Managing hyperglycemia and rash associated with alpelisib: expert consensus recommendations using the Delphi technique

Hyperglycemia and rash are expected but challenging adverse events of phosphatidylinositol-3-kinase inhibition (such as with alpelisib). Two modified Delphi panels were conducted to provide consensus recommendations for managing hyperglycemia and rash in patients taking alpelisib. Experts rated the appropriateness of interventions on a 1-to-9 scale; median scores and dispersion were used to classify the levels of agreement. Per the hyperglycemia panel, it is appropriate to start alpelisib in patients with HbA1c 6.5% (diabetes) to <8%, or at highest risk for developing hyperglycemia, if they have a pre-treatment endocrinology consult. Recommend prophylactic metformin in patients with baseline HbA1c 5.7% to 6.4%. Metformin is the preferred first-line anti-hyperglycemic agent. Per the rash panel, initiate prophylactic nonsedating H1 antihistamines in patients starting alpelisib. Nonsedating H1 antihistamines and topical steroids are the preferred initial management for rash. In addition to clinical trial evidence, these recommendations will help address gaps encountered in clinical practice.


Delphi panel recommendations: Prevention, monitoring, and management* Managing Hyperglycemia and Rash Associated With Alpelisib: Expert Consensus Recommendations Using the Delphi Technique
What is alpelisib?
• Alpelisib is a medicine that is given in combination with fulvestrant (a type of endocrine therapy).It is used to treat HR+, HER2− breast cancer that has spread to other parts of the body and has a mutation or change in the DNA of the PIK3CA gene • Alpelisib is given to people whose cancer got worse while on or after treatment with endocrine therapy • Some people taking alpelisib may have an increase in blood sugar levels and may get a rash

How was this study done?
In this study, we used the Delphi technique • We assembled 2 groups of 10 experts each: 1 panel for high blood sugar, and 1 panel for rash • There were 2 rounds of review for each panel.For each round, we asked experts to rate how appropriate different kinds of treatment and management strategies are for people who are taking alpelisib and experiencing high blood sugar or rash • We combined and analyzed their response scores to identify expert consensus recommendations What is the purpose of this study?
• After the FDA approves a medicine, it can be taken by more people who are not part of a clinical study • We looked at information from people treated in this setting • We then used that information to make practical recommendations for managing common side effects experienced by people taking alpelisib

High Blood Sugar Rash
How can high blood sugar be prevented while taking alpelisib?
How can rash be prevented while taking alpelisib?
How is rash treated?Doctors use two types of medicines to start treating rash: If you develop swelling in the deeper layers of the skin (known as angioedema), your doctor will ask you to: • Temporarily stop taking alpelisib and start taking steroid tablets, or High blood sugar and rash observed in people taking alpelisib 1.

Managing Hyperglycemia and Rash Associated With Alpelisib: Expert Consensus Recommendations Using the Delphi Technique
High blood sugar and rash are 2 common side effects experienced by people taking alpelisib.However, not everyone taking alpelisib will experience high blood sugar or rash, and this does not mean that the drug is not working.Half of people who experienced high blood sugar or rash first experienced them within 1 :

What are the signs and symptoms of high blood sugar?
What does rash look like in people taking alpelisib?
These recommendations are meant to be a guide, and your doctor may manage your condition differently depending on individual circumstances.Defining blood sugar status at baseline, preventing high blood sugar, and preferred medicines to manage high blood sugar 2.

Managing Hyperglycemia and Rash Associated With Alpelisib: Expert Consensus Recommendations Using the Delphi Technique
Your doctor may ask you to take a blood test called HbA1c before you start alpelisib (baseline).This lets your doctor check how much sugar you have had in your blood over the past 3 months.Your blood sugar levels will tell your doctor if you have prediabetes or diabetes:

Delphi panel recommendations
These recommendations are meant to be a guide, and your doctor may manage your condition differently depending on individual circumstances.

Does everyone taking alpelisib need to take metformin to prevent high blood sugar?
Your doctor may ask you to take metformin before you start alpelisib therapy if, based on your HbA1c, your blood sugar levels are in the range of: Metformin is the preferred first medicine that will usually be prescribed by your doctor Sodium-glucose cotransporter-2 (SGLT2) inhibitors, thiazolidinediones, or glucagon-like peptide-1 (GLP-1) receptor agonists may be prescribed as an addition to metformin (or as an alternative to metformin if you cannot take metformin) Dipeptidyl-peptidase 4 (DPP4) inhibitors may also be prescribed by your doctor if your blood sugar is still not controlled by metformin and a second drug

How is high blood sugar treated if it develops while taking alpelisib?
Your doctor may ask you to take the following types of medicines to control high blood sugar while you are on alpelisib: Insulin may be prescribed by your doctor in certain instances.However, insulin should not be used as the first or second drug to treat high blood sugar while on alpelisib Managing high blood sugar while taking alpelisib: Delphi panel recommendations 3.

Managing Hyperglycemia and Rash Associated With Alpelisib: Expert Consensus Recommendations Using the Delphi Technique
Your doctor will first check how high your fasting blood sugar is: Having high blood sugar levels while taking alpelisib does not necessarily mean you have diabetes.Taking alpelisib may cause blood sugar levels to go up in some people, but this is reversible.
The chart below summarizes expert recommendations for managing high blood sugar in people taking alpelisib.Your blood sugar may go higher than normal for a second time.If it does , and depending on how high it is, your doctor may: These recommendations are meant to be a guide, and your doctor may manage your condition differently depending on individual circumstances.

Managing Hyperglycemia and Rash Associated With Alpelisib: Expert Consensus Recommendations Using the Delphi Technique
Your doctor will check to see how much of your body is covered by the rash.Your doctor will then determine the percentage of body surface area (BSA) affected: The chart below summarizes the recommendations from experts for managing rash in people taking alpelisib.Depending on the % BSA affected by the rash, your doctor may recommend you to a dermatologist to determine if the rash is caused by alpelisib.
If your rash does not improve after 1-2 weeks, your doctor may lower your dose of alpelisib or ask you to permanently stop taking alpelisib.
These recommendations are meant to be a guide, and your doctor may manage your condition differently depending on individual circumstances.Managing Hyperglycemia and Rash Associated With Alpelisib: Expert Consensus Recommendations Using the Delphi Technique Glossary Angioedema: Swelling in the deeper layers of the skin, frequently observed in the eyelids, mouth or genitals, usually as a reaction to a medicine or something to which you are allergic.Many people will also have urticaria or hives, which is a rash that is raised and itchy Antihistamine: A type of medicine that stops the effect of histamines, a chemical released by the body as a response to a foreign substance (such as a drug), which can cause allergy symptoms such as rashes and itchy skin Dipeptidyl-peptidase 4 (DPP4) inhibitors: A class of medicines used to treat high blood sugar.Examples include alogliptin, linagliptin, and sitagliptin Endocrine therapy: A class of medicines that adds, blocks, or removes hormones.These medicines are used to stop or slow the growth of certain subtypes of breast cancer that depend on these hormones to grow and spread Endocrinologist: A doctor who specializes in treating hormone-related medical conditions, including diabetes mellitus Fulvestrant: A type of medicine classified as a hormone or endocrine therapy that is used to treat breast cancer Glucagon-like peptide-1 (GLP-1) receptor agonists: A class of medicines used to treat high blood sugar.Examples include dulaglutide, exenatide, liraglutide.and semaglutide H1 antihistamines: Medicines that stop the effect of histamines by blocking their receptors called H1 receptors.Some H1 antihistamines can cause a person to become drowsy or sleepy (drowsy or sedating antihistamines, including diphenhydramine and hydroxyzine), while some do not (non-drowsy or nonsedating antihistamines, including cetirizine, fexofenadine, levocetirizine, and loratadine) H2 antihistamines: Medicines that stop the effect of histamines by blocking their receptors called H2 receptors.Examples of H2 antihistamines include cimetidine, famotidine, and nizatidine HR+, HER2-breast cancer: A subtype of breast cancer wherein the cancer has hormone receptors (HRs) inside the cells, but the cells do not have a protein called human epidermal growth factor receptor 2 (HER2) Insulin: A type of hormone that is normally produced by the pancreas and functions to control and lower blood sugar levels.Insulin is also available as a medicine for certain people that require it Ketogenic diet: A type of diet that is very low in carbohydrates (<50 g/ day), moderate in protein, and high in fat Obese: Weight that is considered high for a given height, determined by calculating a person's body mass index (BMI).The BMI is calculated by dividing a person's weight in kilograms by the square of the person's height in meters (BMI = kg/m 2 ).A BMI of 30 kg/m2 or higher is considered obese Sodium-glucose cotransporter-2 (SGLT2) inhibitors: A class of medicines used to treat high blood sugar.Examples include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin Thiazolidinediones: A class of medicines used to treat high blood sugar.Examples include pioglitazone and rosiglitazone Topical steroid: A type of medicine that is applied to the skin to reduce inflammation and irritation.Examples include triamcinolone acetonide 0.5% and betamethasone dipropionate 0.05% Type 2 diabetes mellitus: : A medical condition in which either the body is not producing enough insulin or the cells are unable to effectively respond to or use insulin, or both.This leads to high blood glucose levels

Glossary
Reprinted from Rugo HS, et al.A multidisciplinary approach to optimizing care of patients treated with alpelisib.Breast.2022;61:156-167. 2 https://doi.org/10.1016/j.breast.2021.12.016 © 2022 Rugo HS, et al. https://creativecommons.org/licenses/by/4.0/Usually small (<1 cm), red, flat, and raised bumps on the skin Usually found on the torso, arms, and legs May be accompanied by itching or a burning sensation Vomiting Confusion The picture below shows what rash looks like in a person taking alpelisib

Fasting
My doctor says I have high blood sugar, what's next?insulin (but not as the first or second drug) fasting blood sugar level, your doctor may Ask you to delay or stop taking alpelisib Managing rash while taking alpelisib: Delphi panel recommendations 4.
My doctor assessed my rash and determined the % BSA affected, what's next?What kinds of antihistamines are used for managing rash in people taking alpelisib?or non-drowsy H1 antihistamines; your doctor may tell you to increase the dose depending on your response Depending on how your rash is responding to treatment, your doctor may tell you to use one or more of the following:Add sedating or drowsy H1 antihistamine

is blood sugar tested? How often should blood sugar be checked? Signs and symptoms of high blood sugar and rash
• Permanently stop taking alpelisib How *These recommendations are meant to be a guide, and your doctor may manage your condition differently depending on individual circumstances.Glossary 1x

Management by blood sugar level Do I need to see an endocrinologist before I start taking alpelisib?
If you do not have obesity and have normal HbA1c: No, your doctor does not need to refer you to an endocrinologist If you have type 2 diabetes mellitus, or If you are 70 years old or older, have obesity and prediabetesIf your HbA1c is 8% or higher, your doctor may need further evaluation to see if you can take alpelisib Yes, your doctor will likely refer you to an endocrinologist for evaluation before starting alpelisib