The hyperglycemia from PI3K/AKT inhibitors is due to insulin resistance, not lack of insulin. Treatment must focus on insulin sensitizers (metformin, SGLT2 inhibitors). Using agents that increase insulin secretion is counterproductive as it can reactivate the PI3K cancer pathway.
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Long-term, high-dose GLP-1 use leads to diminishing returns and significant muscle loss. A more effective strategy is using micro-doses in 90-day cycles, paired with nutritional coaching. This approach uses the drug as a temporary tool to eliminate carb cravings and establish lasting dietary habits.
Many clinicians mistakenly believe insulin's main role is blood glucose control. In reality, it's a master hormone signaling every cell—from brain to bone—to store energy. This function is so powerful it can slow the body's overall metabolic rate to prioritize energy storage.
Many chronic illnesses, including high blood pressure, cancer, and cognitive decline, are not separate issues but symptoms of a single underlying problem: chronically elevated insulin levels. This metabolic “trash” accumulates over years, making the body a breeding ground for disease.
The VICTORIA-1 trial found that gedatolisib, a pan-PI3K/mTOR inhibitor, significantly improves progression-free survival in patients with PIK3CA *wild-type* tumors after CDK4/6 inhibitor progression. This is a crucial finding for a patient group lacking clear targeted options and broadens the utility of targeting the PI3K pathway beyond just mutated tumors.
Despite the presence of PIK3CA mutations in some triple-negative breast cancer (TNBC) tumors, Phase III trials with AKT inhibitors have been negative. Currently, there is insufficient evidence to support using PI3K/AKT pathway inhibitors for TNBC in clinical practice.
The panel suggests AKT inhibitor trials in prostate cancer have been disappointing due to suboptimal biomarker selection (e.g., PTEN IHC). A similar drug in breast cancer showed significant survival benefit when using a more precise NGS-based strategy, indicating a potential path forward if the right patient population is identified genetically.
Testing for PI3K/AKT alterations at the initial diagnosis of metastatic disease, rather than waiting for progression, provides a crucial window of time. This allows clinicians to implement proactive dietary and medical strategies to mitigate future side effects like hyperglycemia before the targeted therapy is even started.
Counterintuitively, if your blood sugar doesn't spike after consuming sugar, it may not mean you're healthy. It could indicate your body is overproducing insulin to compensate, a sign of advanced insulin resistance which often precedes prediabetes.
The mechanism of GLP-1s extends far beyond fat reduction. By increasing insulin sensitivity in every cell—liver, kidney, nerve cells—they effectively help cells process insulin like they did when younger. This positions them as a pervasive longevity product, similar to statins, for pushing back on age-related decline.
The time required to enter ketosis varies dramatically. A healthy person might take a few days, but someone with years of high insulin resistance could need over two weeks of strict low-carb dieting to deplete their massive glycogen stores and begin producing ketones. This manages expectations and prevents premature failure.