ADVANCES IN MANAGING CUSHING S DISEASE Rosario Pivonello Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
Patients with persistent Cushing s disease have higher morbidity and mortality Study Lindholm (n=73) Hammer (n=289) Dekkers (n=74) Clayton (n=60) Overall (I 2 =67.2%, P=0.027) Persistent disease Estimated SMR (95% CI) 5.06 (2.27, 11.26) 2.80 (1.33, 5.87) 4.38 (1.82, 10.52) 16.00 (6.66, 38.44) 5.50 (2.69, 11.26) 0.026 1 38.4 Lindholm (n=73) Hammer (n=289) Dekkers (n=74) Clayton (n=60) Overall (I 2 =82.2%, P=0.001) Remission 0.31 (0.14, 0.69) 1.18 (0.56, 2.48) 1.80 (0.75, 4.32) 3.30 (1.37, 7.93) 1.20 (0.45, 3.18) 0.126 1 7.93 Clayton RN et al. J Clin Endocrinol Metab 2011;96:632 642 Note: Weights are from random effects analysis
Hypercortisolism leads to reduced HRQoL Functional impairments in HRQoL are directly attributable to the effects of prolonged hypercortisolism Most patients with Cushing s disease have physical and psychological symptoms which may lead to impaired HRQoL However, studies with longer follow-up suggest that prolonged exposure to high levels of cortisol may cause persistent deleterious effects on HRQoL Feelders RA et al. Eur J Endocrinol 2012;167:311 326
Prolonged exposure to cortisol excess leads to worse outcome The mean time span between initial physician consultation and final diagnosis of Cushing s disease is 2 5 years 1 6 Duration of hypercortisolism pre-cure has a significant impact on the severity and extent of co-morbidities post-cure Mortality Early diagnosis and prompt treatment are therefore needed Reversibility of complications 0 1 2 3 4 5 6 7 8 9 10 11 12 Duration of hypercortisolism (years) 1 Flitsch J et al. Exp Clin Endocrinol Diabetes 2000;108:480 485; 2 Martínez Ruiz M et al. An Pediatr (Barc) 2003;59:183 186; 3 Etxabe J & Vazquez JA. Clin Endocrinol 1994;40:479 484; 4 Daly AF et al. J Clin Endocrinol Metab 2006;91:4769 4775; 5 Bolland MJ et al. Clin Endocrinol (Oxf) 2011;75:436 442; 6 Valassi E et al. Eur J Endocrinol 2011;165:383 392
Treatment Goals for Cushing s Disease Normalization of cortisol levels with minimal morbidity Removal of tumor mass and/or stabilization of tumor growth Preservation of pituitary function Reversal of morbidity and mortality Improvement of quality of life Long-term control without recurrence Biller et al. J Clin Endocrinol Metab. 2008;93:2454-2462.
Transsphenoidal surgery is first-line therapy in Cushing s disease However Not always successful - Initial success rate 68 98% in patients with a microadenoma 1,2 - Remission rates lower (<65%) in patients with a macroadenoma 1 Patients are not always controlled in the long term - Relapse rate is 2 26% (after 6 240 months) 2 Not always feasible 1 Biller BMK et al. J Clin Endocrinol Metab 2008;93:2454 2462; 2 Tritos NA et al. Nat Rev Endocrinol 2011;104:279 289
Hypopituitarism following first surgery Hypopituitarism has been reported in 1 22% of patients following surgery for Cushing s disease 1,2 Patients with hypopituitarism have decreased HRQoL 3 and approximately 2-fold higher mortality than the general population 4,5 Hypopituitarism requires chronic hormone replacement therapy 1 Sudhakar N et al. Br J Neurosurg 2004;18:507 512; 2 Roelfsema F et al. Pituitary 2012;15:71 83; 3 van Aken MO et al. J Clin Endocrinol Metab 2005;90:3279 3286; 4 Bates AS et al. J Clin Endocrinol Metab 1996;81:1169 1172; 5 Tomlinson JW et al. Lancet 2001;357:425 431
Current second-line therapies in Cushing s disease Patients with persistent disease after surgery Repeat surgery Radiation therapy Medical therapy Bilateral adrenalectomy Biller BMK et al. J Clin Endocrinol Metab 2008;93:2454 2462
Repeat pituitary surgery Repeat surgery 1,2 Potentially curative Pituitary directed Limitations Risk of cerebrospinal fluid leakage Lower success rate (37 73%) with subsequent surgery for patients in specialized centers 3,4 Hypopituitarism is more common after subsequent surgery Rates of 50% 2 compared with 1 22% for patients following first surgery 5 1 Biller BMK et al. BMC Endocr Disord 2010;10:10; 2 Biller BMK et al. J Clin Endocrinol Metab 2008;93:2454 2462; 3 Friedman RB et al. J Neurosurg 1989;71:520 527; 4 Benveniste RJ et al. J Neurosurg 2005;102:1004 1012; 5 Sudhakar N et al. Br J Neurosurg 2004;18:507 512
Bilateral adrenalectomy Bilateral adrenalectomy Involves complete removal of both adrenal glands 1 Provides immediate control of hypercortisolism 1 Procedure has 84 91% success rate 2,3 Limitations Results in permanent hypoadrenalism requiring lifelong glucocorticoid and mineralocorticoid replacement 1 Risk of developing Nelson s syndrome (rapid enlargement of corticotroph adenoma) 4 1 Biller BMK et al. BMC Endocr Disord 2010;10:10; 2 Sonino N et al. J Clin Endocrinol Metab 1996;81:2647 2652; 3 Chow JT et al. Clin Endocrinol (Oxf) 2008;68:513 519; 4 Assié G et al. J Clin Endocrnol Metab 2007;92:172 179
Radiation therapy for persistent Cushing s disease Radiation therapy Stereotactic radiotherapy requires specialized team and visible tumor (by MRI) Achieves disease control in 50 60% of patients 1 Delayed response, control is seen after 3 5 years 2,3 Limitations Associated with a high risk of hypopituitarism 4 Risk of second brain tumor formation, in the range of 1 2% Increased risk of cerebrovascular death 1 Biller BMK et al. J Clin Endocrinol Metab 2008;93:2454 2462; 2 Rim CH et al. Radiation Oncol J 2012;29:156 163; 3 Castinetti F et al. Eur J Endocrinol 2007;156:91 98; 4 Devin JK et al. Stereotact Funct Neurosurg 2004;254 262
Medical Therapy: Indications Severe complications of hypercortisolism Pre-treatment before pituitary surgery Post-treatment after unsuccessful surgery Bridging therapy before, during and after radiation Primary medical therapy (contraindication for surgery or refusal of surgery)
Potential Targets for Medical Therapy in Cushing s Disease Pituitary gland CRH Pasireotide Cabergoline Adrenal glands Ketoconazole Metyrapone Mitotane LCI699 ACTH Cortisol Mifepristone Glucocorticoid receptors
Adrenal-directed medical therapy Steroidogenesis inhibitors Ketoconazole, mitotane, metyrapone, etomidate Reduce cortisol levels via inhibition of steroid synthesis in the adrenal gland Can be used as a palliative treatment Between administration and effect of radiotherapy To lower cortisol levels in patients preparing for surgery Used for long-term management of disease Do not target the underlying corticotroph tumor or restore normal HPA secretory dynamics (ie non-curative) Safety concerns Biller BMK et al. BMC Endocr Disord 2010;10:10
Ketoconazole monotherapy (200 1200 mg/day) Retrospective study of 38 patients with active disease (17 had previous surgery) 17 (45%) had normalized UFC; mean follow-up of 23 months Treatment stopped in first week in five patients (13%) due to clinical intolerance (GI symptoms) or biological intolerance (elevated liver enzymes) AEs included a moderate (<3xULN ) increase in γ-gt (8%), nausea and diarrhea (5%), aspartate aminotransferase/alanine aminotransferase 8xULN (3%) Escape: 15% 1 Castinetti F et al. Eur J Endocrinol 2008;158:91 99;
Cortisol-receptor-targeted medical therapy Mifepristone Blocks the action of cortisol by binding to the GR-II (cortisol) receptor 4-fold higher affinity than dexamethasone Glucocorticoid receptor antagonist 18-fold higher affinity than cortisol Does not target the underlying corticotroph tumor or restore normal HPA secretory dynamics (ie non-curative) Received FDA approval (Corcept Therapeutics; Korlym ) for control of hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing s syndrome who have type 2 diabetes/glucose intolerance and have not responded to, or are not candidates for, surgery
Mifepristone Phase III Trial Design 24-week multicenter, open-label trial of mifepristone 300-1200 mg/day in patients with Cushing s syndrome who had failed standard therapy At baseline, 43 patients had Cushing s disease, 4 had ectopic ACTH secretion, and 3 had adrenal cancer 2 groups of patients were enrolled Patients with glucose intolerance or diabetes (n = 29) Patients with hypertension (n = 21) Screening 42 days Dose escalation until week 10 24-week treatment n = 84 screened Day 1 Week 6 Week 10 Week 16 Week 24 n = 50 enrolled n = 34 completed Fleseriu et al. Endocr Rev. 2011;32:OR09-5.
Mifepristone Phase III Trial: Efficacy Results Primary efficacy analysis group: patients who completed 30 days of mifepristone therapy Response in the primary endpoint was defined as Glucose-intolerant group: 25% improvement in glucose tolerance at 24 weeks compared with baseline Hypertension group: 5 mmhg improvement in diastolic blood pressure at 24 weeks compared with baseline Glucose-intolerant group (n=25) Hypertension group (n=21) Response rate 60% (15/25 patients) 38% (8/21 patients) 95% CI Lower limit 95% CI = 41.7%; P < 0.0001 Lower limit 95% CI = 21%; P value not reported Definition of response: lower bound of the 95% CI for group response rates >20%. Fleseriu et al. Endocr Rev. 2011;32:OR09-5.
Mifepristone Phase III Trial Results: Improvement in Signs and Symptoms At week 24, improvements were seen in body weight, waist circumference, insulin resistance, cushingoid appearance, depression, cognition, and HRQoL Change from baseline (%) 2 1 0 1 2 3 4 5 6 7 8 9 Decrease in weight with treatment D7 D14 D28 W6 W8 W10 W12 W16 W20 W24/ ET Baseline 99.5 ± 4.4 kg (n=46) 5.7 ± 1.5% P<0.001 vs baseline Baseline (cm) 122.4 111.3 117.9 132.5 0 0 Mean change from baseline (cm) 2 4 6 8 10 12 C-DM (N=19) Decrease in waist circumference *P<0.001 vs baseline C-HT (N=13) Females * Overall (N=32) 2 4 6 8 10 12 C-DM (N=6) 111.4 120.4 *P<0.001 vs baseline C-HT (N=8) Males * Overall (N=14) Fleseriu et al. Endocr Rev. 2011;32:OR09-5.
Mifepristone Phase III Trial: Safety 88% of patients experienced a treatment-related AE 16 patients had a serious AE 7 withdrew due to an AE 2 patients died during the study Half of women had an increase in endometrial thickness 2 patients had adrenal insufficiency reported as an AE 3 patients had severe hypokalemia (K 2.5) The treatment was associated with an increase in ACTH UFC Morning serum cortisol Late-night salivary cortisol Fleseriu et al. Endocr Rev. 2011;32:OR09-5.
Pituitary-directed medical therapies for Cushing s disease Despite initial promise, a routine clinical role has not been found for: PPAR-ү agonists such as rosiglitazone 1 Dopamine agonists Cabergoline may be effective in a subset of patients; 2 more trials needed Somatostatin analogues Octreotide and lanreotide are ineffective in Cushing s disease Pasireotide, a multireceptor-targeted somatostatin analogue, has demonstrated efficacy 1 Pecori GF et al. Clin Endocrinol (Oxf) 2006;64:219 224; 2 Pivonello R et al. J Clin Endocrinol Metab 2009;94:223 230
Cabergoline is an option for some patients with Cushing s disease Potent dopamine type 2 (D2) receptor agonist Approximately 80% of ACTH-secreting adenomas express the dopamine D2 receptor 1 D2 receptor might not be greatly downregulated (similar to the resilience of sst 5 ) in the presence of glucocorticoids 2 O NH N N Small studies (n=20 30) have demonstrated the efficacy of cabergoline in a subset of patients 1,3 O N H The phenomenon of escape has been described 3 Studies in larger patient populations are required to establish efficacy and safety NH 1 Pivonello R et al. J Clin Endocrinol Metab 2004;89:2452 2462; 2 de Bruin C et al. J Mol Endocrinol 2009;42:47 56; 3 Godbout A et al. Eur J Endocrinol 2010;163:709 716 sst, somatostatin subtype receptor
Prospective study of cabergoline in Cushing s disease (n=20) Short-term (3 months) efficacy (75%): Eight (40%) partial and seven (35%) full responders; five (25%) non-responders Escape from response occurred after 12 18 months: Three patients with normalized UFC; two partially responsive patients Patients discontinued treatment Urinary cortisol (µg/day) 1000 800 600 400 200 0 2 Patient no. 1 3 1 2 3 3 3 2 1 3 3 Baseline 3 months 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 3 3 3 2 1 3 3 2 3 40% were in full remission after 24 months with a median dose of 3.5 mg/week 1 1000 Baseline 2 12 24 months 800 7 1 Patients with 7 24-month follow-up 600 2 4 7 Patients with 400 3 1 12-month follow-up Number on each arrow indicates the maximal cabergoline dose (mg/week) administered; urinary cortisol levels represent the 200 mean of three different urine collections performed in three different non-consecutive days of the same week 0 Partial response defined as >25% decrease in UFC Patient no. 3 4 6 7 9 12 13 15 16 18 Pivonello R et al. J Clin Endocrinol Metab 2009;94:223 230 Urinary cortisol (µg/day) 7
Retrospective study of cabergoline in Cushing s disease In a study of 30 Canadian/ Argentinian patients: Complete response in 11 patients (36.7%) after average of 4.2 months Partial response in four patients (13.3%); no response in 15 (50.0%) Nine patients (30%) maintained response after a mean of 37 months (up to 60 months) Escape from response observed in two patients after 2 and 5 years No major AEs Complete response defined as normalization of mean UFC Partial response defined as a decrease in UFC to <125% of the upper limit of normal range but without complete normalization of UFC Godbout A et al. Eur J Endocrinol 2012;163:709 716 Proportion of UFC ULN (%) Proportion of UFC ULN (%) 450 400 350 300 250 200 150 100 50 0 3000 2500 2000 1500 1000 500 UFC levels in nine patients with complete response 0 3 6 9 12 18 24 36 48 54 60 72 78 Treatment time (months) UFC levels in two patients with escape from response Cabergoline dose (mg/week) 1.0 2.5 3.0 Pt 10 0.5 1.0 4.0 6.0 0 0 3 6 9 12 18 24 36 48 54 60 72 78 84 Treatment time (months) Pt 11
Ketoconazole in combination with cabergoline After 6 months cabergoline monotherapy (up to 3 mg/ week), 9/12 patients did not adequately respond All 12 patients had undergone previous surgery Addition of ketoconazole (up to 400 mg/day) led to normalized UFC in 6/9 patients (67%) Remaining patients achieved significant reduction in UFC of 44 52% Vilar L et al. Pituitary. 2010 Jun;13(2):123 9
Pasireotide Multireceptor-targeted somatostatin analogue 30-, 5-, and 39-fold higher affinity for sst 1, sst 3 and sst 5 than octreotide, and similar affinity for sst 2 1 N H 2 H N O O O N O N H N H O O H N H N O H N N H O N H 2 Expression of sst 5 predominates in ACTH-secreting pituitary adenomas 2,3 O sst 1, sst 2, and sst 3 are also expressed Broad binding profile means that pasireotide may be an effective treatment for Cushing s disease 1. Bruns et al. Eur J Endocrinol. 2002;146:707-716. 2. Strowski et al. Neuroendocrinology. 2002;75:339-346. 3. Sharma et al. Mol Endocrinol. 1999;13:82-90.
Pasireotide N Engl J Med. 2012;366:914-924.
Phase III Study: Largest Cushing s Disease Trial 18 countries, 62 sites 329 patients screened 162 patients randomized Argentina, Belgium, Brazil, Canada, China, Denmark, Finland, France, Germany, 28 Greece, Israel, Italy, Mexico, Poland, Portugal, Spain, Turkey, United States
Change in UFC From Baseline to Month 6 in 103 Patients With Baseline and Month-6 UFC Measurements 2500 1400 600 µg bid 900 µg bid * Baseline UFC Month-6 UFC Month-6 UFC ULN UFC (µg/24 h) 720 540 360 180 0 Individual patients sorted by baseline UFC ULN Median percent UFC change from baseline was 47.9% in both groups Reference line is the upper limit normal UFC, which is 52.5 µg/24 h (145 nmol/24 h).
Primary Efficacy Results Response status at 6 months 600 µg bid (n=82) 900 µg bid (n=80) Overall (n=162) *Response, n (%) 12 (14.6) 21 (26.3) 33 (20.4) 95% confidence interval (7.0, 22.3) (16.6, 35.9) (14.2, 26.6) 12-month response, n (%) 11 (13.4) 20 (25.0) 31 (19.1) *NOTE: Responder was a patient with UFC ULN who did not require uptitration Predetermined criterion for the primary efficacy endpoint: lower bound of the 95% CI >15% for either of the dose groups; this was met for the 900-µg group
Significant Decrease in Blood Pressure and UFC 450 360 Systolic blood pressure (SBP) 135 133 131 Mean UFC ± SE (µg/24 h) 270 180 90 0 450 360 270 Mean UFC Mean SBP B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12 Diastolic blood pressure (DBP) 129 127 125 123 121 88 87 86 85 Mean BP ± SE (mmhg) Significant change from baseline to month 12 was observed for: SBP 6.1 mmhg (95% CI: 9.8, 2.4) 84 180 90 0 Mean UFC Mean DBP B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12 83 82 81 80 DBP 3.7 mmhg (95% CI: 6.2, 1.2) Month
Mean UFC (µg/24 h) Significant Improvement in HRQoL and UFC Measured via Cushing QoL1 Significant (11.1 points) improvement from baseline to month 12 (95% CI: 6.8, 15.5) 450 360 270 180 90 0 B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12 Month 1. Webb et al. Eur J Endocrinol. 2008;158:623-630. Mean UFC HRQoL score 54 52 50 48 46 44 42 40 HRQoL score
Pasireotide: summary B2305, the large phase III study of pasireotide in Cushing s disease showed Rapid and sustained UFC reduction with pasireotide treatment Decrease in UFC seen from baseline to month 6 in most patients Normalization of UFC in a subset of patients (higher rates for patients with lower baseline UFC) Significant improvement in signs and symptoms seen at 6 months with further improvements by 12 months Pasireotide provides a pituitary-directed medical treatment targeting the underlying cause of the disease
Combination Therapy 17 patients Ketoconazole 200 mg TID Feelders et al. N Engl J Med. 2010;362:1846-1848. Stepwise Medical Treatment Pasireotide 250 µg TID Pasireotide 100 µg TID 0 Cabergoline 1.5 mg QOD Time, d Stepwise Medical Treatment B2402 STUDY 80
Combination Therapy Disease control with pasireotide alone or in combination in 88% of patients with Cushing s disease Feelders et al. N Engl J Med. 2010;362:1846-1848.
LCI699 Is a potent inhibitor of 11β-hydroxylase (CYP11B1), the final step of cortisol synthesis Is a potential new treatment for all forms of Cushing s syndrome, including Cushing s disease This open-label, proof-of-concept study assessed the efficacy and safety/tolerability of LCI699 in adult patients with Cushing s disease over 10 weeks of treatment
LCI699: Anticipated Effects in Cushing s Disease (Fasciculata/reticularis) ACTH + - (Glomerulosa) Renin Cholesterol Cholesterol Pregnenolone Volume expansion Pregnenolone Progesterone DOC Progesterone 17-OH progesterone 11-Deoxycortisol LCI699 X CYP11B1 Androgens 11-Deoxycortisol LCI699 DOC X (Corticosterone) (18-OH corticosterone) CYP11B2 (Cortisol) (Aldosterone)
Recruitment Status (N = 12) Boston, USA (n = 1) Paris, France (n = 3) Ancona, Italy (n = 2) Cleveland, USA (n = 1) Portland, USA (n = 3) Naples, Italy (n = 2)
LCI699: Proof-of-concept study design LCI699 initiated at 4 mg/day (given orally in two divided doses) Dose escalated every 2 weeks until UFC normalized, then maintained until day 70 Followed by a 2-week washout period until day 84 D 64 D 14 D1 D14 D28 D42 D56 D70 D84 Screening Baseline 4 mg 10 mg 20 mg 40 mg 100 mg Washout n=12 enrolled UFC UFC UFC UFC UFC UFC UFC Primary endpoint UFC ULN or 50% decrease from baseline at day 70 Secondary endpoints ACTH, steroid hormone precursors, androgens, body weight, blood pressure, glucose, potassium and sodium levels, AEs Bertagna X et al. J Klin Endokrinol Stoffw 2012;5(Special Issue 3):abst OC04
Urinary Cortisol Over Time in All Patients Mean UFC ± SE (fold ULN) 7 LCI699 dose escalation Washout 6 5 4 3 2 1 0 Day 1 14 28 42 56 70 84 All 12 patients achieved the primary endpoint at day 70 11/12 (92%) had normal urinary cortisol at day 70 Urinary cortisol normalized in all 12 patients at least once
Changes in Clinical and Laboratory Features During LCI699 Treatment Baseline (n=12) Day 70 (n=12) Change from baseline (n=12) SBP (mmhg) 136.5 ± 4.0 129.7 ± 5.6 6.8 ± 4.7 DBP (mmhg) 87.9 ± 3.0 82.8 ± 3.1 5.1 ± 3.7 Weight (kg) 96.7 ± 8.9 100.3 ± 9.5 +3.5 ± 1.3 Glucose (mg/dl) 111.1 ± 14.2 101.9 ± 7.6 9.2 ± 11.8 Potassium (meq/l) 4.3 ± 0.1 3.8 ± 0.2 0.5 ± 0.2 Sodium (meq/l) 141.0 ± 1.1 140.8 ± 0.9 0.2 ± 1.1 Data presented as mean ±SE. SBP, systolic blood pressure; DBP, diastolic blood pressure.
Safety of LCI699 All patients experienced at least 1 AE during treatment Most AEs were mild to moderate AEs requiring dose adjustment were consistent with adrenal insufficiency AEs were easily managed with dose reductions Fatigue, nausea, abdominal pain, and infection were the most common AEs 4 patients had hypokalemia (K+ <3.5 meq/l; min 3.1) 3 patients received oral potassium supplementation No dose reductions needed 1 patient had a serious AE Rapid anemia with palpitations and chest pain History of inflammation-related anemia
Retinoic acid in Cushing s disease Prospective proof-of-concept study in seven patients with Cushing s disease Evaluated the efficacy and safety of escalating doses of retinoic acid (10 80 mg/day) over 6 12 months of treatment Five patients (71.4%) had 50% decrease/normalization of UFC after 6 months Three patients (42.9%) normalized UFC Changes in ACTH were variable and generally less pronounced Treatment was generally well tolerated Treatment duration Urinary free cortisol (µg/24h) 200 150 100 50 200 Retinoic acid Pt 1 Retinoic acid Pt 2 Retinoic acid Pt 3 150 100 50 600 500 400 300 200 100 0 Pretreatment 3 6 9 12 15 18 Months 0 Pretreatment 3 6 9 12 15 18 Months 0 Pretreatment 3 6 9 12 15 Months Urinary free cortisol (µg/24h) 200 150 100 50 Retinoic acid Pt 4 200 150 100 50 Retinoic acid Pt 5 250 200 150 100 50 Retinoic acid Pt 6 200 150 100 50 Retinoic acid Pt 7 0 Pretreatment 3 6 9 12 15 Months 0 Pretreatment 3 6 9 12 15 Months 0 Pretreatment 3 6 Months 0 Pretreatment 3 6 Months Pecori Giraldi F et al. J Clin Endocrinol Metab 2012;97:3577 3583 Shaded area represents normal range
Conclusions Surgery is first-line treatment, but is associated with high relapse rates and is not a viable option in some patients Repeat pituitary surgery, bilateral adrenalectomy and radiotherapy can result in control of hypercortisolism, but they are associated with variable response rates and significant risks Prior to 2012, medical therapy was used in an off-label manner Ketoconazole is the most commonly used steroidogenesis inhibitors, providing control of cortisol in many patients In small studies, cabergoline induced full remission in 30 40% of patients during 2 5-year follow-up Mifepristone leads to significant clinical and metabolic improvements in patients with Cushing s syndrome and diabetes mellitus during 6 months of treatment Pasireotide is the first approved pituitary-targeted medical therapy to rapidly decrease and normalize UFC and improve signs/symptoms
Thanks