Correspondence

Imatinib and Hyperlipidemia

N Engl J Med 2005; 353:2722-2723December 22, 2005DOI: 10.1056/NEJMc052500

Article

To the Editor:

We report on a series of nine patients with hyperlipidemia and either chronic myeloid leukemia or the hypereosinophilic syndrome, in eight of whom plasma lipid levels normalized within one month after imatinib therapy (at a dose of 400 mg daily) was started. All nine patients had hypercholesterolemia (mean plasma total cholesterol level, 254 mg per deciliter; range, 223 to 293); four of them also had hypertriglyceridemia (mean plasma triglyceride level, 264 mg per deciliter; range, 230 to 368). Patients who had concomitant diabetes mellitus, were currently consuming alcohol, or were using oral contraception were excluded. Diet, weight, and levels of physical activity remained unchanged during the course of imatinib therapy. No patient received any drug known to affect lipid metabolism. The normalization (estimated to occur 30 days after imatinib was started) of cholesterolemia in eight of the nine patients (mean plasma total cholesterol level, 176 mg per deciliter; range, 160 to 187) and of triglyceridemia in three of four patients (mean plasma triglyceride level, 130 mg per deciliter; range, 126 to 138) was persistent and long-lasting (median follow-up, 20 months; range, 4 to 30). Both hypercholesterolemia and hypertriglyceridemia were unmodified in the one patient whose condition did not respond to the therapy (Table 1Table 1Plasma Lipid Levels in Nine Patients Receiving Imatinib Therapy.).

Imatinib mesylate (formerly STI571; now Gleevec in the UnitedStates and Glivec in Europe [Novartis]) is a small molecule that has been shown to have potent inhibitory activity against several tyrosine kinases, including ABL, c-Kit, and the platelet-derived growth factor receptor (PDGFR), and has become the primary target of therapy in chronic myeloid leukemia, gastrointestinal stromal tumors, and the hypereosinophilic syndrome, respectively.1 Tyrosine kinases are likely to play a pivotal role in the pathogenesis of several diseases. In particular, PDGFR binds specifically to and phosphorylates the cytoplasmic tail of the low-density lipoprotein (LDL)-receptor–related protein (LRP),2 a member of the LDL-receptor superfamily, which is known to act in areas as diverse as the degradation of proteases, the activation of lysosomal enzymes, cholesterol metabolism, and glucose-induced insulin secretion.3

Increasing evidence suggests that LRP is involved in cellular signaling in a phosphorylation-dependent manner. Inhibition by imatinib of PDGFR-dependent phosphorylation of the cytoplasmic domain of LRP has been shown to prevent intimal hyperplasia after vascular injuries and fibrovascular proliferation in mice with hypercholesterolemia.4 Moreover, imatinib has been shown to delay the development of atherosclerosis and nephropathy in experimental models, especially in the context of diabetes, and in vivo, to induce the regression of type 2 diabetes mellitus.5 Our observations suggest that in vivo modulation of the phosphorylation pathway with the use of tyrosine kinase inhibitors may result in modifications to lipoprotein metabolism that might be useful in the prevention of atherosclerosis.

Michele Gottardi, M.D.
Ca' Foncello Hospital, 31100 Treviso, Italy
michelegottardi@hotmail.com

Enzo Manzato, M.D.
University of Padua, 35128 Padua, Italy

Filippo Gherlinzoni, M.D.
Ca' Foncello Hospital, 31100 Treviso, Italy

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Citing Articles (7)

Citing Articles

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   Radu Gologan, Gabriela Constantinescu, Daniela Georgescu, Daniela Ostroveanu, Didona Vasilache, Camelia Dobrea, Daniela Iancu, Viola Popov. (2009) Hypolipemiant besides antileukemic effect of imatinib mesylate. Leukemia Research 33:9, 1285-1287
   

2. 2

   Massimo Breccia, Giuliana Alimena. (2009) The metabolic consequences of imatinib mesylate: Changes on glucose, lypidic and bone metabolism. Leukemia Research 33:7, 871-875
   

3. 3

   Vishnu Chintalgattu, Shalin S. Patel, Aarif Y. Khakoo. (2009) Cardiovascular Effects of Tyrosine Kinase Inhibitors Used for Gastrointestinal Stromal Tumors. Hematology/Oncology Clinics of North America 23:1, 97-107
   

4. 4

   Apostolos Tsapas, Efthymia Vlachaki, Maria Sarigianni, Filippos Klonizakis, Konstantinos Paletas. (2008) Restoration of insulin sensitivity following treatment with imatinib mesylate (Gleevec) in non-diabetic patients with chronic myelogenic leukemia (CML). Leukemia Research 32:4, 674-675
   

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   Susannah O'Sullivan, Dorit Naot, Karen Callon, Fran Porteous, Anne Horne, Diana Wattie, Maureen Watson, Jill Cornish, Peter Browett, Andrew Grey. (2007) Imatinib Promotes Osteoblast Differentiation by Inhibiting PDGFR Signaling and Inhibits Osteoclastogenesis by Both Direct and Stromal Cell-Dependent Mechanisms. Journal of Bone and Mineral Research 22:11, 1679-1689
   

6. 6

   E. Atallah, J.-B. Durand, H. Kantarjian, J. Cortes. (2007) Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood 110:4, 1233-1237
   

7. 7

   Berman , Ellin , Nicolaides , Maria , Maki , Robert G. , Fleisher , Martin , Chanel , Suzanne , Scheu , Kelly , Wilson , Bri-Anne , Heller , Glenn , Sauter , Nicholas P. , . (2006) Altered Bone and Mineral Metabolism in Patients Receiving Imatinib Mesylate. New England Journal of Medicine 354:19, 2006-2013
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