The clinical course and potential underlying mechanisms of everolimus-induced hyperglycemia

Abstract

The mechanistic target of rapamycin (mTOR) inhibitor everolimus is an antitumor agent known to cause hyperglycemia. However, the clinical course of everolimus-induced hyperglycemia, its pathophysiological basis, and the treatment strategy are not clear. In this case series report, we present the clinical course of everolimus-induced hyperglycemia in four patients. Hyperglycemia occurred 3-8 weeks after the administration of everolimus irrespective of the body mass index (range, 21.3-29.1 kg/m 2) or pre-existing diabetes. Insulin or insulin secretagogues were required for glycemic control in most of the patients. Of note, the hyperglycemia was reversible in all patients, and none of the patients required anti-diabetic agents to achieve adequate glycemic control after cessation of everolimus therapy. To investigate the underlying mechanism of everolimus-induced hyperglycemia, we assessed insulin secretion and sensitivity by 75 g oral glucose tolerance test, arginine challenge test, and/or hyperinsulinemic-euglycemic clamp study using stable isotope-labeled glucose tracer in two patients. Everolimus did not affect insulin sensitivity in the liver, skeletal muscle, or the adipose tissue. In contrast, everolimus impaired insulin secretion and thereby increased basal hepatic glucose production. These findings further our understanding of the role of mTOR in glucose homeostasis in humans and provide insights for treatment strategies against everolimus-induced hyperglycemia.

Chronic everolimus treatment of high‐fat diet mice leads to a reduction in obesity but impaired glucose tolerance

“…mTOR inhibitor may increase the fasting glucose level, contributing to type 2 DM pathogenesis by alleviating glucose tolerance 10,14,44 . According to evidence on everolimus in breast cancer, hyperglycemia is one of the most common high‐grade adverse events, 20 moreover, everolimus induced hyperglycemia by increasing basal hepatic glucose production in diabetic and nondiabetic patients 45 . Our findings for everolimus‐treated obese mice are consistent with previous findings regarding the exacerbation of glucose intolerance.…”

Rapamycin for longevity: opinion article

“…In some cancer patients, high doses of rapamycin or everolimus can cause hyperglycemia, which is usually mild (grade 1-2) and reversible, and does not lead to treatment interruption [87–89]. Hyperglycemia is a common side effect of many oncotargeted drugs and is not a manifestation of diabetes.…”

“…Hyperglycemia is a common side effect of many oncotargeted drugs and is not a manifestation of diabetes. Everolumus, for example, can cause hyperglycemia by decreasing insulin production [89].…”

Fasting and rapamycin: diabetes versus benevolent glucose intolerance

“…In a human study, however, a pan-mTOR inhibitor did not cause hyperglycemia 9 . Furthermore, a mechanistic study in humans showed that prolonged treatment with rapamycin causes hyperglycemia by decreasing insulin production 130 , and insulin production depends on mTORC1. Thus, inhibition of mTORC2 by rapamycin has not yet been proved in humans.…”