Capivasertib Causes Distinctive Glucose Spikes in Breast Cancer Patient, Prompting Japanese Safety Warning
核心洞察
A 73-year-old breast cancer (搜索) patient experienced severe hyperglycemia (搜索) exceeding 500 mg/dL on day 11 of capivasertib treatment, despite having normal baseline glucose levels and no diabetes (搜索) history.
Continuous glucose monitoring revealed that hyperglycemia (搜索) occurred exclusively during capivasertib dosing days, with glucose levels rising 1-2 hours after drug intake and returning to baseline after 12 hours.
The Japan Diabetes Society (搜索) and Japan Breast Cancer Society (搜索) issued a safety warning on April 15, 2025, following a fatal case of diabetic ketoacidosis (搜索) during early capivasertib treatment.
A detailed case report has revealed distinctive patterns of glucose fluctuations in a breast cancer (搜索) patient receiving capivasertib, highlighting critical safety considerations for this AKT (搜索) inhibitor that prompted Japanese medical societies to issue a formal warning.
The case involved a 73-year-old woman with hormone receptor-positive/HER2-negative metastatic breast cancer (搜索) who developed severe hyperglycemia (搜索) while receiving capivasertib combined with fulvestrant. Despite having normal baseline fasting glucose levels (109 mg/dL), no personal or family history of diabetes (搜索), and a body mass index of 18.8 kg/m², the patient experienced marked hyperglycemia exceeding 500 mg/dL on day 11 of treatment.
Unique Glucose Pattern Emerges
Continuous glucose monitoring using the FreeStyle Libre Pro® system revealed a previously undocumented pattern: hyperglycemia (搜索) occurred exclusively on days when capivasertib was administered. The monitoring showed characteristic glucose spikes beginning 1-2 hours after capivasertib intake, with levels returning to baseline approximately 12 hours later, corresponding to the drug's pharmacokinetic profile with a Tmax of 1 hour and half-life of 10 hours.
The patient was initially treated with capivasertib at 400 mg twice daily for 4 days, followed by 3 days off. After the hyperglycemic episode, treatment was resumed at a reduced dose of 320 mg twice daily with the same schedule, accompanied by targeted insulin therapy administered only on dosing days.
Safety Warning Issued
The Japan Diabetes Society (搜索) and Japan Breast Cancer Society (搜索) issued a joint warning on April 15, 2025, regarding hyperglycemia (搜索) and diabetic ketoacidosis (搜索) (DKA) associated with capivasertib. This action followed a fatal case of DKA occurring in the early phase of capivasertib treatment in Japan.
In the pivotal CAPItello-291 trial, grade 3/4 hyperglycemic events occurred in 2.3% of patients, with serious hyperglycemia (搜索) rare at 0.8%. The median time to onset of hyperglycemia was 15 days. However, patients with diabetes (搜索) requiring insulin treatment or with hemoglobin A1c levels of 8.0% or higher were excluded from the trial.
Mechanistic Understanding
Capivasertib's hyperglycemic effects stem from its inhibition of the phosphoinositide 3-kinase (PI3K (搜索))/AKT (搜索)/mTOR (搜索) pathway. AKT signaling normally induces glucose transporter 4-mediated glucose transport into skeletal muscle and adipose tissue. Additionally, AKT phosphorylates glycogen synthase kinase 3 (GSK3), and the resulting inactivation of GSK3 enhances glycogen synthesis. Therefore, AKT pathway inhibition can lead to acute hyperglycemia (搜索).
The case authors noted that glycemic fluctuations observed with continuous glucose monitoring appear more pronounced with capivasertib compared to alpelisib, another PI3K (搜索) pathway inhibitor. Alpelisib caused grade 3/4 hyperglycemia (搜索) in 36.6% of patients in the SOLAR-1 trial, with a reporting odds ratio for DKA events of 9.84.
Clinical Implications for Monitoring
The findings suggest that routine laboratory monitoring may underestimate hyperglycemia (搜索) risk with capivasertib. In the CAPItello-291 trial, fasting glucose levels were assessed on days 1 and 15 of the first cycle, then every 4 weeks. Because routine monitoring typically occurs at the end of capivasertib-free periods, transient hyperglycemia during active treatment may be under-recognized.
The case authors recommend that physicians be aware of potential glycemic spikes during dosing days. Patients at risk for hyperglycemia (搜索) or those with rising blood glucose levels or HbA1c should consider additional glucose monitoring during treatment. The hyperglycemia occurring only during treatment periods suggests a pharmacodynamic correlation and reversible effect of capivasertib on glucose metabolism.
Treatment Management Strategy
The successful management approach in this case involved individualized interventions with targeted insulin treatment only on dosing days. Rapid-acting insulin was administered with a baseline dose of 11 units per day divided into three administrations, with supplemental doses adjusted according to a sliding scale.
Risk factors for severe hyperglycemia (搜索) with AKT (搜索) pathway inhibitors include obesity, history of diabetes (搜索), and baseline blood glucose levels in the diabetic or pre-diabetic range. However, this case demonstrates that severe hyperglycemia can occur even in patients without traditional risk factors, emphasizing the need for vigilant monitoring across all patient populations receiving capivasertib.