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. Capivasertib is a cancer drug that blocks AKT signalling. Because AKT is also involved in insulin action, this drug can affect glucose metabolism. We describe a woman without previously diagnosed diabetes who developed high post-meal glucose very soon after starting capivasertib. Her baseline glycated haemoglobin was 5.6%, although as oral glucose tolerance test was not performed before treatment. Blood tests showed high insulin levels and preserved C-peptide levels, suggesting that the glucose abnormality was mainly related to reduced insulin sensitivity rather than impaired insulin secretion. The changes were most marked during the first treatment medication. Similar but less pronounced changes were observed during later treatment cycles. This case suggests that glucose abnormalities can occur soon after capivasertib is started, even in patients without known diabetes. Glucose monitoring should therefore begin at treatment initiation and should take account of both post-meal glucose levels and the intermittent treatment schedule. Why carry out this study?: Capivasertib-associated hyperglycaemia is recognised, but the early biochemical features of insulin resistance and their changes across treatment cycles remain incompletely characterised in patients without previously diagnosed diabetes. What was learned from this case?: A woman without previously diagnosed diabetes developed postprandial hyperglycaemia soon after starting capivasertib, accompanied by high fasting insulin, preserved C-peptide, and increased HOMA-IR, suggesting reduced insulin sensitivity rather than impaired insulin secretion. What was distinctive?: The metabolic changes were most marked during the first treatment cycle and improved during the drug-free interval without glucose-lowering medication. Similar but less pronounced changes were observed during later treatment cycles. What are the clinical implications?: Glucose monitoring should begin when capivasertib is initiated and should include postprandial measurements and assessments during both dosing and drug-free days, even in patients without known diabetes.