Review
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Jul 15, 2021; 12(7): 1010-1025
Published online Jul 15, 2021. doi: 10.4239/wjd.v12.i7.1010
Current cancer therapies and their influence on glucose control
Carly Yim, Kerry Mansell, Nassrein Hussein, Terra Arnason
Carly Yim, Department of Medicine, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
Kerry Mansell, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada
Nassrein Hussein, Department of Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
Terra Arnason, Departments of Anatomy and Cell Biology and Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
Author contributions: Yim C, Mansell K, Hussein N and Arnason T contributed to the research and writing of distinct sections of the paper; Arnason T and Mansell K edited the manuscript.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Terra Arnason, FRCPC, MD, Academic Research, Doctor, Professor, Departments of Anatomy and Cell Biology and Medicine, Division of Endocrinology, University of Saskatchewan, Room 3654 Royal University Hospital 103 Hospital Drive, Saskatoon S7N 0W8, Saskatchewan, Canada. terra.arnason@usask.ca
Received: February 7, 2021
Peer-review started: February 7, 2021
First decision: March 16, 2021
Revised: April 11, 2021
Accepted: June 25, 2021
Article in press: June 25, 2021
Published online: July 15, 2021
Processing time: 154 Days and 10.4 Hours
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.