Comparison of Glucose and Lipid Metabolism Abnormality during Nilotinib, Imatinib and Dasatinib Therapy – Results of Enigma 2 Study
Authors: Zdenek Racil , Belohlavkova Petra , Cetkovsky Petr , Faber Edgar , Klamova Hana , Ludmila Malaskova , Sacha Tomasz , Jaroslava Voglova , Zackova Daniela , Zak Pavel , Mayer Jiri 
Published: October 2019

Abstract

Background: Recently we have published results of pilot study on CML patients demonstrating fast development of hyperinsulinaemia, peripheral insulin resistance, hypoadiponectinaemia and hypercholesterolemia during nilotinib therapy.
Aims: To analyze results from follow up multicenter study “ENIGMA 2” with the aim to confirm or to exclude results from the pilot study, as well as to analyze whether these abnormalities are detected in control groups of patients treated with other TKIs - imatinib and dasatinib.
Methods: Patients received intensive laboratory workup before the start of TKI and after 3 month of therapy. This included fasting insulin, glucose, adiponectin and lipid serum concentration, HbA1c and oral glucose tolerance test. Patients with TKI treatment interruption for >2 weeks and/or dose reduction for > 25% were excluded.
Results: Between 2/2011-6/2014 in 5 centers 37 CML patients initiated therapy with nilotinib, 18 with imatinib and 8 with dasatinib.
After 3 months patients treated with nilotinib developed significant hypersinulinaemia and hyperglycaemia as result of fast development of peripheral insulin resistance. This was proved by significant increase in HOMA-2 index during 3 months of nilotinib therapy (mean – 1.4 vs. 1.8; p = 0.0023). Moreover, we have proved significant decrease of adiponectin (major insulin sensitizer) concentration as well as significant increase in total and LDL cholesterol concentration after 3 month of nilotinib treatment. Details are presented in Table.
Contrary – none of these abnormalities were detected in the control group of patients treated with imatinib and dasatinib, including any change in insulin resistance measured by HOMA-2 index (means – 0.9 vs. 1.3; p = 0.1046 and 1.1 vs. 1.1; p = 0.9255). Moreover, administration of imatinib (and probably also dasatinib, however only limited data are available at this moment) leads to increase of adiponectin concentration, which serves as major insulin sensitizer in peripheral tissues.
Conclusions: Our study proved fast development of peripheral insulin resistance already during the first 3 months of nilotinib therapy as underlying cause of glucose and secondary also lipid metabolism impairment during this treatment.
Moreover, this was not proved for patients treated with imatinib and dasatinb and significant increase in adiponectin concentration during imatinib (and probably dasatinib) therapy could at least partly explain observed amelioration of diabetes 2 during its administration described in some studies
Supported by the CELL – the Czech Leukemia Study Group – for life
Table. NILOTINIB THERAPY (n=37) Start Month 3 p mean (range) mean (range) Fasting glucose [mmol/l] 5.3 (4.5-6.7) 5.7 (4.6-8.2) <0.0001 Fasting insulin [mU/l] 11.2 (2.4-28.3) 14,1 (2.5-32.7) 0.0037 Fasting C-peptide [pmol/ml] 0.73 (0.53-1.78) 0.76 (0.76-3.31) 0.4953 Fasting HbA1c [mmol/mol] 38.9 (24.0-55.0) 38.2 (25.0-57.0) 0.3900 Fasting adiponectin [mg/l] 16.6 (2.1-45.1) 8.6 (2.6-22.4) 0.0019* Total cholesterol [mmol/l] 4.8 (2.5-6.7) 5.9 (4.4-7.9) <0.0001 LDL cholesterol [mmol/l] 2.8 (1.1-4.9) 3.6 (2.1-5.7) <0.0001 IMATINIB THERAPY (n=18) Start Month 3 p mean (range) mean (range) Fasting glucose [mmol/l] 5.5 (4.4-7.7) 5.6 (4.2-6.4) 0.7567 Fasting insulin [mU/l] 6.7 (2.0-19.0) 9.8 (2.0-37.80) 0.1369 Fasting C-peptide [pmol/ml] 0.77 (0.25-1.55) 0.72 (0.27-1.78) 0.4569 Fasting HbA1c [mmol/mol] 44.8 (33.0-59.0) 41.1 (30.0-55.0) 0.005 Fasting adiponectin [mg/l] 10.8 (2.1-25.7) 26.1 (6.0-45.2) <0.0001** Total cholesterol [mmol/l] 5.1 (3.3-7.1) 4,7 (2.6-7.1) 0.1123 LDL cholesterol [mmol/l] 3.1 (1.7-4.7) 2.7 (1.2-4.7) 0.064 DASATINIB THERAPY (n=8) Start Month 3 p mean (range) mean (range) Fasting glucose [mmol/l] 5.8 (4.6-6.8) 5.3 (3.3-6.7) 0.1764 Fasting insulin [mU/l] 8.1 (2.5-19.3) 8.4 (2.6-17.9) 0.8815 Fasting C-peptide [pmol/ml] 0.63 (0.16-1.11) 0.60 (0.24-1.03) 0.8223 Fasting HbA1c [mmol/mol] 38.8 (31.0-51.0) 37.8 (30.0-56.0) 0.684 Fasting adiponectin [mg/l] 17.3 (9.2-26.7) 12.9 (5.5-21.4) 0.0106*** Total cholesterol [mmol/l] 4.0 (3.0-5.0) 4.5 (3.6-5.8) 0.0831 LDL cholesterol [mmol/l] 2.2 (1.6-3.0) 2.5 (1.9-3.3) 0.1140 *number of paired measurements = 24 **number of paired measurements = 12 ***number of paired measurements = 3

Disclosures
Zdenek: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Klamova:Novartis and Bristol Myers-Squibb: Consultancy, Honoraria. Mayer:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.