From the Guidelines
Metformin is the first-line treatment for alpelisib-induced hyperglycemia, with a starting dose of 500 mg daily, gradually increasing to 500 mg twice daily if needed, as recommended by the most recent guidelines 1.
Treatment Approach
When managing alpelisib-induced hyperglycemia, it is crucial to start with baseline screening and monitoring. Before initiating alpelisib therapy, patients should undergo fasting glucose and HbA1c testing, with those having pre-existing diabetes or prediabetes requiring optimization of glycemic control.
- For mild hyperglycemia (fasting glucose 160-250 mg/dL), metformin is the preferred treatment option.
- For moderate hyperglycemia (fasting glucose >250 mg/dL), metformin should be combined with a DPP-4 inhibitor like sitagliptin 100 mg daily.
- Severe hyperglycemia (>500 mg/dL) requires insulin therapy, typically starting with basal insulin at 0.2-0.3 units/kg/day while temporarily holding alpelisib until glucose levels improve.
Monitoring and Adjustment
Throughout treatment, blood glucose should be monitored daily for the first 2 weeks, then weekly for 4 weeks, and monthly thereafter. Alpelisib inhibits PI3K signaling, which normally mediates insulin's effects on glucose metabolism, explaining why it causes hyperglycemia in approximately 60% of patients, as noted in the study 1. Prompt management is essential as hyperglycemia typically develops within the first 2 weeks of treatment and can lead to treatment discontinuation if not addressed effectively.
Considerations
The choice of treatment should consider the patient's clinical profile, side effects, and the potential for combination therapy. SGLT2 inhibitors and pioglitazone are appropriate second- or third-line agents, depending on the clinical scenario, and may be used in combination with or without metformin, as suggested by the guidelines 1. Insulin and sulfonylureas should be considered last-line agents due to their potential to reactivate the PI3K pathway, negating the effects of alpelisib 1.
From the Research
Treatment Strategies for Alpelisib-Induced Hyperglycemia
- Lifestyle modifications, including a reduced-carbohydrate diet, can help manage hyperglycemia induced by alpelisib 2, 3
- A stepwise, personalized antihyperglycemic regimen, based on metformin, sodium-glucose co-transporter 2 inhibitors, and pioglitazone, can be effective in addressing insulin-resistant hyperglycemia 2
- Intensive insulin regimen may be necessary in some cases, especially when hyperglycemia is severe 4, 5
- Flash glucose monitoring (FGM) can be helpful in understanding the pharmacodynamic aspects of alpelisib and insulin titration 4
- Glucose monitoring should always be performed in patients treated with alpelisib, especially in patients with diabetes and prediabetes 4
Management Considerations
- Early detection of hyperglycemia and timely intervention are crucial in achieving optimal glycemic control and maintaining alpelisib dose intensity 2
- A glycemic support program implemented by an endocrinology-oncology collaborative team may be useful in managing hyperglycemia induced by alpelisib 2
- Diabetic ketoacidosis is a rare complication of alpelisib initiation, which can be quickly resolved with cessation of the agent 5
- Insulin therapy may be required in rare instances, but it has the potential to decrease the antitumor effects of alpelisib 5
Pharmacologic Interventions
- Sodium-glucose co-transporter 2 inhibitors (SGLT2i) can be used to minimize hyperglycemia during alpelisib therapy 3
- Metformin and pioglitazone can be used as part of a stepwise, personalized antihyperglycemic regimen 2
- Insulin sensitizers, such as metformin and pioglitazone, can be used to address insulin-resistant hyperglycemia 2, 5