This report documents marked fluctuations in glucose levels during treatment with capivasertib and fulvestrant in a patient with metastatic breast cancer and hyperlipidemia.

Hyperglycemia is a common adverse event associated with capivasertib, following diarrhea, skin rash, nausea, fatigue, vomiting, headache, and decreased appetite in frequency. It typically occurs early in the course of treatment and can, in some cases, progress to a serious condition known as DKA. AKT signaling induces glucose transporter 4-mediated glucose transport into skeletal muscle and adipose tissue [5, 6]. In addition, AKT phosphorylates glycogen synthase kinase 3 (GSK3), and the resulting inactivation of GSK3 relieves its inhibition of glycogen synthase, thereby enhancing glycogen synthesis [7]. Therefore, inhibition of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway can lead to acute hyperglycemia. The role of AKT1/2 signaling in insulin secretion by pancreatic β cells remains controversial. AKT phosphorylation enhances calcium release from the endoplasmic reticulum and upregulates SNARE protein expression, both of which facilitate insulin secretion. Conversely, the activation of the insulin receptor/insulin receptor substrate/PI3K signaling cascade induces hyperpolarization of membrane KATP channels, thereby suppressing calcium-dependent insulin release [8]. Interestingly, short-term inhibition of the PI3K/AKT pathway has been reported to promote the exocytosis of newcomer granules in pancreatic β cells [9]. Regardless of the pathway involved, peripheral insulin resistance leads to compensatory hyperinsulinemia, which contributes to the gradual deterioration of β-cell function [10].

Alpelisib, an oral PI3Kα inhibitor, caused grade 3/4 hyperglycemia in 36.6% of patients in the SOLAR-1 trial [11]. Risk factors for hyperglycemia included diabetic or prediabetic glycemic status at baseline, body mass index ≥ 30 kg/m2, and age ≥ 75 years [12]. Cases of DKA associated with alpelisib have also been reported, and the reporting odds ratio for DKA events with alpelisib, based on an analysis of the U.S. Food and Drug Administration Adverse Event Reporting System pharmacovigilance database, was 9.84 [13,14,15]. In response, an algorithm for the monitoring and management of alpelisib-induced hyperglycemia has been proposed [5]. After initiating alpelisib, blood glucose should be monitored at least once every 2 weeks, then monthly, with HbA1c assessed every 3 months. Closer monitoring is recommended for patients at high risk of hyperglycemia. The recommended initial therapy is metformin, followed by pioglitazone, SGLT2 inhibitors, and insulin as needed.

Everolimus, an oral mTOR inhibitor, is associated with hyperglycemia. In the BOLERO-2 trial, grade 3/4 hyperglycemia occurred in approximately 5% of everolimus-treated patients [16]. The reporting odds ratio for hyperglycemia with everolimus was 8.56, and a case of DKA has been reported [17, 18]. The present case had previously been treated with everolimus (administered once daily on consecutive days), during which hyperglycemia was mild.

Capivasertib caused grade 3/4 hyperglycemia in 2.3% of patients; however, glycemic fluctuations observed with isCGM appear more pronounced with capivasertib than they do with alpelisib [13, 14]. The hyperglycemic period corresponded to capivasertib’s Tmax (1 h) and half-life (10 h) [19]. Hyperglycemia occurring only during the treatment period suggests a pharmacodynamic correlation and reversible effect of capivasertib on glucose metabolism. In the CAPItello-291 trial, fasting glucose levels were assessed on days 1 and 15 of the first cycle and then every 4 weeks. Because routine laboratory monitoring typically occurs at the end of the capivasertib-free period, transient hyperglycemia during active treatment may be under-recognized. In addition, reliance on HbA1c measurements may underestimate the extent of hyperglycemia. Physicians should be aware of potential glycemic spikes during dosing days. Patients at risk for hyperglycemia or those with rising blood glucose levels or HbA1c should consider additional glucose monitoring during treatment. During capivasertib therapy, individualized interventions—such as targeted treatment only on dosing days—may be necessary.