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Healthier World with Quest Diagnostics
35 - Instant insights: Hypercortisolism in difficult-to-control type 2 diabetes (8 min)
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Foreign welcome to Healthier World with Quest Diagnostics. Our goal is to prompt action from Insight as we keep you up to date on current clinical and diagnostic topics to transform lives and illuminate a path to better health. Welcome to a special episode series called Instant Insights, a podcast episode designed to give you quick and highly impactful clinical pearls in just a few minutes More than 36 million Americans are living with type 2 diabetes and despite significant advances in the treatment landscape, an estimated 30 to 50% of patients remain uncontrolled. I'm Dr. Mason Latsko and today we're going to take a closer look at the clinical condition called hypercortisolism that may be driving difficult to control diabetes. We'll cover what difficult to control diabetes is, explain how cortisol raises blood glucose, review appropriate testing and interpretation for hypercortisolism, and discuss management options. First, let's define what we mean by difficult to control type 2 diabetes. So clinically this includes patients with an HbA1C above 7.5% despite being on three or more glucose lowering medications. Now, this definition can be extended to patients with an A1C above 7.5% who are on two or more glucose lowering medications, plus at least two antihypertensive medications, and further can describe a patient population with an elevated A1C above 7.5 who also have comorbid microvascular or macrovascular complications. So essentially difficult to control diabetes are those patients with a high A1C despite being on glucose lowering therapies. And in this population, elevated cortisol may be an under recognized contributor to persistent hyperglycemia. In fact, recent studies suggest that nearly 25% of patients with difficult to control type 2 diabetes may have hypercortisolism. So how does this happen? Physiologically, hypercortisolism, meaning chronic excessive cortisol exposure, raises blood glucose in two major ways. First, it induces insulin resistance in the liver, skeletal muscle and adipose tissue. Second, it impairs insulin secretion from the pancreas. So with impaired insulin secretion and insulin resistance, the result is sustained high blood sugar reflected in an elevated A1C that often doesn't respond as expected to standard therapies. Now, hypercortisolism exists along a spectrum. Some listeners may be familiar with something called Cushing's syndrome, for example, which represents a more severe and a well defined subset of hypercortisolism that presents with high cortisol and distinct clinical features. But even milder levels of cortisol excess can have a meaningful impact on Metabolic consequences Now that we know how Cortisol and type 2 diabetes are connected, let's talk about what hypercortisol is and how we can test for it. Cortisol itself is a glucocorticoid and it's a key component of the hypothalamic pituitary adrenal axis or the HPA axis. This is a tightly regulated feedback system designed to maintain cortisol homeostasis. Now, under normal healthy circumstances, when circulating cortisol rises, it binds to glucocorticoid receptors and that signals for the HPA axis to decrease further production of cortisol. And because cortisol follows a natural circadian rhythm, meaning it peaks early in the morning and it declines throughout the day, the HPA axis is constantly adjusting to keep this system in balance. In hypercortisolism, however, this feedback loop becomes dysregulated. Despite elevated cortisol levels and increased binding to those glucocorticoid receptors, suppression does not occur appropriately and because of this, cortisol remains high and the body remains in a chronic fight or flight metabolic state, which prioritizes glucose production and limits insulin's effectiveness. And clinically this can look a lot like difficult to control diabetes. So how do we know if a patient is experiencing hypercortisolism? This blood test can be done in a PCP setting. It involves the evaluation of cortisol as well as looking at the ability for the HPA axis to regulate that cortisol. Here's how it works. The first step is to temporarily suppress the HPA axis and see whether cortisol levels decrease as they should in a healthy system. To do this, the patient is prescribed a synthetic glucocorticoid called dexamethasone to take at 11pm in a healthy individual, dexamethasone binds to the glucocorticoid receptors in the HPA axis and signals for the HPA axis to reduce cortisol production overnight. The patient then has a blood draw the following morning to measure serum cortisol. In a patient without hypercortisolism, cortisol should be suppressed below 1.8 micrograms per deciliter. However, if morning cortisol remains elevated, hypercortisolism may be present. At that point. The next step is to confirm that dexamethasone was properly absorbed and present in circulation. This is done by measuring dexamethasone levels in the blood. Adequate levels are typically above 180 nanograms per deciliter. So to summarize if dexamethasone is taken at night, cortisol should be suppressed the next morning. If cortisol is suppressed, hypercortisolism is unlikely, but if cortisol remains elevated, clinicians must confirm that dexamethasone is actually present in circulation. And if cortisol levels are high and dexamethasone levels are high, this suggests that the normal feedback loop is not functioning properly and hypercortisolism is likely. At that point, the patient should be referred to an endocrinologist for further evaluation, and this may include differentiating causes such as Cushing's syndrome, adrenal or pituitary tumors, and even evaluating for other comorbid endocrine disorders such as hyperaldosteronism. Note that the dexamethasone suppression test should be used with extreme caution in certain populations so such as those on oral contraceptives. Given the increased rate of false positives for these patients, identification of hypercortisalism can change the course of treatment for patients with difficult to control type 2 diabetes. In fact, results from the recent Catalyst study show that mifepristone treatment lowered HbA1c values and consequently improved weight and reduced the use of glucose lowering medications in these patients. When diabetes remains uncontrolled despite appropriate escalation of therapy, it may be time to look upstream. Hypercortisolism is both testable and treatable. Assessing for this condition can make all the difference in your patients with difficult to control type 2 diabetes. That's a wrap on this episode of Healthier World with Quest Diagnostics. Please follow us on your favorite podcast app and be sure to check out Quest Diagnostics Clinical Education center for more resources, including educational webinars and research publications. Thank you for joining us today as we work to create a healthier world one life at a time.