UNDERSTANDING CUSHING’S SYNDROME
Prevalence & Impact
Endogenous Cushing’s syndrome (CS) presents a rare challenge with a significant impact
As a serious endocrine disease caused by excess cortisol levels (hypercortisolism), CS puts patients at risk for potentially life-threatening comorbidities.1-3 Diagnosis of CS is often delayed because it can take years after onset for noticeable signs and symptoms to appear.2,3
Incidence:
3.2 cases/million/year4,a
Prevalence:
57 cases/million4,a
Gender Predilection:
3-4x more common in women1,5
Onset:
The average age of onset/diagnosis1
Mortality:
3.5-5x higher risk than the general population, if not treated properly6,b
True incidence and prevalence rates of CS in the United States are unknown. Estimated data are based on a retrospective study using a regional health registry in Sweden between 2002 and 2017.4
Mortality rates vary depending on disease etiology.
Cushing’s disease (CD) is the most common type of endogenous Cushing's syndrome7,8
CD is a rare hormonal disorder caused by a pituitary adenoma that secretes excess adrenocorticotropic hormone (ACTH).9 Excess ACTH stimulates the adrenal glands to overproduce cortisol, leading to the clinical manifestations of CD.
Estimated prevalence of nearly
22 cases per million10
Annual incidence estimated to be
2.4 per million10,c
Generally occurs between
ages 20 and 5011
At least
3x more common
in women than men
70% to 80%
of endogenous CS is caused by CD8
True incidence and prevalence rates for CD in the United States are unknown. Estimated data are pooled rates based on a meta-analysis of global CD epidemiology.10
Prolonged hypercortisolism exposure poses risks in Cushing's syndrome
Uncontrolled chronic hypercortisolism also leads to elevated risks of multisystem morbidity and mortality.12 While the risks of morbidity and mortality can decrease with biochemical remission, they're not entirely eliminated.7
Patients with chronic exposure to excess cortisol are at increased risk for morbidity and mortality13
Venous
thromboembolism
≈6.8x
higher risk
Heart
failure
≈6.0x
higher risk
Stroke
≈4.5x
higher risk
Acute myocardial infarction
≈2.1x
higher risk
Hazard ratios presented are for a 3-year period before CS diagnosis. Model adjusted for age, sex, calendar time, cancer, diabetes, hypertension, chronic obstructive pulmonary disease, liver disease, and alcoholism-related diseases.13
Clinical presentation of CS can overlap with other common conditions14
CS is associated with comorbidities and complications that negatively impact quality of
life and
survival.15
Early diagnosis is key to helping address CS, potentially improving
symptoms.14
Comorbidities and complications of CS1,14-16
Anxiety or
depression
Type 2
diabetes
Hypertension
Hyperlipidemia
Insulin resistance
Obesity
Peripheral edema
Infections
Menstrual
irregularities
Hypercoagulability
Insomnia or
fatigue
Osteoporosis
How CS manifests is different, depending on the etiology5,14
Endogenous CS includes 2 etiologies: ACTH-dependent and ACTH-independent.15
ACTH-DEPENDENT
Cushing's disease (CD)
A benign pituitary adenoma that secretes ACTH5
Ectopic ACTH syndrome (EAS)
Most commonly a lung, mediastinal, pancreas, and medullary thyroid neuroendocrine tumor that secretes ACTH5
ACTH-INDEPENDENT
Adrenal adenoma
Unilateral, cortisol-producing, benign adenomas located on the adrenal cortex5
Adrenal carcinoma
Unilateral malignant neoplasms on the adrenal cortex5
Adrenal hyperplasia
Refers to bilateral adrenal hyperplasia, which is characterized by macronodules or micronodules affecting both adrenal glands, leading to an increase in cortisol secretion5
References: 1. Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BMK, Colao A. Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol. 2016;4(7):611-629. doi:10.1016/S2213-8587(16)00086-3 2. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847-875. doi:10.1016/S2213-8587(21)00235-7 3. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet. 2006;367(9522):1605-1617. doi:10.1016/S0140-6736(06)68699-6 4. Wengander S, Trimpou P, Papakokkinou E, Ragnarsson O. The incidence of endogenous Cushing’s syndrome in the modern era. Clin Endocrinol (Oxf). 2019;91(2):263-270. doi:10.1111/cen.14014 5. Reincke M, Fleseriu M. Cushing syndrome: a review. JAMA. 2023;330(2):170-181. doi:10.1001/jama.2023.11305 6. Fleseriu M, Castinetti F. Updates on the role of adrenal steroidogenesis inhibitors in Cushing’s syndrome: a focus on novel therapies. Pituitary. 2016;19(6):643-653. doi:10.1007/s11102-016-0742-1 7. Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;17(7):281-293. doi:10.2147/CLEP.S44336 8. Lonser RR, Nieman L, Oldfield EH. Cushing’s disease: pathobiology, diagnosis, and management. J Neurosurg. 2017;126(2):404-417. doi:10.3171/2016.1.JNS152119 9. Feelders RA, Pulgar SJ. Kempel A, Pereira AM. The burden of Cushing's disease: clinical and health-related quality of life aspects. Eur J Endocrinol. 2012;167(3):311-326. doi:10.1530/EJE-11-1095 10. Giuffrida G, Crisafulli S, Ferraù F, et al. Global Cushing's disease epidemiology: a systematic review and meta-analysis of observational studies. Endocrinol Invest. 2022;45(6):1235-1246. doi:10.1007/s40618-022-01754-1 11. Nishioka H, Yamada S. Cushing's disease. Clin Med. 2019;8(11):1951. doi:10.3390/jcm8111951 12. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing's syndrome. Lancet. 2015;386(9996):913-927. doi:10.1016/S0140-6736(14)61375-1 13. Dekkers OM, Horváth-Puhó E, Jørgensen JOL, et al. Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab. 2013;98(6):2277-2284. doi:10.1210/jc.2012-3582 14. Nieman LK, Biller BMK, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540. doi:10.1210/jc.2008-0125 15. Gadelha M, Gatto F, Wildemberg LE, Fleseriu M. Cushing’s syndrome. Lancet. 2023;402(10418):2237-2252. doi:10.1016/S0140-6736(23)01961-X 16. Nieman LK. Cushing’s syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol. 2015;173(4):M33-M38. doi:10.1530/ EJE-15-0464
INDICATIONS AND USAGE
ISTURISA® (osilodrostat) is indicated for the treatment of endogenous hypercortisolemia in adults with Cushing’s syndrome for whom surgery is not an option or has not been curative.
IMPORTANT SAFETY INFORMATION
Hypocortisolism: ISTURISA lowers cortisol levels and can lead to hypocortisolism and sometimes life-threatening adrenal insufficiency. Lowering of cortisol can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol may result in hypotension, abnormal electrolyte levels, and hypoglycemia.
Hypocortisolism can occur at any time during ISTURISA treatment. Evaluate patients for precipitating causes of hypocortisolism (infection, physical stress, etc.). Monitor 24-hr urine free cortisol, serum or plasma cortisol, and patient’s signs and symptoms periodically during ISTURISA treatment.
Decrease or temporarily discontinue ISTURISA if urine free cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, and/or patients report symptoms of hypocortisolism. Stop ISTURISA and administer exogenous glucocorticoid replacement therapy if serum or plasma cortisol levels are below target range and patients have symptoms of adrenal insufficiency. After ISTURISA interruption or discontinuation, cortisol suppression may persist beyond the 4-hour half-life of ISTURISA.
Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur.
QTc Prolongation: ISTURISA is associated with a dose-dependent QT interval prolongation which may cause cardiac arrhythmias. Perform an ECG to obtain a baseline QTc interval measurement prior to initiating therapy with ISTURISA and monitor for an effect on the QTc interval thereafter.
Correct hypokalemia and/or hypomagnesemia prior to ISTURISA initiation and monitor periodically during treatment with ISTURISA. Use with caution in patients with risk factors for QT prolongation and consider more frequent ECG monitoring.
Elevations in Adrenal Hormone Precursors and Androgens: ISTURISA blocks cortisol synthesis and may increase circulating levels of cortisol and aldosterone precursors and androgens. This may activate mineralocorticoid receptors and cause hypokalemia, edema and hypertension. Hypokalemia should be corrected prior to initiating ISTURISA. Monitor patients treated with ISTURISA for hypokalemia, worsening of hypertension and edema. Inform patients of the symptoms associated with hyperandrogenism and advise them to contact a healthcare provider if they occur.
The most common adverse reactions (incidence >20%) are adrenal insufficiency, fatigue, nausea, headache, edema, decreased appetite, arthralgia, myalgia, and diarrhea.
To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions:
- CYP3A4 Inhibitor: Reduce the dose of ISTURISA by half with concomitant use of a strong CYP3A4 inhibitor.
- CYP3A4 and CYP2B6 Inducers: An increase of ISTURISA dosage may be needed if ISTURISA is used concomitantly with strong CYP3A4 and CYP2B6 inducers. A reduction in ISTURISA dosage may be needed if strong CYP3A4 and CYP2B6 inducers are discontinued while using ISTURISA.
Use in Specific Populations:
- Lactation: Breastfeeding is not recommended during treatment with ISTURISA and for at least one week after treatment.
Dosage Interruptions and Modifications: If treatment is interrupted, re-initiate ISTURISA at a lower dose when cortisol levels are within target ranges and patient symptoms have been resolved.
ISTURISA® (osilodrostat) tablets, for oral use, is available as 1 mg and 5 mg tablets.
Please see full Prescribing Information.
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Patient portrayal.
BASELINE CHARACTERISTICS
Age: 34
Race: White
Height: 5'6"
Weight: 80.1 kg (177 lb)
BMI: 28.6 kg/m2
Diagnosis
Cushing’s disease: recurrent
Time since diagnosis
6 years
Treatment
- Transsphenoidal surgery was performed within 2 months of diagnosis
- Pituitary radiotherapy was performed 2 years ago
Status
- In remission, but beginning to develop symptoms of recurrence
Symptoms
- Weight gain in the abdomen
- Fatigue and sleep disturbances
- Anxiety and depression
- Easy bruising
- Increased thirst and urination
Comorbidities
- Depression/anxiety
- Hyperlipidemia
- Prediabetes
Vital signs and labs
Blood pressure: 124/86 mm Hg
HR: 72 bpm
Total cholesterol: 213 mg/dL (reference range: <200 mg/dL)
LDL: 112 mg/dL (reference range: <100 mg/dL)
HDL: 45 mg/dL (reference range: >60 mg/dL)
Glucose: 123 mg/dL (reference range: <100 mg/dL)
HbA1c: 6.2% (reference range: <5.7%)
UFC: 217.5 nmol/24 h (78.8 μg/24 h) (reference range: <145
nmol/24 h [approximately 11-53 μg/24 h])
UFC fold ULN: 1.5 x ULN mUFC
Patient portrayal.
Questions to consider when developing a treatment plan
- What would be the consequences if this patient’s cortisol levels remain uncontrolled?
- How do you evaluate severity of disease in your patients?
- What are your treatment goals for this patient?
- What do you consider to be the appropriate next therapy option for this patient?
- Would you consider ISTURISA an appropriate option for this patient? Why or why not?
BMI, body mass index; bpm, beats per minute; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HR, heart rate; LDL, low-density lipoprotein; mUFC, mean urinary free cortisol; UFC, urinary free cortisol; ULN, upper limit of normal.
Patient portrayal.
BASELINE CHARACTERISTICS
Age: 34
Race: White
Height: 5'10”
Weight: 95.9 kg (211 lb)
BMI: 30.3 kg/m2
Diagnosis
Cushing’s syndrome: treatment naive
Time since diagnosis
7 months
Treatment
- Exogenous sources of hypercortisolemia were ruled out
- Standard imaging techniques were unsuccessful in locating the tumor
- Inferior petrosal sinus sampling indicated an ectopic source
- Patient is not a candidate for surgical intervention
Status
- Further imaging investigation is required
- Patient is experiencing symptoms of hypercortisolemia that may benefit from medication therapy
- Cardiometabolic parameters are currently not controlled despite lifestyle changes and maximized treatment
Symptoms
- Weight gain in the abdomen
- Rounded face
- Hypertension
- Diabetes
- Daytime fatigue and nighttime insomnia
- Muscle weakness
Comorbidities
- Hypertension
- Diabetes
- Hyperlipidemia
Vital signs and labs
Blood pressure: 146/92 mm Hg
HR: 68 bpm
Total cholesterol: 238 mg/dL (reference range: <200 mg/dL)
LDL: 121 mg/dL (reference range: <100 mg/dL)
HDL: 42 mg/dL (reference range: >60 mg/dL)
Glucose: 136 mg/dL (reference range: <100 mg/dL)
HbA1c: 7.6% (reference range: <5.7%)
UFC: 304.5 nmol/24 h (110.3 μg/24 h) (reference range: <145
nmol/24 h [approximately 11-53 μg/24 h])
UFC fold ULN: 2.1 x ULN mUFC
Patient portrayal.
Questions to consider when developing a treatment plan
- What would be the consequences if this patient’s cortisol levels remain uncontrolled?
- What are your treatment goals for this patient?
- What do you consider to be the appropriate next therapy option for this patient?
- Would you consider ISTURISA an appropriate option for this patient? Why or why not?
BMI, body mass index; bpm, beats per minute; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HR, heart rate; LDL, low-density lipoprotein; mUFC, mean urinary free cortisol; UFC, urinary free cortisol; ULN, upper limit of normal.
Patient portrayal.
BASELINE CHARACTERISTICS
Age: 31
Race: African American
Height: 5'4”
Weight: 75.0 kg (165 lb)
BMI: 28.3 kg/m2
Diagnosis
High clinical suspicion of hypercortisolemia in Cushing’s syndrome; further testing is
required
Time since diagnosis
Pending diagnosis
Notes
- UFC labs were repeated twice over several weeks with consistent findings of elevated cortisol
- Exogenous sources of hypercortisolemia were ruled out
- Imaging investigation is required
Treatment
- None
Status
- Patient has seen an endocrinologist to discuss lack of symptom relief despite lifestyle modification and reported that symptoms are worsening
Symptoms
- Weight gain in the abdomen
- Weight gain in the face
- Facial plethora
- Muscle weakness
- Menstrual irregularities
- Fatigue and sleep disturbances
- Anxiety and depression
Comorbidities
- Diabetes
- Polycystic ovarian syndrome
Vital signs and labs
Blood pressure: 130/84 mm Hg
HR: 86 bpm
Total cholesterol: 208 mg/dL (reference range: <200 mg/dL)
LDL: 106 mg/dL (reference range: <100 mg/dL)
HDL: 58 mg/dL (reference range: >60 mg/dL)
Glucose: 131 mg/dL (reference range: <100 mg/dL)
HbA1c: 7.2% (reference range: <5.7%)
UFC: 246.5 nmol/24 h (89.3μg/24 h) (reference range: <145 nmol/24
h [approximately 11-53 μg/24 h])
UFC fold ULN: 1.7 x ULN mUFC
Patient portrayal.
Questions to consider when developing a treatment plan
- What symptoms lead you to a high clinical suspicion of hypercortisolemia in Cushing’s syndrome?
- What would be the consequences if this patient’s cortisol levels remain uncontrolled?
- What are your treatment goals for this patient?
BMI, body mass index; bpm, beats per minute; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HR, heart rate; LDL, low-density lipoprotein; mUFC, mean urinary free cortisol; UFC, urinary free cortisol; ULN, upper limit of normal.