Metformin Prophylaxis Cuts High-Risk Hyperglycemia From Alpelisib

The study covered in this summary was published on as a preprint and has not yet been peer reviewed.

Key Takeaway

  • Prophylaxis with an insulin-sensitizer, particularly metformin, almost halves the risk of high-grade hyperglycemia in patients with breast cancer treated with alpelisib.

Why This Matters

  • Alpelisib is approved in combination with fulvestrant for advanced HR-positive/HER2-negative PIK3CA-mutated breast cancer following progression on or after endocrine-based therapy.

  • The rate of grade 3-4 hyperglycemia in phase 3 testing was 36.6%.

  • Current guidelines recommend an insulin sensitizer only after the onset of hyperglycemia.

  • Prophylaxis with an insulin sensitizer, however, has the potential to prevent hyperglycemia, allowing more women to stay on alpelisib without treatment interruptions or discontinuations.

  • The study team recommends starting anti-hyperglycemic prophylaxis, ideally with extended-release metformin, a week before initiating alpelisib.

Study Design

  • Sixteen women started insulin sensitizer prophylaxis a week before alpelisib and remained on it throughout treatment.

  • Women were initially started on metformin, but one patient switched to pioglitazone due to intolerance. Ten patients (63%) required a dose escalation of their anti-hyperglycemic agent, and four eventually required two or more insulin-sensitizer agents at once.

  • Fasting plasma glucose levels were drawn on alpelisib days 8, 15, and 28, then monthly.

Key Results

  • By day 28, six women (38%) had grade 2 hyperglycemia and three patients (19%) had grade 3 hyperglycemia. There were no grade 4 cases.

  • Women who developed hyperglycemia had a median of two risk factors, including elevated BMI or hemoglobin A1c.

  • Hyperglycemia led to temporary holds of alpelisib in five patients (31%) and dose reductions in three women (19%). Only one patient discontinued treatment due to hyperglycemia.


  • The study was tiny and had no placebo arm.

  • The investigator didn’t control for dietary changes or adherence to the regimen.


  • There was no funding for the work.

  • The senior investigator is a consultant for Novartis.

This is a summary of a preprint research study, “Evaluation of alpelisib-induced hyperglycemia prophylaxis and associated risk factors in PIK3CA-mutated hormone-receptor positive, human epidermal growth factor-2 negative advanced breast cancer,” led by Sarah Burnette of Wake Forest Baptist Health. The study has not been peer reviewed. The full text can be found at

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who has worked for several major news outlets before joining Medscape and also an MIT Knight Science Journalism fellow. Email: [email protected]

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