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Hyperglycaemia (PI3K/AKT inhibitor class effect)

aka hyperglycemia, high blood sugar, raised glucose, glucose monitoring, PI3K inhibitor toxicity, PI3Kα inhibitor, metformin prophylaxis, SGLT2 inhibitor, ketogenic diet with PI3K inhibitors

High blood sugar as a side effect of drugs that block the PI3K/AKT pathway, because the same pathway carries insulin's signal in muscle and liver. It is the main reason these otherwise effective breast cancer drugs are hard to give.

Alpelisib causes hyperglycaemia in about 65% of patients (grade 3-4 in a third), capivasertib and everolimus less often; steroids and some immunotherapy-induced diabetes also raise glucose. Management is screening for pre-diabetes, metformin (often prophylactic), SGLT2 inhibitors, dietary carbohydrate restriction and dose modification; mutant-selective PI3Kα inhibitors (inavolisib, RLY-2608) were designed to reduce it. Hyperglycaemia is a textbook on-target toxicity: the pathway that drives PIK3CA-mutant cancers is the same one insulin uses, and the ketogenic-diet-plus-PI3K-inhibitor hypothesis arose directly from this observation.

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Side effects

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