This review focuses on the development of hyperglycemia arising from widely used cancer therapies spanning four drug classes. These groups of medications were selected due to their significant association with new onset hyperglycemia, or of potentially severe clinical consequences when present. These classes include glucocorticoids that are frequently used in addition to chemotherapy treatments, and the antimetabolite class of 5-fluorouracil-related drugs. Both of these classes have been in use in cancer therapy since the 1950s. Also considered are the phosphatidyl inositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-inhibitors that provide cancer response advantages by disrupting cell growth, proliferation and survival signaling pathways, and have been in clinical use as early as 2007. The final class to be reviewed are the monoclonal antibodies selected to function as immune checkpoint inhibitors (ICIs). These were first used in 2011 for advanced melanoma and are rapidly becoming widely utilized in many solid tumors. For each drug class, the literature has been reviewed to answer relevant questions about these medications related specifically to the characteristics of the hyperglycemia that develops with use. The incidence of new glucose elevations in euglycemic individuals, as well as glycemic changes in those with established diabetes has been considered, as has the expected onset of hyperglycemia from their first use. This comparison emphasizes that some classes exhibit very immediate impacts on glucose levels, whereas other classes can have lengthy delays of up to 1 year. A comparison of the spectrum of severity of hyperglycemic consequences stresses that the appearance of diabetic ketoacidosis is rare for all classes except for the ICIs. There are distinct differences in the reversibility of glucose elevations after treatment is stopped, as the mTOR inhibitors and ICI classes have persistent hyperglycemia long term. These four highlighted drug categories differ in their underlying mechanisms driving hyperglycemia, with clinical presentations ranging from potent yet transient insulin resistant states [type 2 diabetes mellitus (T2DM) -like] to rare permanent insulin-deficient causes of hyperglycemia. Knowledge of the relative incidence of new onset hyperglycemia and the underlying causes are critical to appreciate how and when to best screen and treat patients taking any of these cancer drug therapies.

An elderly woman with metastatic breast cancer was admitted with hyperglycaemic hyperosmolar state (HHS) and an elevated haemoglobin A1C. For 1 week, she had experienced confusion, nausea and frequent urination. Preceding this, she had completed seven cycles of capecitabine chemotherapy for her breast cancer. She did not have a history of diabetes prior to chemotherapy. Given the temporal dysglycaemia following the patient’s chemotherapy regimen, capecitabine was thought to be a probable offending agent. The patient was acutely treated for HHS, and was discharged on a basal-bolus insulin regimen. Her capecitabine was held pending review with her oncology team. The patient was ultimately titrated down to basal insulin only by her family doctor. Given the common use of capecitabine, it is important to recognise the risk of hyperglycaemic and hyperglycaemic emergencies as potential adverse effects. This highlights the need to monitor blood glucose throughout treatment to prevent hyperglycaemic emergencies.

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Capecitabine is an orally administered prodrug of 5-fluorouracil (5-FU) which is often used for treatment of solid tumour cancers such as breast cancer and gastrointestinal tumours. Common adverse effects include nausea, diarrhea, anorexia and erythrodysthesia (hand-foot syndrome). However, there have been case reports of metabolic disturbances linked to capecitabine including hyperlipidemia, and less commonly, hyperglycemia. We report a case of a new diagnosis of persistent diabetes mellitus following an acute presentation of hyperosmolar hyperglycemic syndrome (HHS) subsequent to treatment with the chemotherapy agent, capecitabine. A 72 year old female with a history of metastatic breast cancer was admitted to hospital for management of hyperglycemic hyperosmolar state (HHS) after bloodwork from her family doctor revealed an elevated random blood glucose (40.2 mmol/L). Leading up to her presentation, the patient had completed 7 cycles of capecitabine treatment for her breast cancer. Prior to her capecitabine treatment, the patient did not have a history of diabetes mellitus. However, on admission, her hemoglobin A1C (HbA1C) was found to elevated into the diabetic range. Offending medications were considered and given the temporal dysglycemia following the patient’s chemotherapy regimen, capecitabine was thought to be a probable offending agent. The patient was acutely treated for HHS, and eventually transitioned to a basal-bolus insulin regimen at discharge. Her capecitabine was held pending review with her oncology team and she was closely followed up by her family doctor. The patient’s insulin regimen was ultimately titrated down to basal insulin only. Given the increasing use of capecitabine therapy in breast cancer, it is important to recognize the risk of hyperglycemia and hyperglycemic emergencies as a potential adverse effect of this treatment. It highlights the need to ensure that blood glucose is monitored throughout treatment to prevent hyperglycemic emergencies.