Hyperglycemia

Patient Evaluation
Patient Counseling
Patient Monitoring
Medical Intervention

Patient Evaluation

Identify candidates for capivasertib treatment during first-line mBC treatment or earlier to optimize glycemic status.

Hyperglycemia risk factors

BMI ≥30 kg/m²
History of pre-diabetes/diabetes
Use of concomitant medications known to increase FG, such as systemic corticosteroids
Systemic infection
Dehydration

If the patient is being treated with oral/systemic steroids, proactively intensify FG monitoring

Additional glucose testing 1–2 days after steroid initiation

Early assessment of eligible patients

Identify patients who have a PIKC3A, AKT1, and/or PTEN alteration prior to progression on first-line ET to optimize glycemic status.

Control fasting glucose (FG) during first-line therapy

Monitor and control FG levels during first-line therapy to achieve glycemic control, if needed.

Pre-exisiting hyperglycemia

Evaluate and treat pre-existing hyperglycemia and ensure that HbA1C <8%.

Assessing hyperglycemia risk factors

Screen for hyperglycemia risk factors:

Consider endocrinology consultation for patients with risk factors for hyperglycemia

Patient Counseling

Educate patients on dietary and lifestyle modifications, as well as the signs and symptoms of hyperglycemia that require immediate medical attention.

Inform patients that the median time to onset of hyperglycemia is 15 days (range, 1–51 days).

The potential for capivasertib-associated hyperglycemia and symptoms requiring urgent care

Inform patients about the potential for capivasertib to cause hyperglycemia and instruct them to notify the healthcare team at the first occurrence of symptoms of hyperglycemia.

View Incidence

Hyperglycemia signs and symptoms

Excessive thirst
Increased frequency of urination
Blurred vision
Increased appetite
Weight loss and fatigue

Signs and symptoms of hyperglycemia that require immediate medical attention:

Confusion
Difficulty breathing
Nausea
Vomiting
Fruity odor on breath

Lifestyle modifications

Encourage patients to make the following lifestyle adjustments:

Low carbohydrate + high fiber diet
Engage in regular physical activity
Avoid substantial weight gain
Limit alcohol consumption

Tailor recommendations to patient needs

Tailor diet and physical activity recommendations to individual patient needs and consider metabolic status.

Hyperglycemia – incidence

Frequency of increased fasting glucose, time to occurrence, and dose modification of hyperglycemia under treatment with capivasertib + fulvestrant in CAPItello-291
¹

1. Iyengar NM, O'Shaughnessy JA, Moore HN, et al. Optimizing clinical monitoring and management guidelines for capivasertib in HR-positive/HER2-negative advanced breast cancer: expert opinion. npj Breast Cancer. 2025;12(1):16. doi:10.1038/s41523-025-00864-2.

	Capivasertib + fulvestrant Overall population (n=355)
Increased fasting glucose %*	37.0
Grade 2 (FG >160 to 250 mg/dL)	11.0
Grade 3 (FG >250 to 500 mg/dL)	2.0
Grade 4 (FG >500 mg/dL)	1.1
Median days to the first occurrence of hyperglycemia	15 (range 1–51)
Diabetic ketoacidosis %	0.3
Diabetic metabolic decompensation %	0.6
Hyperglycemia leading to dose modification %
Dose interruption	2.5
Dose reduction	0.6
Permanent discontinuation	0.6

Values in the PI may differ slightly from those reported in the Capivasertib Expert Opinion publication due to different cut-off dates and the inclusion of different preferred terms.

*AR grading for increased fasting glucose follows CTCAE V4.03.

1. Iyengar NM, O'Shaughnessy JA, Moore HN, et al. Optimizing clinical monitoring and management guidelines for capivasertib in HR-positive/HER2-negative advanced breast cancer: expert opinion. npj Breast Cancer. 2025;12(1):16. doi:10.1038/s41523-025-00864-2.

Patient Monitoring

Upon treatment with capivasertib, monitor FG pre-dose on day 3 or 4 of the treatment week during weeks 1, 2, 4, 6, and 8, and then monthly thereafter.

Monitoring guidance for FG, HbA1C, and hyperglycemia risk factors

Intensified antihyperglycemic therapy and closer FG monitoring may be required in patients with a history of well-controlled T2D. Closely monitor patients with risk factors for hyperglycemia.

If patients can self-monitor at home, assist in obtaining necessary supplies and educate on their correct use, providing clear instructions on appropriate testing.

Provide teaching sessions with a calendar to track FG levels, with instructions on when and how to report results to the clinic.

Instruct patients to notify the healthcare team if FG level ≥160 mg/dL.

Establish workstreams within the clinical team to monitor, triage, and manage elevated FG results.

Medical Intervention

Consider prophylaxis with metformin for patients at elevated risk of developing hyperglycemia (ie, HbA1C ≥5.7%, prediabetes, BMI ≥30 kg/m2, elevated baseline FG). Start or escalate metformin and add other agents to treat hyperglycemia.

Prophylaxis with metformin

Prophylactic use of insulin sensitizers, such as metformin, can mitigate PI3K/AKT inhibitor-induced hyperglycemia.

Assess eGFR before initiating metformin

In patients with eGFR >30 mL/min/1.73 m2, or as indicated per local institutional protocols, withhold metformin prior to contrast imaging and 48 hours after imaging to minimize the risk of acute kidney injury

Metformin dosing guidance

Initiate prophylactic extended-release metformin 500 mg/day one week before initiating capivasertib, escalating to 2000 mg/day as needed and tolerated for patients at elevated risk for hyperglycemia
Standard release metformin can be utilized at a dose of 500 mg/day, escalating to 1000 mg BID as needed and tolerated
Extended-release metformin may reduce the risk of metformin-related diarrhea in combination with capivasertib

Capivasertib dose modifications:

Maintain same dose

PI Recommendation

Begin treatment with extended-release or standard-release metformin 500 mg/day escalating as outlined above.

Capivasertib dose modifications:

Initial dose modification:

Withhold dose until FG decreases to <160 mg/dL or ≤8.9 mmol/L

Dosing at recovery: If FG 161-250 mg/dL or 9–13.9 mmol/L

Recovery ≤28 days – resume at the same dose
Recovery >28 days – resume at one lower dose

If FG 251-500 mg/dL or 14–13.9 mmol/L

Recovery ≤28 days – resume at one lower dose
Recovery >28 days – permanently discontinue

PI Recommendation

Patients not receiving metformin

Initiate extended-release metformin at 2000 mg QD if FG 161–250 mg/dL, or 1000 mg QD if FG 251–500 mg/dL
Alternatively, initiate standard release metformin at 500 mg/day and escalate to 1000 mg BID as needed and tolerated

Patients already taking prophylactic metformin

Consider dose escalation and endocrinology consultation

Consider additional agents that do not impact the PI3K/AKT/PTEN pathway if FG remains high despite metformin or if metformin dose escalation is limited by toxicities. The additional agents that can be used in combination with metformin include: SGLT2i:

Ertugliflozin 15 mg QD
Dapagliflozin 5 mg or 10 mg QD
Empagliflozin 25 mg QD
Canagliflozin 100 mg QD for 1 week, escalating to 300 mg QD if needed

TZD:

Pioglitazone starting at 15 mg QD with escalation to a maximum of 30 mg QD

α-glucosidase inhibitors:

FG 161–250 mg/dL or 9–13.9 mmol/L and FG 251–500 mg/dL or 14–27.8 mmol/L - Acarbose 25 mg TID, escalating to a maximum of 100 mg TID if needed
FG >500 mg/dL (27.8 mmol/L) or life-threatening complications of hyperglycemia at any FG level - Acarbose 50 mg BID, escalating to a maximum of 100 mg TID if needed

Avoid insulin secretagogues such as sulfonylureas, GLP-1R agonists, dipeptidyl peptidase-4 inhibitors, and meglitinides, as they are associated with AEs such as GI AEs (GLP-1R agonists) and hypoglycemia

Monitoring euglycemic DKA in patients receiving SGLT2i

In patients receiving SGLT2i, monitor for euglycemic DKA and advise urgent care if DKA symptoms appear. Monitor for DKA by measuring:

Serum bicarbonate
Electrolytes
Ketones
Anion gap
White blood cell count

FG >400 mg/dL (22.2 mmol/L)

Insulin (0.1 U/kg/h) for the shortest required duration to normalize blood glucose while optimizing the dose of other agents

Capivasertib dose modifications:

Initial dose modification:

Withhold dose

Dosing at recovery:

If FG ≤500 mg/dL (or ≤27.8 mmol/L) within 24 hours, then follow the guidance in the table for the relevant grade above
For life-threatening sequelae of hyperglycemia or if FG persists at ≥500 mg/dL after 24 hours, permanently discontinue capivasertib

PI Recommendation

Aggressive hydration with electrolyte management as clinically indicated, and insulin (0.9 U/kg/h) for shortest required duration before optimizing other agents. Once blood glucose stabilizes, optimize FG with metformin and second-line agents as clinically indicated.

Permanently discontinue capivasertib for confirmed DKA, or if FG persists at ≥500 mg/dL for ≥24 hours

Important Safety Information

TRUQAP is contraindicated in patients with severe hypersensitivity to TRUQAP or any of its components.

Hyperglycemia

TRUQAP can cause severe hyperglycemia, including diabetic ketoacidosis and fatal outcomes.

Increased fasting glucose (FG) from baseline occurred in 37% of patients treated with TRUQAP, including 11% of patients with Grade 2 (FG >160 to 250 mg/dL), 2% with Grade 3 (FG >250 to 500 mg/dL), and 1.1% with Grade 4 (FG >500 mg/dL) events. The median time to first occurrence of hyperglycemia was 15 days (range: 1 to 367). Dose reduction for hyperglycemia was required in 0.6% of patients and permanent discontinuation was required in 0.6% of patients. Diabetic metabolic decompensation occurred in 0.6% of patients, including diabetic ketoacidosis in 0.3%.

In CAPItello-291, 12% (43/355) of patients who received TRUQAP had an anti-hyperglycemic medication either initiated or changed during the study, including treatment with insulin in 4.8% (17/355) of patients.

The safety of TRUQAP has not been established in patients with Type 1 diabetes or Type 2 diabetes that is uncontrolled or requiring insulin at baseline as these patients were excluded from clinical studies. Before initiating treatment with TRUQAP, test fasting glucose levels (fasting plasma glucose or fasting blood glucose), hemoglobin A1C (HbA1C) levels, and optimize fasting glucose. After initiating treatment with TRUQAP, monitor or self-monitor FG levels on Day 3 or 4 of the dosing week during weeks 1, 2, 4, 6, and 8; then monthly while on treatment with TRUQAP; and as clinically indicated. Monitor HbA1C levels every 3 months during treatment with TRUQAP and as clinically indicated. Patients with a history of well-controlled Type 2 diabetes mellitus may require intensified anti-hyperglycemic treatment and close monitoring of FG levels.

For patients who experience hyperglycemia during treatment with TRUQAP, monitor FG at least twice weekly, on days on and off TRUQAP, until FG decreases to baseline levels. During treatment with anti-diabetic medications, monitor FG at least once a week for 2 months, followed by once every 2 weeks, or as clinically indicated. Consider consultation with a healthcare practitioner with expertise in the treatment of hyperglycemia and initiation of FG monitoring at home for patients who have risk factors for hyperglycemia or who experience hyperglycemia. Advise patients on the signs and symptoms of hyperglycemia and counsel patients on lifestyle changes.

Withhold TRUQAP immediately when ketoacidosis is suspected. If ketoacidosis is confirmed, permanently discontinue TRUQAP. Withhold TRUQAP in clinical situations known to increase the risk of severe hyperglycemia or ketoacidosis (eg, suspected serious infection or acute illness). Based on the severity of hyperglycemia, withhold, reduce dose, or permanently discontinue TRUQAP.

Diarrhea

TRUQAP can cause severe diarrhea associated with dehydration.

Diarrhea occurred in 72% of patients. Grade 3 or 4 diarrhea occurred in 9% of patients. The median time to first occurrence was 8 days (range: 1 to 519). In the 257 patients with diarrhea, 59% required antidiarrheal medications to manage symptoms. Dose reductions were required in 8% of patients and 2% of patients permanently discontinued TRUQAP due to diarrhea. In patients with Grade ≥2 diarrhea (n=93) with at least 1 grade improvement (n=89), median time to improvement from the first event was 4 days (range: 1 to 154).

Monitor patients for signs and symptoms of diarrhea. Advise patients to increase oral fluids and start antidiarrheal treatment at the first sign of diarrhea while taking TRUQAP. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity.

Cutaneous Adverse Reactions

TRUQAP can cause cutaneous adverse reactions, which can be severe, including erythema multiforme (EM), palmar-plantar erythrodysesthesia (PPE), and drug reaction with eosinophilia and systemic symptoms (DRESS).

Cutaneous adverse reactions occurred in 58% of patients. Grade 3 or 4 cutaneous adverse reactions occurred in 17% of patients receiving TRUQAP. EM occurred in 1.7% of patients and DRESS occurred in 0.3% of patients. Dose reduction was required in 7% of patients and 7% of patients permanently discontinued TRUQAP due to cutaneous adverse reactions.

Monitor patients for signs and symptoms of cutaneous adverse reactions. Early consultation with a dermatologist is recommended. Withhold, dose reduce, or permanently discontinue TRUQAP based on severity.

Embryo-Fetal Toxicity

Based on findings from animals and mechanism of action, TRUQAP can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRUQAP and for 1 month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRUQAP and for 4 months after the last dose.

TRUQAP is used in combination with fulvestrant. Refer to the full Prescribing Information of fulvestrant for pregnancy and contraception information.

Among the 355 patients who received TRUQAP in CAPItello-291, the most common (≥20%) adverse reactions, including laboratory abnormalities, were diarrhea (72%), cutaneous adverse reactions (58%), increased random glucose (57%), decreased lymphocytes (47%), decreased hemoglobin (45%), increased fasting glucose (37%), nausea and fatigue (35% each), decreased leukocytes (32%), increased triglycerides (27%), decreased neutrophils (23%), increased creatinine (22%), vomiting (21%), and stomatitis (20%).

In the 155 patients with PIK3CA/AKT1/PTEN alterations treated with TRUQAP + fulvestrant, dose reductions due to adverse reactions were reported in 21% of patients. Permanent TRUQAP discontinuation due to an adverse reaction occurred in 10% of patients. Dose interruptions of TRUQAP occurred in 39% of patients.

Strong CYP3A Inhibitors: Avoid concomitant use with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce the dose of TRUQAP and monitor patients for adverse reactions.

Moderate CYP3A Inhibitors: When concomitantly used with a moderate CYP3A inhibitor, reduce the dose of TRUQAP and monitor patients for adverse reactions.

Strong or Moderate CYP3A Inducers: Avoid concomitant use of TRUQAP with strong or moderate CYP3A inducers.

TRUQAP in combination with fulvestrant is indicated for the treatment of adult patients with hormone receptor (HR)‑positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN alteration as detected by an FDA-authorized test following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.

Please see full Prescribing Information, including Patient Information for TRUQAP.

You may report side effects related to AstraZeneca products

ADL	activities of daily living
AE	adverse event
AKT1/2/3	serine/threonine protein kinase 1/2/3
BID	twice daily
BMI	body mass index
BSA	body surface area
CYP3A	cytochrome P450, family 3, subfamily A
DKA	diabetic ketoacidosis
DRESS	drug reaction with eosinophilia and systemic symptoms
eGFR	estimated glomerular filtration rate
EM	erythema multiforme
ET	endocrine therapy
FDA	US Food and Drug Administration
FG	fasting glucose
GI	gastrointestinal

GLP-1R	glucagon-like peptide-1 receptor
HbA1c	hemoglobin A1C
HCP	healthcare professional
IV	intravenous
mBC	metastatic breast cancer
PI3K	phosphoinositide 3-kinase
PIK3CA	phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
PTEN	phosphatase and tensin homolog
QD	once daily
SGLT2i	sodium-glucose co-transporter-2 inhibitor
spp	species
T2D	type 2 diabetes
TID	three times daily
TZD	thiazolidinedione
ULN	upper limit of normal

2. TRUQAP. Prescribing information.

3. Rugo HS, Oliveira M, Howell SJ, et al. Capivasertib and fulvestrant for patients with hormone receptor-positive advanced breast cancer: characterization, time course, and management of frequent adverse events from the phase III CAPItello-291 study. ESMO Open. 2024;9(9):103697. doi:10.1016/j.esmoop.2024.103697.

Hyperglycemia

Summary PDF:

Early assessment of eligible patients

Control fasting glucose (FG) during first-line therapy

Pre-exisiting hyperglycemia

Assessing hyperglycemia risk factors

Lifestyle modifications

Tailor recommendations to patient needs

Hyperglycemia – incidence

Prophylaxis with metformin

Assess eGFR before initiating metformin

Metformin dosing guidance

Capivasertib dose modifications:

Capivasertib dose modifications:

Patients not receiving metformin

Patients already taking prophylactic metformin

Monitoring euglycemic DKA in patients receiving SGLT2i

FG >400 mg/dL (22.2 mmol/L)

Capivasertib dose modifications:

Permanently discontinue capivasertib for confirmed DKA, or if FG persists at ≥500 mg/dL for ≥24 hours

Important Safety Information

IMPORTANT SAFETY INFORMATION ABOUT TRUQAP® (capivasertib) tablets

ADVERSE REACTIONS

DRUG INTERACTIONS

INDICATION AND USAGE

Abbreviations

References