Examining the Clinical Impact of Hypercortisolism in Patients

Diagnosis and Causes of Hypercortisolism

Introduction

Hypercortisolism is a condition that results from chronic exposure to excess glucocorticoids.¹ Exogenous, endogenous, or cyclic steroid exposure can result in hypercortisolism, and hypercortisolism is associated with an extensive list of comorbidities, including cardiovascular disease, metabolic disorders, mood changes, and musculoskeletal changes.^1,2 As such, early recognition is crucial to prevent associated morbidity and mortality in affected patients.¹

Clinical Presentation

Some of the most common clinical signs of hypercortisolism include weight gain, facial rounding (commonly referred to as moon face), facial plethora, and muscle weakness and atrophy.² Hypercortisolism may also present with comorbidities; some of the most prevalent include hypertension, obesity, insulin resistance and glucose intolerance, neuropsychiatric changes, hyperlipidemia, and hypogonadotropic hypogonadism.² Symptoms can be subtle (nonspecific) and variable depending on several factors such as patient age, sex, and duration of cortisol excess; therefore, a high index of suspicion is necessary.² Hypercortisolism can also present very similarly to other pseudo-Cushing states, such as obesity and polycystic ovary syndrome.²

Testing for hypercortisolism is recommended in certain patients, such as those with adenomas; Cushingoid-related features uncommon for their age, such as early onset hypertension; patients with multiple symptoms that have been progressive over time; or pediatric patients with a combination of increasing weight and decreasing height.² A higher suspicion of hypercortisolism should also be considered in patients with difficult-to-control chronic conditions such as diabetes, hypertension, and obesity.² As such, clinicians should have a low threshold for hypercortisolism in these less traditional patient presentations and consider diagnostic screening.²

Diagnostic Evaluation

In patients with suspected hypercortisolism in whom exogenous glucocorticoid use is excluded, 1 of 3 initial first-line screening tests should be performed.² Initial screening tests include a 24-hour urinary free cortisol (UFC), a late-night salivary cortisol (LNSC), or a low-dose dexamethasone suppression test (DST).² Each initial screening test has caveats for use. Due to day-to-day cortisol variations, UFC and LNSC should be performed at least twice.² The UFC requires a high degree of patient adherence, and false negatives can result in patients with renal impairment.² The LNSC can be falsely positive with night-shifts, variable bedtimes, and in patients chewing or smoking tobacco or with licorice supplementation/ingestion.² The DST suppresses corticotropin-releasing hormone-adrenocorticotropic hormone (ACTH) secretion in normal individuals, and following dexamethasone administration, cortisol levels will be less than 50 nmol/l in normal individuals.³ The DST is 85% to 90% sensitive and 95% to 99% specific, indicating a strong negative predictive value.³ However, the DST has high interpatient variations due to variable clearance of dexamethasone, which other medications, alcohol, liver, or renal failure can impact.² It has a high positive rate in patients on estrogen-containing medications and in those who are pregnant.² DST may also be falsely negative in patients with low albumin, such as those with nephrotic syndrome, critical illness, and malnutrition.² If the results of initial screening tests are normal, hypercortisolism is unlikely, and reevaluation can be considered in 6 months if the condition is likely or suspected.² If the results are abnormal, then confirmatory testing with the initial screening tests should be reperformed. If the results are then abnormal, the diagnosis of endogenous hypercortisolism is made.²

Determining Etiology

Following the diagnosis of hypercortisolism, a morning ACTH plasma level can be drawn and evaluated to determine the etiology and whether the disease is ACTH-dependent or ACTH-independent.^2,3 ACTH-dependent hypercortisolism results from ACTH excess either from a pituitary or nonpituitary (ectopic) source or tumor.⁴ Imaging studies with pituitary MRI can help to detect pituitary adenomas, which may be responsible for ectopic ACTH secretion and account for a common cause of ACTH-dependent hypercortisolism.² ACTH-independent primary adrenal overproduction of cortisol can result from adenomas, carcinomas, and bilateral macronodular or micronodular hyperplasia.⁴ An 8-mg dexamethasone suppression test should also be considered in those with normal or elevated ACTH.⁴ Measurement of dehydroepiandrosterone sulfate (DHEAS) concentration and a corticotropin-releasing hormone (CRH) test can be helpful for differentiating adrenal from pituitary causes in ACTH-independent hypercortisolism.² Adrenal gland imaging with computed MRI should then be undertaken to identify masses.⁴ These additional factors for identifying etiology are essential to allow surgical resection of abnormal ACTH- or cortisol-producing tissue or tumors to allow for remission of hypercortisolism.⁴

Follow-Up and Monitoring

After establishing diagnosis and etiology, surgery is often undertaken, or medical therapy may be implemented to normalize cortisol levels.⁴ Regular monitoring for comorbid conditions, including weight assessment, blood glucose levels, and blood pressure measurement, is essential in patients with hypercortisolism.⁵ Regular monitoring of the therapeutic efficacy of disease management should be conducted, including measurement of cortisol, except in patients on mifepristone medical therapy.⁵ Morning cortisol and/or LNSC may be considered for efficacy monitoring and to determine if a change in treatment regimen is required.⁵

Chronic Effects of Hypercortisolism

Although long-term remission of hypercortisolism often results in improvement in comorbidities, the risk of these may persist even after normalization of excess cortisol levels (remission).⁶ Persistent effects of hypercortisolism can include worsened cardiometabolic risk from hypertension, diabetes, and dyslipidemia.⁶ Patients in long-term remission may have higher rates of central adiposity and low-grade inflammation compared with matched control patients, leading to increased cardiovascular risk despite long-term remission. A risk of thromboembolic events is associated with hypercortisolism, and the risk of venous thromboembolism in the postoperative period may be similar to that of patients undergoing major orthopedic surgery.⁶ It remains to be seen whether thrombogenic comorbidities are resolved by long-term remission of hypercortisolism.⁶ As cortisol excess impacts bone metabolism, the prevalence of osteoporosis and nontraumatic fractures is high in patients with hypercortisolism.⁶ Data regarding the reversibility of worsened bone mineral density metrics due to hypercortisolism are contradictory.⁶ There is supporting literature that long-term muscle morbidity following normalization of cortisol levels persists.⁶ Patients with hypercortisolism are more likely to experience psychiatric symptoms, including anxiety and depression, which significantly impact quality of life.⁶ Evidence on the resolution of these symptoms is mixed; while some studies describe residual impairment as evidenced by antidepressant and hypnotic use, others describe normalization of depression rates.⁶ However, cognitive test performances in some studies are not different between patients in hypercortisolism remission compared to healthy controls.⁶ Finally, increased mortality rates are associated with those who do not achieve remission following surgery.⁶

Prevalence of Hypercortisolism in Difficult-to-Control Type 2 Diabetes

Introduction

Type 2 diabetes (T2D) may remain uncontrolled despite multiple glucose-lowering medications. When adherence has been verified, other contributing factors to the inability to meet glycemic targets should be considered.⁷ Hypercortisolism, characterized by elevated cortisol levels, may contribute to poor glycemic control in T2D patients due to impaired beta cell function, inhibiting insulinotropic effects of glucagon-like peptide (GLP-1) or glucose-dependent insulinotropic polypeptide (GIP), and increasing hepatic glucose output.⁷

Study Objective

CATALYST (NCT05772169) was a prospective study designed to assess the prevalence of hypercortisolism in individuals with difficult-to-control T2D.⁷

Research Design and Methods

This was a prospective, observational study involving adult participants with T2D and HbA_1c levels between 7.5% and 11.5%.⁷ Participants were uncontrolled despite taking multiple standard-of-care therapies, which were defined as either taking 3 or more glucose-lowering medications, taking insulin and any other glucose-lowering medications; taking 2 or more glucose-lowering medications and experiencing 1 or more microvascular or macrovascular complications, or taking 2 or more glucose-lowering medications plus 2 or more blood pressure-lowering medications.⁷ Patients were excluded if taking a medication or experiencing a condition that may have resulted in a false-positive dexamethasone suppression test (DST).⁷ Screening for hypercortisolism was conducted using a 1-mg DST, with a cutoff of greater than 1.8 mcg/dL.⁷ This was confirmed with serum dexamethasone levels greater than or equal to 140 ng/L to ensure adequate adherence and absorption of dexamethasone.⁷

Key Findings

One thousand fifty-seven participants were screened in the CATALYST trial,⁷ and hypercortisolism was identified in 23.8% of participants.⁷ A higher prevalence of cardiac disorders overall (33.3%) was seen in patients with T2D and hypercortisolism.⁷ Patients with T2D and hypercortisolism also had a significantly higher prevalence of coronary artery disease (16.7%), atrial fibrillation (8.3%), congestive heart failure (6.7%), vascular disorders (90.5%), and hypertension (89.3%).⁷ Patients with hypertension and hypercortisolism were more likely to be taking 3 or more blood pressure-lowering medications (36.6%).⁷

Adrenal imaging abnormalities were present in 34.7% of participants with hypercortisolism and T2D.⁷ Patients with hypercortisolism and T2D also had a significant increase in likelihood of being on certain antidiabetic medications (sodium-glucose cotransporter 2 [SLGT2] inhibitors, glucagon-like peptide-1 [GLP-1] receptor agonists, or tirzepatide).⁷ Patients with T2D and hypercortisolism were also more likely to be older, have a BMI less than 30 kg/m², and be of non-Latino/Hispanic ethnicity.⁷ They were also more likely to be on other medication types: any lipid medication (including statins and fibrates), analgesic medications, psychiatric medications, and other cardiovascular medications, including peripheral vasodilators and vasoprotective medications.⁷

Study Conclusions

Based on the results of this study, hypercortisolism appears to be prevalent among individuals with difficult-to-control T2D. Patients with T2D and hyper-cortisolism also seemed to have several comorbidities, such as cardiovascular disorders and psychiatric disorders, and were on more medications to control these conditions. Screening for hypercortisolism may be beneficial in managing patients with T2D who do not achieve glycemic targets despite multiple medications.

Pharmacist Support

Pharmacists can provide support in several key areas in the management of hypercortisolism, including confirming appropriate medication management and dosing; monitoring for efficacy and toxicity of medication management; providing guidance on dose adjustment for drug interactions; educating patients on medication therapy, such as how to identify efficacy and what adverse effects to expect; educating patients on the importance of seeking medical attention for symptoms suggestive of adrenal insufficiency; advising on emergency hydrocortisone use; and referring patients to community resources and support.⁸

Pharmacists play a crucial role in managing common comorbidities associated with hypercortisolism, including lipid-modifying medication therapy management, cardiovascular risk management, and T2D management. As part of an interprofessional team, pharmacists can develop and implement screening mechanisms for patients with uncontrolled comorbidities to identify undetected hypercortisolism. Hypercortisolism screening should be considered in patients whose combination of multiple diabetic medications has failed or who have diabetes and cardiovascular comorbidities, such as those identified in the CATALYST trial. Key medication indicators for the need for screening could include prescription of medications such as SGLT2 inhibitors, GLP-1 agonists, and tirzepatide, or those patients on 2 or more glucose-lowering medications, 2 or more glucose-lowering medications with micro- or macrovascular complications, or those with 2 or more glucose-lowering medications plus 2 or more blood pressure-lowering medications. Instead of a switch to insulin therapy, patients may be more successful initiating management for hypercortisolism.

Conclusion

Hypercortisolism results from exposure to exogenous, endogenous, or cyclic steroids. Patients presenting with either the classic clinical signs of hypercortisolism, including weight gain, facial rounding, and muscle changes, may only represent a portion of those who require screening and intervention. The prevention of comorbidities of hypercortisolism, including hypertension, obesity, insulin resistance and glucose intolerance leading to T2D, neuropsychiatric changes, hyperlipidemia, and hypogonadotropic hypogonadism, is important for addressing the significant morbidity and mortality associated with the disease. Patients with hypercortisolism who are considered in remission may require continued monitoring due to a potential for persistent risk.

In patients with suspected hypercortisolism in whom exogenous glucocorticoid use is excluded, 1 of 3 initial first-line screening tests should be performed (UFC, LNSC, or DST). However, each screening test is susceptible to inaccurate results in certain patient groups. A high suspicion of hypercortisolism should be considered in patients with difficult-to-control chronic conditions such as T2D. Key medication and therapy indicators can be used to identify those patients who may have undiagnosed hypercortisolism. Pharmacists can be essential in the identification and management of these patients.

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