Postmenopausal patients with metastatic breast cancer (mBC) may live years with their disease on therapies with minimal toxicities but they will eventually progress on first-line therapy. For those eligible for second-line therapy, PIK3CA mutation testing is recommended in estrogen receptor-positive, her2-negative disease. If present, alpelisib, a PI3K inhibitor, has been shown to improve progression-free survival. Hyperglycemia is a common side effect of alpelisib. We describe a case of diabetic ketoacidosis (DKA) necessitating treatment in the intensive care unit (ICU) in a woman with type 2 diabetes mellitus (T2DM) started on alpelisib. A 76-year-old female with diet-controlled T2DM and mBC was placed on second-line treatment with alpelisib after progression on first-line therapy. After more than 2 weeks of treatment, the patient presented to the emergency department with nausea and vomiting. Lab results showed DKA and she was admitted to the ICU for further management. This case highlights the need for a multidisciplinary approach to caring for patients who are started on a PI3K inhibitor. We propose 5 guidelines to prevent hyperglycemia in those started on apelisib: (1) strict criteria for initiating alpelisib, (2) understand the steps needed to prevent hyperglycemia, (3) get help from a multidisciplinary team, (4) act immediately when hyperglycemia is noted, and (5) record blood glucose values. By implementing these steps, we hope to prevent critical hyperglycemic episodes in vulnerable patients on alpelisib.