PMID- 35212193 OWN - NLM STAT- MEDLINE DCOM- 20220428 LR - 20220716 IS - 2045-7634 (Electronic) IS - 2045-7634 (Linking) VI - 11 IP - 8 DP - 2022 Apr TI - Characterization, management, and risk factors of hyperglycemia during PI3K or AKT inhibitor treatment. PG - 1796-1804 LID - 10.1002/cam4.4579 [doi] AB - PURPOSE: The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway controls insulin sensitivity and glucose metabolism. Hyperglycemia is one of the most common on-target adverse effects (AEs) of PI3K/AKT inhibitors. As several PI3K and AKT inhibitors are approved by the United States Food and Drug Administration or are being studied in clinical trials, characterizing this AE and developing a management strategy is essential. METHODS: Patients with hematologic or solid malignancies treated at Memorial Sloan Kettering Cancer Center with a PI3K or AKT inhibitor were included in this retrospective analysis. A search for patients experiencing hyperglycemia was performed. The frequency, management interventions and outcomes were characterized. RESULTS: Four hundred and ninety-one patients with 10 unique cancer types who received a PI3K or AKT inhibitor were included. Twelve percent of patients required a dose interruption, 6% of patients required a dose reduction and 2% of patients were hospitalized to manage hyperglycemia. No events occurred among patients receiving beta-, gamma-, or delta- specific PI3K inhibitor. There was one case where the PI3K or AKT inhibitor was permanently discontinued due to hyperglycemia. Metformin was the most commonly used antidiabetic medication, followed by insulin, sodium-glucose transport protein 2 (SGLT2) inhibitors, and sulfonylurea. SGLT2 inhibitors were associated with the greatest reductions in blood sugar, followed by metformin. At least one case of euglycemic diabetic ketoacidosis (DKA) occurred in a patient on PI3K inhibitor and SGLT2 inhibitor. Body mass index >/= 25 and HbA(1c) >/= 5.7 are were independently significant predictors of developing hyperglycemia. CONCLUSION: Hyperglycemia is one of the major on-target side effects of PI3K and AKT inhibitors. It is manageable with antidiabetic medications, treatment interruption and/or dose modification. We summarize pharmacological interventions that may be considered for PI3K/AKT inhibitor induced hyperglycemia. SGLT2-inhibitor may be a particularly effective second-line option after metformin but there is a low risk of euglycemic DKA, which can be deadly. To our knowledge, our report is the largest study of hyperglycemia in patients receiving PI3K/AKT inhibitors. CI - (c) 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. FAU - Liu, Dazhi AU - Liu D AUID- ORCID: 0000-0003-3296-8203 AD - Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, New York, USA. FAU - Weintraub, Michael A AU - Weintraub MA AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. AD - Department of Medicine, Weill Cornell Medical College, New York, New York, USA. FAU - Garcia, Christine AU - Garcia C AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. FAU - Goncalves, Marcus D AU - Goncalves MD AD - Department of Medicine, Weill Cornell Medical College, New York, New York, USA. FAU - Sisk, Ann Elizabeth AU - Sisk AE AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. FAU - Casas, Alissa AU - Casas A AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. FAU - Harding, James J AU - Harding JJ AUID- ORCID: 0000-0002-7029-4310 AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. AD - Department of Medicine, Weill Cornell Medical College, New York, New York, USA. FAU - Harnicar, Stephen AU - Harnicar S AD - Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, New York, USA. FAU - Drilon, Alexander AU - Drilon A AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. AD - Department of Medicine, Weill Cornell Medical College, New York, New York, USA. FAU - Jhaveri, Komal AU - Jhaveri K AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. AD - Department of Medicine, Weill Cornell Medical College, New York, New York, USA. FAU - Flory, James H AU - Flory JH AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. AD - Department of Medicine, Weill Cornell Medical College, New York, New York, USA. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20220225 PL - United States TA - Cancer Med JT - Cancer medicine JID - 101595310 RN - 0 (Hypoglycemic Agents) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Sodium-Glucose Transporter 2) RN - 9100L32L2N (Metformin) RN - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - *Diabetes Mellitus, Type 2/drug therapy MH - Humans MH - *Hyperglycemia/chemically induced/drug therapy MH - Hypoglycemic Agents/therapeutic use MH - *Metformin/adverse effects MH - Phosphatidylinositol 3-Kinase/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - Phosphoinositide-3 Kinase Inhibitors MH - Protein Kinase Inhibitors/adverse effects MH - Proto-Oncogene Proteins c-akt/metabolism MH - Retrospective Studies MH - Risk Factors MH - Sodium-Glucose Transporter 2/adverse effects PMC - PMC9041081 OTO - NOTNLM OT - PI3K/AKT inhibitors OT - SGLT2 inhibitors OT - hyperglycemia OT - risk factors OT - toxicity management COIS- JJH has received research funding from Boehringer Ingelheim, Bristol-Myers Squibb, CytomX, Debiopharm, Eli Lilly, Genoscience, Novartis, Pfizer, Polaris, Loxo Oncology, Yiviva, Zymework, and personal fees from Adaptimmune, CytomX, Eisai, Eli Lilly, Exelexis, Merck, QED, Research to Practice, MORE Health, HCC Connect. EDAT- 2022/02/26 06:00 MHDA- 2022/04/29 06:00 PMCR- 2022/02/25 CRDT- 2022/02/25 05:44 PHST- 2021/12/31 00:00 [revised] PHST- 2021/11/22 00:00 [received] PHST- 2022/01/03 00:00 [accepted] PHST- 2022/02/26 06:00 [pubmed] PHST- 2022/04/29 06:00 [medline] PHST- 2022/02/25 05:44 [entrez] PHST- 2022/02/25 00:00 [pmc-release] AID - CAM44579 [pii] AID - 10.1002/cam4.4579 [doi] PST - ppublish SO - Cancer Med. 2022 Apr;11(8):1796-1804. doi: 10.1002/cam4.4579. Epub 2022 Feb 25.