The PI3K pathway is involved in numerous physiological functions, including cell growth, metabolism, survival, angiogenesis, and glucose metabolism. It is estimated that mutations in PIK3CA occur in approximately 40% of hormone receptor–positive (HR+)/HER- or HER2+ breast cancers (BCs) and in up to 14% of triple-negative BC.

Alpelisib is an alpha-selective P13K inhibitor (P13Ki) that is indicated for HR+, HER2-negative, and PIK2CA-mutated advanced or metastatic BC. When used with fulvestrant, alpelisib has been shown to improve progression-free survival compared with fulvestrant monotherapy.

Product labeling for alpelisib carries a warning that it can cause severe hyperglycemia, and some cases hyperglycemic hyperosmolar nonketonic syndrome or ketoacidosis have been associated with its use. The mechanism for PI3Ki-induced hyperglycemia involves decreases in glucose transport and increased glycogenolysis and gluconeogenesis. Glucose transport capacity, glycogen synthesis, and glycolysis are reduced about 60%.

Since many clinicians lack knowledge about P13Ki-related glucose elevations, a recent review paper was published to explore the etiology of hyperglycemia and to provide recommendations on how to prevent and manage P13Ki-associated hyperglycemia. This is especially important for patients who have an absolute or relative insulin deficiency as they are particularly prone to developing P13Ki-induced hyperglycemia.

Prior to initiating alpelisib, baseline assessment of glycemic status is essential. Risk factors for drug-induced hyperglycemia include patients aged 75 years or older, being overweight or having obesity, positive family history for diabetes, African American, Latino, Native American, Asian American, or Pacific Islander ethnicity, prediabetes, cardiovascular disease, hypertension, polycystic ovarian syndrome or gestational diabetes, low HDL cholesterol levels (<35 mg/dL), elevated triglyceride level (>250 mg/dL), sedentary lifestyle, acanthosis nigricans, elevated fructosamine and glycated albumin levels, and patients who are already diabetic.

The median time to onset of alpelisib-induced hyperglycemia is 15 days. PI3Ki should not be initiated in patients without good blood glucose control. The safety of alpelisib has not been established in patients with type 1 or uncontrolled type 2 diabetes. Before initiating treatment, a fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) should be obtained. A FPG or fasting blood glucose (FBG) should be drawn at least once weekly for the first 2 weeks then at least once every 4 weeks. HbA1C should be assessed every 3 months. Home fingerstick blood glucose monitoring or continuous blood glucose monitoring are recommended for patients at high-risk of developing hyperglycemia.

If hyperglycemia develops secondary to P13Ki therapy, it should initially be treated with metformin. Metformin inhibits hepatic gluconeogenesis. However, maximal benefit of metformin takes weeks to occur, it is contraindicated in severe renal dysfunction, and may not adequately control FPG or FBG. Second-line agents for PI3Ki-induced hyperglycemia include sodium-glucose cotransporter 2 inhibitors.

Caution is advised as euglycemic ketoacidosis can rarely occur. Patients should be taught to recognize possible symptoms of ketoacidosis, which include nausea, vomiting, and fatigue. Thiazolidinediones also inhibit hepatic gluconeogenesis, but this class of medications is characterized by a slow onset to maximal effect (up to 6 weeks) and fluid retention. Other second-line agents include alpha-glucosidase inhibitors, glucagon-like peptide 1 receptor agonists, and dipeptidyl peptidase-4 inhibitors. Third–line antihyperglycemic therapy includes meglitinides and sulfonylureas.

Insulin therapy is considered a treatment of last resort, as insulin has been found to partially reactivate the P13K pathway, thereby reversing the effect of the P13Ki and leading to cell proliferation.

This paper provides pharmacists with detailed, practical advice on how to manage P13Ki-induced hyperglycemia.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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