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 and 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 and 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

  • Niacin (nicotinic acid)

    • Nicotinic Acid (Niacin)

    • Overview: niacin

      • Decreases VLDL and LDL plasma levels

    • Chemistry and pharmacokinetics: niacin

      •   Water-soluble vitamin

      •   Urinary excretion:

    • Some Mechanisms of Action: niacin

      • Probable: VLDL secretion inhibition which decreases LDL production

      • Pncreased 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)

  • 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 and symptoms of CHD

•  Bile Acid-Binding Resins

  • Overview: Bile Acid-Binding Resins

    • Colestipol (Colestid)

    •  

      Cholestyramine (Questran)

      Colestipol (Colestid) and 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 and 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)

• 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), rosuvastatin (Crestor).

        •  

          Lovastatin (Mevacor)

        •  

          Atorvastatin (Lipitor)

        •  

          Fluvastatin (Lescol)

        •  

          Pravastatin (Pravachol)

        •  

          Simvastatin (Zocor)

        •  

          Rosuvastatin (Crestor)

   

  • Chemistry and Pharmacokinetics:  reductase inhibitors

    • Prodrugs: lovastatin (Mevacor)and 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) and 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

• Drug Combination Treatment

  • Overview: drug combination treatment

    • Appropriate under some conditions

    • Gemfibrozil (Lopid) and Bile Acid-Binding Resin

      • May be useful: familial combined hyperlipidemia (e.g. if patient niacin intolerant)

        • Possible increase cholelithiasis risk

    • Reductase inhibitor and 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 and Bile Acid-Binding Resin

  • Niacin and Reductase Inhibitor:

  • Combination of Resin, Niacin, and Reductase Inhibitor.

Primary Reference: Malloy, M. J, and Kane, J. P., Agents Used in Hyperlipidemia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 563-577.

Primary Reference: Ginsberg, H. N and Goldberg, I. J. Disorders of Intermediary Metabolism: Disorders of Lipoprotein Metabolism, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2138-2149.

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