reduction ¯ in some patients

    • Omega-6 fatty acids (vegetable oils): may increase­ triglyceride levels in these patients

Pharmacological Management of Hyperlipidemia

• Overview:drug management

  •  Diet: adjunct to drug treatment

  •  Avoid drug therapy in women likely to become pregnant or if lactating

  •  Bile acid resins treatment for childrent (> 7 years old) with heterozygous familial hypercholesterolemia

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• Niacin (nicotinic acid)
  • Overview:niacin
    • decreases VLDL and LDL plasma levels
  • Chemistry & pharmacokinetics:niacin
    •   water-soluble vitamin
    •   Urinary excretion:
  • Some Mechanisms of Action:niacin
    • probable: VLDL secretion inhibition which decreases LDL production
    • increased VLDL clearance
    • Decreased cholesterol synthesis
    • Decreased HDL catabolism (increasing HDL cholesterol plasma levels)
  • Clinical Use:  niacin (vitamin B3)
    • Heterozygous familial hypercholesterolemia:
    • Severe mixed lipemia (inadequately responsive to diet)
    • Combined hyperlipoproteinemia
    • Familial dysbetalipoproteinemia
    • Hypercholesterolemia:
    • Most effective agent in increasing HDL cholesterol
  •  Toxicity: niacin (vitamin B3)
    • Treatment initiation or upon increasing dosage: cutaneous vasodilation; sensation of warmth.
      • aspirin pre-treatment (30 minutes before dosing) reduces this effect {prostaglandin-mediated}
      • Ibuprofen (once daily) alleviates us affect also
    • Acanthosis appearance: contraindication for continued niacin treatment;  association with insulin resistance
    • In patients with severe peptic disease: avoid niacin
    • Hyperuricemia (frequency: 20%; gout may occur; allopurinol may be given with niacin to manage hyperuricemia)
    • Hypotension, especially in patients receiving antihypertensive medication

• Gemfibrozil (Lopid)

  • Overview:gemfibrozil (Lopid)

    • Reduces VLDL plasma levels

    • Increases lipoprotein lipases activity

  • Pharmacokinetics:gemfibrozil

    • well absorbed (intestine)

    • renal excretion: 70%; primarily unmodified

  • Mechanism of Action:gemfibrozil (Lopid)

    • Probably increases lipoprotein triglyceride lipolysis through lipoprotein lipase action

  • Clinical Use:gemfibrozil (Lopid)

    • Hypertriglyceridemia -- (VLDL predominates)

    • Dysbetalipoproteinemia

  • Toxicity:gemfibrozil

    • gastrointestinal upset, myopathy, arrhythmias, hypokalemia, aminotransferase elevation, alkaline phosphatase elevation, skin rashes

    •  Avoid in patients with hepatic or renal dysfunction

    • small increase in gallstone incidence

    •  Gemfibrozil should not be used in patients with combined hyperlipidemia & symptoms of CHD

Bile Acid-Binding Resins

•  Overview: Bile Acid-Binding Resins
  • Colestipol (Colestid) & cholestyramine (Questran, Questran Light): clinical use --
    • management of elevated LDL levels
    • resin treatment in patients with hypertriglyceridemia + elevated LDL  VLDL levels may be further increased

• Chemistry & Pharmacokinetics: Bile acid-binding resins
  • Colestipol (Colestid) andcholestyramine (Questran, Questran Light):
    • polymeric cationic exchange resins
    • water insoluble
    • prevent reabsorption to bile acids by binding to them in the intestine
    • resin: not absorbed systemically
• Mechanism of Action: Bile acid-binding resins:
  • Bile acids (cholesterol metabolites): 95% reabsorbed in the jejunum and ileum
    • In the presence of binding resins: excretion ­increases up to 10X
    • Increased bile acid clearance causes increased conversion of cholesterol to bile acids (in the liver, 7-a hydroxylation)
• Clinical Uses: Bile acid-binding resins:
  • In patients with familial hypercholesterolemia:
    • 20% reduction in LDL cholesterol ( at maximal bile acid-binding resin dosages)
    • in less severe hypercholesterolemia: there is greater response at  lower dosages
    • in patients with combined hyperlipidemia (LDL elevation) bile acid-binding resins lead to increased VLDL {requiring use of second drug (e.g. niacin)}
•  Toxicity:Bile acid-binding resins:
  •  Most common:
    • constipation
    • bloating {managed by increasing dietary fiber or adding psyllium seed to the resin preparation}
  •  Drug-Drug Interactions:-- reduced absorption (neutral, cationic, anionic drugs)

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Reductase Inhibitors (Competitive Inhibitors of HMG-CoA reductase)

• Overview: reductase inhibitors
  • Drugs: structural analogs HMG-CoA
    •  Listing: lovastatin (Mevacor), atorvastatin (Lipitor), fluvastatin (Lescol), pravastatin (Pravachol), simvastatin (Zocor).

• Chemistry & Pharmacokinetics:reductase inhibitors
  • Prodrugs: lovastatin (Mevacor)& simvastatin (Zocor)
  • Active drugs: atorvastatin (Lipitor), pravastatin (Pravachol), fluvastatin (Lescol).
  • Variable levels of absorption
  • All reductase inhibitors: high first pass effect

• Mechanism of Action:reductase inhibitors
  • HMG-CoA reductase:
    • catalyzes first committed sterol biosynthesis step
  • Lovastatin (active form) & congeners: HMG-CoA structural analogs causes partial inhibition of HMG-CoA reductase
  • Reductase inhibitor leads to an  increase in LDL high-affinity receptors
    • Reduces plasma LDL
  • Primary hepatic site of action
  • Small decreases in plasma triglycerides; slight increase in HDL cholesterol

• Clinical Use: reductase inhibitors
  • Treatment of elevated LDL plasma levels:-- monotherapy or with bile acid-binding resins or niacin
  •  Contraindications:
    •  Women: do not use of pregnant, lactating or likely to become pregnant
    •  Children: only use in children with:
      • heterozygous familial hypercholesterolemia
      • homozygous familial hypercholesterolemia with some LDL receptor function
• Toxicity:reductase inhibitors
  • some increase in creatinine kinase (frequency: 10%, intermittent)
    •  Reductase inhibitor-induced myopathy: more likely to the presence of other drugs such as:
      •  cyclosporine, fibric acid derivatives, azole antifungal drugs (particularly itraconazole (Sporanox)), macrolide antibiotics (e.g. erythromycin), danazol, and perhaps niacin (vitamin B3)
      • Frequent measures of creatinine kinase activity is recommended

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Drug Combination Treatment

• Overview:drug combination treatment

  •  Appropriate under some conditions

  • Gemfibrozil (Lopid)& Bile Acid-Binding Resin

    • may be useful: familial combined hyperlipidemia (patient niacin intolerant)

      • possible increase cholelithiasis risk

  • Reductase inhibitor & Binding Acid-Binding Resin

    • HMG-CoA reductase inhibitors + bile acid-binding resins are highly synergistic effects

    •  Useful: familial hypercholesterolemia

    • may not control elevated VLDL in patients with familial combined hyperlipidemia

• Niacin & Bile Acid-Binding Resin

  • Controls VLDL levels during resin treatment of familial combined hyperlipidemia

  • Effective when both VLDL and LDL plasma levels are increased

  • Niacin + colestipol: very efficacious for heterozygous familial hypercholesterolemia (decreased plasma LDL, VLDL, Lp(a) {often}, increased HDL cholesterol)

• Niacin & Reductase Inhibitor:

  • Most effective treatment available for familial combined hyperlipidemia

• Combination of Resin, Niacin, & Reductase Inhibitor

  • Effective management of severe LDL plasma elevation

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