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)
StartMonth 3p
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  
NILOTINIB THERAPY (n=37)
StartMonth 3p
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  
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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.

Topics:
dasatinib, fat metabolism, glucose, imatinib mesylate, nilotinib, adiponectin, hemoglobin a, glycosylated, insulin, ldl cholesterol lipoproteins, c-peptide

Author notes

*

Asterisk with author names denotes non-ASH members.

This icon denotes a clinically relevant abstract

© 2014 by The American Society of Hematology
2014
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