The risk of hyperglycemia with PI3K inhibitors in cancer patients: A meta-analysis.

e15128 Background: Phosphoinositide 3-kinase (PI3K) inhibitors are a promising therapeutic class in cancer treatment and their clinical utility has been limited by toxicity, particularly high-grade hyperglycemia. Currently the overall risk of hyperglycemia in patients treated with PI3K inhibitors has not been well understood. We performed a meta-analysis on the risk of hyperglycemia in patients treated with PI3K inhibitors based on currently available published randomized control trial (RCT) data. Methods: A systematic meta-analysis was conducted including phase II–III RCTs evaluating PI3K inhibitors in cancer patients. The primary endpoints were the incidence and relative risk of all-grade and high-grade hyperglycemia. Pooled effect sizes were calculated using random- or fixed-effects models based on the heterogeneity of included studies. Results: A total of 5199 patients across 14 eligible RCTs were included for analysis. The summary incidences of all-grade and high-grade hyperglycemia were 32% (1654/5199; 95% CI, 24%-37%) and 13% (637/4977; 95% CI, 5%-16%), respectively. In comparison with placebo controls, PI3K inhibition significantly increased the risk of all-grade hyperglycemia (RR: 1.39; 95% CI, 1.04–1.75, P<0.01). Compared to controls, PI3K inhibition was associated with a significantly increased risk of high-grade hyperglycemia (RR: 2.27; 95% CI, 1.74–2.80; p < 0.001), with moderate heterogeneity (I² = 38.9%). Subgroup analyses revealed that control type significantly moderated toxicity risk (p < 0.001), with the greatest risk observed in trials with placebo controls (RR: 2.60; 95% CI, 2.05–3.15) and active controls (RR:1.50; 95% CI, 0.49–2.52). PI3K inhibitor subtype also moderated risk (p < 0.001). PI3K-α selective inhibitors were associated with the highest risk (RR: 3.80; 95% CI, 2.50–5.11), followed by pan-PI3K (RR: 2.15; 95% CI, 1.79–2.52) and PI3K/mTOR dual inhibitors (RR:1.46; 95% CI, 0.61–2.31). Class I α/β/δ inhibitors showed no significant elevation (RR: 1.38; 95% CI, -0.782–3.53). Conclusions: PI3K inhibitors substantially increased the risk of all-grade and high-grade hyperglycemia, and may vary with inhibitor subtypes.