What Could Cortisol Tell Us About Difficult-to-Control Type 2 Diabetes?

Robert Jacks discusses why researchers are examining excess cortisol as one possible contributor to poor glucose control despite treatment with multiple diabetes therapies.

Many patients with type 2 diabetes stay above their glycemic targets despite multiple glucose-lowering therapies, which may include agents such as semaglutide, tirzepatide or empagliflozin. For clinicians and drug developers, that raises another question: what else could be contributing to poor glucose control?

One area under investigation is excess cortisol. Commonly associated with the body’s stress response, cortisol also helps regulate glucose metabolism, blood pressure, fat metabolism and other aspects of metabolic health. Although the connection between excess cortisol and impaired glucose control is well understood, its role in difficult-to-control cardiometabolic disease has received less attention.

In an exclusive interview with Xtalks, Robert Jacks, President & CEO of Sparrow Pharmaceuticals, discussed why this biology is attracting interest and its potential role in treating difficult-to-control type 2 diabetes.

Drawing on 25 years in the biopharmaceutical industry, Robert also shared how his experience in Phase II development has shaped the way he thinks about unmet medical need and the clinical questions that can help determine whether an investigational therapy offers value to patients.

Phase II Asks Whether a Therapy Can Address an Unmet Need

Robert began his pharmaceutical career at Pfizer, where he spent time in a new product development group working with programs around Phase II.

For him, this is where development begins to test a therapy’s clinical value.

“And in Phase II is when you really design clinical trials to say, can we meet the unmet medical needs?” Robert said.

This perspective has continued to guide the clinical-stage opportunities Robert pursues, particularly those with a clear clinical question and a patient need not fully addressed by existing treatments.

Sparrow is studying whether altered cortisol metabolism may be contributing to poor glucose control in some patients with type 2 diabetes despite therapy, and whether targeting that pathway could provide another treatment approach.

Cortisol Does More Than Regulate the Stress Response

Cortisol is frequently associated with stress, but it has many other functions in the body. It helps regulate blood pressure, fat and bone metabolism, sleep, mood and glucose metabolism.

Its effects on glucose involve several metabolically active tissues, including the liver, pancreas, muscle and fat. When cortisol levels become excessive, these normal regulatory functions can be disrupted, contributing to problems such as high blood pressure, fat accumulation and impaired glucose control.

The biological connection between excess cortisol and glucose dysregulation is well understood. What Robert sees as less recognized is the possible role of cortisol in people whose cardiometabolic disease is difficult to control.

“The driver in more refractory cardiometabolic disease has not been as well recognized as I think it should have been,” he said.

Excess cortisol is not expected to explain every case of difficult-to-control type 2 diabetes. Instead, researchers are examining whether excess cortisol could be one factor contributing to poor glucose control in some patients whose HbA1c stays above target, a standard measure of long-term blood glucose control, despite treatment.

Looking at the Patient Beyond HbA1c

Robert sees a growing trend toward considering related cardiometabolic conditions together instead of treating each one in isolation.

Diabetes, hypertension, abnormal lipid levels and obesity are often managed through separate clinical measures and treatments. But these conditions frequently overlap, and some of the biological processes involved can affect several aspects of metabolic health at once.

“I think that we’re trying to look at the patient holistically,” Robert said.

While HbA1c is an important measure of glucose control, changes in blood pressure, lipid levels, weight and other cardiometabolic parameters can provide additional information about how a biological pathway is affecting a patient.

Because cortisol acts across multiple tissues, studying its metabolism requires looking beyond glucose to assess a broader range of cardiometabolic measures.

Investigating What Drives Treatment Resistance

Robert said some patients are already taking three or more glucose-lowering agents, including semaglutide, tirzepatide and empagliflozin.

“What’s driving that phenomenon? Is it that these patients are not taking their medicine? Is it that these patients are not eating well?” Robert asked.

He believes other biological factors may also be at play, including excess cortisol.

Cortisol naturally rises and falls throughout the day, making a single measurement difficult to interpret.

Robert discussed the low-dose dexamethasone suppression test as one way of assessing cortisol regulation. Dexamethasone is a synthetic steroid that should suppress cortisol production in people whose cortisol system is functioning normally. When cortisol does not suppress as expected, it can indicate abnormal regulation.

Robert said Sparrow’s recent findings validated earlier research suggesting that inappropriate cortisol production may be more common in people with difficult-to-control diabetes than previously appreciated.

The company’s Phase IIb program is evaluating an investigational approach that affects cortisol metabolism in patients with difficult-to-control type 2 diabetes who show evidence of elevated cortisol.

So, what could researchers learn by looking more closely at the drivers of that resistance?

“I think if we can start to explore what is driving resistance, why are patients not responding well and then start to address some of those underlying drivers specifically, I’m very optimistic that we can continue to make gains and improve metabolic health,” Robert concluded.

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