|Year : 2017 | Volume
| Issue : 1 | Page : 136-143
Effect of tyrosine kinase inhibitors on the glucose levels in diabetic and nondiabetic patients
EY Romero-Ventosa, L Otero-Millán, S González-Costas, P Vilasoa-Boo, A Silva-López, C Arroyo-Conde, G Piñeiro-Corrales
Department of Pharmacy, Hospital Álvaro Cunqueiro, Vigo, Spain
|Date of Web Publication||1-Dec-2017|
Dr. E Y Romero-Ventosa
Department of Pharmacy, Hospital Álvaro Cunqueiro, Vigo
Source of Support: None, Conflict of Interest: None
CONTEXT: Tyrosine kinase inhibitors (TKIs) are used in different types of cancers due to their good profile of adverse reactions and their convenience in the oral administration. Some studies describe that certain TKIs are associated with changes in the glycemic profile of the patients. AIMS: This study aims to determine if treatment with ITK affects to serum glucose levels in clinical practice. SETTINGS AND DESIGN: A retrospective study was carried out in 136 episodes (112 patients treated with sorafenib, sunitinib, imatinib, dasatinib, or nilotinib). SUBJECTS AND METHODS: The serum glucose levels were analyzed before treatment and after months 1, 2, 3, 6, 9, and 12 of treatment. STATISTICAL ANALYSIS USED: Statistical analysis was completed with SPSS version 20 for Windows. RESULTS: There were significant differences in the serum glucose levels before treatment between diabetic and nondiabetic patients, but not between the average blood glucose readings before treatment and the average of the subsequent readings, once their treatment had begun. CONCLUSIONS: The results of this study do not reproduce the results of the literature since changes in the serum glucose levels have not been found in this sample of patients.
Keywords: Adverse reactions, glycemia, tyrosine kinase inhibitors
|How to cite this article:|
Romero-Ventosa E Y, Otero-Millán L, González-Costas S, Vilasoa-Boo P, Silva-López A, Arroyo-Conde C, Piñeiro-Corrales G. Effect of tyrosine kinase inhibitors on the glucose levels in diabetic and nondiabetic patients. Indian J Cancer 2017;54:136-43
|How to cite this URL:|
Romero-Ventosa E Y, Otero-Millán L, González-Costas S, Vilasoa-Boo P, Silva-López A, Arroyo-Conde C, Piñeiro-Corrales G. Effect of tyrosine kinase inhibitors on the glucose levels in diabetic and nondiabetic patients. Indian J Cancer [serial online] 2017 [cited 2019 Nov 13];54:136-43. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/136/219560
| » Introduction|| |
Tyrosine kinase inhibitors (TKIs) are a set of drugs, aimed at some specific targets that are active in the tyrosine kinase domain of intracellular receptors. Its mechanism of action is to block the chemical changes produced in the intracellular space of the membrane receptors, interfering the cascade of signal transduction of growth to the nucleus. When a membrane receptor receives a signal from outside the cell, there is a change in its intracellular space that causes an intracellular enzymatic reaction. In many cases, this enzymatic reaction is catalyzed by tyrosine kinase. Drugs targeted to inhibit this tyrosine kinase reaction are the so-called TKIs. They are usually well-tolerated oral drugs that in most cases are given uninterruptedly until the progression of the disease or an unacceptable toxicity is developed.
As described in the literature, all of the TKIs analyzed can affect serum glucose levels,, which is the variable that is being discussed in this paper.
These alterations in the blood glucose levels are not adverse effects as described in the summary of product characteristics for the TKIs. However, improvements to the glycemic control of diabetic patients who received imatinib, dasatinib, and sunitinib ,, have been described in various recent scientific articles. In addition, hypoglycemia has also been reported in one nondiabetic patient who received imatinib.
Before the data published in the literature, the aim of this paper is to analyze whether there were differences between the blood glucose levels before treatment and after treatment for different types of cancer and leukemia treated with different TKIs and analyze whether there are differences in the variation of the glycemia readings in diabetic and nondiabetic patients.
| » Subjects and Methods|| |
Patients and samples
This is a retrospective, observational noninterventional study, in which the data were obtained from clinical trials of 125 episodes in 112 patients diagnosed with various types of pathologies that had been treated with some TKIs according to the standard clinical practice. The follow-up period was 1 year.
The variables included in our study were patients' data (age, diabetes), data of disease (type, date of diagnosis), and treatment data (TKI used, dosage, start date, end date, and cause of discontinuation of treatment). Some patients received more than one drug during the study.
For the evaluation of the patients' blood glucose levels, fasting glycemia readings were collected at 0, 1, 2, 3, 6, 9, and 12 months of treatment with the TKI. Blood glucose values were obtained from laboratory tests and not from capillary glycemia measurements. All patients' fasting state was not available for us, but blood was collected early in the morning, and no fasting assays were requested.
The type of diabetes and their treatment was also collected, where appropriate.
The study follows the principles of the Declaration of Helsinki as revised in 2013. The data were registered in an encrypted database where patients could not be identified, apart from being rendered completely anonymous and patient's personal data have been secured. The study outcomes will not affect the future management of the patients.
Statistical treatment of data
The statistical treatment of the data was performed with the Statistical Package for the Social Sciences for Windows, version 15 (Copyright© SPSS Inc. 1989-2002, Chicago, IL, USA).
After collecting the values of serum concentrations of markers before and after treatment, we examined whether they followed a normal distribution. To this end, the distribution of frequencies was examined, and the nonparametric Kolmogorov–Smirnov test was used. The samples showed a normal distribution if P > 0.05. It was also assessed whether there was homogeneity of variances or not using the Levene test. There is a homogeneity of variances if P > 0.05.
The skewness coefficient was also calculated. When this coefficient is >1, the minority of the data is on the right side of the arithmetic mean. This type of distribution presents an elongation to the right, i.e. the data distribution has a longer tail to the right than to the left.
The coefficient of kurtosis was also calculated to measure the peakedness of the sample. When this value is >0, it indicates that it is leptokurtic. Kurtosis measures the tailedness of distribution as compared against a normal distribution. It is said that measures how peaked a distribution is.
In this study, the number of individuals analyzed is >30, which would allow us to make a parametric test. However, due to the loss of some data and since not all cases meet the normal conditions, nonparametric tests (Mann–Whitney U test and Wilcoxon test) have been used. These tests are considered statistically significant if P < 0.05.
The average glucose levels versus time of the treatment were also represented to determine if treatment could modify serum glucose levels over time. Other charts were also created to sort patients by group of TKI.
We used the nonparametric test, the Mann–Whitney U test for two independent samples to analyze whether there were differences in the serum glucose levels before and after treatment depending on whether the patients were diabetic or nondiabetic. Moreover, to study the existence of variations in the serum levels of these markers between the sample before treatment and the first sample after treatment, a global analysis was carried in all patients. The nonparametric test, the Wilcoxon test, were used for two paired samples.
With regard to diabetes, statistical analysis – the Mann–Whitney U test – was applied to compare a qualitative variable (diabetes mellitus [DM]) with a quantitative variable (blood glucose levels before treatment). The former variable (DM) was also compared with the successive blood glucose sample readings over the time of treatment (Wilcoxon test for paired samples).
| » Results|| |
Clinical characteristics of the patients
During the study, 135 episodes of treatment with the TKIs studied (imatinib, nilotinib, dasatinib, sorafenib, and sunitinib) were identified, corresponding to the diagnostics: chronic myeloid leukemia (CML), hepatocellular carcinoma, renal cell carcinoma (RCC), carcinoma of the thyroid, osteosarcoma, gastrointestinal stromal tumor (GIST), hypereosinophilic syndrome, graft versus host disease (GvHD), melanoma, acute myeloid leukemia (AML), and acute lymphocytic leukemia (ALL). A total of 10 patients were excluded from the study due to the absence of data and so were those patients treated for <1 month.
Eleven patients received two different TKIs, and one patient received three TKIs during the study. In [Table 1], the TKIs analyzed are described together with the types of pathologies treated with them and [Table 2] shows the clinical characteristics of the patients.
|Table 1: Episodes of patients with tyrosine kinase inhibitors and types of tumors analyzed|
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The mean age of the patients at the start of treatment was 57.1 years (standard deviation: SD 15.0). The median was 58 years (interquartile range: 19.5; Q1: 48.7 – Q3: 68.2).
Overall, most of the treatments were initiated according to the indications and dose stated in the summary of product characteristics for each of the TKIs analyzed although there were some few cases where indications and doses were different from the summary (a patient with ALL, a patient with AML, four patients with GvHD, a patient with melanoma, and a patient with hypereosinophilic syndrome).
The standard dose at the beginning of treatment for each indication stated in the summary of product characteristics is listed in [Table 3]. This table also shows the percentage of patients who began their treatment with standard doses for each of these drugs and the percentage of patients who began these treatments with nonstandard doses.
|Table 3: Standar dose, indication and percentage of patients starting with the standard dose stated in the summary of product characteristics according to the tyrosine kinase inhibitor analyzed|
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If we analyze the episodes of treatment and not only the patients included in the study but also in 26.4% of these episodes, there had been a previous treatment with a different TKI or with several TKIs. This could be a single previous treatment (this case corresponds to patients with two lines of treatment) or more than one (patients with three or four lines of treatment). The percentage of patients with more than one line of treatment is shown in [Table 4].
|Table 4: Description of the patients' treatment treated with one or more tyrosine kinase inhibitors before the tyrosine kinase inhibitor in the study|
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When we finished our study, 52.8% of the episodes was still on treatment. The average TKI treatment duration of the episodes completed was 13.4 months (standard deviation: 16.3), and the median was 7.8 months (interquartile range: 12.1; Q1: 3.4 – Q3: 15.5). [Table 5] shows these data broken down by TKI in our research.
|Table 5: Average length of treatment depending on the tyrosine kinase inhibitor analyzed|
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The main causes of suspension of the treatment with TKI were progression (27.2%), toxicity (8.0%), or death of the patient (8.0%). There was a case, in which the suspension of the treatment was decided due to the patient's gestational desire (0.8%), and the rest were suspended due to transplantation (1.6%) or by completion of the adjuvant treatment (0.8%). In one episode, this information is unknown.
In our study, 15.2% of the patients were diabetic patients and all of them with type 2 DM. This diabetes was treated with oral antidiabetic agents (10.4%), insulin (1.6%), or both (2.4%). The patient's treatment was unknown in one case.
The antidiabetic treatment was suspended in two patients and was reduced without being suspended in 5.3% of patients with DM on treatment.
Serum glucose levels in patients treated with tyrosine kinase inhibitors
One of the objectives was to examine whether treatment with the TKIs selected (imatinib, nilotinib, dasatinib, sunitinib, and sorafenib) affected the serum glucose levels in some way. For this paper, we reviewed the clinical history of each patient and collected the blood glucose value as described in the section of materials and methods.
First, serum samples before treatment were analyzed, and then, the serum samples according to the time of treatment with these TKI.
Blood glucose levels before treatment
The average of the serum glucose concentration before starting treatment with TKIs was 104.4 mg/dL (SD: 16.2), with a median of 97 mg/dL (Q1: 88.0 – Q3: 111.7). According to the Kolmogorov–Smirnov test (P = 0.002), these data do not follow a normal distribution.
The skewness coefficient is >1 (2.49), indicating a positive skewness and the kurtosis coefficient is >0 (7.49), indicating that the sample is leptokurtic.
The distribution of the blood glucose levels before treatment is normal for diabetic patients (P = 0.200) and not normal for nondiabetic patients (P< 0.001).
The average serum glucose level is 129.6 mg/dL (SD: 45.5) in diabetic patients and 99.8 mg/dL (SD: 20.6) in nondiabetic patients. According to the Mann–Whitney U test (P = 0.002), there are significant differences in the means of the serum levels before the treatment of diabetic and nondiabetic patients.
The levels of glycemia before treatment with imatinib, nilotinib, and sorafenib did not follow a normal distribution while the levels with dasatinib and sunitinib followed a normal distribution. Therefore, according to the Kruskal–Wallis test (P = 0.862), there were no differences between the levels of glycemia before treatment with each TKI used. [Figure 1] shows the distribution of the serum glucose levels before treatment depending on the TKI analyzed.
|Figure 1: Boxplot showing the serum glucose levels (mg/dL) before treatment depending on the tyrosine kinase inhibitor therapy that is about to start|
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Blood glucose levels after starting treatment
The serum glucose concentration was analyzed after starting treatment with TKI. [Figure 2] shows a boxplot where we can observe the serum glucose levels in months 0, 1, 2, 3, 6, 9, and 12 from the beginning of treatment and [Table 6] shows the data of mean, median, dispersion values, and distribution of serum glucose levels over the course of treatment with TKI.
|Figure 2: Boxplot showing the serum glucose levels (mg/dL) in patients treated with tyrosine kinase inhibitors over the course of their treatment|
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|Table 6: Analysis of the variation in blood glucose levels over the time of treatment with tyrosine kinase inhibitors|
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The serum glucose concentration follows a normal distribution in month 3 and does not follow a normal distribution in the other months analyzed. It was discussed later whether the beginning of treatment with TKI has an effect on the patients' glycemia readings or not. Thus, analyzing all the months of treatment according to the analysis for K paired samples, blood glucose levels do not differ before and after treatment with TKI (W = −0.428, P = 0.669). Analyzing only the test for two paired samples (blood glucose level before treatment and after a month of treatment), we do not obtain significant results either (W = −0.374, P = 0.709).
The average serum glucose level throughout the treatment in diabetic and nondiabetic patients is shown in [Table 7]. There are statistically significant differences in the mean of the serum glucose values in diabetic and nondiabetic patients in the months on treatment with TKI.
|Table 7: Average serum glucose level throughout the treatment with tyrosine kinase inhibitors in diabetic and nondiabetic patients|
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| » Discussion|| |
The substantial progress that has been achieved in recent years in the management of CML is the emergence of treatments based on therapeutic agents that act in a specific way as in the case of the TKIs of the first generation (imatinib) and of second generation (dasatinib and nilotinib). In the treatment for hepatocellular carcinoma, renal cell cancer and thyroid cancer TKIs (sorafenib and sunitinib) are also used. The majority of patients included in this study suffered from CML, hepatocellular carcinoma, GIST, renal cell cancer, or carcinoma of the thyroid, which were expected pathologies.
However, we could also see some less widespread uses, such as the use of TKIs for GvHD or hypereosinophilic syndrome although they also described in the literature., The use of imatinib for the hypereosinophilic syndrome is an authorized indication; however, there are very few patients with this pathology, considered as a rare disease and with an unknown prevalence.
The use of some of the TKIs involved for GvHD, melanoma, osteosarcoma and AML are not authorized by the Spanish Agency for Medicines and Health Products. These treatments are processed under the Royal Decree 1015/2009, as off-label drugs.
TKIs are usually well-tolerated drugs. They are administered on a continuous basis being sometimes necessary to reduce the dose or to suspend temporarily and/or permanently the treatment because of toxicity. The toxicities that occur frequently due to these drugs have already been described in the introduction and are reproducible in numerous studies. However, the alterations in the serum glucose level are not described as adverse reactions and/or frequent toxicities driven by these drugs.,,,,
An aim of this paper was to check whether the treatment with those TKIs has an influence on patients' serum glucose levels or not apart from clinical trials since the results of the trials are obtained in ideal situations, sometimes not similar to the usual clinical practice. This makes investigating and studying data on patients in usual practice really interesting.
The aims of this paper are consistent with the objectives set by the cancer research and with the demand for medical care in cases of cancer and leukemia, by seeking for a better understanding of the toxicities of these drugs that allow us to manage them better. The fact that existing studies are scarce and with small samples of patients justifies the interest of this research.
Casuistry of patients included in this study
In this population of patients, there is a substantial difference that we believe it is very important, namely, that CML is a chronic pathology that is going to receive treatment with TKIs for a long time, and the other cancers begin their treatment with these TKIs in advanced stages. However, we have found a study where various pathologies are analyzed jointly: CML, RCC, GIST, and ALL. Other studies are limited to analyze different TKIs but for the same pathology.
However, we expected that the glucose concentrations changed in all patients, if they changed, due to a mechanism dependent on the drug and not on the pathology.
This paper sought to conform as closely as possible to the clinical practice of health care and the actual use of TKIs in a hospital, and this is why sometimes there were difficulties analyzing data. Two difficulties were the most noteworthy for this paper: the different doses to begin treatment and the previous use of TKIs.
One of the features identified in this study is that not all patients started treatment according to the dose described in the summaries of product characteristics. Not starting with standard doses can be understood in those indications not authorized by the summaries since the indication itself is not even usual. However, some treatments started at nonstandard doses for indications authorized, especially hepatocellular carcinomas. Whatever the case is, this could affect our results since a lower or higher dose of a drug could make the effect be more, less, or simply not have any effect on serum glucose levels after starting treatment with TKIs.
The profile of the patients included in this study coincides with the one described in other articles as far as the patients' age , and the use of other TKIs before the treatment analyzed., These researchers have also analyzed patients previously treated with other TKIs as in our study.
The use of TKIs previous to the one studied in this paper can be a limitation for us. Some patients in the study had already received one, two, or three TKIs before the treatment studied. This may mean that the serum level before treatment with the TKI studied can be influenced by the use of other TKIs administered previously. Moreover, this may happen not only in the sample before treatment but also to the levels of months 1, 2, 3, 6, 9, or 12. Another limitation of this study is that the patients' fasting state is not known exactly, which can have an influence on the serum glucose levels in the patients studied. Early in the morning, the patients came to the consultations of hematology and oncology so that their blood samples could be drawn, but we cannot assure that the same conditions always applied.
As regards the presence of diabetes, we find a greater number of diabetic patients in Agostino et al.'s study  than in ours even when the number of patients in our study is greater. This information was not collected for Iurlo's et al. study.
The dose reductions are very common in patients treated until disease progression or toxicity with this type of drugs. Thus, we found changes in doses in more than 50% of our patients as it is also described in other studies (59%).
Serum glucose levels in patients treated with tyrosine kinase inhibitors
The mechanism by which the TKIs decrease serum glucose levels is unknown. There are several models developed in animals to try to explain what the role of TKIs is in the regulation of glucose levels in the blood. Krishnamurthy et al. were able to demonstrate in in vitro studies with mice that c-kit tyrosine kinase is essential for the survival of ß cells in the pancreas. They developed a model of mice with a mutation in c-kit, and the mutant mice were glucose intolerant and suffered from alterations in the secretion of insulin and a reduction in the number of ß cells of the pancreas. In a review, Fountas et al. proposed four potential mechanisms by which TKIs could have an antidiabetic effect. One would be due to the inhibition of c-Abl, the second would be due to a greater insulin secretion as a result of the increased expression of NKX2.2 and glucose transporter type 2 and to the increase of phosphorylated extracellular signal-regulated kinase. Third, due to vascular endothelial cell growth factor receptor 2 and fourth, due to epidermal growth factor receptor (EGFR) (the inhibition of EGFR would reduce the resistance to insulin because of the decrease of tumor necrosis factor alpha and interleukin 6).
The fact of affecting patients with both DM type 1 and type 2 also suggests that there should be multiple mechanisms by which the TKIs may affect the metabolism of glucose.
Finding differences in the serum glucose levels before treatment between diabetic and nondiabetic patients were expected since at this point; the treatment has no effect because it has not begun yet. Although it is true that these data could be affected by the previous use of TKIs before the episode analyzed or by the administered dose, we feel that having diabetes is more potent than a treatment with TKIs.
Serum glucose levels after treatment with TKIs were measured in different months to see if there were changes along the course of treatment with TKIs.
Several months were chosen because in the literature it is not clear the time when this reduction of levels takes place if it happens. Thus, in a mouse model, these changes occurred in males at week 8 and in females at week 40, which suggests that the sex hormones may also play a role in the deficiency of c-kit.
The data in humans are less frequent, and most of them are descriptions of isolated cases of a patient on treatment. Thus, the case of a symptomatic hypoglycemia has been reported to appear 3 months after treatment with sunitinib; we found another case of lowering doses of insulin sequentially until the total suspension of it 3 months after treatment  and another case, in which the average glycosylated hemoglobin was tested and decreased significantly after 4 months of treatment with sunitinib.
In the literature, there have been several studies, in which the treatments with TKIs affect the serum glucose levels  not only as hypoglycemia but even also with hyperglycemia. The latter study evaluates other drugs not included in our paper and gives recommendations to monitor blood glucose levels during the treatment with drugs that might affect them. One of these recommendations is to monitor the serum or urinary levels on a weekly basis during the first or the first 2 months and then on a monthly basis. In our study, with the exception of GIST and CML, there was a monthly control. If a patient has a more serious hypo/hyperglycemia, the control is recommended to be more frequent.
Vergès et al. analyze the incidence of hyperglycemia and hypoglycemia described in phase III trials for some of the TKIs studied in our paper (nilotinib, imatinib, and sunitinib) noting that they are associated with hyperglycemia rather than with hypoglycemia. They also analyze the phase III trial of another TKI not studied in our paper (pazopanib) that was associated with hypoglycemia.
The size of these studies is very varied ranging from isolated cases ,,,, to studies with a greater number of patients  or with an intermediate number (7–10 patients)., Some authors have even suggested that TKIs could be used as a treatment for DM. Some other studies, in addition to measuring alterations in the metabolism of glucose with some of the TKIs studied in this paper, measure other clinical parameters such as total cholesterol, the high-density lipoprotein cholesterol or low-density lipoprotein cholesterol, with differences between the treatments studied.
When data are obtained from isolated patients, it is more difficult to draw conclusions, but in Agostino's et al. research, we can see that the blood glucose concentrations in diabetic patients treated with dasatinib decreased by 52 mg/dL. In nondiabetic patients, imatinib caused a modest reduction in levels without any statistical significance. The treatment with sorafenib was associated with a decrease of 12 mg/dL during the treatment, and the average glucose levels in diabetic patients treated with sunitinib fell in 14 mg/dL.
These findings have not been replicated in our research, which suggests that it is necessary to undertake further studies designed to be able to say that these treatments affect glucose levels in clinical practice.
According to Agostino et al., 47% of diabetic patients were able to discontinue their antidiabetic medication during treatment with TKIs. However, in our study, only two cases of suspension took place while another patient only reduced the dose.
In a study carried out in patients with RCC, it was found that in diabetic patients with metastatic RCC treated with sunitinib, the use of metformin (oral antidiabetic drug) was associated with an improvement in overall survival compared to diabetic patients who used other antidiabetic agents (29.3 vs. 20.9 months; hazard ratio: 0.051; 95% confidence interval: 0.009–0.292). Very few patients were diabetic in our sample to measure these differences.
Targeted therapies are widely used in onco-hematological patients and considering our findings; we cannot exclude that there is a risk of metabolic complications although it was not possible to detect in our sample of patients. If this risk exists as it is described in the literature, we must pay attention to the follow-up of patients on treatment with these drugs.
| » Conclusions|| |
There is no difference between blood glucose levels before treatment and after treatment in patients treated with TKIs, so we cannot affirm that the treatment with TKIs may have an influence on the patients' glycemia.
There are differences in the blood glucose levels before treatment in diabetics and nondiabetics.
In the serum levels after treatment, there are also differences in diabetic and nondiabetic patients.
We are grateful to all health professionals of the Integrated Healthcare Management Service in Vigo who contributed to this research directly or indirectly.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]
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