Journal of
Oncology Pharmacy Practice
Case Report
Sunitinib-induced severe hypoglycemia in a diabetic patient
J Oncol Pharm Practice 2014, Vol. 20(6) 469–472 ! The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155213508441 opp.sagepub.com
¨ znur Bal, Ays¸e Durnali, Ahmet S¸ Ekinci, Ays¸e Demirci, O ¨ ksu¨zog˘lu Onur Es¸bah, Necati Alkis¸ and Berna O
Abstract Introduction: Sunitinib is an oral inhibitor of tyrosine kinase that was used for the treatment of mRCC. The general side effects are fatigue, asthenia, diarrhea, mucositis, nausea, vomiting, skin changes, hypertension, hypothyroidism and hematologic side effects. In addition, sunitinib-induced hypoglycemia has also been reported. There are limited number of case reports related to sunitinib-induced hypoglycemia. Case presentation: In this case report, we have presented a patient with type 2 diabetes mellitus (DM) with emerging severe hypoglycemia after sunitinib treatment. It was shown that blood glucose levels were normalized two weeks after the interruption of sunitinib. Conclusion: Although the underlying mechanism of sunitinib-induced hypoglycemia is not completely understood, sunitinib can be regarded to have an antidiabetic effect. In the literature, there are some reports about sunitinib/ other TKI induced hypoglycemia; however, life threatening hypoglycemia is rare. There is no case report of severe hypoglycemia due to imatinib; however, there are two case reports with severe hypoglycemia due to sunitinib treatment. Symptomatic hypoglycemic episodes due to sunitinib may lead to hospital admission. Diabetic patients may develop severe hypoglycaemia and it should be kept in mind that the discontinuation of antihyperglycemic treatment may be required. Therefore, blood glucose levels should be closely monitored in diabetic patients with mRCC during sunitinib therapy.
Keywords Sunitinib, hypoglycemia, diabetes
Introduction Sunitinib is a multitargeted tyrosine kinase inhibitor which inhibits vascular endothelial growth factor receptor type 1–3, platelet-derived growth factor receptor a and b, FMS-like tyrosine kinase 3, Kit (stem cell factor receptor), colony stimulating factor type 1 and glial cell line derived-neurotrophic factor receptor.1 In clinical practice, sunitinib is not infrequently used for the treatment of metastatic renal cell carcinoma in the first or second line of treatment.2 Sunitinib is an oral inhibitor of tyrosine kinase that was used for the treatment of metastatic renal cell carcinoma, gastrointestinal stromal tumors and neuroendocrine tumors. In patients treated with sunitinib, longer progression-free survival and higher response rates were reported compared to interferon.3,4 The general side effects are fatigue, asthenia, diarrhea, mucositis, nausea, vomiting, skin changes, hypertension, hypothyroidism, and
hematologic side effects. Although the exact mechanism is not clear, sunitinib and other tyrosine kinase inhibitors may reduce blood glucose levels. Hypoglycemia and severe hypoglycemia are defined as a blood sugar level less than 3.9 mmol/L and 2.2 mmol/L, respectively.13 There are studies reporting about the development of hypoglycemia due to various tyrosine kinase inhibitors, especially with imatinib.4,5 In this case, we have presented severe hypoglycemia which required dose reduction with the use of sunitinib in a patient with type 2 diabetes with renal cell carcinoma. Review of the literature including the terms of Department of Medical Oncology, Ankara Oncology Education and Research Hospital, Ankara, Turkey Corresponding author: Ays¸e Demirci, Department of Medical Oncology, Ankara Oncology Education and Research Hospital, Yenimahalle, Ankara 06200, Turkey. Email: [email protected]
Downloaded from opp.sagepub.com at NORTH DAKOTA STATE UNIV LIB on May 27, 2015
470
Journal of Oncology Pharmacy Practice 20(6)
hypoglycemia, diabetes and the use of sunitinib has performed between November 2012 and January 2013 by using PubMed database, in English language.
Case A 60-year-old man was admitted to the hospital with symptoms of hoarseness, difficulty in swallowing and shortness of breath in January 2012. In his medical history, he had undergone left nephrectomy due to renal cell carcinoma in 1995, and after nephrectomy radiotherapy and interferon therapy for six months. He had a diagnosis of type 2 diabetes and hypotyroidism which emerged in 2009. The patient was taking an oral antidiabetic drug (glymepride). On physical examination, bilateral breath sounds were coarse and an approximately 3 cm lymphadenopathy was palpated in the left axilla. On laboratory tests there was a mild anemia (hemoglobin: 6.94 mmol/L) and fasting blood glucose level: 7.10 (3.88–5.55) mmol/L, creatinine: 88.4 mmol/L Na: 135 mmol/L, K: 4.6 mmol/L, Ca: 2.27 mmol/L, Alb: 41 gr/L, AST: 15 U/L ALT:17 U/L and TSH:3.7 mU/L. Chest x-ray showed an enlargement of the upper mediastinum and on chest computed tomography (CT), a nodular lesion 3.5 2.0 cm in size compressing the vena cava superior (VCS) was found. The patient was given palliative radiotherapy to the region of mediastinum because of the superior vena cava syndrome (SVCS). The positron emission tomography (PET-CT) scan showed an increased fluorodeoxyglucose mmol/L 12 blood glucose levels 10 8 6 4 2 0
(FDG) uptake in the subcutaneous tissue of left axillary region, left cervical lymph node, mediastinal soft tissue mass of 3.5 2.7 cm in size and the surrounding lymph nodes, the two separate focus in right kidney and the soft tissue of 3.7 cm in size in the body of pancreas. An excisional biopsy from the left axillary region was performed and pathological examination was reported as renal cell carcinoma metastasis. Afterwards, sunitinib 50 mg/day orally was started. On the 14th day of sunitinib treatment, grade 3 thrombocytopenia and hypoglycemic episodes developed and sunitinib and antidiabetic medication was interrupted. We queried the patients of overdose using glimeprid and sunitinib, as a result, we detected no overdosage. The dosage form prescribed to take the glymepride was 2 mg and there was no nonprescription medication or recreational drug. Five days later, the patient was admitted to the emergency department with complaints of fatigue and loss of consciousness. At the emergency room, blood glucose level was 2.33 mmol/L. The patient was hospitalized in the medical oncology clinics, and blood glucose levels were monitored. Even though the patient’s oral nutritional intake was normal, continuous infusion of dextrose solution was required (Figure 1). In spite of oral intake and intravenous dextrose solution infusion, the patient continued to have episodes of symptomatic hypoglycemia. Because of the involvement of the pancreas on PET-CT, serum insulin and C-peptide levels were measured. Insulin and C peptide levels were normal, so the possibility of synchronous insulinoma was excluded. He was not using any complementary medication or herbal medicine. Hypoglycemic episodes decreased gradually over a two-week period and the patient was discharged from hospital with the glucose level of normal range. The patient did not have an experience of hypoglycemic episode; at home, the lowest blood glucose level was 4.44 mmol/L. So he was started to use sunitinib daily 37.5 mg again after a 28-day interruption. After commencement of sunitinib, again the lowest fasting blood glucose level at home was 2.77 mmol/L only once, and the highest postprandial glucose level was 9.10 mmol/L; he did not need any anti-diabetic medication (Figure 2). We demonstrated a causal relationship between sunitinib and hypoglycemia by Naranjo nomogram with a total score of 11 and it was definite adverse drug reaction score. The patient has been using sunitinib for about six months and is being followed without progression.
Discussion Figure 1. Blood glucose levels after hospitalisation (without sunitinib and without antidiabetic drug). The lowest blood glucose level: 1.88 mmol/L and continuous infusion of dextrose solution was applied on the first nine days. When blood sugar dropped below 3.80 mmol/L, a bolus infusion of dextrose was given immediately.
In this case report, we have presented a patient with type 2 diabetes with emerging severe hypoglycemia after sunitinib treatment. It was shown that blood glucose levels were normalized two weeks after the interruption of sunitinib.
Downloaded from opp.sagepub.com at NORTH DAKOTA STATE UNIV LIB on May 27, 2015
Demirci et al.
471
The mechanism of development of hypoglycemia with sunitinib treatment has not been elucidated. However, there have been several mechanisms to be proposed. In the animal study reported by Kamba et al.,6 imatinib was shown to enhance beta-cell survival via vascular endothelial growth factor receptor (VEGFR) inhibition. According to the authors, this phenomenon could be related to capillary regression. Imatinib has an antiapoptotic effect on beta cells via nuclear factor kappa B (NFkB) but there are no studies indicating the direct effect of sunitinib in this regard.7,8 Billemont et al.,9 measured blood glucose levels of 19 patients with diabetes while receiving sunitinib. Antidiabetic treatment was discontinued in two patients and the blood glucose levels were normalized in five patients. To investigate their hypotesis, serum insulin-like growth factor 1 (IGF1) levels were measured in five patients and a decrease in levels of serum IGF1 was obtained at the fourth week of treatment. Therefore, Billemont et al.9 hypothesized that sunitinib presented a hypoglycemic effect by reducing insulin resistance through IGF1 pathway. There is a limited number of case reports related to sunitinib-induced hypoglycemia and only one lifethreatening hypoglycemia was reported by Yenna Lee et al.10 They presented a neuroendocrine tumor patient who had a life-threatening hypoglycemia after treatment with sunitinib. In this case, hypoglycemia is prevented with the systemic administration of low-dose prednisolone. Agostino et al.11 published a study in which tyrosine kinase inhibitor (TKI)-induced hypoglycemia was described in detail. In this study, blood glucose levels of 78 patients treated with dasatinib, imatinib, sorafenib or sunitinib were analysed,
mmol/L 12 blood glucose levels 10 8 6 4 2
retrospectively. The majority of patients was treated with imatinib (n ¼ 39) and sunitinib (n ¼ 30). In 47% of patients with diabetes some changes were required on the dose of antidiabetic treatment. However, only one patient treated with sunitinib had experienced symptomatic hypoglycemia. Templeton et al.5 reported a 61-year-old metastatic renal cell carcinoma (mRCC) patient medicated with insulin for the late onset type 1 diabetes mellitus (DM), who was normoglycemic without insulin treatment during the sunitinib therapy. Jin Jong Oh et al.12 analysed blood sugar levels of the sunitinib-treated patients with and without diabetes RCC cases, retrospectively. Among patients without diabetes, no significant alterations in blood sugar levels were observed during the period of sunitinib treatment. One of the 10 (20.8%) patients with diabetes was required to discontinue antidiabetic drugs during a four-week treatment period and three other patients needed reduced dosages of antidiabetic drugs. None of the patients experienced severe hypoglycemic episode. Although the underlying mechanism of sunitinibinduced hypoglycemia is not completely understood, sunitinib can be regarded to have an antidiabetic effect. In the literature, there are some reports about sunitinib/other TKI-induced hypoglycemia; however, life-threatening hypoglycemia is rare. There is no case report of severe hypoglycemia due to imatinib; however, there are two case reports with severe hypoglycemia due to sunitinib treatment. Symptomatic hypoglycemic episodes due to sunitinib may lead to hospital admissions. Patients with diabetes may develop severe hypoglycaemia and it should be kept in mind that the discontinuation of antihyperglycemic treatment may be required. Therefore, blood glucose levels should be closely monitored in patients with diabetes with mRCC during sunitinib therapy. As in our case, after the hypoglycemic side effect, lower doses of sunitinib may be considered. Especially, in patients with no other treatment option, sunitinib may be continued with reduced doses or without dose reduction with the addition of steroid therapy. During sunitinib or other TKI treatment, the blood sugar level or other glycemic parameters (for example, HbA1C) monitoring should be considered. The limitation of this case report was the short follow-up period. To evaluate sunitinibrelated hypoglycemia and relationship between the development of hypoglycemia and response to sunitinib treatment, studies with greater number of patients are needed.
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Funding Figure 2. Blood glucose levels at home with 37.5 mg sunitinib and no antidiabetic drug.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Downloaded from opp.sagepub.com at NORTH DAKOTA STATE UNIV LIB on May 27, 2015
472
Journal of Oncology Pharmacy Practice 20(6)
Conflict of interest The authors declare that they have no conflict of interests.
References 1. Faivre S, Demetri G, Sargent W, et al. Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 2007; 6: 734–745. Review. 2. Schmidinger M, Arnold D, Szczylik C, et al. Optimizing the use of sunitinib in metastatic renal cell carcinoma: an update from clinical practice. Cancer Invest 2010; 28: 856–864. 3. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib vs interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 2: 115–124. 4. Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006; 21: 2516–2524. 5. Templeton A, Bra¨ndle M, Cerny T, et al. Remission of diabetes while on sunitinib treatment for renal cell carcinoma. Ann Oncol 2008; 4: 824–825. 6. Kamba T, Tam BY, Hashizume H, et al. VEGF-dependant plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol 2006; 290: H560–H576. 7. Hagerkvist R, Sandler S, Mokhtari D, et al. Amelioration of diabetes by imatinib mesylate (Gleevec): role of beta-cell NF-kappaB activation and anti-apoptotic preconditioning. FASEB J 2007; 21: 618–628.
8. Veneri D, Franchini M and Bonora E. Imatinib and regression of type 2 diabetes. N Engl J Med 2005; 10: 1049–1050. 9. Billemont B, Medioni J, Taillade L, et al. Blood glucose levels in patients with metastatic renal cell carcinoma treated with sunitinib. Br J Cancer 2008; 99: 1380–1382. 10. Lee Y, Jung HS, Choi HJ, et al. Life-threatening hypoglycemia induced by a tyrosine kinase inhibitor in a patient with neuroendocrine tumor: a case report. Diabetes Res Clin Pract 2011; 93: e68–e70. 11. Agostino NM, Chinchilli VM, Lynch CJ, et al. Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levelsin diabetic and nondiabetic patients in general clinical practice. J Oncol Pharm Pract 2011; 17: 197–202. 12. Oh JJ, Hong SK, Joo YM, et al. Impact of sunitinib treatment on blood glucose levels in patients with metastatic renal cell carcinoma. Jpn J Clin Oncol 2012; 42: 314–317. 13. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting hypoglycemia in diabetes. Diabetes Care 2005; 28: 1245–1249.
Downloaded from opp.sagepub.com at NORTH DAKOTA STATE UNIV LIB on May 27, 2015
Oncology Pharmacy Practice
Case Report
Sunitinib-induced severe hypoglycemia in a diabetic patient
J Oncol Pharm Practice 2014, Vol. 20(6) 469–472 ! The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155213508441 opp.sagepub.com
¨ znur Bal, Ays¸e Durnali, Ahmet S¸ Ekinci, Ays¸e Demirci, O ¨ ksu¨zog˘lu Onur Es¸bah, Necati Alkis¸ and Berna O
Abstract Introduction: Sunitinib is an oral inhibitor of tyrosine kinase that was used for the treatment of mRCC. The general side effects are fatigue, asthenia, diarrhea, mucositis, nausea, vomiting, skin changes, hypertension, hypothyroidism and hematologic side effects. In addition, sunitinib-induced hypoglycemia has also been reported. There are limited number of case reports related to sunitinib-induced hypoglycemia. Case presentation: In this case report, we have presented a patient with type 2 diabetes mellitus (DM) with emerging severe hypoglycemia after sunitinib treatment. It was shown that blood glucose levels were normalized two weeks after the interruption of sunitinib. Conclusion: Although the underlying mechanism of sunitinib-induced hypoglycemia is not completely understood, sunitinib can be regarded to have an antidiabetic effect. In the literature, there are some reports about sunitinib/ other TKI induced hypoglycemia; however, life threatening hypoglycemia is rare. There is no case report of severe hypoglycemia due to imatinib; however, there are two case reports with severe hypoglycemia due to sunitinib treatment. Symptomatic hypoglycemic episodes due to sunitinib may lead to hospital admission. Diabetic patients may develop severe hypoglycaemia and it should be kept in mind that the discontinuation of antihyperglycemic treatment may be required. Therefore, blood glucose levels should be closely monitored in diabetic patients with mRCC during sunitinib therapy.
Keywords Sunitinib, hypoglycemia, diabetes
Introduction Sunitinib is a multitargeted tyrosine kinase inhibitor which inhibits vascular endothelial growth factor receptor type 1–3, platelet-derived growth factor receptor a and b, FMS-like tyrosine kinase 3, Kit (stem cell factor receptor), colony stimulating factor type 1 and glial cell line derived-neurotrophic factor receptor.1 In clinical practice, sunitinib is not infrequently used for the treatment of metastatic renal cell carcinoma in the first or second line of treatment.2 Sunitinib is an oral inhibitor of tyrosine kinase that was used for the treatment of metastatic renal cell carcinoma, gastrointestinal stromal tumors and neuroendocrine tumors. In patients treated with sunitinib, longer progression-free survival and higher response rates were reported compared to interferon.3,4 The general side effects are fatigue, asthenia, diarrhea, mucositis, nausea, vomiting, skin changes, hypertension, hypothyroidism, and
hematologic side effects. Although the exact mechanism is not clear, sunitinib and other tyrosine kinase inhibitors may reduce blood glucose levels. Hypoglycemia and severe hypoglycemia are defined as a blood sugar level less than 3.9 mmol/L and 2.2 mmol/L, respectively.13 There are studies reporting about the development of hypoglycemia due to various tyrosine kinase inhibitors, especially with imatinib.4,5 In this case, we have presented severe hypoglycemia which required dose reduction with the use of sunitinib in a patient with type 2 diabetes with renal cell carcinoma. Review of the literature including the terms of Department of Medical Oncology, Ankara Oncology Education and Research Hospital, Ankara, Turkey Corresponding author: Ays¸e Demirci, Department of Medical Oncology, Ankara Oncology Education and Research Hospital, Yenimahalle, Ankara 06200, Turkey. Email: [email protected]
Downloaded from opp.sagepub.com at NORTH DAKOTA STATE UNIV LIB on May 27, 2015
470
Journal of Oncology Pharmacy Practice 20(6)
hypoglycemia, diabetes and the use of sunitinib has performed between November 2012 and January 2013 by using PubMed database, in English language.
Case A 60-year-old man was admitted to the hospital with symptoms of hoarseness, difficulty in swallowing and shortness of breath in January 2012. In his medical history, he had undergone left nephrectomy due to renal cell carcinoma in 1995, and after nephrectomy radiotherapy and interferon therapy for six months. He had a diagnosis of type 2 diabetes and hypotyroidism which emerged in 2009. The patient was taking an oral antidiabetic drug (glymepride). On physical examination, bilateral breath sounds were coarse and an approximately 3 cm lymphadenopathy was palpated in the left axilla. On laboratory tests there was a mild anemia (hemoglobin: 6.94 mmol/L) and fasting blood glucose level: 7.10 (3.88–5.55) mmol/L, creatinine: 88.4 mmol/L Na: 135 mmol/L, K: 4.6 mmol/L, Ca: 2.27 mmol/L, Alb: 41 gr/L, AST: 15 U/L ALT:17 U/L and TSH:3.7 mU/L. Chest x-ray showed an enlargement of the upper mediastinum and on chest computed tomography (CT), a nodular lesion 3.5 2.0 cm in size compressing the vena cava superior (VCS) was found. The patient was given palliative radiotherapy to the region of mediastinum because of the superior vena cava syndrome (SVCS). The positron emission tomography (PET-CT) scan showed an increased fluorodeoxyglucose mmol/L 12 blood glucose levels 10 8 6 4 2 0
(FDG) uptake in the subcutaneous tissue of left axillary region, left cervical lymph node, mediastinal soft tissue mass of 3.5 2.7 cm in size and the surrounding lymph nodes, the two separate focus in right kidney and the soft tissue of 3.7 cm in size in the body of pancreas. An excisional biopsy from the left axillary region was performed and pathological examination was reported as renal cell carcinoma metastasis. Afterwards, sunitinib 50 mg/day orally was started. On the 14th day of sunitinib treatment, grade 3 thrombocytopenia and hypoglycemic episodes developed and sunitinib and antidiabetic medication was interrupted. We queried the patients of overdose using glimeprid and sunitinib, as a result, we detected no overdosage. The dosage form prescribed to take the glymepride was 2 mg and there was no nonprescription medication or recreational drug. Five days later, the patient was admitted to the emergency department with complaints of fatigue and loss of consciousness. At the emergency room, blood glucose level was 2.33 mmol/L. The patient was hospitalized in the medical oncology clinics, and blood glucose levels were monitored. Even though the patient’s oral nutritional intake was normal, continuous infusion of dextrose solution was required (Figure 1). In spite of oral intake and intravenous dextrose solution infusion, the patient continued to have episodes of symptomatic hypoglycemia. Because of the involvement of the pancreas on PET-CT, serum insulin and C-peptide levels were measured. Insulin and C peptide levels were normal, so the possibility of synchronous insulinoma was excluded. He was not using any complementary medication or herbal medicine. Hypoglycemic episodes decreased gradually over a two-week period and the patient was discharged from hospital with the glucose level of normal range. The patient did not have an experience of hypoglycemic episode; at home, the lowest blood glucose level was 4.44 mmol/L. So he was started to use sunitinib daily 37.5 mg again after a 28-day interruption. After commencement of sunitinib, again the lowest fasting blood glucose level at home was 2.77 mmol/L only once, and the highest postprandial glucose level was 9.10 mmol/L; he did not need any anti-diabetic medication (Figure 2). We demonstrated a causal relationship between sunitinib and hypoglycemia by Naranjo nomogram with a total score of 11 and it was definite adverse drug reaction score. The patient has been using sunitinib for about six months and is being followed without progression.
Discussion Figure 1. Blood glucose levels after hospitalisation (without sunitinib and without antidiabetic drug). The lowest blood glucose level: 1.88 mmol/L and continuous infusion of dextrose solution was applied on the first nine days. When blood sugar dropped below 3.80 mmol/L, a bolus infusion of dextrose was given immediately.
In this case report, we have presented a patient with type 2 diabetes with emerging severe hypoglycemia after sunitinib treatment. It was shown that blood glucose levels were normalized two weeks after the interruption of sunitinib.
Downloaded from opp.sagepub.com at NORTH DAKOTA STATE UNIV LIB on May 27, 2015
Demirci et al.
471
The mechanism of development of hypoglycemia with sunitinib treatment has not been elucidated. However, there have been several mechanisms to be proposed. In the animal study reported by Kamba et al.,6 imatinib was shown to enhance beta-cell survival via vascular endothelial growth factor receptor (VEGFR) inhibition. According to the authors, this phenomenon could be related to capillary regression. Imatinib has an antiapoptotic effect on beta cells via nuclear factor kappa B (NFkB) but there are no studies indicating the direct effect of sunitinib in this regard.7,8 Billemont et al.,9 measured blood glucose levels of 19 patients with diabetes while receiving sunitinib. Antidiabetic treatment was discontinued in two patients and the blood glucose levels were normalized in five patients. To investigate their hypotesis, serum insulin-like growth factor 1 (IGF1) levels were measured in five patients and a decrease in levels of serum IGF1 was obtained at the fourth week of treatment. Therefore, Billemont et al.9 hypothesized that sunitinib presented a hypoglycemic effect by reducing insulin resistance through IGF1 pathway. There is a limited number of case reports related to sunitinib-induced hypoglycemia and only one lifethreatening hypoglycemia was reported by Yenna Lee et al.10 They presented a neuroendocrine tumor patient who had a life-threatening hypoglycemia after treatment with sunitinib. In this case, hypoglycemia is prevented with the systemic administration of low-dose prednisolone. Agostino et al.11 published a study in which tyrosine kinase inhibitor (TKI)-induced hypoglycemia was described in detail. In this study, blood glucose levels of 78 patients treated with dasatinib, imatinib, sorafenib or sunitinib were analysed,
mmol/L 12 blood glucose levels 10 8 6 4 2
retrospectively. The majority of patients was treated with imatinib (n ¼ 39) and sunitinib (n ¼ 30). In 47% of patients with diabetes some changes were required on the dose of antidiabetic treatment. However, only one patient treated with sunitinib had experienced symptomatic hypoglycemia. Templeton et al.5 reported a 61-year-old metastatic renal cell carcinoma (mRCC) patient medicated with insulin for the late onset type 1 diabetes mellitus (DM), who was normoglycemic without insulin treatment during the sunitinib therapy. Jin Jong Oh et al.12 analysed blood sugar levels of the sunitinib-treated patients with and without diabetes RCC cases, retrospectively. Among patients without diabetes, no significant alterations in blood sugar levels were observed during the period of sunitinib treatment. One of the 10 (20.8%) patients with diabetes was required to discontinue antidiabetic drugs during a four-week treatment period and three other patients needed reduced dosages of antidiabetic drugs. None of the patients experienced severe hypoglycemic episode. Although the underlying mechanism of sunitinibinduced hypoglycemia is not completely understood, sunitinib can be regarded to have an antidiabetic effect. In the literature, there are some reports about sunitinib/other TKI-induced hypoglycemia; however, life-threatening hypoglycemia is rare. There is no case report of severe hypoglycemia due to imatinib; however, there are two case reports with severe hypoglycemia due to sunitinib treatment. Symptomatic hypoglycemic episodes due to sunitinib may lead to hospital admissions. Patients with diabetes may develop severe hypoglycaemia and it should be kept in mind that the discontinuation of antihyperglycemic treatment may be required. Therefore, blood glucose levels should be closely monitored in patients with diabetes with mRCC during sunitinib therapy. As in our case, after the hypoglycemic side effect, lower doses of sunitinib may be considered. Especially, in patients with no other treatment option, sunitinib may be continued with reduced doses or without dose reduction with the addition of steroid therapy. During sunitinib or other TKI treatment, the blood sugar level or other glycemic parameters (for example, HbA1C) monitoring should be considered. The limitation of this case report was the short follow-up period. To evaluate sunitinibrelated hypoglycemia and relationship between the development of hypoglycemia and response to sunitinib treatment, studies with greater number of patients are needed.
0 day1
day2
day3
day4
day5
day6
Funding Figure 2. Blood glucose levels at home with 37.5 mg sunitinib and no antidiabetic drug.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Downloaded from opp.sagepub.com at NORTH DAKOTA STATE UNIV LIB on May 27, 2015
472
Journal of Oncology Pharmacy Practice 20(6)
Conflict of interest The authors declare that they have no conflict of interests.
References 1. Faivre S, Demetri G, Sargent W, et al. Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 2007; 6: 734–745. Review. 2. Schmidinger M, Arnold D, Szczylik C, et al. Optimizing the use of sunitinib in metastatic renal cell carcinoma: an update from clinical practice. Cancer Invest 2010; 28: 856–864. 3. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib vs interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 2: 115–124. 4. Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006; 21: 2516–2524. 5. Templeton A, Bra¨ndle M, Cerny T, et al. Remission of diabetes while on sunitinib treatment for renal cell carcinoma. Ann Oncol 2008; 4: 824–825. 6. Kamba T, Tam BY, Hashizume H, et al. VEGF-dependant plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol 2006; 290: H560–H576. 7. Hagerkvist R, Sandler S, Mokhtari D, et al. Amelioration of diabetes by imatinib mesylate (Gleevec): role of beta-cell NF-kappaB activation and anti-apoptotic preconditioning. FASEB J 2007; 21: 618–628.
8. Veneri D, Franchini M and Bonora E. Imatinib and regression of type 2 diabetes. N Engl J Med 2005; 10: 1049–1050. 9. Billemont B, Medioni J, Taillade L, et al. Blood glucose levels in patients with metastatic renal cell carcinoma treated with sunitinib. Br J Cancer 2008; 99: 1380–1382. 10. Lee Y, Jung HS, Choi HJ, et al. Life-threatening hypoglycemia induced by a tyrosine kinase inhibitor in a patient with neuroendocrine tumor: a case report. Diabetes Res Clin Pract 2011; 93: e68–e70. 11. Agostino NM, Chinchilli VM, Lynch CJ, et al. Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levelsin diabetic and nondiabetic patients in general clinical practice. J Oncol Pharm Pract 2011; 17: 197–202. 12. Oh JJ, Hong SK, Joo YM, et al. Impact of sunitinib treatment on blood glucose levels in patients with metastatic renal cell carcinoma. Jpn J Clin Oncol 2012; 42: 314–317. 13. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting hypoglycemia in diabetes. Diabetes Care 2005; 28: 1245–1249.
Downloaded from opp.sagepub.com at NORTH DAKOTA STATE UNIV LIB on May 27, 2015
