ALPELISIB - INDUCED HYPERGLYCEMIA

Abstract

Context

Phosphoinositide-3-kinase (PI3K) pathway inhibitors are increasingly used as targeted therapy in malignancies. We discuss here three cases of PI3K inhibitor induced hyperglycemia and discuss the mechanism of action of these medications and treatment of this class side effect.

Objectives

Alpelisib (Piqray) is the newest PI3K inhibitor used in conjunction with Fulvestrant to treat specific types of breast cancer. Since PI3K is a critical mediator of insulin signaling, hyperglycemia is an on-target, unfortunate side effect of this treatment. We present a case series of severe hyperglycemia induced by the alpelisib in three women without a history of diabetes.

Design

All three women in this study had hormone receptor (HR) positive, human epidermal growth factor receptor 2 (Her2) negative, PI3K mutated breast cancer. They were referred to our clinic by Oncology for alpelisib-induced hyperglycemia.

Subjects and Methods

Review of laboratory values and glucometer values were conducted during each visit allowing treatment decisions. Two of these women are actively managed by us for their diabetes. One woman recently died due to progression of malignancy.

Results

All three women presented with new onset of severe hyperglycemia after the initiation of PI3K inhibitor, alpelisib. At least one case noted maximal glucose elevation in the hours following drug ingestion. In another, cessation of Alpelisib reversed the hyperglycemia within the span of one week.

Conclusion

Hyperglycemia induced by PI3K inhibitors can be recalcitrant and might necessitate interruption of chemotherapy. Optimal glucose-lowering therapy remains unclear as exogenous insulin has the theoretical potential to overcome PI3K inhibition.

Introduction

The phosphoinositide-3-kinase (PI3K) family consists of highly conserved enzymes that are key intermediaries in signal transduction, regulating cell survival and mitogenesis within the intracellular PI3K/Akt/mammalian target of rapamycin (mTOR) signaling axis (1). This pathway has been implicated in many types of cancers. In breast cancer, activating mutations in PI3K are common (25%) (2). In 2019, the United States Food and Drug Administration (FDA) approved Alpelisib (Piqray), a reversible inhibitor specific to the PI3Kα subunit, in combination with fulvestrant, to treat hormone receptor (HR) positive, human epidermal growth factor receptor 2 (Her2) negative, PI3K mutated breast cancer. This approval followed results of the SOLAR-1 trial showing a 35% risk reduction in cancer progression or death with alpelisib-fulvestrant compared to placebo-fulvestrant in a cohort with PI3K mutated breast cancer (3).

PI3K plays a critical role in the insulin signaling pathway. The p110α subunit of PI3K is the primary determinant of insulin signaling and insulin activity in vivo. Murine models with deletion or inhibition of this alpha catalytic subunit demonstrated hyperinsulinemia and glucose intolerance, mediated by impaired peripheral cellular uptake of glucose, and increased hepatic gluconeogenesis (4, 5). Alpelisib has been shown to cause a dose dependent rise in plasma glucose, insulin and C-peptide concentrations. Moreover, a decrease in glucose uptake was also observed via [18F]-fluorodeoxyglucose positron emission tomography at doses higher than 180mg/day. All these metabolic changes have been shown to occur within cycle 1 and at least by day 24 (6). However, these effects can be managed with dose interruption/reduction of alpelisib and with addition of antihyperglycemic agents like metformin and insulin. The incidence of hyperglycemia was 64% in alpelisib-treated patients in the SOLAR-1 trial, despite exclusion of patients with type 1 diabetes, and those with suboptimal control of type 2 diabetes (HbA1c>6.4%, 46 mmol/mol). Discontinuation of alpelisib for uncontrolled hyperglycemia occurred in 6.3% of the treatment group.

Currently the FDA defines 4 grades of hyperglycemia with alpelisib and provides specific guidance for dose modification for each category. Grades 3 and 4 hyperglycemia, respectively defined as blood glucoses > 13.9-27.8 mmol/L and ≥ 27.8 mmol/L, warrants a transient cessation of alpelisib until blood glucoses are below 8.9 mmol/L, at which point, alpelisib can to re-initiated at a lower dose. In our case series, we highlight the potential severity of this adverse effect with 3 cases of alpelisib-induced hyperglycemia.

Materials AND Methods

We performed chart reviews on electronic medical record of three recent cases seen by the endocrinology service (both hospital and outpatient clinics). Data abstracted included prior diabetes history, serial results from home glucose monitoring and clinical course.

Results

A 44-year-old woman with HR+(Estrogen Receptor/ER)/Her2(-), PI3K mutation positive metastatic breast cancer was started on alpelisib 300mg. At that visit, HbA1C was normal at 5.4% (36 mmol/mol) and there was no personal or family history of diabetes. Hyperglycemia developed slowly and for the next several months, self-monitored glucose values were 10-11 mmol/L. However, by 10 months following initiation of alpelisib, HbA1c rose to 9.0% (75 mmol/mol). She started metformin and empagliflozin, which she was unable to tolerate consistently due to nausea and vomiting. Her self-monitored blood glucoses were 17-22 mmol/L, mainly within hours after her morning alpelisib dose. We discontinued empagliflozin when she developed metabolic acidosis with an increased anion gap. However, prior to the addition of insulin or any dose reduction/interruption of alpelisib, the cancer treatment was discontinued due to evidence of cancer progression. One week later, she had normal fasting glucoses and improved postprandial glucose (8-11 mmol/L). She will be monitored by endocrinology department until there is evidence that her glucoses and HbA1C have fully reverted to normal ranges.

Second case is of a 64-year-old woman with stage IV HR(ER)+/Her2(-) breast cancer with bone metastases, referred to the endocrinology department for recently discovered hyperglycemia. Due to paclitaxel intolerance and her cancer having PI3K mutation, she started alpelisib at 50 mg/day with dose increase to 250 mg/day within the course of a month. Her prior HbA1C values had been normal (5.5%, 37 mmol/mol) but she had a family history of type 2 diabetes. Ten days after initiation of alpelisib, she developed grade 3 hyperglycemia (self- monitored blood glucoses 11-27 mmol/L). She was started on metformin 1000mg morning and evening, with alpelisib dosed at noon. However, she noted a marked rise in blood glucose starting at 3pm, few hours after the alpelisib dose. Thus, changing the administration time of alpelisib to bedtime allowed better control of glycemia by using overnight insulin glargine, currently at 30 units.

Similarly, a 37-year-old woman with a history of HR(ER)+/Her2(-) stage IV metastatic breast cancer to the liver, with PI3K mutation, was admitted for hyperbilirubinemia. Incidentally, during this admission, she was found to have acute, severe hyperglycemia with blood glucose of 16.7 mmol/L, despite HbA1C being only 4.7% (28 mmol/mol). Although she had a history of gestational diabetes mellitus during both prior pregnancies, she did not have active prediabetes or diabetes prior to this presentation. Thus, her acute hyperglycemia was attributed to initiation of alpelisib 150mg twice daily, 2 days prior to admission. Given the severity of her insulin resistance (requiring > 100 units of insulin daily), alpelisib dose was reduced from 300mg to 150mg/day. On discharge, she was placed on metformin 850mg twice a day, dulaglutide 0.75mg weekly, insulin detemir 20 units twice daily, and insulin lispro 20 units with meals. Her HbA1C rose to 9.4% (79 mmol/mol) within 3 months of alpelisib initiation.

Discussion

The case series above may be of great interest to endocrinologists as we encounter these novel chemotherapy agents with adverse effects on insulin signaling. It is important to determine whether the occurrence of severe hyperglycemia, suggesting effective PI3K inhibition, predicts better anti-cancer efficacy, like that predicted by anti-oncogenic immunotherapy agents. A second area of interest is whether the use of insulin or insulin secretagogues may blunt or negate the anti-oncogenic properties of PI3K inhibitors. Third, although multiple antidiabetic medications can be used in PI3K inhibitor-induced hyperglycemia, caution is advised with SGLT2 inhibitors as euglycemic ketoacidosis has been reported in combination with a different PI3K inhibitor (7).

The treatment of alpelisib induced hyperglycemia is complicated as patients frequently have substantial insulin resistance immediately after the ingestion of the medication with improved insulin sensitivity by the next dose. This presents a predicament to optimize the timing of insulin to combat the PI3K inhibition without causing hypoglycemia when the alpelisib effects have worn off. Future studies aimed at creating a more efficient treatment algorithm for this infrequent but severe side effect of alpelisib may allow patients to benefit greatly from the anti-oncogenic properties of this medication without the need to interrupt therapy.

In conclusion, even patients without diabetes might develop life-threatening hyperglycemia during breast cancer therapy with alpelisib. Although insulin therapy has the potential to oppose the anti-cancer effect of PI3K inhibitors, it is usually needed in such cases.

Conflict of interest

The authors declare that they have no conflict of interest.