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`
`R E V I E W
`
`The Treatment of Cushing’s Disease
`
`Rosario Pivonello, Monica De Leo, Alessia Cozzolino, and Annamaria Colao
`
`Dipartimento Di Medicina Clinica E Chirurgia, Sezione Di Endocrinologia, Universita’ Federico II di Napoli, 80131
`Naples, Italy
`
`Cushing’s disease (CD), or pituitary-dependent Cushing’s syndrome, is a severe endocrine disease caused by a cor-
`ticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is
`pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during
`the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery
`and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treat-
`ments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective
`in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypop-
`ituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but
`it induces adrenal insufficiency. Medical therapy has recently acquired a more important role compared to the past,
`due to the recent employment of novel compounds able to control cortisol secretion or action. Currently, medical
`therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of
`failure or incomplete surgical tumor resection; or as bridging therapy before, during, and after radiotherapy while
`waiting for disease control; or, in selected cases, as primary therapy, mainly when surgery is not an option. The
`adrenal-directed drug ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas
`the glucocorticoid receptor antagonist, mifepristone, is highly effective in controlling clinical comorbidities, mainly
`glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus. Pituitary-
`directed drugs have the advantage of acting at the site responsible for CD, the pituitary tumor. Among this group
`of drugs, the dopamine agonist cabergoline and the somatostatin analog pasireotide result in disease remission in
`a consistent subgroup of patients with CD. Recently, pasireotide has been approved for the treatment of CD when
`surgery has failed or when surgery is not an option, and mifepristone has been approved for the treatment of
`Cushing’s syndrome when associated with impairment of glucose metabolism in case of the lack of a surgical
`indication. Recent experience suggests that the combination of different drugs may be able to control cortisol excess
`in a great majority of patients with CD. (Endocrine Reviews 36: 385–486, 2015)
`
`I. Introduction
`II. Mortality and Morbidity in Cushing’s Disease
`A. Mortality
`B. Cardiovascular disease
`C. Metabolic syndrome
`D. Infectious diseases
`E. Neuropsychiatric disorders
`III. The First-line Treatment of Cushing’s Disease
`A. Treatment algorithm
`B. Criteria for remission and cure
`C. Pituitary surgery
`IV. The Second-line Treatment of Cushing’s Disease
`A. Repeat pituitary surgery
`B. Pituitary radiotherapy
`C. Adrenal surgery
`V. The Medical Therapy of Cushing’s Disease
`A. Classification of medical therapy
`B. Adrenal-directed therapy
`C. Pituitary-directed therapy
`
`ISSN Print 0163-769X ISSN Online 1945-7189
`Printed in USA
`Copyright © 2015 by the Endocrine Society
`Received May 2, 2013. Accepted May 13, 2015.
`First Published Online June 11, 2015
`
`D. Glucocorticoid receptor antagonists
`E. Combination therapy
`F. Experimental therapy
`VI. Summary
`
`I. Introduction
`
`Cushing’s disease (CD), or pituitary-dependent Cush-
`
`ing’s syndrome (CS), is the most common form of
`endogenous CS, accounting for around 70% of the forms
`of chronic endogenous hypercortisolism (1, 2). CD is a
`
`Abbreviations: BMI, body mass index; CBG, cortisol-binding globulin; CD, Cushing’s disease; CRT,
`conventional radiotherapy; CS, Cushing’s syndrome; CSF, cerebrospinal fluid; DDAVP, desmopres-
`sin; DDD, dichloro-diphenyl-dichloroethane; DI, diabetes insipidus; D2R, dopamine 2 receptor;
`EGFR, epidermal growth factor receptor; GABA, ␥-aminobutyric acid; GI, gastrointestinal; GK,
`Gamma Knife; HPA, hypothalamus-pituitary-adrenal; LBA, laparoscopic bilateral adrenalectomy;
`LDDST, low-dose dexamethasone suppression test; LINAC, linear accelerator; MLC, multileaf col-
`limator; MRI, magnetic resonance imaging; NS, Nelson’s syndrome; OBA, open bilateral adrenal-
`ectomy;OGTT,oralglucosetolerancetest;PDI,permanentDI;POMC,proopiomelanocortin;PPAR,
`peroxisome proliferator-activated receptor; PRL, prolactin; SCRT, stereotactic conformal radiother-
`apy; SIADH, syndrome of inappropriate antidiuretic hormone secretion; SMR, standardized mor-
`tality ratio; SRS, stereotactic radiosurgery; SRT, stereotactic radiotherapy; SSTR, somatostatin re-
`ceptor; TCS, transcranial surgery; TDI, transient DI; TSS, transsphenoidal surgery.
`
`doi: 10.1210/er.2013-1048
`
`Endocrine Reviews, August 2015, 36(4):385– 486
`
`press.endocrine.org/journal/edrv
`
`385
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`386
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`Treatment of Cushing’s Disease
`
`Endocrine Reviews, August 2015, 36(4):385– 486
`
`serious endocrine disease caused by excessive secretion of
`cortisol from the adrenal glands as a consequence of ex-
`cessive ACTH secretion from a pituitary tumor (1, 2). The
`pituitary tumor responsible for CD is generally an ade-
`noma, whereas a pituitary carcinoma is a very rare cause
`of the disease. The pituitary adenoma responsible for CD
`is a microadenoma in more than 90% of cases, and a
`macroadenoma in less than 10% of cases; microadenomas
`are not visible during radiological examination in up to
`40% of cases, and macroadenomas may occasionally ac-
`quire an aggressive behavior, characterized by a rapid
`growth and invasiveness of surrounding structures (1, 2).
`The prevalence of CD is estimated to be nearly 40 cases
`per million, whereas the incidence of CD ranges from 1.2
`to 2.4 per million per year. CD is at least three times more
`prevalent in women than in men, and mainly occurs during
`the fourth to sixth decades of life (1–3).
`CD is characterized by a disruption of the hypothala-
`mus-pituitary-adrenal (HPA) axis with consequent in-
`crease in circulating serum and urinary cortisol levels and
`lack of cortisol circadian rhythm (1, 2). The clinical picture
`of CD mainly includes weight gain with central obesity,
`fatigue with proximal myopathy, skin thinning with pur-
`plish striae, and diffuse bruising. The clinical picture is
`commonly complicated by several comorbidities, mainly
`including systemic arterial hypertension, diabetes melli-
`tus, dyslipidemia, osteoporosis, and depression, together
`with an impairment of sexual function in men; menstrual
`disorders, acne, and hirsutism in women; and infertility in
`both men and women (1, 2).
`The diagnosis of CD is a real challenge because of the
`variability of the clinical presentation of the disease and, par-
`ticularly, the lack of discriminatory symptoms and signs in
`patients with CD (1, 2). As a consequence, a series of hor-
`monal tests are required for a definitive diagnosis; however,
`these tests have a variable sensitivity and specificity and fail
`toreach100%accuracy(4–6).Therefore,efficientscreening
`and confirmatory diagnosis are essential before considering
`therapy (7). Moreover, a prompt and effective treatment is
`crucial to prevent the development and/or worsening of the
`comorbidities and clinical complications responsible for the
`increased mortality associated with the disease (8).
`The current review summarizes the available treatments
`for CD, describing efficacy, in terms of control on hormone
`secretion and tumor mass, and safety, associated with the
`different treatments, and detailing specific effects on the clin-
`ical picture as well as on comorbidities and clinical compli-
`cations that are the most important causes of death for pa-
`tientswithCD.Anintroductiononthemortalityandmorbidity
`ofCDisincludedtoemphasizetheseverityofthediseaseandthe
`need for a treatment. Future available treatments and experi-
`mental therapeutic approaches are also considered to offer the
`
`largestpossibleviewonperspectivesinthediseasemanagement.
`This review systematically evaluates the efficacy and safety of
`the different treatments, considering the available literature
`published until December 31, 2014.
`
`II. Mortality and Morbidity in Cushing’s
`Disease
`
`CD is associated with excessive mortality, which is mainly
`duetocardiovascularorinfectiousdiseases,andtheirorganicor
`systemic clinical complications. The excessive mortality is usu-
`ally observed in patients who do not achieve initial surgical re-
`mission, whereas those patients who do achieve an imme-
`diate surgical cure generally have a mortality rate
`similar to that of the normal population (9).
`
`A. Mortality
`The studies on mortality in CD have reported nonho-
`mogeneous results. Mortality in patients with CD has been
`analyzed in a series of studies, which reported the stan-
`dardized mortality ratio (SMR). In these studies, the SMR
`of the total population of patients with CD ranged from
`0.98 to 9.3 (10 –20), being significantly different from the
`normal population in six studies, where SMR ranged from
`2.39 to 9.3 (10, 15–18, 20), and similar to the normal
`population in five studies, where SMR ranged from 0.98
`to 2.67 (11–14, 19). Moreover, eight of these studies eval-
`uated mortality in patients submitted to surgical treat-
`ment, considering separately those who had disease re-
`mission and those with persistent disease; the results of
`these studies demonstrated that patients with persistent
`disease consistently had the highest mortality (13–20),
`whereas the patients with disease remission after pituitary
`surgery had a mortality rate generally similar to that of the
`general population (13–15, 17, 19). This finding suggests
`the importance of surgical removal of the pituitary tumor
`and disease remission. However, in contrast with these
`previous studies, the persistence of an increased mortality
`rate in patients who achieved disease remission after pi-
`tuitary surgery has been reported in three different retro-
`spective studies conducted in the United Kingdom (16, 18,
`20). In the first of these studies, the SMR of the total pop-
`ulation of CD patients was 4.8, with patients achieving
`surgical cure maintaining a significantly increased mor-
`tality (SMR, 3.3). Interestingly, patients with persistent or
`recurrent disease displayed a dramatically increased mor-
`tality (SMR, 16) compared with the normal population
`(16). In a recent study, the SMR of the total population of
`CD patients was 3.17, with an increased mortality rate
`both in patients achieving surgical cure (SMR, 2.47) and
`in patients with persistence or recurrence of the disease
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`after surgery (SMR, 4.12), although these values were re-
`ported to be not significantly different from that of the
`normal population (18). Finally, another recent study has
`demonstrated a similar mortality rate between patients
`cured or not cured by surgery, displaying an SMR of
`around 10, compared with the normal population (20). It
`is worthwhile noting a study conducted in New Zealand
`that demonstrated a persistently increased mortality rate
`in patients harboring either a pituitary microadenoma or
`macroadenoma, despite long-term remission after pitu-
`itary surgery (17). In contrast to the discordant evidence of
`the mortality risk in patients cured by surgery, there is
`consistent evidence that patients with persistent disease
`after initial surgery have the highest mortality rate. This
`finding has been clearly reported in a Danish study in
`which patients not cured after initial surgery had a SMR
`of 5.06; interestingly, patients with possible CD whose
`disease etiology was unproven had an SMR of 11.5. The
`group with unproven CD included those without clear
`identification of a pituitary tumor, those who did not
`achieve remission after surgery, and those who died before
`a full investigation could be performed (13).
`The major cause of death in patients with CD reported
`in the literature is represented by cardiovascular disease
`and consequent cardiovascular events, although infec-
`tious diseases and consequent sepsis seem to play an im-
`portant role in determining or precipitating death, and
`suicide associated with psychiatric disorders is also de-
`scribed in patients with CD (8 –20).
`The predictive factors for mortality have not been
`clearly identified in patients with CD. Indeed, whereas age
`at disease diagnosis seems to have a clear negative role in
`determining premature death (10, 11, 17, 19, 20), the ev-
`idence regarding the role of gender is discordant because
`an increased mortality in females (10), a similar mortality
`in females and males (13), and an increased mortality in
`males (19) have each been reported. Moreover, the higher
`prevalence of deaths in patients during active disease,
`compared with patients after surgical remission in most
`studies suggests a pivotal role for the exposure to cortisol
`excess in mortality. The presence and duration of active
`disease have been clearly confirmed as an important pre-
`dictive factor for mortality (13–16, 19). However, the role
`of exposure to cortisol excess, in terms of extent and du-
`ration, still needs to be clarified. The presence of comor-
`bidities, including systemic arterial hypertension and di-
`abetes mellitus, has been indicated as a predictive factor
`for mortality in different studies (10, 16, 17). Two recent
`studies in a large number of patients with CD have ad-
`dressed the issue of the predictive factors for mortality.
`One study confirmed that cardiovascular disease repre-
`sents the main cause of death in patients with CD, with
`
`male gender, age at diagnosis, disease duration, and clin-
`ical complications elevating the risk of cardiovascular dis-
`ease (21). In particular, age at diagnosis, duration of ex-
`posure to cortisol excess, and preoperative plasma ACTH
`concentration elevated the risk of death in the total cohort
`of patients; on the other hand, male gender, age at the
`diagnosis, and depression were the main determinants for
`mortality in patients who achieved immediate remission
`after pituitary surgery or late remission after second-line
`treatments (21). In the second study, mortality associated
`with CS was demonstrated to be strongly dependent on the
`multisystem morbidity of CS, although mainly cardiovas-
`cular disease and infectious diseases (22).
`Table 1 summarizes the results of the main studies on
`mortality, including the evaluation of the SMR, in CD.
`It should be taken into account that geographic vari-
`ability in the management of CD can induce differences in
`reported mortality rates. The recent MISSION (Mortality
`in Cushing’s Syndrome: an International and Observa-
`tional Study of the European Neuroendocrine Associa-
`tion) study collected information on nearly 5000 patients
`with CS from around the world and confirmed that pa-
`tients with CD had an increased mortality (crude mortality
`rate, 4.25), mainly associated with disease activity (crude
`mortality rate of patients with active CD, 24.45) and
`mostly secondary to cardiovascular disease, often result-
`ing in fatal cardiovascular events, and infectious diseases,
`especially when leading to generalized sepsis, since myo-
`cardial infarction or heart failure represents 17.5% and
`severe infection or sepsis represents 17.3% of the causes of
`death (23). A recent meta-analysis on mortality in patients
`with CS, including six studies that focused on patients
`with CD, confirmed that CD is associated with an in-
`creased mortality, documented by an estimated cumula-
`tive SMR of 1.84. Patients with persistent or recurrent
`disease after surgery had a strong association with an in-
`creased mortality, with an SMR of 3.73, whereas the SMR
`of patients with cured disease after surgery, with an SMR
`of 1.2, was not significantly different from that of the
`normal population (24). This meta-analysis, in accor-
`dance with most of the available studies, seems to suggest
`that surgical cure is fundamental for protecting patients
`with CD from a premature death. This conclusion should,
`however, be interpreted with caution. Although a meta-
`analysis has the strength of a systematic approach, with
`the inclusion of only those studies with a clear SMR cal-
`culated from available data, it also has the drawback of a
`limited number of studies that include a relatively small
`number of patients with a relatively short period of fol-
`low-up and few analyzable events.
`In summary, the results of the studies on mortality in
`CD demonstrate that patients with active disease, mainly
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`388
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`Treatment of Cushing’s Disease
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`Endocrine Reviews, August 2015, 36(4):385– 486
`
`Table 1. Results of the Main Studies on Mortality in CD
`
`First
`Author,
`Year (Ref.)
`
`Etxabe,
`1994
`(10)
`
`Country
`
`Spain
`
`Patient
`Type (n)
`
`CD (49)
`
`Sex
`Ratio
`(F/M), n
`
`46/3
`
`Duration
`of Follow-
`Up
`as Mean ⴞ
`SE or
`Median
`(Range), y
`6.3 ⫾ 0.8
`
`SMR Total
`Population
`(95% CI)
`
`SMR
`Cured
`Disease
`(95% CI)
`
`SMR
`Persistent/
`Recurrent
`Disease
`(95% CI)
`
`Study Design
`
`Population-based
`study
`
`3.8 (2.5–
`17.9)a
`
`NA
`
`NA
`
`Swearingen,
`1999
`(11)
`Pikkarainen,
`1999
`(12)
`
`United States
`
`CD (161)
`
`129/32
`
`8.7 (1–20)
`
`Finland
`
`CS (74),
`CD (43)
`
`7.4 (0 –15)
`
`CS 64/
`10
`CD
`38/5
`
`Retrospective
`single-center
`study
`Retrospective
`single-center
`study
`
`0.98
`(0.44 –
`2.2)
`2.67
`(0.89 –
`5.25)
`
`NA
`
`NA
`
`NA
`
`NA
`
`Main Causes of
`Death
`
`Cardiovascular disease;
`infectious diseases
`
`Cardiovascular disease;
`stroke
`
`Predictive Factors
`
`Age at diagnosis;
`female gender;
`persistence of
`hypertension
`and
`abnormalities of
`glucose
`metabolism
`Age at diagnosis
`
`NA
`
`Denmark
`
`CS (166),
`CD (73)b
`
`CD 50/
`23b
`
`8.1 (3.1–
`14.0)
`
`National registry
`study
`
`1.7 (0.68 –
`3.5)
`
`United States
`
`CD (289)
`
`239/50
`
`11.1 (0.6 –
`24.1)
`
`1.42
`(0.95–
`2.1)
`
`Disease persistence
`
`0.31
`(0.01–
`1.72)
`1.18 (0.7–
`1.9)
`
`5.06
`(1.86 –
`11.0)a
`2.8 (1.35–
`5.9)a
`
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`Coronary heart disease;
`mitral valve
`insufficiency and
`heart failure; acute
`myocardial
`infarction;
`pancreatitis
`Stroke; malignancy;
`sepsis; rupture of
`aortic aneurysmb
`Disease persistence Myocardial infarction
`and/or cardiac
`failure; cardiac
`arrestc
`Cardiovascular disease;
`malignancy;
`infectious diseases
`Cardiovascular disease;
`cerebrovascular
`disease; malignancy;
`rupture of aortic
`aneurysm
`Malignancy; ischemic
`heart disease;
`stroke; sepsis;
`pulmunary
`embolismd
`
`Disease duration
`
`Disease
`persistence;
`hypertension;
`diabetes
`
`Age at diagnosis;
`diabetes
`mellitus at last
`follow-up;
`treatment with
`pituitary surgery
`or bilateral
`adrenalectomy
`NA
`
`Age at diagnosis;
`male gender;
`disease
`duration;
`disease activity
`Age at diagnosis
`
`Cardiovascular disease;
`malignancy;
`infectious diseases
`
`Cardiovascular disease;
`cerebrovascular
`disease; infectious
`diseases and sepsis
`
`Cardiovascular disease;
`infectious diseases
`and sepsis;
`malignancy
`
`Lindholm,
`2001
`(13)
`Hammer,
`2004
`(14)
`
`Dekkers,
`2007
`(15)
`Clayton,
`2011
`(16)
`
`Bolland,
`2011
`(17)
`
`Hassan-
`Smith,
`2012
`(18)
`Yaneva,
`2013
`(19)
`
`The Netherlands
`
`CD (74)
`
`56/18
`
`12.8 ⫾ 7.3
`
`United Kingdom CD (60)
`
`51/9
`
`15 (0.5– 41)
`
`New Zealand
`
`CS (253),
`CD (188)
`
`CS 192/
`61
`CD
`142/
`46
`
`Macro, 6.9
`(0 –30);
`micro,
`7.5 (0 –
`46)
`
`Retrospective
`single-center
`study
`
`Retrospective
`single-center
`study
`Retrospective
`single-center
`study
`
`Nationwide
`retrospective
`survey
`
`United Kingdom CD (80)
`
`63/17
`
`10.9 (4.9 –
`15.6)
`
`Retrospective
`single-center
`study
`
`2.39
`(1.22–
`3.9)a
`4.8 (2.8 –
`8.3)a
`
`1.8 (0.71–
`3.37)
`
`3.3 (1.7–
`6.7)a
`
`4.38
`(1.38 –
`9.07)a
`16 (6.7–
`38.4)a
`
`Macro, 3.5
`(1.3–
`7.8)a;
`micro,
`3.2
`(2.0 –
`4.8)a
`
`Macro, 2.3
`(0.4 –
`7.5);
`micro,
`3.1
`(1.8 –
`4.9)a
`
`3.17 (1.7–
`5.43)a
`
`2.47 (0.8 –
`5.77)a
`
`Macro, 5.7
`(1.4 –
`15.4)a;
`micro,
`2.4
`(0.4 –
`7.8)a
`
`4.12
`(1.12–
`10.54)
`
`2.4 (0.87–
`8.19)a,f
`
`Bulgaria
`
`CS (386),
`CD (240)
`
`8.8
`(0 – 41.2)
`
`Retrospective
`single-center
`study
`
`1.88
`(0.69 –
`4.08)
`
`1.67
`(0.61–
`3.62)e
`
`CS 324/
`62,
`CD
`197/
`43
`CS 157/
`52,
`CD
`137/
`45
`
`Ntali, 2013
`(20)
`
`United Kingdom CS (209),
`CD (182)
`
`12 (0.1– 46)
`
`Retrospective
`multicenter
`study
`
`9.3 (6.2–
`13.4)a
`
`8.3 (5.1–
`12.7)a
`
`9.9 (3.6 –
`21.9)a
`
`This table includes studies including the calculation of SMR. Abbreviations: CI, confidence interval; F, female; M, male; NA, not available.
`a The SMR is significantly different from the general population.
`b The population of CD considered was that with proven pituitary etiology.
`c The main causes of death described in this study are exclusively related to the short-term follow-up (within six months after surgery), whereas information on causes
`of death after long-term follow-up is not available.
`d The main causes of death are related to the entire population of patients with CS.
`e The SMR is related to the entire population of CS.
`f The SMR is the related to the entire population of active CS.
`
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`
`389
`
`those with persistent or recurrent disease after surgery,
`have a seriously increased mortality, whereas some dis-
`crepancies are evident regarding the data on patients who
`achieved surgical cure. It cannot be excluded that these
`discrepancies may partially depend on the definition of
`“cure” applied in the single studies, considering that a
`consensus has never been reached on this issue. Nonethe-
`less, it is clear that the normalization of cortisol secretion
`improves mortality, most likely because of the positive
`effects on the clinical comorbidities associated with CD,
`
`including cardiovascular disease, metabolic syndrome, in-
`fectious diseases, and neuropsychiatric disorders, which
`affect quality of life and represent the important risk of
`death for patients with CD (8).
`Figure 1 shows the main comorbidities and clinical com-
`plications associated with mortality in patients with CD.
`
`B. Cardiovascular disease
`Cardiovascular disease represents the direst complica-
`tion and the leading cause of death in patients with CD (8).
`
`Figure 1.
`
`Figure 1. Comorbidities and clinical complications associated with excessive mortality in CD.
`
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`390
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`Pivonello et al
`
`Treatment of Cushing’s Disease
`
`Endocrine Reviews, August 2015, 36(4):385– 486
`
`Cardiovascular risk is increased in CD because of the co-
`morbidities associated with the disease and including vis-
`ceral obesity, impairment of glucose tolerance or diabetes
`mellitus, dyslipidemia, and systemic arterial hypertension,
`which are constituent elements of metabolic syndrome, as
`well as thrombosis diathesis (25–27). Cardiovascular dis-
`ease associated with CD includes both vascular and car-
`diac diseases.
`
`1. Vascular diseases
`Arterial atherosclerosis is the main vascular disease as-
`sociated with CD. Indeed, carotid artery wall thickness, a
`strong predictor of systemic atherosclerosis, was found to
`be significantly increased and associated with the prema-
`ture development of plaques in patients with CD during
`active disease, partially persisting after a short-term re-
`mission (28). Moreover, an increased prevalence of
`preatherosclerotic and atherosclerotic lesions was also
`found after long-term disease remission from CD (29).
`The carotid vascular damage was significantly and inde-
`pendently correlated with the degree of visceral obesity
`and insulin resistance, demonstrating that these two fac-
`tors mainly contribute to the presence and persistence of
`vascular damage in patients with CD, both before and
`after disease remission (28, 29). In patients with CS, in-
`cluding both patients with CD and adrenal-dependent CS,
`an increased wall thickness and an increased prevalence of
`atherosclerotic plaques were described in multiple vascu-
`lar locations (30), whereas in patients with CS, mainly
`represented by ectopic CS, an increased prevalence of ath-
`erosclerotic plaques was documented in the coronary ar-
`tery system (31), confirming that hypercortisolism induces
`a premature arterial atherosclerosis in the entire vascular
`system with a consequent predisposition to coronary heart
`disease and myocardial infarction, as well as to cerebro-
`vascular diseases and stroke. A functional alteration of the
`vascular system, evaluated by an endothelium-dependent
`flow-mediated vasodilation, was reported to be impaired
`in patients with CS compared with controls, contributing
`to the vascular damage associated with CS (32). The de-
`velopment of vascular disease is strictly dependent on two
`of the main cardiovascular clinical features of CS, includ-
`ing systemic arterial hypertension and thrombosis diathe-
`sis, the latter of which is due to coagulation disorders.
`
`2. Systemic arterial hypertension
`Hypertension is a common feature of CS, and it has
`been reported in 55– 85% of patients with CD, where it
`represents an important factor for the development of
`both vascular and cardiac damage (8). The most impor-
`tant mechanism underlying the hypertension associated
`with CS lies in the activation of the mineralcorticoid re-
`
`ceptor by the excessive cortisol levels (33–36). In addition,
`multiple factors including the activation of the renin-an-
`giotensin system, together with increased reactivity of va-
`soconstrictor and decreased reactivity to the vasodilatory
`system, increased cardiac output and peripheral resis-
`tance, mainly the consequence of an increased sensitivity
`to catecholamines, may contribute to the development of
`hypertension in CS (33–36). The circadian blood pressure
`rhythm is generally altered in patients with CD, showing
`the typical nondipping pattern, which is related to greater
`end-organ damage and increased mortality (37). Hyper-
`tension associated with CS can be difficult to treat without
`the direct relief from hypercortisolism (36). However, be-
`sides the control of hypercortisolism, different antihyper-
`tensive drugs often need to be used to control hypertension
`in patients with CS during active disease; recently, a patho-
`physiology-oriented therapeutic algorithm has been de-
`veloped, and it could serve as a first attempt to rationalize
`the treatment of hypertension in CS (36). Moreover, hy-
`pertension can persist even after remission; this is because
`of either a possible coexistence of essential hypertension or
`permanent damage incurred by cortisol excess in the car-
`diovascular system (33–37).
`
`3. Thrombosis diathesis
`Thrombosis diathesis is a dangerous feature associated
`with CD, where hemostasis abnormalities have been de-
`scribed in around 54% of patients and consequent vascu-
`lar events in 10% of patients with CD (8). The increase in
`thrombosis risk associated with CD is not only a conse-
`quence of metabolic syndrome, but also a consequence of
`a specific coagulopathy, which represents another impor-
`tant factor contributing to the increase in cardiovascular
`risk in patients with CS, and particularly in patients with
`CD (38 – 40). Indeed, the cortisol excess stimulates the
`synthesis of several clotting factors, such as fibrinogen by
`the liver and von Willebrand factor by endothelial cells,
`and also induces the synthesis of plasminogen activator
`inhibitor, which is the main inhibitor of the fibrinolysis
`(38 – 40). The hypercoagulable state is considered a crucial
`factor predisposing patients with CS to thromboembolic
`events, mostly after surgery, suggesting the usefulness of
`an anticoagulant prophylaxis in patients with CS before
`being subjected to surgery in order to prevent postopera-
`tive thrombotic events (38 – 40). Moreover, the increased
`homocysteine and decreased taurine levels, which have
`been described in patients with CD, complicate the pro-
`thrombotic state and the cardiovascular risk associated
`with CD (41, 42).
`
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`4. Cardiac diseases
`In contrast to the vascular system, cardiac morphology
`and performance have not been extensively studied in CD.
`An abnormal left ventricular geometry has been described
`to be associated with an increase in left ventricular mass in
`patients with CS (43, 44). These structural abnormalities
`were associated with diastolic dysfunction (43) or with
`normal diastolic function (44), and generally with a pre-
`served systolic function (43, 44). Abnormalities in cardiac
`morphology and performance have been reported to be
`partially (44) or totally reversible (45) upon normalization
`of hypercortisolism and disease remission, independently
`on change in blood pressure. An alteration of the sympa-
`thovagal balance of heart rate variability has also been
`found to be associated with an increased risk of cardiac
`events, suggesting the possible occurrence of silent ar-
`rhythmias and/or myocardial ischemia in patients with CS
`(46). Indeed, an increased prevalence of coronary artery
`disease has been documented in patients with cured CS, so
`that patients, especially young and female patients, re-
`mained at risk of myocardial infarction even after long-
`term cure (47).
`
`C. Metabolic syndrome
`The increased cardiovascular risk of patients with CD
`is associated with metabolic syndrome (26). Metabolic
`syndrome is a severe clinical condition affecting approx-
`imately 30 – 40% of the general population, being char-
`acterized by systemic arterial hypertension, together with
`visceral obesity, impairment of glucose metabolism, and
`dyslipidemia (48). Metabolic syndrome is common in de-
`veloped countries, due to obesity and sedentary lifestyles,
`but whether it is a true syndrome or a chance association
`of unrelated phenotypes is controversial (49). However,
`there is general agreement that metabolic syndrome is as-
`sociated with an increased risk to health; in particular, it
`is associated with a 5-fold risk of developing diabetes mel-
`litus and a 2-fold risk of developing cardiovascular disease
`after 5–10 years (49). A considerable disagreement also
`exists regarding the diagnostic criteria for metabolic syn-
`drome, which however are based on the following specific
`clinical and biochemical features: 1) visceral obesity, rep-
`resented by an increased waist circumference; 2) dyslipi-
`demia, represented by increased serum triglycerides or de-
`creased high-density lipoprotein-cholesterol, or
`the
`presence of antidyslipidemic treatments; 3) impairment of
`glucose metabolism, represented by increased fasting
`plasma glucose levels, or the presence of antidiabetic treat-
`ments; and 4) hypertension, represented by increased
`blood pressure or the presence of antihypertensive treat-
`ment (49). These criteria are frequently met in CS, which
`appears as a severe form of metabolic syndrome, suggest-
`
`ing a crucial role of cortisol excess in the genesis of met-
`abolic syndrome, probably through the development of
`visceral obesity and insulin resistance (49). The role of
`cortisol excess on the development of metabolic syndrome
`is confirmed by the evidence that metabolic syndrome is
`more severe in patients with CS who demonstrate a pecu-
`liar abdominal obesity and a severe insulin resistance, as-
`sociated with dramatically elevated cortisol levels, as op-
`posed to patients with obesity but without CS, usually
`characterized by a more generalized obesity and a variable
`insulin resistance associated with absent or slightly ele-
`vated cortisol levels. This confirms a role for visceral ad-
`iposity and the associated insulin resistance