ODP173 Control of Alpelisib-Induced Hyperglycemia With DPP4- Inhibitors as add on to Metformin and Insulin
Authors: Hee Nicholas Ken Yoong , Lim Quan Hziung , Lim Lee-Ling , Paramasivam Sharmila , Vethakkan Shireene , Chan Siew Pheng , Ratnasingam Jeyakantha 
Published: November 2022

Abstract

Context
Alpelisib is an oral phosphatidylinositol-3-kinase alpha (PI3Ka) inhibitor approved in 2019 for treatment of ER/PR+, HER2-negative advanced breast cancer. The main side effect of PI3Ka inhibition is hyperglycemia.

Case
A 38 year-old woman was started on alpelisib and fulvestrant therapy for Stage IV bilateral breast carcinoma (ER+, PR+, HER2-negative) with multiple distant metastases. She had previously received multiple courses of systemic therapy with palbociclib, letrozole, and everolimus, in combination with fulvestrant. She was lean (BMI 20.6 kg/m 2), had a prior history of GDM only requiring diet control, and pre-existing pre-diabetes, with a baseline FPG of 5.6 mmol/L and HbA1c of 5.9%. She developed hyperglycemia after 2 months of Alpelisib 200 mg OD (FPG 138.6 mg/dL; HbA1c 5.8%) and was started on metformin 500 mg BD. Glucose levels remained under control (fasting BG of 108-126 mg/dL) until alpelisib dose was increased to 300 mg OD. Within 6 weeks of dose increment, her fasting BG markedly increased to 324 mg/dL and HbA1c to 10%. Metformin dose was increased to 1000 mg BD, linagliptin 5 mg OD and isophane insulin at 8 units once daily, was introduced in addition to lifestyle modifications. Due to the side effects resulting in diarrhea, alpelisib was discontinued temporarily for 3 weeks before subsequent reintroduction and titration to a maximum tolerable dose of 200 mg OD. Glycemic control subsequently improved with metformin, linagliptin and titration of insulin to 14units daily, with HbA1c reduction to 6. 0% and fasting BG of 84.6 mg/dL, without any hypoglycemia. Oncological assessment showed disease response, with smaller primary tumour and stable metastatic lesions.

Discussion
The PI3K/AKT pathway plays a central role in cellular growth and glucose metabolism. This pathway is a potent target of anticancer therapy. In physiological glucose homeostasis, postprandial insulin secretion activates the PI3Ka pathway, subsequently upregulating glucose transporters for cellular uptake and utilization of glucose. In the phase III clinical trial (SOLAR-1), the incidence of alpelisib-induced hyperglycemia was 63.7%, and was treated with insulin sensitizers such as metformin and pioglitazone. Subsequent case series have reported effective glycemic control using very low calorie diet (VLCD), SGLT2-inhibitors and insulin therapy 1 . In our patient, linagliptin, was chosen as an adjunct therapy in addition to metformin due to its mechanism of action that address insulin resistance and favourable safety profile. We also note that the severity of alpelisib side effects appeared to be dose-dependent, as seen in the clinical trial.

Conclusion
We demonstrated effective control of alpelisib-induced hyperglycemia using DPP4-inhibitors as an option, in combination with metformin and insulin. References: 1. Blow T, Hyde PN, Falcone JN, et al. Treating Alpelisib-Induced Hyperglycemia with Very Low Carbohydrate Diets and Sodium-Glucose Co-Transporter 2 Inhibitors: A Case Series. Integrative Cancer Therapies 2021;20: 15347354211032283.
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