Early-onset, treatment-cycle-linked hyperinsulinaemic insulin resistance during capivasertib therapy: a case report

Capivasertib is an oral AKT inhibitor used with fulvestrant for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer with relevant pathway alterations. Hyperglycaemia is a recognised on-target adverse effect, but its early biochemical phenotype has not been fully characterised in patients without known diabetes.

A 43-year-old Japanese woman with metastatic breast cancer and no history or family history of diabetes started capivasertib on a 4-days-on/3-days-off schedule. Before treatment, fasting plasma glucose was 89 mg/dL and glycated haemoglobin was 5.6%. Although this glycated haemoglobin was within the non-diabetic range, impared glucose tolerance could not be excluded because a pre-treatment oral glucose tolerance test was not performed. On the day after treatment initiation, the 2-h postprandial plasma glucose level increased to 256 mg/dL. On day 2, fasting plasma glucose was 103 mg/dL, fasting insulin was 22.8 µU/mL, C-peptide was 3.40 ng/mL, and HOMA-IR was 5.80, indicating hyperinsulinaemic insulin resistance with preserved endogenous insulin secretion. During a subsequent drug-free interval, fasting plasma glucose decreased to 87 mg/dL, fasting insulin to 5.4 µU/mL, and HOMA-IR to 1.16 without glucose-lowering medication. HOMA-IR measured on day 4 declined form 3.16 in the first cycle to 2.50 and 1.52 in the 10th and 19th cycles, respectively, suggesting that the metabolic effect was greatest early after treatment initiation and may have partially attenuated during repeated treatment. Glycoalbumin gradually increased from 14.9% to 17.9%.

Capivasertib may induce very early hyperinsulinaemic insulin resistance, even in patients without known diabetes. In this patient, the initial metabolic disturbance improved during the drug-free interval and appeared less pronounced during later cycles. Early, cycle-aware glucose monitoring, including postprandial assessment, should be considered from treatment initiation.