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Sodium-glucose cotransporter-2 inhibitors for hypergycemia in phosphoinositide 3-kinase pathway inhibition

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Abstract

Purpose

Phosphoinositide 3-kinase (PI3K) inhibition is used for the treatment of certain cancers, but can cause profound hyperglycemia and insulin resistance, for which sodium-glucose cotransporter-2 (SGLT2) inhibitors have been proposed as a preferred therapy. The objective of this research is to assess the effectiveness and safety of SGLT2 inhibitors for hyperglycemia in PI3K inhibition.

Methods

We conducted a single-center retrospective review of adults initiating the PI3K inhibitor alpelisib. Exposure to different antidiabetic drugs and adverse events including diabetic ketoacidosis (DKA) were assessed through chart review. Plasma and point-of-care blood glucoses were extracted from the electronic medical record. Change in serum glucose and the rate of DKA on SGLT2 inhibitor versus other antidiabetic drugs were examined as co-primary outcomes.

Results

We identified 103 patients meeting eligibility criteria with median follow-up of 92 days after starting alpelisib. When SGLT2 inhibitors were used to treat hyperglycemia, they were associated with a decrease in mean random glucose by -46 mg/dL (95% CI − 77 to − 15) in adjusted linear modeling. Five cases of DKA were identified, two occurring in patients on alpelisib plus SGLT2 inhibitor. Estimated incidence of DKA was: alpelisib plus SGLT2 inhibitor, 48 DKA cases per 100 patient-years (95% CI 6, 171); alpelisib with non-SGLT2 inhibitor antidiabetic drugs, 15 (95% CI 2, 53); alpelisib only, 4 (95% CI 0.1, 22).

Conclusions

SGLT2 inhibitors are effective treatments for hyperglycemia in the setting of PI3K inhibition.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

Editorial assistance at Memorial Sloan Kettering Cancer Center was provided by Katharine Olla Inoue, MA, and Clare Wilhelm, PhD.

Funding

This work has been supported in part by the Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748) from the National Cancer Institute of the National Institutes of Health. Division of Cancer Epidemiology and Genetics, National Cancer Institute, P30 CA008748

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Authors and Affiliations

  1. New York University Diabetes & Endocrine Associates, 222 East 41st Street, 23rd Floor, New York, NY, 10017, USA

    Michael A. Weintraub

  2. Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Dazhi Liu & Raymond DeMatteo

  3. Goncalves Lab, Weill Cornell Medicine, 413 East 69th Street, New York, NY, 10021, USA

    Marcus DaSilva Goncalves

  4. Endocrinology Service, Division of Subspecialty Medicine, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    James H. Flory

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  1. Michael A. Weintraub
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  4. Marcus DaSilva Goncalves
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  5. James H. Flory
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Contributions

MAW, DLRD, MDG, and JHF were involved in the conception, design, and conduct of the study and the analysis and interpretation of the results. JHF wrote the first draft of the manuscript, and all authors edited, reviewed, and approved the final version of the manuscript. JF is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding author

Correspondence to James H. Flory.

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Conflict of interest

M.A.W.: None to report. D.L., R.D.: None to report. M.D.G.: Received consulting fees from Novartis, Pfizer, and Scorpion Therapeutics; he is an inventor on a patent (pending) for Combination Therapy for PI3K-associated Disease or Disorder; and he is a co-founder, shareholder, and consultant of Faeth Therapeutics. J.F.: Hagens Berman Sobol Shapiro LLP (provision of services). J.H.F: None to report.

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Weintraub, M.A., Liu, D., DeMatteo, R. et al. Sodium-glucose cotransporter-2 inhibitors for hypergycemia in phosphoinositide 3-kinase pathway inhibition. Breast Cancer Res Treat 203, 85–93 (2024). https://doi.org/10.1007/s10549-023-07110-y

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  • DOI: https://doi.org/10.1007/s10549-023-07110-y

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