Alpelisib plus fulvestrant is approved for the treatment of PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Hyperglycemia, an on-target effect of PI3K alpha inhibitors such as alpelisib, was the most frequently observed adverse event (AE; 63.7%) in the SOLAR-1 trial. A protocol amendment updating the study eligibility criteria (excluding patients with glycosylated hemoglobin [Hb1Ac] ≥6.5%) and AE management guidelines led to reduced treatment discontinuations due to any-grade hyperglycemia (9% vs 3.6%, before and after amendment, respectively). Therefore, strategies that optimize management can play a role in keeping patients on therapy and may have an impact on outcomes. The purpose of this project was to provide recommendations for managing PI3K inhibitor-associated hyperglycemia to reduce incidence/severity--particularly for patients at risk of experiencing high-grade events. Authors reviewed AE management strategies implemented in the SOLAR-1 and BYLieve trials of alpelisib-based treatments in ABC. Recommendations are also based on experience from healthcare providers (HCPs) from 2 institutions specialized in the treatment of cancer. Preparation and early intervention are essential. Educate patients and optimize lifestyle (eg, diet) prior to starting alpelisib to prevent/mitigate hyperglycemia. Initiate lifestyle optimization before administering alpelisib (possibly while patient with a PIK3CA-mutated tumor is still receiving another agent). Consider adding a nutritionist to the care team. Perform a thorough baseline assessment of patients' personal medical history, diet/exercise habits, and risk factors for developing hyperglycemia. For patients with prediabetes/diabetes (fasting plasma glucose ≥100 mg/dL; HbA1c ≥5.7%), consultation with an endocrinologist/diabetologist is advised; do not assume these patients have received prior education per their condition--refer to an educator (nurse practitioner). For patients with BMI ≥30, subclinical insulin resistance may be present; advise weight loss. For patients aged ≥75 years, closely monitor as patients may not notice hyperglycemia-associated symptoms. Consider at-home glucose monitoring. Continuous glucose monitoring devices are preferable over traditional prick glucometers based on ease of use and ability to share results remotely with HCPs. Identifying patients at risk of developing alpelisib-associated hyperglycemia and proactively tailoring management to the individual will likely result in increased patient compliance and better outcomes of this AE. These recommendations for nurses may help optimize hyperglycemia management in patients treated with alpelisib, a relatively new agent.