What are the treatment options for hypercortisolism (Cushing's syndrome) as a cause of uncontrolled diabetes mellitus?

From the Guidelines

Treating hypercortisolism is crucial for managing uncontrolled diabetes, and the primary approach involves addressing the underlying cause of hypercortisolism, with the goal of rapid normalization of cortisol levels. The most recent and highest quality study, published in 2021 in The Lancet Diabetes and Endocrinology 1, recommends that for patients with severe disease, rapid normalization of cortisol is the most important goal, and medications like osilodrostat and metyrapone can achieve this within hours.

Key Considerations

• For patients with severe hypercortisolism, combinations of steroidogenesis inhibitors may be necessary, as stated in the 2021 guideline update 1.
• If hypercortisolism is very severe and not responsive to optimized medical therapy, including combinations, Bilateral Adrenalectomy (BLA) should be considered to avoid worsening outcomes, as recommended in the same guideline update 1.
• During treatment, diabetes management should be intensified with insulin therapy, as oral agents are often insufficient, and blood glucose typically improves as cortisol levels normalize, but diabetes medications should be adjusted gradually to prevent hypoglycemia.

Treatment Approach

• The treatment approach should prioritize the underlying cause of hypercortisolism, which may be Cushing's syndrome from pituitary adenoma, adrenal tumor, or exogenous steroid use.
• For pituitary-dependent Cushing's, first-line treatment is typically transsphenoidal surgery to remove the adenoma, as recommended in the 2021 consensus on diagnosis and management of Cushing's disease 1.
• If surgery isn't possible or fails, medications like ketoconazole, metyrapone, or mifepristone can reduce cortisol production or block its effects.

Monitoring and Adjustment

• Patients require close monitoring of both cortisol levels and blood glucose during treatment, as the relationship between these parameters is dynamic.
• Diabetes medications should be adjusted gradually to prevent hypoglycemia, and the treatment plan should be tailored to the individual patient's needs and response to therapy.

From the FDA Drug Label

Treatment of patients with poorly controlled diabetes mellitus should be intensively optimized with anti-diabetic therapy prior to starting SIGNIFOR [see Warnings and Precautions (5.2)]. In patients with uncontrolled diabetes mellitus, optimize anti-diabetic therapy prior to SIGNIFOR initiation. If hyperglycemia develops, initiate or adjust anti-diabetic treatment per standard of care. If uncontrolled hyperglycemia persists despite appropriate treatment, reduce the dose or discontinue SIGNIFOR and perform glycemic monitoring according to clinical practice

Treating hypercortisolism as a cause of uncontrolled diabetes with pasireotide (PO) requires:

• Intensive optimization of anti-diabetic therapy prior to starting treatment
• Close monitoring of glycemic status
• Adjustment of anti-diabetic treatment as needed
• Consideration of dose reduction or discontinuation of pasireotide if uncontrolled hyperglycemia persists despite appropriate treatment 2

From the Research

Treating Hypercortisolism as a Cause of Uncontrolled Diabetes

• Hypercortisolism is a condition characterized by excessive cortisol secretion, which can lead to various health problems, including uncontrolled diabetes 3.
• The prevalence of hypercortisolism in patients with uncontrolled diabetes is estimated to be around 5% 4.
• Measuring cortisol after a 1 mg overnight dexamethasone suppression test is the first-line test for diagnosing hypercortisolism, and additional tests such as basal morning plasma adrenocorticotroph hormone, 24-h urinary free cortisol, and late-night salivary cortisol may be used to confirm the diagnosis 3.
• Treatment options for hypercortisolism include surgery, medical therapy, and lifestyle modifications.
• Surgery is considered a possible therapeutic option in patients with unilateral adrenal incidentalomas and hypercortisolism, as it can improve diabetes and hypertension and reduce the risk of fractures 3.
• Medical therapy, such as steroidogenesis inhibitors (e.g., metyrapone, osilodrostat, and levoketoconazole) and glucocorticoid receptor antagonists (e.g., mifepristone and relacorilant), may be used to treat hypercortisolism, especially in patients who are not candidates for surgery or have bilateral adrenal adenomas 3, 5.
• Pasireotide, a multireceptor ligand somatostatin analog, has been approved for the treatment of Cushing's disease and may be used in combination with other medications to achieve better control of cortisol secretion 6.

Management of Hypercortisolism in Diabetes

• Early diagnosis and treatment of hypercortisolism are crucial to prevent long-term complications, such as cardiovascular events, mortality, and uncontrolled diabetes 7.
• The treatment of hypercortisolism in patients with diabetes should be individualized, taking into account the underlying cause of hypercortisolism, the presence of other health problems, and the patient's overall health status.
• A multidisciplinary approach, involving endocrinologists, surgeons, and other healthcare professionals, may be necessary to manage hypercortisolism in patients with diabetes effectively.
• Further research is needed to determine the optimal treatment strategies for hypercortisolism in patients with diabetes and to develop new therapies that can improve outcomes in these patients 3, 7, 4.