Current cancer therapies and their influence on glucose control

Table 1 Summary of reported characteristics of hyperglycemia incidence, onset and severity with the use of current chemotherapy agents

Characteristics by drug class	Glucocorticoids	5-FU and analogs	PI3K/mTor inhibitors	Immune checkpoint inhibitors
Incidence of new or worsening hyperglycemia	Significant, 34%-94%	Common, 11.6% DM, 11.3% IFG	Significant, 12%-50%	Rare, 0.2%-4.9%
Onset of hyperglycemia after first use	Acutely	Majority by 3 mo; 3/4 early (3rd cycle); 1/4 up to 1 yr later	Majority after first use	Majority by 4 mo, can be after first use, can be up to 1 yr later
Severity of hyperglycemic events	Usually mild, Severe possible, Multiple reports of DKA and some HHS	Mild, Case reports of DKA	Mild, No DKA	Moderate to severe, 77.8% DKA

5-FU: 5-fluorouracil; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; PI3K: Phosphatidyl inositol-3-kinase; mTOR: Mammalian target of rapamycin; DKA: Diabetic ketoacidosis; HHS: Hyperglycemic hyperosmolar syndrome; IFG: Impaired fasting glucose.

Table 2 Hyperglycemia can be a class or drug-specific effect and may not be reversible with discontinuation

Characteristics by drug class	Glucocorticoids	5-FU and analogs	PI3K/mTOR inhibitors	Immune checkpoint inhibitors
Class effect on hyperglycemia	Yes	Yes	Yes	Negligible risk with the CTLA-4 inhibitor, ipililmumab
				Does occur with all PD-1 and PD-L1 inhibitors, most significantly when combined
Reversibility of hyperglycemia	Yes	No	Yes	No

5-FU: 5-fluorouracil; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; PI3K: Phosphatidyl inositol-3-kinase; mTOR: Mammalian target of rapamycin; PD-1: Programmed cell death-1; PD-L1: Programmed cell death-Ligand 1.

Table 3 The underlying mechanisms and treatment considerations of hyperglycemia differ between chemotherapy classes

	Etiology of hyperglycemia	Treatment considerations
Glucocorticoids	Major: Insulin resistance	Oral hypoglycemics possible for mild
	Minor: Decreased insulin release	Consider selecting insulins with duration of action to match that of the steroid being given
5-FU and analogs	Major: Decreased insulin release and production	Diet or oral hypoglycemics for mild
		Insulin for severe
PI3K/mTOR inhibitors	Major: Insulin resistance	Diet or metformin for mild
Immune checkpoint inhibitors	Major: Profound insulin deficiency	Immediate initiation of insulin in new onset hyperglycemia
		Switch to insulin in pre-existing T2DM

5-FU: 5-fluorouracil; PI3K: Phosphatidyl inositol-3-kinase; mTOR: Mammalian target of rapamycin; T2DM: Type 2 diabetes mellitus.