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The October 2024 approval of inavolisib for advanced breast cancer spotlighted a growing problem in breast oncology: Managing the hyperglycemia caused by phosphoinositide 3-kinase (PI3K)/Akt pathway inhibitors.

Inavolisib is one of a growing class of inhibitors targeting the PI3K/Akt pathway in certain patients with advanced or metastatic breast cancer.

Targeting the pathway, however, has consequences. While the PI3K/Akt pathway is often a major player in tumor growth, it also plays a key role in insulin signaling. Blocking that pathway can induce insulin resistance, leading to a spike in blood glucose levels and ultimately hyperglycemia.

“These drugs definitely cause significant hyperglycemia that can be difficult to manage,” explained Neil Iyengar, MD, a medical breast oncologist at Memorial Sloan Kettering Cancer Center in New York City.

Challenges managing this common, often severe side effect are leading some oncologists to rethink prescribing PI3K/Akt inhibitors altogether.

Alarming Glucose Profiles

Last year, inavolisib joined alpelisib, another US Food and Drug Administration (FDA)–approved PI3Kα inhibitor, as well as a related agent, the Akt inhibitor capivasertib, approved in 2023.

The three drugs are indicated for advanced or metastatic hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer in combination regimens following progression on previous treatments. Alpelisib and inavolisib are approved specifically for tumors with PIK3CA mutations, while capivasertib is indicated for cancers with broader alterations in PIK3CA, AKT1, or PTEN. Roughly 40% of these breast cancers are driven by some form of PI3K/Akt pathway aberration.

In clinical trials, many patients receiving a PI3K/Akt inhibitor exhibited increased fasting blood glucose levels — the percent was lowest for those on capivasertib at 37% of patients, about twice that for alpelisib, and reached 85% with inavolisib, as detailed in the FDA drug labels.

Hyperglycemia occurred in 18% of patients on capivasertib, all of whom either paused or discontinued treatment; in about two thirds of those on alpelisib, with 37% pausing or discontinuing treatment; and 34.6% of those on inavolisib, with 29.2% of those interrupting or discontinuing therapy.

Hyperglycemia in patients with cancer is more than just a lab abnormality — it’s linked to worse clinical outcomes, including longer hospital stays, increased intensive care unit admissions, and higher mortality.

There’s also the rare risk of diabetic ketoacidosis, a life-threatening complication of diabetes when the body can’t make enough insulin and the body ends up producing too much acid in the blood. Diabetic ketoacidosis has reportedly occurred in 0.7% of patients receiving alpelisib and 0.3% receiving capivasertib.

“I’ve definitely seen diabetic ketoacidosis with alpelisib. It’s a serious risk with inavolisib as well. It’s theoretically possible” with capivasertib,” Iyengar said.

Given the elevated blood glucose levels and other serious risks, some oncologists are opting not to use these inhibitors.

“A lot of my colleagues have given up on this class,” Iyengar said. “It’s too hard to control the hyperglycemia, and so they’ll go to a completely different mechanism of action.” Alternative cancer agents can include the antibody drug conjugate sacituzumab govitecan, which is also indicated for pretreated HR-positive, HER2-negative disease, Iyengar said.

A Burden for Oncologists

FDA labeling for all three drugs includes baseline and ongoing monitoring of fasting blood glucose and A1c, as well as recommendations to pause treatment to address fasting blood glucose levels > 160 mg/dL for inavolisib and capivasertib and > 250 mg/dL for alpelisib.

The labeling also recommends the use of antidiabetic medications to control blood glucose levels and, for alpelisib, suggests clinicians consider pretreatment with metformin, particularly for those who are prediabetic or at increased risk of diabetes.

The requirements mean that, in addition to treating cancer, breast oncologists using the drugs also find themselves managing severe hyperglycemia, which can lead to diabetes.

“We are dealing with how to manage hyperglycemia and diabetes now because of these drugs, but we’re not experts in adjusting these medicines. It adds complexity to what we do, and patients fall through the cracks,” said Virginia Kaklamani, MD, a medical breast oncologist at The University of Texas Health Science Center at San Antonio.

For now, Kaklamani uses metformin to manage as much of the hyperglycemia from PI3K/Akt blockers as she can but avoids newer antidiabetic agents, such as glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter 2 (SGLT-2) inhibitors because she’s less familiar with them.

“I don’t know how to give the GLP-1 agonists and SGLT-2 inhibitors,” Kaklamani said.

Oncologists are often comfortable with metformin, Iyengar said, because it has the most data backing it up for PI3K/Akt hyperglycemia. “Once you go past metformin, most oncologists want to get an endocrinologist involved,” he added.

But often there aren’t many places to turn for help because there’s a nationwide shortage of endocrinologists.

“We don't have enough endocrinologists,” Kaklamani said. “It’s a problem everywhere.”

Zoe Quandt, MD, an onco-endocrinologist at the University of California, San Francisco, echoed the sentiment.

“Even at places that have more robust endocrine departments, we have long wait times,” Quandt said. On top of that, she added, endocrinologists often aren’t comfortable managing hyperglycemia from cancer treatments.

What that means is the onus often falls to breast oncologists, Iyengar said.

Some oncologists are looking beyond metformin to newer approaches. Iyengar, for instance, prefers to start patients on the SGLT2 inhibitor canagliflozin instead of metformin.

“It’s very straightforward and less tricky than metformin,” Iyengar said. “Essentially, it makes you urinate out the glucose.”

Metformin, Iyengar explained, requires titration and often high doses, raising the risk for gastrointestinal toxicity, lactic acidosis, and elevated liver enzymes. With canagliflozin, on the other hand, “you start it off at 100 mg for the first week, and then you bump it up to 300 mg, and that’s it,” Iyengar said. “In my experience, it’s an easier way to manage the hyperglycemia.”

He acknowledged canagliflozin does carry its own rare risks — like Fournier’s gangrene — but emphasized that those warnings come from patients with florid diabetes, not cancer.

Diet also plays a role, said Emily Gallagher, MD, PhD, an onco-endocrinologist at Mount Sinai Hospital in New York City.

It’s not about cutting calories but shifting away from carbohydrates to fats and other calorie sources. With insulin resistance, glucose from carbohydrates builds up in the blood because it can’t enter cells efficiently, so reducing carbohydrate intake helps, she said.

Gallagher recalled a patient on alpelisib whose blood glucose remained stubbornly high despite medications, but working with a dietician to lower carb intake made a marked difference.

“The diet was the thing that actually improved it most. Her blood sugar came down very quickly, and she was able to stay on the medication,” Gallagher said. “Hyperglycemia can be turned around pretty quickly with diet.”

Iyengar also emphasized the importance of proactive planning. Most patients are on endocrine therapy for a year or more before progressing to second-line PI3K/Akt inhibitors — creating an opportunity.

“If you know a patient has a PI3 kinase mutation and you’re going to be using one of these drugs in the second line, you have all of that time in the first line, usually at least 1.5-2 years, to optimize their A1c and their glycemic status, and you can do that through lifestyle interventions,” Iyengar said.

“If you can’t get their A1c down, then refer them to an endocrinologist early. Don’t wait until you start one of these drugs” to address the issues, he said.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape Medical News. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com