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Lomitapide is a cholesterol lowering agent that acts by inhibition of the microsomal triglyceride transfer protein and is used to treat the severe lipid abnormalities of familial hypercholesterolemia.  Lomitapide is associated with mild, asymptomatic and self-limited serum aminotransferase elevations during therapy that are usually accompanied by an increase in hepatic fat.  Long term therapy with lomitapide has been linked to development of steatohepatitis and hepatic fibrosis.



Lomitapide (loe mi' ta pide) is a potent, orally available inhibitor of the hepatic microsomal triglyceride transfer protein (MTTP) and is used to treat severe forms of familial hypercholesterolemia.  MTTP is responsible for transferring triglyceride to apolipoprotein B in the liver which is necessary for the assembly of very low density lipoproteins, the precursors of low density lipoproteins (LDL).  Inhibition of apolipoprotein B assembly leads to a marked decrease in circulating LDL cholesterol and triglycerides.  Lomitapide is typically used in combination with statins and was approved for use in the United States in 2012, but its indications were limited to patients with homozygous familial hypercholesterolemia.  Use of lomitapide can be associated with serum aminotransferase elevations and increase in hepatic fat.  Because of the risk of liver injury, lomitapide is available only as a part of a "Risk Evaluation and Mitigation Strategy" [REMS] that requires regular monitoring of liver tests.  Lomitapide is available in capsules of 5, 10, 20, 30, 40 and 60 mg under the trade name Juxtapid.  The recommended dose is 5 mg daily initially, with subsequent increases based upon tolerance and effectiveness to a maximum of 60 mg daily.  Side effects are not uncommon and include diarrhea, nausea, dyspepsia and abdominal pain that are ameliorated and partially prevented by strict adherence to a low fat diet.  Lomitapide can also cause marked drug-drug interactions and increase toxicities of other medications (statins, warfarin, antibiotics).  Chronic use of lomitapide can result in fat-soluble vitamin malabsorption and deficiencies.



Lomitapide is associated with a moderately high rate of serum aminotransferase elevations during therapy, levels above 3 times the upper limit of normal (ULN) occurring in 34% of patients.  Aminotransferase elevations above 10 times ULN have also been reported which can necessitate drug discontinuation.  Despite the frequency of ALT elevations, however, increases in serum bilirubin and alkaline phosphatase levels are rare and there have been no reports of clinically apparent acute liver injury with jaundice.  Chronic therapy with lomitapide can be associated with fluctuations in serum aminotransferase levels and accumulation of liver fat.  In some instances, the increase in liver fat is from baseline levels of <2% to as high as 10% to 40%.  At least one instance of steatohepatitis and progressive hepatic fibrosis has been reported in a patient receiving lomitapide long term.  The hepatic steatosis is reversed upon stopping lomitapide and generally does not progressively accumulate.  The reason why some patients develop liver test abnormalities and accumulate significant amounts of liver fat on lomitapide therapy while others do not, is not clear.  The frequency of liver test abnormalities and their association with steatohepatitis led to the requirement for a Risk Evaluation and Mitigation Strategy for lomitapide and it is only available for patients registered in a REMS program.

Likelihood score: C (probable cause of clinically significant liver injury).


Mechanism of Injury

The cause of hepatic injury from lomitapide appears to be related to its mechanism of action in inhibiting triglyceride transport out of hepatocytes, which leads to hepatocyte steatosis.  Lomitapide is also extensively metabolized in the liver, primarily via CYP 3A4 and is very sensitive to inhibitors of this microsomal enzyme.  Thus, strong CYP 3A4 inhibitors can cause a marked increase in lomitapide levels.  Furthermore, lomitapide can compete with other medications in CYP 3A4 metabolism and cause increases in their levels.  Lomitapide is also an inhibitor of P-glycoprotein and can increase the absorption of its substrates.


Outcome and Management

The ALT elevations associated with lomitapide therapy are not uncommon and are often accompanied by increases in hepatic steatosis which may ultimately lead to steatohepatitis and significant chronic liver injury.  The REMS management program calls for dose adjustment or drug discontinuation based upon the degree of serum aminotransferase elevations.  Patients receiving lomitapide should also be advised to follow a low fat diet and take fat soluble vitamin supplements.  Lomitapide can also cause drug-drug interactions and caution should be used in co-administration of lomitapide with other inhibitors or substrates of CYP 3A4, P-glycoprotein substrates and warfarin.


Drug Class:  Antilipemic Agents


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Lomitapide – Juxtapid®


Antilipemic Agents



Product labeling at DailyMed, National Library of Medicine, NIH


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Lomitapide 182431-12-5 C39-H37-F6-N3-O2 Lomitapide Chemical Structure

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References updated: 23 August 2016


  1. Zimmerman HJ. Drugs used in the treatment of hypercholesterolemia and hyperlipidemia. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 660-2.  (Expert review of hepatotoxicity published in 1999, before the availability of lomitapide).

  2. De Marzio DH, Navarro VJ. Hepatotoxicity of cardiovascular and antidiabetic medications. Lipid lowering agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 519-40.  (Review of hepatotoxicity of lipid lowering agents; lomitapide is not discussed).

  3. Bersot TP. Drug therapy for hypercholesterolemia and dyslipidemia. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 877-908.  (Textbook of pharmacology and therapeutics).

  4. Cuchel M, Bloedon LT, Szapary PO, Kolansky DM, Wolfe ML, Sarkis A, Millar JS, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med 2007; 356: 148-56. PubMed Citation  (Among 6 patients with familial hypercholesterolemia treated with 4 doses of lomitapide for 4 weeks, LDL cholesterol levels decreased by 51% and triglycerides by 65% at the highest dose and ALT elevations arose in 4 patients, all of whom also had increases in hepatic fat by MRI [10-40%]).

  5. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, including 6 due to statins, but none to lomitapide).

  6. Two new drugs for homozygous familial hypercholesterolemia. Med Lett Drugs Ther 2013; 55 (1413): 25-7. PubMed Citation  (Concise review of the mechanism of action, efficacy, safety and costs of lomitapide shortly after its approval for use in the US; mentions that it can cause elevations in aminotransferase levels and increases in hepatic steatosis for which reason it is only available through a restricted access program).

  7. Cuchel M, Meagher EA, du Toit Theron H, Blom DJ, Marais AD, Hegele RA, Averna MR, et al.; Phase 3 HoFH Lomitapide Study investigators. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013; 381 (9860): 40-6. PubMed Citation  (Among 28 patients with familial hypercholesterolemia treated with escalating doses of lomitapide [5 to 60 mg daily], LDL cholesterol decreased by 50%, but side effects were common, mostly gastrointestinal [>90%] and ALT elevations above 3 times ULN occurred in 10 [36%] and above 5 times ULN in 4 [14%], but none required drug discontinuation and none were associated with jaundice or symptoms, but were accompanied by increases in liver fat [from <2% to ~8%]).

  8. Raal FJ. Lomitapide for homozygous familial hypercholesterolaemia. Lancet 2013; 381 (9860): 7-8. PubMed Citation  (Editorial on familial hypercholesterolemia in response to article by Cuchel et al. [2013]).

  9. Davis KA, Miyares MA. Lomitapide: A novel agent for the treatment of homozygous familial hypercholesterolemia. Am J Health Syst Pharm 2014; 71: 1001-8. PubMed Citation  (Review of the mechanism of action, efficacy and side effects of lomitapide).

  10. Rader DJ, Kastelein JJ. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation 2014; 129: 1022-32. PubMed Citation  (Summary of mechanism of action of microsomal triglyceride transport protein [MTTP] inhibitors, their efficacy, adverse event rates, clinical usefulness and need for further research).

  11. Sacks FM, Stanesa M, Hegele RA. Progression to hepatitis and fibrosis secondary to lomitapide use--reply. JAMA Intern Med 2014; 174: 1522-3. PubMed Citation  (44 year old woman with severe hypertriglyceridemia and recurrent pancreatitis was treated with lomitapide for 13 years with excellent control of lipid levels, but with fluctuating ALT levels and development of steatohepatitis eventually with significant fibrosis).

  12. Miyares MA. Progression to hepatitis and fibrosis secondary to lomitapide use: selecting the next course of action. JAMA Intern Med 2014; 174: 1522. PubMed Citation  (Letter in response to article by Sacks [2014] questioning the use of lomitapide for 13 years in the face of signs of steatohepatitis).

  13. Cuchel M, Blom DJ, Averna MR. Clinical experience of lomitapide therapy in patients with homozygous familial hypercholesterolaemia. Atheroscler Suppl 2014; 15: 33-45. PubMed Citation  (Clinical review of efficacy and safety of lomitapide in 29 patients with familial hypercholesterolemia [Cuchel 2013] with indepth discussion of management of side effects including serum ALT elevations).

  14. Goulooze SC, Cohen AF, Rissmann R. Lomitapide. Br J Clin Pharmacol 2015; 80: 179-81. PubMed Citation  (Brief review of the mechanism of action and clinical use of lomitapide).

  15. Roeters van Lennep J, Averna M, Alonso R. Treating homozygous familial hypercholesterolemia in a real-world setting: Experiences with lomitapide. J Clin Lipidol 2015; 9: 607-17. PubMed Citation  (Details of 4 patients with familial hypercholesterolemia treated in the "real-world" including one who developed recurrent serum ALT elevations and increased liver fat with modest doses of lomitapide [5-10 mg daily], ultimately requiring drug discontinuation).

  16. Raper A, Kolansky DM, Sachais BS, Meagher EA, Baer AL, Cuchel M. Long-term clinical results of microsomal triglyceride transfer protein inhibitor use in a patient with homozygous familial hypercholesterolemia. J Clin Lipidol 2015; 9: 107-12. PubMed Citation  (49 year old woman with familial hypercholesterolemia and cardiac complications was treated with lomitapide [40-60 mg daily] and had intermittent ALT elevations [peak ~10 times ULN, but without jaundice or symptoms], but responded to discontinuation and abnormalities did not recur on restarting).

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  1. PubMed logoRecent References on Lomitapide

  2. Clinical Trials logoTrials on Lomitapide

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