Current cancer therapies and their influence on glucose control

Abstract

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.

Keywords: Cancer therapy, Hyperglycemia, adverse drug effects, Immune checkpoint inhibitors, mTOR inhibitors, 5-fluorouracil analogs, Glucocorticoids, Diabetes mellitus

Core Tip: Immune checkpoint inhibitors (ICI) rarely cause hyperglycemia, but glucose monitoring from their initiation is critical as rapid diabetic ketoacidosis can develop from underlying immune-mediated pancreatic beta-cell destruction. Therapy with mammalian target of rapamycin (mTOR) inhibitors, 5-fluorouracil (5-FU)-analogs and glucocorticoids have higher rates of hyperglycemia early in therapy that is not generally severe, but needs to be recognized and treated to optimize patient outcomes. The hyperglycemia occurring from the 5-FU and ICI classes is not reversible. The diabetes from ICIs arises from an absolute insulin deficiency vs the partial deficiency from the 5-FU class. Glucocorticoids and mTOR inhibitors predominantly cause insulin resistance.