Hyperglycemia in HR+ Breast Cancer: Prevention and Management Strategies for Oncology Pharmacists

Hormone receptor-positive (HR+) breast cancer (BC) is one of the most common BC subtypes, accounting for approximately 70% of all diagnoses. Of these cases, PIK3CA mutations occur in about 47% of patients. PIK3CA mutations carry various consequences for patients with HR+ BC, including hyperglycemia. In a session at the Community Oncology Alliance 2025 Community Oncology Conference, experts focused on hyperglycemia management in patients with HR+ BC treated with PI3K and AKT inhibitors. They offer key insights about the mechanisms driving hyperglycemia in this population, as well as approaches for prevention and management.¹

Woman measuring glucose levels | Image Credit: © fizkes - stock.adobe.com

Hyperglycemia, PIK3CA Inhibitors, and Mechanisms of Action

Hyperglycemia occurs in 80% of patients with HR+ BC receiving PIK3CA inhibitors, such as alpelisib (Piqray, Novartis Pharmaceuticals Corporation), capivasertib (Truqap; AstraZeneca), and inavolisib (Itovebi; Genentech), due to disruptions in insulin signaling.¹

“When we inhibit PIK3 with one of these drugs, then we can see impaired insulin signaling and how that plays out in different areas of the body,” said Cassandra Perkey, PharmD, BCOP, oncology pharmacist and regional clinical pharmacist for the American Oncology Network. “We see reduced glucose uptake in adipose tissue and skeletal muscle. We also will see increased glycogenolysis and decreased glycogen synthesis in the liver, and then a compensatory increase in insulin released by the pancreas to try to control that rise in blood glucose.”¹

These underlying mechanisms lead to systemic insulin resistance, hyperinsulinemia, and an increased risk of developing metabolic disorders such as type 2 diabetes and obesity-associated complications. PIK3CA mutations also affect estrogen-independent estrogen receptor signaling by increasing transcription of the estrogen receptor, resulting in potential resistance to treatment.¹

Prevalence of hyperglycemia varies depending on which of the aforementioned agents a patient is treated with. Alpelisib is an orally bioavailable, small-molecule, α-specific PI3K inhibitor approved by the FDA in combination with fulvestrant (Faslodex; AstaZeneca) for postmenopausal women and men with HR+, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic BC. Compared with the other agents, hyperglycemia is highly prevalent with alpelisib therapy at a rate of approximately 64% of patients in the SOLAR-1 trial (NCT02437318), of which more than one-third had grade 3 or higher hyperglycemia. Real-world evidence studies showed even higher rates of 80% of patients with any grade of hyperglycemia, with 40% experiencing grade 3 or higher hyperglycemia.^1-3

Capivasertib is an AKT inhibitor approved for HR+, protein-negative metastatic BC in combination with fulvestrant and is associated with reduced rates of hyperglycemia compared with alpelisib, as well as having the lowest hyperglycemia rates of the 3 agents presented in the session. The mechanism underlying this reduced prevalence is unclear, but Perkey attributed this to the agent’s unique dosing schedule of 4 days on and 3 days off.¹

Preventing Hyperglycemia

Prevention is key for mitigating the risk of the adverse effects (AEs) associated with BC treatment and ensuring optimal health outcomes for patients. There are multiple approaches to preventing and mitigating hyperglycemia in these high-risk patients, such as comprehensive endocrinology evaluations, treatment with prophylactic metformin, and diet and lifestyle modifications.¹

Endocrinology evaluations can be significantly beneficial for identifying high-risk patients, such as those who are pre-diabetic or have diabetes— including those with a history of gestational diabetes— an elevated BMI over 25, hemoglobin levels of A1c above 5.7, and older age. Prophylactic metformin is recommended for these patients due to its capabilities in increasing insulin sensitivity and reducing insulin levels through activation of the PI3K pathway, as well as possible antitumor activity due to this insulin-lowering effect.¹

The efficacy of prophylactic metformin in this setting was observed in the METALLICA trial (NCT04300790). According to the trial data, in patients with normal blood sugar, 44% had hyperglycemia, of which 6% were greater than or equal to grade 3. In patients with pre-diabetes, 70% had any grade of hyperglycemia versus 15% with a grade greater than or equal to 3. There was no discontinuation of alpelisib due to hyperglycemia, and only 4 patients required dose reduction.^1,4

Perkey also highlighted the advantages of prophylaxis, including the use of an extended-release formulation, which reduces gastrointestinal side effects, such as less diarrhea compared with immediate-release.¹

Diet and lifestyle modifications are essential across various disease states and treatment regimens to encourage optimal treatment outcomes, as well as reduce the incidence of AEs that may arise due to treatment with specific agents, such as hyperglycemia. Perkey cited established modifications, including avoiding added sugars, increasing fiber intake, moderating carb intake, and exercising for 20 to 30 minutes a day (150 minutes per week).¹

“But considering these patients have advanced [BC], we have to look at their performance status to make modifications to [diet and lifestyle modifications],” she said. “But incorporating these different lifestyle modifications will all help with setting patients up for success when getting started on a PIK3CA inhibitor.”¹

Hyperglycemia Management

Monitoring, early detection, and proper dosing are essential for successful hyperglycemia management for balancing glycemic control while maintaining cancer treatment effectiveness. Christin Molnar, PharmD, BCOP, clinical pharmacy coordinator at The Cancer and Hematology Centers, provided comprehensive insights for approaching hyperglycemia management in patients with HR+ BC receiving therapy with PIK3CA inhibitors.¹

“The most important piece to remember is that early detection is essential,” she said. “The earlier we detect hyperglycemia, the earlier we can intervene, and that can allow us to effectively balance glycemic control and allow for continued clinical benefit of their PIK3CA or ATK inhibitor.”¹

First-line treatment involves metformin at a target dose of 1000 to 2000 mg daily—this is preferred for most patients—using the extended-release formulation to reduce gastrointestinal AEs. For high-risk patients, it is recommended to begin metformin 7 days prior to starting PI3K inhibitor therapy. In the second line, hyperglycemia management in patients with HR+ BC includes treatment with SGLT2 inhibitors and thiazolidinediones as alternatives for metformin-intolerant patients. When progressing to the third line, it is recommended to use GLP-1 receptor agonists, sulfonylureas, and DPP-4 inhibitors. Insulin can be used, but this must be done with caution to avoid compromising cancer treatment efficacy.¹

Monitoring is essential for ensuring optimal treatment outcomes with managing hyperglycemia in patients with HR+ BC. Molnar recommended early detection, frequent blood glucose monitoring, and hemoglobin A1c every 3 months. It is critical to also consider patient-specific characteristics and potential drug interactions that may influence approaches to hyperglycemia management.¹

“This is a great role for the pharmacist to intervene and make sure that we are maximizing the patient’s outcomes when we consider what we're going to be doing with our PIK3CA or ATK inhibitor while these patients are experiencing hyperglycemia,” Molnar said.¹

Effectively managing hyperglycemia in patients with HR+ breast cancer receiving PI3K or AKT inhibitors is critical to ensuring both safety and sustained therapeutic benefit. Multidisciplinary collaboration—particularly the involvement of oncology pharmacists—plays a key role in balancing glycemic control with cancer treatment efficacy. By anticipating and addressing hyperglycemia early, health care professionals can help patients remain on life-prolonging therapies while minimizing serious metabolic complications.

REFERENCES

1. Perkey C, Molnar C. Streamlining Pharmacist-Led Hyperglycemia Management in HR+ Breast Cancer: Overcoming PI3K/AKT Inhibitor Challenges. Community Oncology Alliance 2025 Community Oncology Conference. April 29, 2025 to April 30, 2025. Orlando, FL

2. Study assessing the efficacy and safety of alpelisib plus fulvestrant in men and postmenopausal women with advanced breast cancer which progressed on or after aromatase inhibitor treatment. (SOLAR-1). Updated February 13, 2025. Accessed April 29, 2025. https://clinicaltrials.gov/study/NCT02437318

3. FDA approves alpelisib for metastatic breast cancer. FDA. May 24, 2019. Accessed April 29, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-alpelisib-metastatic-breast-cancer#:~:text=On%20May%2024%2C%202019%2C%20the,PIK3CA%2Dmutated%2C%20advanced%20or%20metastatic

4. Study to evaluate the effect of metformin in the prevention of HG in HR[+]/​HER2[-] PIK3CA-mut advanced BC patients (METALLICA). Updated April 4, 2025. Accessed April 29, 2025. https://clinicaltrials.gov/study/NCT04300790