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.

Metabolic Implications of Immune Checkpoint Proteins in Cancer

“…There are several cases of autoimmune diabetes with the treatment of immune checkpoint inhibitors. It is reported that hyperglycemia is associated with checkpoint blockade and can occur in up to approximately 5% of treated patients [ 149 ]. Furthermore, in patients with diabetes, the use of immune checkpoint blockades can worsen glucose control, in particular, PD-1/PD-L1 therapies, as PD-L1 is expressed on pancreatic beta cells.…”

“…While the onset of hyperglycemia may not require treatment cessation, in some cases, immune checkpoint blockade can result in rapid ketosis. Thus, monitoring glucose levels in patients undergoing treatment is warranted [ 149 ]. These studies begin to provide insight into irAE that can develop due to immune checkpoint blockade therapy for patients with autoimmune disease, providing a foundation to continue to examine alternative treatment regimens and treatments to reduce irAE for cancer patients.…”

Stationäre Patienten mit der Nebendiagnose Diabetes mellitus: klinische Relevanz

“…Aufgrund ihres zunehmenden Einsatzes in der modernen onkologischen Therapie verdienen insbesondere Immuncheckpointinhibitoren Aufmerksamkeit. Wenngleich selten (0,2–4,9 %), manifestiert sich der autoimmun vermittelte Diabetes hier mit sehr variabler Latenz oft hochakut und in 78 % der Fälle mit einer Ketoazidose [ 31 , 83 ]. Besondere Risikofaktoren für Hyperglykämien sind auch eine Glukokortikoidbehandlung [ 41 , 77 ] sowie enterale und parenterale Ernährung [ 17 , 39 , 52 , 71 ].…”

“…Diabetes mellitus Besonderheiten Künstliche Ernährung Enteral 20–35 % [ 28 , 71 ] Negativer Prognosemarker; abhängig von Zusammensetzung (Kohlenhydrate, Ballaststoffe), Applikation (Bolus, diskontinuierlich, kontinuierlich; gastral vs. jejunal) und patientenindividuellen Faktoren (akute Erkrankung, Magenentleerungsstörung); reduziert durch kohlenhydratarme Lösungen [ 10 , 28 , 52 , 71 ] Parenteral > 50 % [ 17 , 39 , 71 ] Negativer Prognosemarker; abhängig von Zusammensetzung (Glukose, Lipidtyp, Glutamin), Timing (früher vs. verzögerter Beginn), Kombination mit enteraler Ernährung und patientenindividuellen Faktoren (akute Erkrankung; [ 17 , 39 , 71 ]) Medikamentöse Therapien Glukokortikoide Neue oder verschlechterte Hyperglykämie: 34–94 % [ 31 , 41 , 77 , 83 ] Hyperglykämie in 32,3 % und Diabetes mellitus in 18,6 % aller Patienten ohne vorbestehenden Diabetes [ 41 ]; frühe Manifestation nach Therapiebeginn (94 %), milde und selten komplikationsreiche Ausprägung, prinzipiell reversibel Risiko abhängig von Präparat, Dosis, Therapiedauer, Indikation (rheumatische Erkrankungen vs. Transplantation vs. Onkologie) und patientenindividuellen Faktoren (Alter, Gewicht, Familienanamnese Diabetes, ethnische Zugehörigkeit, vorbekannte Glukoseintoleranz; [ 77 ]) SSRI Die Einnahme von SSRI erhöht das Risiko für die Entwicklung eines Diabetes mellitus um 38 % [ 82 ] – Kalzineurininhibitoren: Tacrolimus, Sirolimus Medikation mit Tacrolimus erhöht die Inzidenz des insulinabhängigen Diabetes mellitus signifikant von 4,5 % auf 10,4 % [ 20 ] Die diabetogene Wirkung von Sirolimus (besonders 5–10 Jahre nach Transplantation) und Tacrolimus (besonders 1–3 Jahre nach Transplantation) ist eine Ursache der organunabhängig erhöhten Diabetesinzidenz nach solider Organtransplantation [ 20 , 30 ] Tumorspezifische medikamentöse Therapie 5‑FU und Analoga …”

Onkodiabetológia III.

“…A két kórforma specifikus terápiája közti összefüggés fordítva is fennáll. Az antineoplasztikumok számottevő része, saját felmérésünk alapján minden harmadik hatóanyag, szignifikánsan ront hatja a meglévő szénhidrátanyagcsere-zavarokat, sőt elhúzódó hyperglykaemiát, praediabetest (IR, IFG, IGT) vagy akár manifeszt cukorbetegséget okozhat [14][15][16][17][18]. A glükokortikoidok és egyéb endokrin készítmények ismert diabetogén effektusai mellett egyre több hagyományos citosztatikumról és modern célzott biológiai terápiáról bizonyosodik be, hogy akár súlyosan megzavarhatják a glükózanyagcserét.…”