Abstract
Objective
This study aimed to examine the risk of diabetes mellitus induced by nilotinib, a second-generation tyrosine kinase inhibitor.
Methods
This retrospective study included 25 patients with chronic myeloid leukemia (CML) treated with nilotinib at our hospital. Four patients had diabetes mellitus at the start of nilotinib administration (prior DM group), and five patients were newly diagnosed with diabetes mellitus after the start of nilotinib administration (new DM group). Sixteen patients who were not diagnosed with diabetes mellitus were classified into the non-DM group. Changes in the blood glucose and HbA1c levels were evaluated in each group at the time of nilotinib administration and two years later.
Results
Molecular genetic remission of CML was achieved in 81.8% of patients with diabetes and 72.2% of patients without non-DM group. There were no cases in this study in which nilotinib was changed or discontinued owing to hyperglycemia. There was no difference in the blood glucose levels at the start of nilotinib treatment among the groups. Two years after starting nilotinib, the blood glucose levels in the new DM group [232 (186-296) mg/dL] and prior DM group [168 (123-269) mg/dL] were significantly higher than those in the non-DM group [100 (91-115) mg/dL]. ΔHbA1c levels in the new DM group [1.3 (0.9-2.2) %] and prior DM group [1.6 (0.7-1.7) %] were significantly higher than those in the non-DM group [-0.2 (-0.3-0.1) %].
Conclusion
Nilotinib caused diabetes in 23.8% of the participants, but there were no hyperglycemia-related severe adverse events. Therefore, nilotinib may be safely continued with regular monitoring for the development of diabetes after nilotinib administration.
Keywords: nilotinib, tyrosine kinase inhibitor, diabetes mellitus, chronic myeloid leukemia, dyslipidemia
Introduction
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by excess pluripotent hematopoietic stem cells and it is characterized by the Philadelphia (Ph) chromosome formed by t (9;22) (q34;q11). The BCR::ABL1 tyrosine kinase (TK), encoded and produced by the BCR::ABL1 fusion gene on the Ph chromosome, is permanently activated and is involved in leukemic cell growth (1). TK inhibitors (TKIs) for CML are the mainstay of treatment during the chronic phase. Nilotinib, a second-generation TKI developed for the treatment of imatinib-resistant CML refractory to imatinib, is the drug of choice for first-episode chronic-phase CML in Japan.
All TKIs have been reported to cause specific adverse events, such as cytopenia, rash, nausea, edema, and diarrhea (2). In addition, an adverse event characteristic of nilotinib is nilotinib-induced diabetes (3). Nilotinib has been reported to cause insulin resistance and impaired insulin secretion; however, the exact mechanism underlying this phenomenon is not known. In addition, the incidence of nilotinib-induced diabetes in Japan has been reported to be 28.9% (4), but the number of reports is small and there have been no reports on the clinical course of patients who continued nilotinib treatment after developing nilotinib-induced diabetes. However, a clinical trial in Americans reported that the percentage of patients who developed type 2 diabetes after receiving nilotinib was 40.4 out of 1,000 (5). This study aimed to determine the frequency and clinical course of nilotinib-induced diabetes in Japanese patients with CML treated with nilotinib.
Materials and Methods
Study population and patient preparation
This was a single-center retrospective observational study. The study included 33 patients with CML who received nilotinib at the Department of Hematology, Kawasaki Medical School Hospital, between January 1, 2010, and December 31, 2021. The Kawasaki Medical School Institutional Review Board (No. 5890-00) approved the study protocol and all subjects provided their informed consent. This study was conducted in accordance with the principles of the Declaration of Helsinki. The flow of the study participants is shown in Fig. 1. First, among the 33 CML patients who received nilotinib from January 1, 2010, to December 31, 2021, three patients whose blood glucose and HbA1c levels were never measured after receiving nilotinib were excluded from the study. One patient who died within six months and four patients whose nilotinib was discontinued within six months due to serious side non-hyperglycemia-related effects were also excluded from the study. The side effects that caused discontinuation were interstitial pneumonia in two patients, coronary angina in one patient, and nausea and vomiting in one patient. None of the patients in the study discontinued nilotinib owing to hyperglycemia. Among the 25 patients who participated in the study, nine were classified as having been diagnosed with diabetes mellitus after receiving nilotinib (DM group) and 16 were classified as having maintained normoglycemia after receiving nilotinib (non-DM group). In the DM group, four patients were classified as having been diagnosed with diabetes mellitus (DM) prior to nilotinib administration (prior DM group), and five patients were newly diagnosed with diabetes after nilotinib administration (new DM group).
Figure 1.
Flow chart regarding the participants in this study. DM: diabetes mellitus
All patients with CML underwent a bone marrow examination, and pathology proved that they had Ph chromosomes. The diagnostic criteria for diabetes mellitus in this study were a fasting blood glucose level of ≥126 mg/dL or a blood glucose level of ≥200 mg/dL at any time on multiple days or an HbA1c level of ≥6.5% in addition to hyperglycemia.
Statistical analysis
Data are expressed as the median (interquartile range). The primary endpoint was the incidence of nilotinib-induced diabetes in CML patients who received nilotinib. The secondary endpoints were to assess the clinical presentation of nilotinib-induced diabetes and other metabolic disorders. The Mann-Whitney U test and chi-square test were used to assess differences in patient background with and without diabetes. The Kruskal-Wallis test was used for the three-group comparison of prior DM, new DM, and non-DM, and the Dunn test was used as a post hoc test. Information on age, sex, height, weight, and BMI at the time of the first nilotinib administration was used. The difference in each diabetes-related parameter measured before and 2±1 years after nilotinib administration is denoted as Δ. JMP version 17.0.1 (SAS Institute, Cary, USA) was used for all statistical analyses, and Microsoft Excel for Mac version 16.71 (Microsoft, Redmond, USA) was used to generate figures.
Results
Clinical characteristics and blood glucose and HbA1c levels in each group
The clinical characteristics of the study participants are shown in Table 1. The age of the participants was 63 (50-73) years. The participants received nilotinib at 300-800 mg BID, with no dose difference between the DM and non-DM groups. A major molecular response was achieved in 81.8% of the participants with diabetes and 72.2% of the non-DM group without nilotinib dose change or interruption due to hyperglycemia.
Table 1.
Various Clinical Parameters in This Study Subjects at the Time of Nilotinib Administration.
| Parameters | All subjects (n=25) | Prior DM group (n=4) | New DM group (n=5) | Non-DM group (n=16) | p value |
|---|---|---|---|---|---|
| Male / female | 15 / 10 | 4 / 0 | 1 / 4 | 10 / 6 | 0.048 |
| Age (years) | 63 (50-73) | 75 (62-76) | 68 (56-76) | 60 (47-68) | 0.090 |
| Body weight (kg) | 56 (49-66) | 60 (55-75) | 43 (35-56) | 56 (51-73) | 0.077 |
| BMI (kg/m2) | 21 (20-24) | 21 (20-26) | 20 (15-24) | 22 (20-24) | 0.41 |
| Smoking history (never/past/current) | 14 / 8 / 3 | 2 / 2 / 0 | 4 / 1 / 0 | 8 / 5 / 3 | 0.56 |
| Drinking history (never/habitual) | 21 / 4 | 4 / 0 | 5 / 0 | 12 / 4 | 0.62 |
| Nilotinib dosage (mg/day) | 300-800 | 400-600 | 400-600 | 300-800 | 0.45 |
| Systolic blood pressure (mmHg) | 118 (110-133) | 111 (97-126) | 123 (117-149) | 120 (110-136) | 0.36 |
| Diastolic blood pressure (mmHg) | 67 (59-73) | 66 (54-69) | 61 (58-69) | 72 (63-78) | 0.23 |
| Pulse rate (beats per minutes) | 77 (67-89) | 93 (88-98) | 81 (78-89) | 68 (63-75) | 0.073 |
| Body temperature (°C) | 36.7 (36.3-36.7) | 36.7 (36.6-36.8) | 36.6 (36.2-37.1) | 36.5 (36.0-36.6) | 0.32 |
| Blood glucose (mg/dL) | 98 (94-121) | 115 (99-165) | 105 (93-164) | 97 (92-110) | 0.20 |
| HbA1c (%) | 5.7 (5.4-6.0) | 6.3 (6.0-7.3) | 5.4 (5.0-6.3) | 5.7 (5.4-5.8) | 0.041 |
| Total cholesterol (mg/dL) | 174 (152-195) | 181 (138-195) | 185 (158-254) | 165 (148-190) | 0.68 |
| Triglyceride (mg/dL) | 129 (112-176) | 124 (115-355) | 176 (176-177) | 125 (93-164) | 0.31 |
| LDL-cholesterol (mg/dL) | 95 (83-117) | 107 (80-121) | 99 (86-112) | 94 (81-121) | 0.93 |
| HDL-cholesterol (mg/dL) | 44 (35-50) | 33 (33-40) | 44 (38-49) | 46 (37-52) | 0.29 |
| AST (U/L) | 25 (21-32) | 25 (17-32) | 25 (21-47) | 25 (20-38) | 0.89 |
| ALT (U/L) | 19 (14-28) | 15 (11-21) | 17 (11-37) | 22 (15-38) | 0.36 |
| γGTP (U/L) | 29 (19-44) | 32 (19-49) | 26 (19-40) | 29 (17-49) | 0.94 |
| Urea nitrogen (mg/dL) | 13 (11-18) | 12 (10-31) | 13 (11-17) | 22 (14-31) | 0.18 |
| Creatinine (mg/dL) | 0.8 (0.6-0.9) | 1.0 (0.9-1.8) | 0.7 (0.6-1.3) | 0.7 (0.6-0.9) | 0.13 |
Data are presented as median (interquartile range). Nilotinib dosage was expressed as minimum dose-maximum dose. DM: diabetes mellitus, BMI: body mass index, LDL: low density lipoprotein, HDL: high density lipoprotein, AST: aspartate aminotransferase, ALT: alanine aminotransferase, γGTP: gamma-glutamyl transpeptidase, CRP: C-reactive protein. Kruskal-Wallis test, chi-square test was used for analysis.
First, we evaluated the blood glucose trends at nilotinib initiation and two years after initiation (Fig. 2A). There was no difference in the blood glucose levels at the start of nilotinib treatment among the non-DM group [97 (92-110) mg/dL], new DM group [105 (93-164) mg/dL], and prior DM group [115 (99-165) mg/dL]. Two years after nilotinib initiation, the blood glucose levels in the new DM group [232 (186-296) mg/dL] and prior DM group [168 (123-269) mg/dL] were significantly higher than those in the non-DM group [100 (91-115) mg/dL]. While the blood glucose levels increased by only 1(-7-14) mg/dL in the non-DM group, they increased by 98 (92-148) mg/dL in the new DM group and 60 (18-104) mg/dL in the DM group. HbA1c trends were similarly evaluated (Fig. 2B). At the start of nilotinib treatment, HbA1c levels in the prior DM group [6.3 (6.0-7.3) %] were significantly higher than those in the non-DM group [5.7 (5.4-5.8) %] and new DM group [5.4 (5.0-6.3) %] (p=0.010). Two years after nilotinib treatment, the HbA1c levels in the new DM group [7.0 (6.7-7.5) %] and the prior DM group [7.6 (7.0-9.0) %] were significantly higher than those in the non-DM group [5.4 (5.3-5.8) %]. ΔHbA1c was -0.2 (-0.3-0.1) % in the non-DM group, 1.3 (0.9-2.2) % in the new DM group, and 1.6 (0.7-1.7) % in the prior DM group.
Figure 2.
(A) The blood glucose levels at the start of nilotinib treatment and 2 years after treatment (left). The delta blood glucose levels which show differences between the blood glucose levels at the start of treatment and 2 years after treatment (right). (B) The HbA1c levels at the start of nilotinib treatment and 2 years after treatment (left). The delta HbA1c levels which show differences between HbA1c levels at the start of nilotinib treatment and 2 years after the start of nilotinib treatment (right). The graph of the difference in the blood glucose levels between before the start of treatment and 2 years after treatment is shown in median (error bars are IQR). *p<0.05, **p<0.005, Kruskal-Wallis test and post hoc test by Dunn test. The delta blood glucose and delta HbA1c levels are shown as IQR (error bars are 90% confidence interval). (C) The percentage of participants with diabetes mellitus 2 years after nilotinib treatment. The chi-square test was used to evaluate the results.
DM: diabetes mellitus, HbA1c: hemoglobin A1c, DPP4i: dipeptidyl peptidase-4 inhibitor, Alpha GI: alpha glucosidase inhibitor, SGLT2i: sodium glucose cotransporter 2 inhibitor
Other clinical characteristics included more men in the non-DM and prior DM groups and more women in the new DM group (p=0.048). Although not statistically significant, there was a trend toward a lower body weight in the new DM group than in the other groups (p=0.077). BMI, blood pressure, lipid parameters, and liver and kidney function did not differ between the groups.
Treatment of participants with complications of diabetes mellitus
Fig. 2C shows a breakdown of the diabetes treatment administered to the nine patients who received nilotinib for two years and were ultimately diagnosed with diabetes. Of the four patients in the prior DM group, three were on diabetes therapy prior to nilotinib treatment. Of these, one patient was treated with a dipeptidyl peptidase-4 (DPP4) inhibitor, one with a DPP4 inhibitor and sodium glucose cotransporter 2 (SGLT2) inhibitor, and one with a DPP4 inhibitor, alpha-glucosidase inhibitor, and thiazolidinedione. Three patients (33%) required insulin therapy after receiving nilotinib: two in the prior DM group and one in the new DM group. One patient (11%) started sulfonylurea, and one patient started biguanide. None of the study participants experienced any hyperglycemia-related severe adverse events after receiving nilotinib.
Discussion
This study provides valuable long-term observations regarding the effects of nilotinib on glucose tolerance after administration in Japanese patients. In this study, we found no cases of hyperglycemia-related severe adverse events after nilotinib administration. In contrast, new insulin therapy was introduced to 12% of the participants (n=3) after nilotinib initiation. Monitoring diabetes with nilotinib and early therapeutic intervention may allow for safer continuation of nilotinib; however, caution should be exercised because insulin therapy or oral hypoglycemic agents may be required after initiation.
Table 2 shows the studies that evaluated glucose tolerance after nilotinib treatment by searching for “nilotinib” in Pubmed (4-13). The incidence of nilotinib-induced diabetes ranged from 3.7 to 33.3%. Insulin sensitivity and insulin secretion capacity differ by race, with East Asians characterized by a higher insulin sensitivity and lower insulin secretion capacity than Africans and Caucasians (14). In a study of East Asians only, the incidence of nilotinib ranged from 23.1-28.9%. Of the 21 participants in the study, excluding the “prior DM group”, five (23.8%) developed new diabetes after receiving nilotinib, which is consistent with the frequency reported in previous studies.
Table 2.
Previous Reports of Incidence of Diabetes Mellitus after Nilotinib Treatment.
| References | Number of study participants | Incidence of diabetes mellitus (%) | Areas of the study |
|---|---|---|---|
| (4) | 74 | 28.9% | Japan |
| (5) | 435 | 4.0% | United States |
| (6) | 447 | 8.9% | Several countries |
| (7) | 62 | 11.0% | Italy |
| (8) | 220 | 10.0% | Australia |
| (9) | 1,112 | 21.6% | Italy |
| (10) | 27 | 3.7% | France |
| (11) | 82 | 23.1% | Several countries |
| (12) | 36 | 33.3% | France |
| (13) | 13 | 23.1% | Thailand |
Most nilotinib-induced diabetes cases were reversible, and nilotinib discontinuation resulted in an improvement in hyperglycemia. However, treatment interruption may affect the CML outcomes. However, there are no reports on the outcome of CML after discontinuation of nilotinib. Therefore, it is difficult to compare the merits and demerits of nilotinib discontinuation when diabetes is induced by nilotinib. Indeed, to date, there has not been a consistent view regarding the decision to continue or discontinue nilotinib-induced diabetes when it occurs (3). It is noted, that in this study we continued nilotinib even when diabetes was induced, but there were not hyperglycemia-related severe adverse events at all. In contrast, the blood glucose levels were elevated in the DM and DM groups, despite an increase in the use of diabetes medications after the initiation of nilotinib. From the clinical information obtained in this study, no statistically significant differences were identified between the patients who developed diabetes after nilotinib treatment and those who did not. Therefore, it is very important to regularly monitor glycemic control during nilotinib treatment and to initiate diabetes treatment, if necessary. It is noted here that the definition of safety in diabetes treatment is not clear; thus, we think it is difficult to precisely argue the safety issue only with the data obtained in this study.
Nilotinib reduces insulin sensitivity in muscles and induces hyperglycemia (15). Limited data indicate that nilotinib improves subcutaneous fat and pancreatic inflammation (12,16). Nilotinib has also been reported to reversibly decrease the pancreatic insulin secretory capacity (17). Although there are several reports on the mechanism by which nilotinib induces diabetes, its detailed molecular mechanism remains unknown. It has been reported that nilotinib is associated with the development of vascular adverse events, such as cardiovascular disease (18,19), cerebrovascular disease (20,21), and peripheral arterial disease (22). Nilotinib upregulates the expression of cytokines and chemokines, thus leading to a complex cascade that results in atherosclerotic plaque formation and destruction of atherosclerotic plaques (23). Additionally, increased insulin resistance increases the risk of cardiovascular events (24,25). When nilotinib is used clinically, it is advisable to detect high-risk patients early by assessing their glucose tolerance and vascular adverse events. On the other hand, intriguingly, there have been a few reports showing that TKIs rather exert favorable effects, but not negative effects, on glucose tolerance in animal and in vitro studies (26,27). The administration of TKI to non-obese diabetic (NOD) mice resulted in remission of diabetes in 80% (28). TKI also improves β-cell survival in NOD mice and human islets (29,30). Although TKIs have shown promise in the treatment of diabetes, nilotinib has been associated with a higher incidence of diabetes than other TKIs in previous observational studies (31). Interestingly, nilotinib inhibits insulin signaling in insulin target organs and pancreatic beta cells and it may be associated with a higher rate of glucose intolerance than other TKIs, but other TKIs improve glucose intolerance in NOD mice. Further studies are required to elucidate the mechanisms by which nilotinib affects glucose intolerance.
This study is associated with several limitations. This was a single-center retrospective observational study. This study had a limited number of participants and was likely to include selection bias. Concomitant medications, other than nilotinib, were not included in this analysis. The choice of diabetes medication for the prior DM group and the new DM group was determined at the discretion of the attending physician without a fixed protocol. In addition, since the incidence of diabetes when other TKIs were used at our institution was not assessed in this study, it was not possible to determine whether diabetes was caused directly by nilotinib.
Taken together, 23.8% of the participants who had not originally been diagnosed with diabetes developed new diabetes because of nilotinib. No severe adverse events related to hyperglycemia were observed after nilotinib treatment, including in the prior DM group. Therefore, even if diabetes develops after nilotinib administration, nilotinib should be continued with careful monitoring of hyperglycemia-related adverse events. The continued administration of nilotinib after the onset of hyperglycemia may require the administration of new diabetes medications, including insulin therapy. It should be noted that this study was based on a limited number of patients, and future analyses with a larger number of patients are needed to determine treatment outcomes when nilotinib is continued after the development of nilotinib-induced DM.
Consent was obtained from the participants in this study via an opt-out on the Kawasaki Medical School website.
Author’s disclosure of potential Conflicts of Interest (COI).
Shuhei Nakanishi: Honoraria, Novo Nordisk Pharma and Daiichi Sankyo. Kohei Kaku: Advisory role, Novo Nordisk Pharma, Sanwa Kagaku, Taisho Pharma, Kowa, Sumitomo Pharma, Mitsubishi Tanabe Pharma, Astellas and Boehringer Ingelheim; Honoraria, Novo Nordisk Pharma, Sanwa Kagaku, Taisho Pharma, Kowa, Sumitomo Pharma, Mitsubishi Tanabe Pharma, Astellas and Boehringer Ingelheim; Scholarship Grants, Novo Nordisk Pharma, Sanwa Kagaku, Taisho Pharma, Kowa, Sumitomo Pharma, Mitsubishi Tanabe Pharma, Astellas and Boehringer Ingelheim. Hideaki Kaneto: Honoraria, Novo Nordisk Pharma, Sanofi, Eli Lilly, Boehringer Ingelheim, Taisho Pharma, Sumitomo Pharma, Takeda Pharma, Ono Pharma, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Kissei Pharma, MSD, AstraZeneca, Astellas, Novartis, Kowa and Abbott; Research funding, Novo Nordisk Pharma, Sanofi, Eli Lilly, Boehringer Ingelheim, Taisho Pharma, Sumitomo Pharma, Takeda Pharma, Ono Pharma, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Kissei Pharma, MSD, AstraZeneca, Astellas, Novartis, Kowa and Abbott; Scholarship Grants, Novo Nordisk Pharma, Sanofi, Eli Lilly, Boehringer Ingelheim, Taisho Pharma, Sumitomo Pharma, Takeda Pharma, Ono Pharma, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Kissei Pharma, MSD, AstraZeneca, Astellas, Novartis, Kowa and Abbott.
Acknowledgments
The results of this study are reported in abstract form at the 129th Chugoku Regional Meeting of the Japanese Society of Internal Medicine.
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