Blog Viewer

Considerations for Management of Alpelisib Induced Hyperglycemia

HR-Positive, HER2-Negative Breast Cancer

Breast cancer is one of the most common cancers in women, affecting approximately 250,000 women in the US and 1,000,000 women in the 8 major markets⁺⁺. ^1-9 About 73% of these patients are diagnosed with HR-positive, HER2-negative disease.

Alpelisib and PI3K mutations

Because the treatment landscape for HR-positive, HER-2-negative breast cancer continues to show significant and persistent unmet need, newer treatment options have been developed based on the complex mechanisms of breast cancer pathophysiology. One recent addition is alpelisib (PIQRAY), a kinase inhibitor targeting PI3K mutations.¹⁰ PI3K is a kinase enzyme which plays a role in growth-factor signaling. Mutations in PI3K occur in about 40% of patients with HR-positive, HER-2 negative metastatic breast cancer and has been linked to the proliferation of cancer cells.¹¹  

Alpelisib is indicated for use with fulvestrant for HR-positive, HER-2-negative, PIK3CA-mutated, advanced or metastatic breast cancer as second or later line treatment.¹⁰ The pivotal SOLAR-1 randomized phase 3 trial compared alpelisib 300mg daily and fulvestrant 500mg with fulvestrant 500mg alone on days 1 and 15 of the first 28-day cycle, then monthly thereafter.¹² In the trial, alpelisib resulted in a 35% reduction in risk of disease progression or death in patients with PI3Ka mutations which was found to be significant. SOLAR-1 found that 63.7% of patients taking alpelisib experienced hyperglycemia, including 6.3% of patients who ultimately discontinued treatment.

Management of Alpelisib Hyperglycemia

Due to risk of hyperglycemia complications such as ketoacidosis, diabetes monitoring is a crucial component for the care of patients taking alpelisib. Patients should monitor fasting blood glucose (FBG) based on clinical condition (Table1).¹⁰ Additionally, patient should monitor A1c at initiation and every 3 months after as needed.

Medical management of alpelisib hyperglycemia varies depending on 4 levels of hyperglycemia.¹⁰ Hyperglycemia with glucose levels <250mg/dL requires diabetes management with original or reduced dose of alpelisib while hyperglycemia with glucose levels >250mg/dL require interruption of alpelisib in addition to diabetes management (Figure 1).

⁺⁺8 major markets include the US, UK, Germany, France, Spain, Italy, Japan and China

Figure 1

Given the scarcity of clinical data on the treatment of alpelisib hyperglycemia, management should be based on American Diabetes Association guidelines¹³ and may be further guided on limited case reports and preclinical data.

Lifestyle Management

Lifestyle management is an important aspect of diabetes management and may be incorporated in the management of alpelisib hyperglycemia. ADA guidelines recommend at least 150 minutes of exercise every week.¹³ Patients should engage in aerobic exercise on most days and resistance exercise 2-3 times per week as tolerated. In addition to exercise, patients should monitor diet closely. Principles of diet management should include reducing carbohydrates and increasing fiber and protein intake. In fact, a ketogenic diet (<50g carbohydrates/day) was shown in preclinical studies to reduce blood glucose and insulin/glucose spikes better than metformin pretreatment in murine models of alpelisib hyperglycemia.^14.15 Similar improvements in glucose maintenance were seen in a clinical case study.¹⁶

Metformin

Metformin is considered first line therapy for alpelisb hyperglycemia and has the greatest clinical experience, with 76% of patients in the pivotal SOLAR-1 trial utilizing it as monotherapy or with other anti-diabetic medications.¹² Additionally, some clinicians have started metformin prior to alpelisib as prevention for hyperglycemia; however clinical data are lacking though a trial studying pretreatment is ongoing.¹⁸ Still metformin alone may not be enough for some patients. A case series of six patients showed inadequate glycemic control in patients taking only metformin for alpelisib hyperglycemia.¹⁷ Additionally metformin should be used with caution due to gastrointestinal adverse effects, as they are seen commonly with alpelisib as well.¹²

SGLT2 inhibitors

SGLT2 inhibitors are an option in alpelisib hyperglycemia and may have cardiovascular and renal benefits as well based on diabetes clinical trials. Additionally, this class of medications has been shown to decrease hyperglycemia in preclinical murine models and patient cases of alpelisib hyperglycemia.^16,17,19,20 However, potential common adverse events such as genitourinary infections and hypotension should be considered. Additionally, there are case reports of patients with alpelisib hyperglycemia treated with SGLT2 inhibitors experiencing serious euglycemic ketoacidosis and metabolic acidosis.^{21, 22}

GLP-1 agonist/DPP4 inhibitors

In diabetes, glucagon-like-peptide (GLP)-1 targeting medications are useful medications with significant glucose lowering abilities and cardiovascular and renal benefits in the case of GLP-1 agonists. Additionally, have been found to inhibit PI3K signaling pathways.²³ However, they may have more limited clinical experience in the treatment alpelisib hyperglycemia. One case report showed that a patient treated with metformin, dulaglutide and basal and prandial insulin still experienced an increase in A1c from 5.5% prior to administration of alpelisib to 9.4% at the 3 month follow-up.¹⁶ Additionally, common side effects of GLP-1 targeting medications such as nausea, vomiting and diarrhea are also common with administration of alpelisib.

Thiazolidinediones

Thiazolidinediones are an option in diabetes management. One case report described a patient with alpelisib hyperglycemia well controlled on metformin and pioglitazone, though the edition of empagliflozin was needed upon dose escalation of alpelisib.¹⁶ Thiazolidinediones should be used with caution due to increased risk or fluid retention and edema. They are also associated with increased risk of congestive heart failure, fractures and bladder cancer.

Sulfonylurea

Sulfonylureas can be used to target post-prandial glucose levels in patients with diabetes. However, there may be little evidence for its use in alpelisib hyperglycemia. Additionally, past studies have revealed a potential increase in cardiovascular adverse outcomes with sulfonylureas.²⁴ While not studied, this may interact with the hypercoagulable state in cancer patients with unknown outcomes. Additionally, caution is needed due to common adverse effects of hypoglycemia and weight gain.

Insulin

Insulin is commonly used in diabetes with severe hyperglycemia. Additionally, case reports have shown its ability to control blood sugars in patients with alpelisib hyperglycemia.^{16, 20, 22} However, insulin may not be the best option as preclinical data have shown that insulin partially reactivates the PI3K pathway, despite treatment with a PI3K inhibitor in various tumor cell lines, leading to cellular proliferation.¹⁹   

Role of Pharmacist/CDCES

With over 50% of patients taking alpelisib experiencing hyperglycemia, close management by healthcare professionals is crucial for successful therapeutic outcomes. As medication experts and the most accessible healthcare professional, pharmacists can play a role in management of alpelisib hyperglycemia. Pharmacists CDCES’s are well positioned to guide patients with glucometer training and lifestyle interventions and consult with physicians for medication initiation to manage hyperglycemia. Furthermore, pharmacists are trained to address patient specific factors such as barriers to adherence and insurance issues. Thus, pharmacists can add great value to a multidisciplinary team managing breast cancer patients using alpelisib.

References

1. Countries in the world by population (2022). Worldometer. https://www.worldometers.info/world-population/population-by-country/. Accessed February 3, 2022.
2. International Agency for Research on Cancer. World Health Organization (2020). United States of America Breast Cancer Fact Sheet. https://gco.iarc.fr/today/data/factsheets/populations/840-united-states-of-america-fact-sheets.pdf
3. International Agency for Research on Cancer. World Health Organization (2020). United Kingdom Breast Cancer Fact Sheet. https://gco.iarc.fr/today/data/factsheets/populations/826-united-kingdom-fact-sheets.pdf
4. International Agency for Research on Cancer. World Health Organization (2020). Spain Breast Cancer Fact Sheet. https://gco.iarc.fr/today/data/factsheets/populations/724-spain-fact-sheets.pdf
5. International Agency for Research on Cancer. World Health Organization (2020). France Breast Cancer Fact Sheet. https://gco.iarc.fr/today/data/factsheets/populations/250-france-fact-sheets.pdf
6. International Agency for Research on Cancer. World Health Organization (2020). Italy Breast Cancer Fact Sheet. https://gco.iarc.fr/today/data/factsheets/populations/380-italy-fact-sheets.pdf
7. International Agency for Research on Cancer. World Health Organization (2020). Germany Breast Cancer Fact Sheet. https://gco.iarc.fr/today/data/factsheets/populations/276-germany-fact-sheets.pdf
8. International Agency for Research on Cancer. World Health Organization (2020). Japan Breast Cancer Fact Sheet. https://gco.iarc.fr/today/data/factsheets/populations/392-japan-fact-sheets.pdf
9. International Agency for Research on Cancer. World Health Organization (2020). China Breast Cancer Fact Sheet. https://gco.iarc.fr/today/data/factsheets/populations/160-china-fact-sheets.pdf
10. Package insert. Norvartis; 2019
11. Goncalves MD, Hopkins BD, Cantley LC, et al. Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer. N Engl J Med2018;379:2052-62.
12. Andre F, Ciruelos E, Rubovszky G, et al. Alpelisib for PI3KA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med2019;380:1929-40.
13. American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care2020;43(1):S98-110.
14. Crouthamel, MC, Kahana, JA, Korenchuk, S, et alMechanism and management of AKT inhibitor-induced hyperglycemia. Clin Cancer Res. 2009;15:217-225. doi:1158/1078-0432.CCR-08-1253
15. Zou, Y, Fineberg, S, Pearlman, A, Feinman, RD, Fine, EJ. The effect of a ketogenic diet and synergy with rapamycin in a mouse model of breast cancer. PLoS One. 2020;15:e0233662. doi:0231371/journal.pone.0233662
16. 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;20:153473542110322. doi:10.1177/15347354211032283
17. Lu Y-S, Chiu J, Airoldi M, et al. 301p sodium-glucose cotransporter-2 (SGLT-2) inhibitors for alpelisib (alp)-induced hyperglycemia: A report of 6 cases from solar-1. Annals of Oncology. 2020;31. doi:10.1016/j.annonc.2020.08.403
18. Llombart Cussac A, Pérez-Garcia JM, Blanch S, et al. 129TiP metformin (MF) in the prevention of hyperglycemia (HG) in patients (PTS) with PIK3CA-mutated, hormone receptor (HR)[+]/HER2[–] advanced breast cancer (ABC) treated with alpelisib (ALP) plus fulvestrant (F): Metallica. Annals of Oncology. 2021;32. doi:10.1016/j.annonc.2021.03.143
19. Hopkins BD, Pauli C, Du X, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018;560(7719):499-503. doi:10.1038/s41586-018-0343-4
20. Carrillo M, Rodriguez RM, Walsh CL, Mcgarvey M. Alpelisib-induced diabetic ketoacidosis: A case report and review of literature. AACE Clinical Case Reports. 2021;7(2):127-131. doi:10.1016/j.aace.2020.11.028
21. Bowman C, Abramson V, Wellons M. Ketoacidosis with Canagliflozin prescribed for phosphoinositide 3-kinase inhibitor–induced hyperglycemia: A case report. Journal of Investigative Medicine High Impact Case Reports. 2017;5(3):232470961772535. doi:10.1177/2324709617725351
22. Ekanayake PS, Gerwer JE, McCowen KC. Alpelisib-induced hyperglycemia- a small case series. Journal of the Endocrine Society. 2021;5(Supplement_1). doi:10.1210/jendso/bvab048.744
23. Zhao X, Wang M, Wen Z, et al. GLP-1 receptor agonists: Beyond their pancreatic effects. Frontiers in Endocrinology. 2021;12. doi:10.3389/fendo.2021.721135
24. Phung OJ, Schwartzman E, Allen RW, Engel SS, Rajpathak SN. Sulphonylureas and risk of cardiovascular disease: Systematic Review and meta-analysis. Diabetic Medicine. 2013;30(10):1160-1171. doi:10.1111/dme.12232