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Mechanism for Heparin's Ability to Lower TGs in Hypertriglyceridemia

Summary:

  • Heparin can initially lower triglyceride (TG) concentrations in patients with severe hypertriglyceridemia by directly stimulating the release of lipoprotein lipase (LPL), therefore, increasing its activity. 
  • The process to synthesize LPL is slow that continued use of heparin may lead to depletion of LPL.
  • Due to the slow process of replenishing LPL, a rebound hypertriglyceridemia may occur after the discontinuation of heparin. 
  • Treatment of hypertriglyceridemia with heparin should be done after insufficient lowering of triglycerides with making the patient NPO (nothing by mouth), intravenous (IV) fluids, and insulin infusions.

Author: Mike Maccia, PharmD
Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Content Editors: Donald S. Nuzum, PharmD, BCACP, BC-ADM, CDE, CPP and Sabrina W. Cole, PharmD, BCPS
Last Reviewed: August 2015

Explanation

  • Throughout the process of digestion, triglycerides are broken down to monoglycerides and fatty acids within the small intestine. After breakdown, both components are transported through the intestinal epithelium and resynthesized into triglycerides. The resynthesized triglycerides enter the intestinal lymph from the basolateral side as small particles and are referred to as chylomicrons. Chylomicrons then travel by lymph to be released into venous circulation at the connection of the jugular and subclavian veins.(1,2)

    After a high-fat meal, triglyceride and chylomicron concentrations significantly increase and potentially become as much as 1 to 2% of plasma, causing it to become turbid. To remove chylomicrons from circulation, lipoprotein lipase (LPL) is produced in certain tissues, including adipose, skeletal muscle, and cardiac. When chylomicrons pass through the epithelium of these tissue types, LPL is released and hydrolyzes the triglycerides into fatty acids and glycerol. After hydrolysis, fatty acids can be absorbed by various tissues, including adipose and muscle to be stored for use in energy production (i.e., eventually ATP production). Remnants of chylomicrons are then rapidly cleared from circulation.(1,2)

    Heparin is a glycosaminoglycan found endogenously in mast cells or synthesized from porcine intestinal mucosa mast cells.(3,4) While the primary pharmacological use of heparin is anticoagulation, another effect of heparin is direct stimulation of LPL release into plasma from epithelial cells. The increase in LPL will enhance the body's ability to remove triglycerides, lowering plasma concentrations.(2,5,6)

    In patients with severe hypertriglyceridemia, heparin can be used to reduce triglyceride concentrations to levels < 1,000 mg/dL within 72 hours. Stimulation of LPL peaks approximately 1 hour following administration of heparin. However, the effect rapidly declines and repeat dosing of heparin produces LPL concentrations 15 to 35% of the original peak. Additional doses of heparin can result in continually decreasing concentrations of LPL, thereby causing a reduction in hydrolysis of chylomicrons. Ultimately, heparin will deplete LPL at a more rapid pace than new enzyme is synthesized.(6-8)

    Continued administration of heparin leads to the absence of sufficient LPL to hydrolyze chylomicrons, thereby resulting in an inability to remove triglycerides from plasma. Since the process to synthesize new LPL is slow, the use of heparin may lead to long-term suppression of LPL and its ability to remove triglycerides from circulation. As a result, the discontinuation of heparin may lead to a rebound hypertriglyceridemia until sufficient quantities of LPL can be resynthesized.(7,9)

    To our knowledge there are no official dosing guidelines for the use of heparin in this situation. Based on case reports, heparin was initiated after insufficient lowering of triglycerides with making the patient NPO (nothing by mouth), intravenous (IV) fluids, and insulin infusions.  Both subcutaneous heparin and heparin intravenous (IV) infusions have been used, with most requiring IV heparin infusions to achieve sufficient lowering of triglycerides even if initially starting with subcutaneous heparin.  If heparin is needed despite other interventions, starting with a standard weight based infusion to keep the PTT 1.5 - 2 times the upper limit of normal and to achieve triglyceride levels of at least < 1,000 mg/dL is reasonable, while keeping in mind that the effectiveness of heparin can decline with continued use.  Lastly, it is most important to treat the underlying cause for the hypertriglyceridemia as well give consideration to the initiation of a fibric acid derivative and/or fish oil.

    References:

    1. Hall JE. Guyton and Hall Textbook of Medical Physiology. 12th ed. Philadelphia, PA: Saunders Elsevier; 2011. 1120 p. 
    2. Talbert RL. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: McGraw-Hill; c2008. Chapter 23, Hyperlipidemia; p. 385-7.
    3. Weitz JI. Goodman & Gilman's the Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; c2011. Chapter 30, Blood coagulation and anticoagulant, fibrinolytic, and antiplatelet drugs; p. 853-5. 
    4. Jain D, Zimmerschied J. Heparin and insulin for hypertriglyceridemia-induced pancreatitis: a case report. Scien World J. 2009;9:1230-2. 
    5. Heparin. DRUGDEX® System [Internet] Greenwood Village, CO: Truven Health Analytics. 2013 - [cited: 2013 Nov 14]. 
    6. Weintraub M, Rassin T, Eisenberg S, et al. Continuous intravenous heparin administration in humans causes a decrease in serum lipolytic activity and accumulation of chylomicrons in circulation. J Lipid Res. 1994;35:229-38.
    7. Näsström B, Olivecrona G, Olivecrona T, Stegmayr BG. Lipoprotein lipase during continuous heparin infusion: tissue stores become partially depleted. J Lab Clin Med. 2001;138(3):206-13. 
    8. Twilla JD, Mancell J. Hypertriglyceridemia-induced acute pancreatitis treated with insulin and heparin. Am J Health-Syst Pharm. 2012;69:213-6. 
    9. Cole RP. Heparin treatment for severe hypertriglyceridemia in diabetic ketoacidosis. Arch Intern Med. 2009;169(15):1439-41.

MESH Terms & Keywords

  • heparin, Heparin triglycerides, heparin lowering triglycerides, heparin reduce triglycerides, hypertriglyceridemia heparin treatment, heparin lipoprotein lipase, heparin mechanism lower triglycerides, triglycerides