Insulin resistance is an underlying mechanism of impaired glucose metabolism during nilotinib therapy
Authors: Zdenek Racil, Eva Koritakova, Tomasz Sacha, Hana Klamova, Petra Belohlavkova, Edgar Faber, Delphine Rea, Ludmila Malaskova, Jirina Prochazkova, Daniela Zackova, Jaroslava Voglova, Joanna Wącław, Petr Cetkovsky, Pavel Zak, Jiri Mayer
Journal: American Journal of Hematology (2018)

Impaired glucose metabolism (IGM) with hyperglycemia represents one of the most frequently observed adverse events (AE) during nilotinib therapy of chronic myeloid leukemia (CML). The exact mechanism of IGM remains controversial. Although a case report has shown a decrease in insulin secretion1, our previous pilot data suggested development of insulin resistance as a possible mechanism.2 In this prospective study we aimed to confirm results from our pilot study using a larger cohort of CML patients treated with nilotinib and to compare results with data obtained on control groups receiving imatinib and dasatinib. Patients with CML without known diabetes mellitus (DM) who had newly initiated tyrosine kinase inhibitor (TKI) therapy were included in this multicenter study. Patients received intensive diagnostic workup (including oral glucose tolerance test) after 3 (M3) and 12 months (M12) of TKI treatment and prior to the start of this study. HOMA2-IR/ISI0,120 models were used to estimate insulin resistance/sensitivity.3, 4 Assessment of DM/pre-DM (impaired fasting glucose and impaired glucose tolerance) and cardiovascular (CV) risk was performed.5, 6 TKI dose reduction >25%, interruption >2 weeks (start - M3)/>4 weeks (M4 - M12), change/stop of TKI, and start of glucose lowering therapy excluded patients from the analysis at M3 or M12. Patients excluded from analysis at M3 were removed from the study. Initiation of lipid lowering therapy only excluded patients from the serum lipid analysis. A total of 51 patients with CML treated with nilotinib were included in the study. Twenty-eight patients receiving imatinib and 15 receiving dasatinib served as control groups. There were no differences in baseline characteristics between groups, with the exception of a significantly higher incidence of peripheral arterial occlusions in the medical history (Supporting Information Table 1) of patients treated with imatinib. Compare to baseline, fasting glycaemia increased in 74.5% of patients receiving nilotinib. The elevation of glycaemia was significant at M3 and M12 (Table 1). Using CTCAE4.0 criteria, the maximal detected grade of fasting (but not postprandial) hyperglycemia was grade 1, which was detected in 29.4%, 56.9%, and 45.2% of patients at baseline, M3, and M12, respectively. Moreover, 11/51 (21.6%) patients fulfilled criteria of newly diagnosed DM/pre-DM (Supporting material Table 1) at baseline, which persisted during treatment in 10/11 (90.9%) patients at M3 and 7/11 (63.6%) at M12. An additional 9/51 (17.6%) patients developed DM/pre-DM at M3 (in three persisting to M12) and 8/42 (19.0%) at M12. Therefore, IGM was detected in 37.3% of patients receiving nilotinib therapy at M3 and 42.9% at M12 (P = .021 and .022 compared to baseline). Only 1/51 (1.9%) patients discontinued nilotinib due to glucose lowering therapy. Importantly, nilotinib significantly increased fasting insulinemia in 72.5% of patients at M3, which persisted until M12. Insulin resistance (HOMA2-IR) significantly increased in 70.6% of subjects, and insulin sensitivity (ISI0,120) significantly decreased in 85.1% of patients during this period (Table 1). Although the role of dasatinib in glucose metabolism appears to be neutral (Table 1), the results obtained from the imatinib control group are subject to controversy. We proved that imatinib does not influence fasting insulinemia or insulin resistance (HOMA2-IR). Furthermore, imatinib significantly increased insulin sensitivity (ISI0,120) at M3, which could be at least partially explained by the significant increase of adiponectin concentration (Table 1). However, we also detected isolated increase in fasting glucose at M3 and M12, which does not have a clear explanation. The higher frequency of IGM at baseline compared to the nilotinib group does not seem to be the answer. In fact, of the 11/28 (39.3%) patients with IGM at initiation, we observed improvement during imatinib treatment in 5/11 (45.5%). Only 1/28 (3.6%) and 1/24 (4.2%) patients had IGM at M3 and M12, respectively. Together with the increased insulin sensitivity, these data more likely reflect the positive role of imatinib on glucose metabolism. The exact mechanism of insulin resistance under nilotinib exposure at the cellular level remains unknown. While our pilot study suggested a possible role of a fast decrease of adiponectin (an insulin-sensitizer)2 after initiation of nilotinib in insulin resistance, this was not confirmed in our larger cohort. Analysis of all nilotinib patients again identified a significant decrease in adiponectin (Table 1). However, the sub-analysis based on line of therapy showed that the adiponectin decrease only in patients receiving nilotinib as second line therapy, and thus only reflects a spontaneous decrease of elevated adiponectin by previous imatinib administration after its withdrawal. We also analyzed several clinical parameters to identify possible risk factors for development of IGM during nilotinib therapy; however, none of them were significant (Supporting material Table 2). Since hyperinsulinemia and insulin resistance play critical roles in the development of dyslipidemia, this could at least partially explain the increase in total, LDL, and non-HDL cholesterol in patients receiving nilotinib (Table 1) in this study, confirming our pilot data.2 Lipid metabolism abnormalities were not observed in the dasatinib group, and imatinib administration was associated with improvement of these parameters (Table 1). Finally, nilotinib treatment was associated with a significant increase in body weight and BMI at M12. This could be due to decreased catabolism after TKI initiation, though weight gain was also observed in imatinib patients. However, this could also reflect an increase of abdominal fat tissue enhanced by nilotinib-induced hyperinsulinemia. Indeed, a significant increase in waist circumference was only observed in the nilotinib cohort (Table 1). In conclusion, this prospective study proved the fast development of insulin resistance and compensatory hyperinsulinemia as a mechanism of IGM in CML patients treated with nilotinib, which contrasts with patients receiving imatinib and dasatinib. Although hyperglycemia was mild and caused treatment discontinuation in rare exceptions, the percentage of patients with confirmed IGM significantly increased with nilotinib administration duration. Therefore, together with dyslipidemia and central obesity, nilotinib leads to latent metabolic syndrome, which is a cluster of metabolic abnormalities characterized by insulin resistance that substantially increases the risk of CV events. Thus the results from our study strongly support the need for close monitoring of glucose and lipid metabolism during its administration. Whether early intervention will reduce the risk of this potentially life-threatening AE will require additional studies. The study was supported by the CELL - the CzEch Leukemia Study Group - for Life, by BMS Grant CA 180-594 and by Ministry of Health of the Czech Republic, Grant No. 17-30397A (all rights reserved). Z.R. received research funding from Novartis, Bristol Mayer Squibb and serve on a speakers bureau for Novartis and Bristol Myers Squibb; E.K. declare no relevant conflict of interest; T.S. received research funding from Novartis, Pfizer and serve on a speakers bureau for Novartis, Bristol Myers Squibb, Pfizer, Angelini; H.K. declare no relevant conflict of interest; PB - no relevant conflict of interest; E.F. received research funding from Novartis and serve on a speakers bureau for Angelini, Novartis and BMS; D.R. received honoraria from Novartis, Pfizer, Incyte and Bristol Myers Squibb; L.M. declare no relevant conflict of interest; J.P. declare no relevant conflict of interest; D.Z. serve as a consultant for Novartis, Bristol Myers Squibb, and Incyte; J.V. declare no relevant conflict of interest; J.W. serve on a speakers bureau for Novartis, Bristol Myers Squibb, Angelini; P.C. declare no relevant conflict of interest; P.Z. declare no relevant conflict of interest; J.M. received research funding from Novartis, Angelini, Bristol Mayer Squibb and serve on a speakers bureau for Novartis and Bristol Myers Squibb. Supplementary Table 1 Patients' characteristics (TKI - tyrosine kinase inhibitor, CML - chronic myeloid leukemia, CP - chronic phase, NA - not applicable, DM - diabetes mellitus, PAO - peripheral arterial collusion, pre-DM - pre-diabetes mellitus, IFG - impaired fasting glucose, IGT - impaired glucose tolerance, CV - cardiovascular, BMI - body mass index) Supplementary Table 2. - Univariate analysis - factors possibly influencing analyzed glucose metabolism parameters in patients treated with nilotinib (DM - diabetes mellitus, PAO - peripheral arterial collusion, pre-DM - pre-diabetes mellitus, CV - cardiovascular, BMI - body mass index) Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.