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. 2015 Dec 1;113(11):1541-7.
doi: 10.1038/bjc.2015.373. Epub 2015 Nov 10.

Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials

E Geuna  1   2 , D Roda  1 , S Rafii  1 , B Jimenez  1 , M Capelan  1 , K Rihawi  1 , F Montemurro  2 , T A Yap  1 , S B Kaye  1 , J S De Bono  1 , L R Molife  1 , U Banerji  1
Affiliations

Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials

E Geuna et al. Br J Cancer. .

Abstract

Background: PI3K-AKT-mTOR inhibitors (PAMi) are promising anticancer treatments. Hyperglycaemia is a mechanism-based toxicity of these agents and is becoming increasingly important with their use in larger numbers of patients.

Methods: Retrospective case-control study comparing incidence and severity of hyperglycaemia (all grades) between a case group of 387 patients treated on 18 phase I clinical trials with PAMi (78 patients with PI3Ki, 138 with mTORi, 144 with AKTi and 27 with PI3K/mTORi) and a control group of 109 patients treated on 10 phase I clinical trials with agents not directly targeting the PAM pathway. Diabetic patients were excluded in both groups.

Results: The incidence of hyperglycaemia was not significantly different between cases and controls (86.6% vs 80.7%, respectively, P=0.129). However, high grade (grade 3-4) hyperglycaemia was more frequent in the PAMi group than in controls (6.7% vs 0%, respectively, P=0.005). The incidence of grade 3-4 hyperglycaemia was greater with AKT and multikinase inhibitors compared with other PAMi (P<0.001). All patients with high-grade hyperglycaemia received antihyperglycemic treatment and none developed severe metabolic complications (diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic state). High-grade hyperglycaemia was the cause of permanent PAMi discontinuation in nine patients.

Conclusions: PI3K-AKT-mTOR inhibitors are associated with small (6.7%) but statistically significant increased risk of high-grade hyperglycaemia compared with non-PAM targeting agents. However, PAMi-induced hyperglycaemia was not found to be associated with severe metabolic complications in this non-diabetic population of patients with advanced cancers.

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Conflict of interest statement

DR and BJ were the recipients of a grant from the Spanish Medical Oncology Society ‘BECA SEOM para la Investigación en el Extranjero'. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Baseline serum glucose levels and highest serum glucose levels during study drug exposure according to group.
See this image and copyright information in PMC

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