Severe Hyperglycemia Induced by Alpelisib in Advanced Breast Cancer: Two Case Reports and A Call for Early Glycemic Monitoring

    

    

    Table 1: Patients information summary. BMI - body mass index;
HbA1c - plasma glycated hemoglobin; FCG - fasting capillary glucose.
    

After 20 days without treatment, the Oncologist restarted alpelisib at a dose of 200 mg/day. The very next day, the patient presented an FCG of 380 mg/dL. Basal insulin (initial dose 10 IU/day) was associated with metformin treatment. Over the next month, there was the need to increase basal insulin dose (until 18 IU/day) and add prandial insulin. Alpelisib was definitively interrupted after 1 month of treatment due to disease progression, and glycemia normalized in 48 hours with no need for anti-diabetic treatment.

Discussion

The role of PI3K in regulating glucose metabolism and cellular proliferation is crucial for understanding the effects of alpelisib in patients with advanced or metastatic breast cancer. The PI3K/AKT signalling pathway plays a central role in insulin actions, promoting glucose uptake by skeletal muscle and adipose tissue and glycogen storage in the liver. Activation of this pathway is triggered by insulin binding to its receptor, resulting in receptor phosphorylation and subsequent activation of PI3K and AKT, leading to GLUT4 glucose transporter translocation to the plasma membrane in insulin target organs. Any alteration in the PI3K/AKT pathway can result in insulin resistance and hyperglycemia [3,7]. Alpelisib, a PI3K inhibitor, disrupts this signalling pathway, blocking glucose uptake by skeletal muscle and adipose tissue, and activating hepatic gluconeogenesis [3- 5].

Hyperglycemia is the main adverse effect of alpelisib, being a factor for dose reduction in 20% of patients and a cause of permanent treatment discontinuation in 6.3% of patients [3].

Based on our clinical experience, we observed that patient 1 developed hyperglycemia within two weeks of starting the treatment, while patient 2 developed it after one month. This finding is consistent with the results reported in SOLAR-1 study, where hyperglycemia occurred early during treatment, with a median onset time of 15 days after initiating the treatment, and onset time ranged from 5 to 395 days [5,8].

Obesity (BMI =30kg/m2), age =70 years, HbA1c between 5.7 and 6.4%, and gestational diabetes are all risk factors for alpelisib induced hyperglycemia because it implies a baseline propensity to insulin resistance [4,9]. These risk factors were present in 74.7% of patients with any grade of hyperglycemia and 86.2% of patients with grade 3 or 4 hyperglycemia in SOLAR-1 [3-5].

The presence of two of these risk factors (age and obesity) may have contributed to the early development of hyperglycemia observed in patient 1. However, Patient 2 did not exhibit any of these risk factors yet developed a severe hyperglycemic condition requiring more intensive treatment.

After the initiation of alpelisib, blood glucose should be monitored at least once every week in the first 2 weeks, once every 2 weeks during the next 8 weeks and at least once a month thereafter with the assessment of FCG in fingerprick samples or by assessing fasting plasma glucose (FPG) in a peripheral blood sample; HbA1c should be monitored 4 weeks after initiating treatment and every 3 months thereafter [4,5]. Compared to self-monitoring of FCG, a continuous glucose monitoring system provides a close monitoring of glycemic behavior in a non-invasive way, allowing the early detection and treatment of hyperglycemia; therefore, if available, continuous glucose monitoring devices should be considered, especially in patients with one or more risk factors [3,4]. Given that hyperglycemia occurred in >50% of patients with previous normal glycemic status and normal BMI who received alpelisib in the SOLAR-1 study [5,8] all patients require lifestyle management advice on how to minimize the risk of hyperglycemia [4]. For all patients with type 2 diabetes mellitus, it is inappropriate to start alpelisib treatment without a previous endocrinological evaluation [9]. The safety of alpelisib in patients with type 1 and uncontrolled type 2 diabetes has not been established as these patients were excluded from clinical trials [5].

The hyperinsulinemia that occurs in patients with alpelisibinduced hyperglycemia may provide breast cancer cells with a survival mechanism and reduce its efficacy [3,4]. Furthermore, if not successfully managed, hyperglycemia can lead to alpelisib dose reductions, treatment interruption or discontinuation. As seen in our patients, grade 3/4 (FPG 250-500 mg/dL) hyperglycemia require alpelisib interruption [4,5]. Grade 1 (FPG < 160 mg/dl) and grade 2 (FPG 160-250 mg/dl) hyperglycemia are usually asymptomatic and manageable without alpelisib dose adjustment [4,5]. Optimal hyperglycemia management is therefore required to maintain alpelisib dose and maximize treatment benefit [3,4].

Based on the mechanism of action of alpelisib and to attenuate the pronounced insulin resistance and hyperglycemia associated with it, it is pertinent to note that insulin sensitizers may be preferable over insulin secretagogues for treatment [4]. Metformin is widely recognized as a standard treatment in these cases (4,10). Despite the potential for diarrhea as an adverse effect of both alpelisib and metformin [8,10], the incidence and severity of diarrhea were comparable in patients who received concomitant metformin and those who did not in the SOLAR-1 trial [5,8]. To mitigate gastrointestinal adverse effects, metformin dosage should be titrated gradually [4]. The initiation of metformin at a dose of 850 mg, three times a day in patient 1 may have accounted for its poor tolerability.

Currently there is no secondary agent that is widely accepted when hyperglycemia remains uncontrolled with metformin [10]. Other non-insulin antihyperglycemic medications that can be used in conjunction with metformin or as alternatives to it include the insulin sensitizer pioglitazone and the sodium-glucose co-transporter 2 (SGLT2) inhibitors [4]. Based on their mechanism of action, SGLT2 inhibitors have been proposed as the second line, and potentially first line, treatment options in cases of metformin intolerance [4,10]. Pioglitazone cannot be used as a first-line agent due to its delayed onset of action (6–8 weeks) [4]. GLP-1 receptor agonists are potential therapeutic agents; however, there is limited experience regarding their use in settings PI3K inhibitions. Additionally, the common gastrointestinal side effects of GLP-1 receptor agonists overlap with those seen with the administration of alpelisib (10). Dipeptidyl Peptidase-4 (DPP-4) inhibitors could be an option since they are well-tolerated drugs with few adverse effects. However, the limited available evidence suggests they have low efficacy in treating alpelisib-induced hyperglycemia. Sulfonylureas should be avoided as primary treatment for this type of hyperglycemia because they function as insulin secretagogues and elevate insulin levels, potentially diminishing the primary antitumor effect of alpelisib [4]. Insulin, and/or sulfonylureas can be utilized as rescue medication for hyperglycemia >250 mg/dL, not adequately controlled by non-insulin antihyperglycemic agents alone [4], as illustrated in our cases. Given the short half-life of alpelisib, 8 to 9 hours, renders the hyperglycemic effect negligible for at least 24-72 hours after treatment is interrupted [3,4]. Insulin administration requires careful consideration due to the risk of hypoglycemia after the half-life effect of alpelisib.

Although our two patients needed to interrupt alpelisib treatment in the moment of hyperglycemia diagnosis, both achieved adequate glycemic control and were able to continue alpelisib treatment after the use of anti-hyperglycemic agents. Insulin use was necessary in both cases, underscoring the safety of its usage when coupled with close monitoring of glycemic profiles, particularly in instances of alpelisib discontinuation.

Conclusion

Alpelisib is a selective alpha inhibitor of PI3K, whose use has experienced a notable increase in recent years, particularly in cases of HR+ breast cancer [4]. Hyperglycemia stands out as its most frequent adverse effect, manifesting in approximately 59% of patients [6]. Consequently, the expansion of alpelisib utilization is expected to correlate with a significant uptick in secondary hyperglycemia cases.

The hyperglycemia induced by alpelisib typically emerges around 15 days following the initiation of therapy, primarily stemming from a state of insulin resistance [5,8]. Therefore, treatment should involve insulin sensitizer medication, being metformin the preferred choice. Insulin and/or other insulin secretagogue drugs should be reserved for situations where hyperglycemia remains uncontrolled despite initial treatment [4]. Blood glucose levels are expected to normalize within one week of treatment cessation, requiring special care for patients taking insulin due to the associated risk of hypoglycemia.

A delayed diagnosis can significantly impact metabolic control, potentially leading to alpelisib dose adjustments or discontinuation, and compromising treatment efficacy and patient survival.

With these 2 case reports, we want to highlight the rapid onset of severe asymptomatic but still benign course of the hyperglycemia in this setting, and therefore to emphasize the need for close monitoring of the patients to maintain the benefit of the oncological treatment, which necessarily requires a multidisciplinary approach.

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