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SGLT2 Inhibitors As Potentially Helpful Drugs in PI3K Inhibitor-Induced

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SGLT2 Inhibitors As Potentially Helpful Drugs in PI3K Inhibitor-Induced Sahakian et al. Clin Diabetes Endocrinol (2021) 7:17 https://doi.org/10.1186/s40842-021-00125-8 CASE REPORT Open Access SGLT2 inhibitors as potentially helpful drugs in PI3K inhibitor-induced diabetes: a case report Nicolas Sahakian1, Lauranne Cattieuw1, Clotilde Ramillon‑Cury1, Audrey Bégu‑Le Corroller1, Pascale Silvestre‑Aillaud1, Sophie Béliard1,2 and René Valéro1,2,3* Abstract Background: Hyperglycemia is the most common side‑efect of phosphatidylinositol 3‑kinase (PI3K) inhibitors that are approved for the treatment of some advanced or metastatic breast cancers. This side‑efect is likely due to the central role of PI3K in insulin signalling. Here we report the use of a sodium‑glucose cotransporter 2 (SGLT2) inhibitor to manage severe hyperglycemia. Case presentation: We describe a 74‑year‑old woman who developed severe uncontrolled hyperglycemia after commencing alpelisib, a new oral PI3K inhibitor indicated for a metastatic breast cancer, despite taking oral anti‑ diabetic drugs, metformin and vildagliptin, combined with intravenous insulin infusion of up to 250 units/day. The introduction of the SGLT2 inhibitor dapaglifozin rapidly improved blood glucose with a drastic reduction in insulin dosage, from 250 to 12 units/day, and without signifcant side‑efects. Conclusions: We report the successful management of hyperglycemia induced by alpelisib using a SGLT2 inhibitor without the need to discontinue efective cancer treatment. Keywords: Cancer treatment, Case report, Diabetes, Hyperglycemia, Insulin resistance, Metabolic side efects, PI3K, PI3K inhibitor, SGLT2 inhibitor Background metabolism [3], particularly insulin signalling, previously Alpelisib is a new oral α-specifc inhibitor of class I phos- used PI3K inhibitors such as idelisib and copanlisib have phatidylinositol 3-kinase (PI3K) [1] approved in sev- already been associated with hyperglycemia [4]. In the eral countries, in combination with fulvestrant, for the SOLAR-1 trial, hyperglycemia was the most commonly treatment of postmenopausal women with hormone reported adverse event with 63.7% vs 9.8% reporting receptor (HR)-positive, human epidermal growth fac- any grade hyperglycemia, 36.6% vs 0.7% grade 3 (blood tor receptor-2 (HER2)-negative, PIK3CA-mutated, glucose > 250–500 mg/dL) and grade 4 (blood glu- advanced or metastatic breast cancer. SOLAR-1, a phase cose > 500 mg/dL) hyperglycemia, respectively, compar- 3 trial, reported prolonged progression-free survival ing alpelisib-fulvestrant to placebo-fulvestrant treatment. with alpelisib-fulvestrant compared to placebo-fulves- Tis led to cessation of alpelisib in 6.3% of patients vs 0% trant treatment in patients with PIK3CA mutations [2]. in the placebo group [2]. Recommendations for manag- Due to the central role of PI3Kα in regulating glucose ing hyperglycemia indicate dose adjustment or inter- ruption of alpelisib and initiation or intensifcation of anti-diabetic treatment. Te preferred option for treating *Correspondence: [email protected]‑hm.fr alpelisib-induced hyperglycemia is metformin. Tiazoli- 3 Service de Nutrition, Maladies Métaboliques Et Endocrinologie, Centre Hospitalo‑Universitaire de La Conception, 147 Boulevard Baille, dinediones or dipeptidyl peptidase IV (DPPIV) inhibitors 13005 Marseille, France may be added or used in case of metformin intolerance. Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Sahakian et al. Clin Diabetes Endocrinol (2021) 7:17 Page 2 of 4 Insulin may be used until hyperglycemia resolves, usually improved glycemic control within 3 days (blood glucose in 1–2 days due to the short half-life of alpelisib [2, 5]. levels 100—150 mg/dL), with a decreased intravenous Here, we report a case of successful management insulin dose from 250 to 100 units/day. of severe hyperglycemia induced by alpelisib, using a Good treatment tolerance was observed over one week, sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapa- with no weight loss or other side-efects. Alpelisib was glifozin, without the need for discontinuing alpelisib thus maintained at a dose of 200 mg/day. Treatment after treatment. discharge from hospital was metformin (1000 mg three times/day), dapaglifozin (10 mg/day) and subcutaneous Case presentation insulin (lispro 48 units/day and glargine 50 units/day). A 74-year-old woman was diagnosed in 2011 with HR- After discharge, glycemic control continued to improve positive, HER2-negative, PI3KCA-mutated breast allowing discontinuation of fast-acting insulin (lispro) cancer, initially treated by surgery, radiotherapy, chemo- and a drastic reduction in dose of long-acting insulin therapy, hormonotherapy, then hormonotherapy plus (glargine) from 50 to 12 units/day. Tree months after the protein kinase inhibitor palbociclib. Her breast can- discharge the estimated HbA1c (fash glucose monitor- cer progressed, with bone metastases in 2015 and liver ing) over 2 months was 5.9% (41 mmol/mol). However, metastases in 2019. In accordance with recommenda- in view of 3 kg or 5% body weight loss, the oncologist tions, treatment with alpelisib plus fulvestrant was initi- elected to stop dapaglifozin, necessitating reintroduction ated. Alpelisib was introduced at a dose of 300 mg/day. of subcutaneous lispro at up to 10 units/day combined She had no history of diabetes. Fasting blood glucose and with glargine (13 units/day), in view of the deteriora- HbA1c were respectively 104 mg/dL and 5.9% (41 mmol/ tion in glycemic control (mean blood glucose increased mol) before the initiation of alpelisib. from 109 mg/dL to 163 mg/dL with blood glucose up to A few weeks after commencing alpelisib, she developed 262 mg/dL). One month after dapaglifozin withdrawal severe hyperglycemia up to 300 mg/dL with the loss of HbA1c was 6.7% (50 mmol/mol). Fasting C-peptide lev- 4 kg or 6% body weight, but without ketosis. Follow- els remained elevated at 1.42 nmol/L. Dapaglifozin was ing management guidelines, treatment with metformin reintroduced at a dose of 10 mg/day, giving good glyce- (1000 mg twice daily) and a DPPIV inhibitor vildaglip- mic control after one week (blood glucose approximately tin (50 mg twice daily) was started, subsequently sub- 120 mg/dL and estimated HbA1c (fash glucose moni- cutaneous and intravenous insulin therapy was added, toring) over 1 month 6.2% (44 mmol/mol)). Subcuta- with insulin doses up to 150 units/day. Finally, she was neous Lispro was again discontinued and alpelisib was referred to our tertiary diabetes department due to per- maintained at a dose of 200 mg/day (Fig. 1). Te regular sistent poor glycemic control despite these treatments monitoring of ketone capillary blood measurement (beta- including intravenous insulin therapy. Her weight at hydroxybutyrate) using the Optium FreeStyle glucose/ entry was 64 kg, body mass index (BMI) 26.3 kg/m2 and ketone system was normal (< 0.5 mmol/L) during the HbA1c was 9.2% (77 mmol/mol). Etiological assessment follow-up, both before and after the start of dapaglifozin. of diabetes identifed no cause other than iatrogenic dia- betes due to alpelisib. Anti-GAD (glutamic acid decar- Discussion boxylase), anti-IA2 (tyrosine phosphatase 2) and ZnT8 New anti-cancer drugs have become available recently, (Zinc transporter 8) antibodies were negative and pan- with efcacy in treating cancer but with the challenge creatic CT scan showed no abnormality. Fasting plasma of managing side efects such as hyperglycemia. Indeed, C-peptide concentration was elevated (1.75 nmol/L). severe hyperglycemia can lead to life-threatening acute Following published guidance for managing adverse complications of diabetes including ketoacidosis or events of alpelisib [6], the dose of alpelisib was reduced hyperosmolar coma, leading to dose adjustment or per- to 250 mg/day then 200 mg/day, treatment with met- manent withdrawal of the drug, even where treatment formin was increased to 1000 mg three times/day, vilda- is efective in controlling cancer evolution, potentially gliptin was stopped and continuous intravenous insulin impacting patient life expectancy. Hyperglycemia is was increased to 250 units/day. Despite optimized insulin the most common side-efect in patients treated with treatment combined with oral anti-diabetic drugs, severe PI3K inhibitors, including alpelisib. Although age is an hyperglycemia (from 200 to 300 mg/dL) persisted. important risk factor for the development of iatrogenic Before stopping alpelisib as recommended [6], since
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