Management of Phosphatidylinositol-3-Kinase Inhibitor-Associated Hyperglycemia

Abstract

Phosphatidylinositol-3-kinase (PI3K) pathway hyperactivation has been associated with the development of cancer and treatment resistance. PI3K inhibitors are now used to treat hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2−), PIK3CA-mutated advanced breast cancer. Hyperglycemia, a frequently observed adverse event with PI3K inhibitors (PI3Ki), is regarded as an on-target effect because inhibition of the PI3K pathway has been shown to decrease glucose transport and increase glycogenolysis and gluconeogenesis. PI3Ki-induced hyperglycemia results in a compensatory increase in insulin release, which has been shown to reduce the efficacy of treatment by reactivating the PI3K pathway in preclinical models. Patients with an absolute or relative deficiency in insulin, and those with insulin resistance or pancreatic dysfunction, may experience exacerbated or prolonged hyperglycemia. Therefore, the effective management of PI3Ki-associated hyperglycemia depends on early identification of patients at risk, frequent monitoring to allow prompt recognition of hyperglycemia and its sequelae, and initiating appropriate management strategies. Risk factors for the development of hyperglycemia include older age (≥75 years), overweight/obese at baseline, and family history of diabetes. Consultation with an endocrinologist is recommended for patients considered high risk. The management of PI3Ki-induced hyperglycemia requires an integrative approach that combines diets low in carbohydrates and glucose-lowering medications. Medications that do not affect the PI3K pathway are preferred as the primary and secondary agents for the management of hyperglycemia. These include metformin, sodium-glucose co-transporter 2 inhibitors, thiazolidinediones, and α-glucosidase inhibitors. Insulin should only be considered as a last-line agent for PI3Ki-associated hyperglycemia due to its stimulatory effect of PI3K signaling. Clinical studies show that alpelisib-associated hyperglycemia is reversible and manageable, rarely leading to treatment discontinuation. Management of PI3Ki-associated hyperglycemia in patients with breast cancer should focus on the prevention of acute and subacute complications of hyperglycemia, allowing patients to remain on anticancer treatment longer.

Gedatolisib shows superior potency and efficacy versus single-node PI3K/AKT/mTOR inhibitors in breast cancer models

“…Some PAM inhibitors can induce systemic hyperglycemia and hyperinsulinemia if they attain high concentrations in either the liver or pancreas, or both, before being systemically distributed. Goncalves et al reviewed three steps for how PI3K pathway inhibitors can lead to sustained hyperglycemia in patients via a suppressed intracellular response to insulin: reduction in glucose uptake with glycolysis, increased glycogenolysis, and increased gluconeogenesis 34 . Multi-node PAM inhibitors like gedatolisib clearly reduce glucose consumption and glycolysis in cells more effectively than single-node PAM inhibitors.…”

Immune checkpoint inhibitor– and phosphatidylinositol-3-kinase inhibitor–related diabetes induced by antineoplastic drugs: two case reports and a literature review

“…PI3K has four subtypes (α, β, γ, and δ); the α subtype mediates most of the metabolic effects of the PI3K pathway, including insulin signaling in muscle, liver, and adipose tissues ( 26 ). The inhibition of the PI3K pathway blocks glucose uptake by skeletal and adipose tissues and promotes glycogen breakdown and liver gluconeogenesis, leading to hyperinsulinemia, hyperglycemia, and insulin resistance ( 27 ), is also the pathogenesis of type 2 diabetes ( 28 ). Although the SOLAR-1 study showed that the combination of alpelisib, an orally bioavailable PI3Kα-specific inhibitor blocking the The activation of PI3K by influencing the formation of heterodimer composed of the combination of p110 catalytic subunit and p85 regulatory subunit ( 29 )( Figure 4 ), used to treat HR + , HER2 – , PIK3CA-mutated advanced or metastatic breast cancer, and fulvestrant significantly improves progression-free survival in patients with such cancer, it also revealed that the incidence of hyperglycemia in these patients was up to 65% after medication use and that 6.3% of patients interrupted treatment due to poor blood sugar control ( 4 ).…”

“…The risk of alpelisib-induced DKA is increased and the onset of the condition is earlier in patients with long-term T2DM than in those without diabetes. Screening for diabetes risk factors before PI3Ki use and education in advance on diabetes symptoms and diagnostic criteria are recommended; PI3Ki treatment initiation is not recommended for patients with poorly controlled diabetes and those at high risk of developing hyperglycemia-related complications ( 27 ). Fasting blood glucose measurement once a week for 2 weeks before treatment initiation and monthly thereafter, and HbA1c monitoring every 3 months, are recommended.…”

“…The insulin sensitizer metformin can alleviate insulin resistance, inhibit liver gluconeogenesis and glycogen breakdown, and promote glucose uptake, but only after several weeks of use. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are recommended as second-line options and are often used in combination with metformin ( 27 ). In case 2 presented here, the patient was given alpelisib alone, alpelisib combined with insulin pump treatment, insulin pump treatment alone, alpelisib combined with metformin, and alpelisib combined with metformin and dapagliflozin, and her blood glucose level was monitored closely before and after meals to ensure the progression of the treatments’ hypoglycemic effect.…”

Molecular Cascade of Neolignan as A Natural Anti-Diabetics Agent: A Bioinformatics Approach

“…20 The impeded activity of αglucosidase disrupts the absorption of carbohydrates in the intestine, with a rapid onset of action but relatively low effectiveness. 21 Neolignans linked to 2-styryl-1,3-dioxane at 8-9' containing Torreya yunnanensis inhibited in vitro phosphodiesterase 9A (PDE9A) activity which plays a crucial role in insulin secretion. 22 Thus, neolignancontaining extract of the leaves of Eugenia sonderiana has shown remarkable effectiveness in both in vitro and in vivo for decreasing blood glucose levels and enhancing diabetic conditions through the inhibition of amylase and glucosidase activity, as evidenced in studies involving diabetic mice.…”