Alpelisib-induced coexisting of Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State in Metastatic Breast Cancer

Abstract Background: Hyperglycemia is a frequently reported adverse effect of alpelisib, an isoform specific phosphoinositide 3 kinase inhibitor, which is recently approved for use in hormone receptor positive advanced or metastatic breast cancer. Though two patients in clinical trials with alpelisib developed diabetic ketoacidosis (DKA), there have been no case reports to date characterizing this complication after drug approval. We present the first case of DKA in patients on alpelisib therapy. Clinical Case: A 55-year-old woman with a history of hormone-receptor positive metastatic breast cancer was started on treatment with fulvestrant and alpelisib. The patient did not have any previous history of diabetes nor gestational diabetes, though she had evidence of prediabetes prior to starting treatment. Patient was non-obese and had a family history of type 2 diabetes. Baseline hemoglobin A1c was 5.6% (n <5.7%) with impaired fasting glucose of 108 mg/dl (n<105 mg/dL) immediately prior to starting therapy. One week after starting alpelisib, she presented to the emergency center in diabetic ketoacidosis. Initial laboratory evaluation showed serum glucose 690 mg/dl, anion gap metabolic acidosis, with undetectable serum bicarbonate and ketonuria. C-peptide on hospital day 1 was found to be 2.8 ng/ml (n 0.5 - 3.4 ng/ml) with a concurrent glucose of 479 mg/dl. GAD65 and Islet Antigen 2 antibodies were negative. Diabetic ketoacidosis quickly resolved with continuous insulin infusion and stopping alpelisib. The patient was able to come off all insulin therapy prior to discharge and was discharged on metformin with adequate glycemic control. Conclusions: Current manufacturer guidelines for alpelisib recommend screening for diabetes mellitus at baseline and monitoring blood glucose and/or fasting plasma glucose weekly for the first two weeks of treatment and monthly thereafter. However, patients with no pre-existing history of diabetes mellitus may be at risk for life-threatening hyperglycemic crises which may develop within a week of initiation of alpelisib and more frequent monitoring may be indicated. The hyperglycemic effect of alpelisib appears to be reversible upon stopping the drug.

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Alpelisib-Induced Diabetic Ketoacidosis

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.742 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A364-A365

Author(s):

Luis Borges Espinosa ◽

Francesco Vendrame

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Glucose Uptake ◽

Diabetic Ketoacidosis ◽

Hormone Receptor ◽

Kinase Inhibitor ◽

Case Reports ◽

Metastatic Breast ◽

Arterial Blood ◽

Increased Risk

Abstract Introduction: Alpelisib is a alpha-specific phosphoinositide 3-kinase inhibitor (PI3K) recently approved for patients with advanced or metastatic breast cancer with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, and activating mutations in the PIK3CA gene. PI3K is involved in the insulin receptor signaling pathway that leads to glucose uptake. Hyperglycemia is a frequent adverse effect of Alpisilib but diabetic ketoacidosis (DKA) is considered a rare occurrence. Case ReportA 53 year-old woman with metastatic breast cancer presented with 5 days of worsening polydipsia, fatigue, nausea, vomiting, slurred speech and altered mental status. She was started on Alpelisib 300 mg daily two weeks prior to admission and instructed to check glucose twice weekly but did not follow directions. Family history was significant for type 2 diabetes. On physical exam blood pressure was 150/90, heart rate 120 beats/minute, respiratory rate 120 breaths/minute; BMI was 27 Kg/m2. The neurological exam was significant for a lethargic state with the patient arousable to verbal stimuli. The skin exam was negative for acanthosis nigricans or skin tags. Laboratory tests showed glucose at 1425 mg/dl, bicarbonate 11 mEq/l (19–34), anion gap 39 (6–22), sodium 138 mmol/l (135–146), potassium 5.0 mmol/l (3.5–5.5), serum osmolality 378 mosm/kg (275–295), Cr 3.99 mg/dl (0.4–1.1), lactic acid 3.5 mmol/l (0.5–2.0), ketonuria and glucosuria. No arterial blood gas was performed. HbA1c was 5.9% before starting Alpelisib. Results were consistent with DKA and hyperosmolar hyperglycemic state. Additional tests showed HbA1c 10.5 %, c-peptide 1.2 ng/ml (1.1–4.4) with glucose 183 mg/dl; type 1 diabetes autoantibodies were negative. Alpesilib was held and the patient managed with insulin drip and then insulin basal/bolus regimen. Patient was discharged on basal insulin and metformin with the plan to resume alpelisib at a lower dose and monitor. ConclusionIn the SOLAR-1 trial hyperglycemia was reported in 63% of patients taking alpesilib and two cases of DKA were observed. A case of a patient who developed DKA with Alpesilib was also recently reported. The mechanism underlying DKA in these patients is unclear. PI3K inhibitors may prevent the transcription of the insulin gene in response to high concentrations of glucose and the combination of impaired peripheral glucose uptake with impaired insulin secretion trigger DKA. Further studies are needed to identify which patients on Alpelisib are at increased risk of developing DKA. Clinicians should be aware of this life threatening complication. References: F André, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med 2019; 380.SJ. Farah, et al. Diabetic ketoacidosis associated with alpelisib treatment of metastatic breast cancer. AACE Clinical Case Reports 2020; Vol. 6, No. 6.

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Alpelisib-Induced Diabetic Ketoacidosis- A Case Report

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.743 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A365-A365

Author(s):

Lisette Patricia Rodriguez ◽

Wilhelmine Wiese-Rometsch ◽

Christian Lorenzo

Keyword(s):

Breast Cancer ◽

Diabetes Mellitus ◽

Metastatic Breast Cancer ◽

Diabetic Ketoacidosis ◽

Side Effect ◽

Pik3ca Mutation ◽

Metastatic Breast ◽

Serum Glucose ◽

Anion Gap ◽

Diagnosis Of Diabetes Mellitus

Abstract Background: Alpelisib, in combination with Fulvestrant, was approved in 2019 by the Food and Drug Administration for treatment of HR+, HER2- advanced or metastatic breast cancer in patients with PIK3CA mutation. a This combination is currently on phase III of study. One of the most common side effects is hyperglycemia. Rarely, this can be severe enough to induce diabetes ketoacidosis, which is an indication for interrupting Alpelisib treatment. Clinical Case: A 78 year old female presented to our emergency department with altered mentation. Her past medical history is significant for metastatic breast cancer, with known PIK3CA mutation, started on alpelisib three months prior. Concomitantly, despite not carrying a diagnosis of diabetes mellitus, the patient was started on metformin, due to the known side effect of hyperglycemia. Upon admission, the patient was found to be tachycardic and otherwise hemodynamically stable. Pertinent laboratory studies revealed an initial serum glucose of 600 (nl 70–100) mg/dL, potassium of 5.4 (nl 3.5–5.1) mmol/L, serum carbon dioxide of 8 (nl 21–32) mmol/L, calculated anion gap of 25 (nl <12) mEq/L, and a serum beta-hydroxybutyrate > 4.50(nl 0.02–0.27) mmol/l. ABG revealed a pH of 7.11, PaO2 of 102, pCO2 of 11, and a lactate of 4.0 mmol/L. Glycated hemoglobin was 10.7% (nl <6.5%). EKG revealed sinus tachycardia with PACs, abnormal anterolateral T wave inversion, and a QTc of 519 msec. Initial troponin was elevated at 0.15 with a max troponin at 1.40 ng/mL. Urinalysis revealed glucosuria. Chest x-ray showed no acute cardiopulmonary process. Blood cultures were negative to completion. Patient was admitted for diabetic ketoacidosis and was started on DKA protocol which included aggressive hydration with sodium chloride and insulin drip. Alpelisib was discontinued immediately. Upon resolution of the anion gap metabolic acidosis, the patient’s encephalopathy significantly improved. She was transitioned to subcutaneous insulin. During the same hospitalization, the patient’s serum glucose rapidly normalized and she did not require insulin at the time of discharge. Conclusion: Diabetic ketoacidosis is an unusual but life-threatening side effect of Alpelisib, even in patients without an underlying diagnosis of diabetes mellitus. This case suggests that such patients should have a close monitoring of glycemic control and intensification of their anti-diabetic medications if required, to prevent hyperglycemic crises.

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