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
| 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 | |||
| 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 | |||
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.
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