Transcript Comorbidities in Acromegaly

Accreditation Statement
• The Endocrine Society is accredited by the Accreditation
Council for Continuing Medical Education to provide
continuing medical education for physicians.
• The Endocrine Society has achieved Accreditation with
Commendation.
• The Endocrine Society designates this live activity for a
maximum of 2.0 AMA PRA Category 1 Credits™.
Physicians should claim only the credit commensurate
with the extent of their participation in the activity.
Learning Objectives
Upon completion of this educational activity, learners will be
able to:
• Examine principle recommendations of the latest
evidence-based clinical practice guidelines for the
diagnosis and management of acromegaly
• evaluate surgery, radiotherapy, and pharmacological
treatments, as well as the use of biochemical control, in
the overall management of acromegaly
• Assess the effect of acromegaly and its comorbidities on
patients’ quality of life to better assist and manage these
patients
• Assess novel therapeutic targets and emerging drug
formulations for the treatment of acromegaly
Disclosures
The Endocrine Society has reviewed all disclosures and resolved or managed all
identified conflicts of interest, as applicable.
The following faculty reported relevant financial relationships:
Andrea Giustina, MD: Consultant, Ipsen, Novartis Pharmaceuticals, Pfizer, Inc.
Shlomo Melmed, MD: Consultant, Genentech, Inc.; Principal Investigator, Ipsen, Pfizer,
Inc.
Roberto Salvatori, MD: Advisory Board, Novartis Pharmaceuticals, Pfizer, Inc.; Advisory
Board and Investigator, Ipsen
The following faculty reported no relevant financial relationships: David R. Clemmons,
MD
The following SPC member who planned and reviewed content for this activity reported
relevant financial relationships:
Andrea L. Utz, MD, PhD: Advisory Board, Corcept, Ipsen
Disclosures - continued
The following SPC members reported relevant financial relationships:
Benjamin Leder, MD: Consultant and Investigator, Amgen Inc.; Investigator, Eli Lilly & Co.
Sarah Berga, MD: Advisory Board, Agile Therapeutics, Noven Pharmaceuticals, Inc.,
Watson Pharmaceuticals, Teva Pharmaceuticals Industries, Shionogi, Inc.; Consultant,
AHC Media, LLC, Shionogi, Inc.
Paresh Dandona, MD, PhD, FRCP: Consultant and Speaker, AstraZeneca, Bristol-Myers
Squibb, Janssen, Merck, Novo Nordisk
Henry Fein, MD: Investigator, Corcept Therapeutics
Irl Hirsch, MD: Consultant, Abbott Laboratories, Johnson & Johnson, Roche Diagnostics,
Valeritas; Investigator, Sanofi
Anton Luger, MD: Advisory Board, Investigator and Speaker, Novo Nordisk; Advisory
Board and Speaker, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Ipsen, Merck, Merck,
Sharp & Dohme, Novartis, Pfizer, Reckitt Benckiser, Takeda; Investigator, Roche
The following SPC members reported no relevant financial relationships: Jeffrey Boord,
MD, MPH; Larry Fox, MD; Ann Kearns, MD, PhD; Connie Newman, MD
Endocrine Society and Vindico Medical Education staff associated with the development of
content for this activity reported no relevant financial relationships
COMORBIDITIES OF
ACROMEGALY
Andrea Giustina
Chair of Endocrinology
University of Brescia
Italy
Disclosure
Consultant: Ipsen, Novartis Pharmaceuticals,
Pfizer, Inc.
Comorbidities in Acromegaly
Cerebrovascular events, headache
Hypertension, cardiomyopathy,
valvular disease
•Na+-fluid retention
•peripheral vasomotor dysfunction
• endothelial disturbances
•Myocardial fibrosis
Hypopituitarism, hypogonadism
Acromegaly
comorbidities
Respiratory
complications,
sleep apnea
•Craniofacial deformations
•Soft tissue hypertrophy
•Increased bone resorption
•Cartilage hypertrophy
•Osteophytosis
•Insulin resistance
•Impairment of insulin
secretion
Colon polyps
Osteoarthritis,
osteoporotic fractures
Glucose
intolerance/
Katznelson L, et al. Endocr Pract. 2011;17 Suppl 4:1-44. diabetes mellitus
Mortality in Acromegaly
Biochemical Determinants
Holdaway IM, et al. Eur J Endocrinol. 2008;159:89-95.
Mortality in Acromegaly
Clinical Determinants
Rajasoorya C, et al. Clin Endocrinol (Oxf). 1994;41:95-102.
Hypertension in Acromegaly
• Present in ≥40% of patients
– Exacerbated by sleep apnea
• Baseline BP measurement recommended
• Early, aggressive treatment important
• Unclear effect of different medical treatments for
acromegaly on hypertension
Katznelson L, et al. Endocr Pract. 2011;17 Suppl 4:1-44.
Vitale G, et al. Clin Endocrinol (Oxf). 2005;63:470-476.
Cardiovascular Disease in
Acromegaly
SURGERY
NEUROSURGERY +
SOMATOSTATIN ANALOGS
Interventricular septum thickness (cm)
300
1,8
SURGERY
NEUROSURGERY +
SOMATOSTATIN ANALOGS
1,6
1,4
200
1,2
1,0
100
,8
,6
0
,4
Cured
Controlled
Pts Groups
De Marinis L, et al. Pituitary. 2008;11:13-20.
Poorly controlled
Cured
Controlled
Pts Groups
Poorly controlled
Sleep Apnea in Acromegaly/1
• Underassessed
– Prevalence up to 70%
•
All patients require careful assessment
– Symptomatic
– Laboratory
•
Improved compliance with CPAP and other devices needed
• Maxillofacial consultation advised
•
SAS only partially reversible with biochemical control of acromegaly
Davi' MV, et al. Eur J Endocrinol. 2008;159:533-540. Katznelson L, et al. Endocr Pract. 2011;17 Suppl 4:1-44.
Sleep Apnea in Acromegaly/2
N° of patients
with improved
SAS/Total
Mean AHI
before therapy
Mean AHI
after therapy
Paper
Type of therapy
Grunstein et al., 1994
SRLs
NA
39
19
Ip et al., 2001
SRLs
NA
29
13
Herrmann et al., 2004
SRLs
9/14
NA
NA
Berg et al., 2009
PEG
9/12
23
18
S
1/3
20,6
18,3
S
6/6
41
11,3
Davì et al., 2008
S, SRLs, RT
5/6
31,2
21,3
Rosenow et al., 1996
S, SRLs, RT, 24/32
DA
NA
NA
Pekkarinen et
1987
Sze et al., 2007
al.,
Davì MV, et al. Exp Rev Endocrinol Metab. 2012;7:55-62.
Diabetes in Acromegaly
Dreval AV, et al. Endocr Connect. 2014;3:93-98.
Skeletal Fragility in Acromegaly
Clinical evidence!
Skeletal Fragility in Acromegaly
1° Author (year)
Non vertebral (Clinical)
Vertebral (RX)
Vestergaard (2002)
↓
-
Vestergaard (2004)
↔
-
Bonadonna (2005)
-
↑
Mazziotti (2008)
-
↑
Wassenaar (2011)
-
↑
Padova (2011)
↑
Madeira (2013)
↑
All cross-sectional studies
a,b,c
90
a,b,c
Incidence of VF (%)
80
a
70
120
100
60
80
50
40
60
a
30
40
20
20
10
0
0
Controls
Controlled/Cured
for 36 months
Active for 1-12
months
Active for 13-24
months
Median of total duration of active
acromegaly (months)
Skeletal Fragility in Acromegaly
Active for 25-36
months
OUTCOME OF ACROMEGALY DURING 3-YEAR FOLLOW-UP
a,
p<0.05 vs. control subjects; b, p<0.05 vs. controlled/cured disease; c, p<0.05 vs. active disease for
1-12 months
Adapted from: Mazziotti G, et al. J Clin Endocrinol Metab. 2009;94:1500-1508.
Outcome of Comorbidities in Acromegaly
Comorbidities
Generally improved with medical treatment
•
•
•
•
Left ventricular hypertrophy
Left ventricular dysfunction
Hypertension
Obstructive sleep apnea
Melmed S, et al. Pituitary. 2013;16:294-302.
Variable or uncertain response to medical
treatment
• Arthropathy
• Diabetes/glucose intolerance
• No reversal of skeletal changes
Summary
• Severe comorbidities make acromegaly a life-
threatening disease heavily impairing quality of life of
affected patients
• Early diagnosis and effective and sometimes
aggressive treatment is mandatory to avoid the onset,
stop the progression, or reverse comorbidities
• All patients with acromegaly, including those in
biochemical remission, should undergo structured
follow-up in order to monitor evolution of
comorbidities
CHALLENGES IN
DIAGNOSING AND
FOLLOWING ACROMEGALY
David R. Clemmons, MD
Sarah Graham Kenan Professor of Medicine
Director, Diabetes Center of Excellence
University of North Carolina-Chapel Hill
Chapel Hill, NC
Diagnosis of Acromegaly
•
Single measurement of growth hormone (GH) is not an accurate
indicator of elevation since secretion is pulsatile
– Random GH sampling results in both false-positive and
false-negative results
– Patients can have active disease even though GH levels fall within
normal range
– Diagnosis can be confirmed by demonstrating failure to suppress
GH <1 ng/mL after glucose administration
•
Measurement of insulin-like growth factor (IGF)-I levels is a reliable
marker for the diagnosis of acromegaly
– Representative of average daily GH secretion
– Levels remain stable throughout the day; not affected by meals
Freda PU. Endocrinologist. 2000;10:237-244.
Melmed S, et al. J Clin Endocrinol Metab. 1998;83:2646-2652.
Correlation Between IGF-I and
Clinical Indices
fasting GH: r = 0.08
fasting GH: r = 0.12
2200
2200
r = 0.73
P<0.00001
IGF-I (ng/mL)
1800
r = 0.74
P<0.00001
1800
nadir GH: r = 0.36
nadir GH: r = 0.34
1400
1400
1000
1000
600
600
22
26
30
34
38
Heel Pad Thickness (mm)
Adapted from: Clemmons DR, et al. N Engl J Med. 1979;301:1138-1142.
100
140
180
Fasting Blood
Glucose (mg/dL)
360
Why Measure GH?
•
•
•
•
Provides a direct measure of tumor output
Necessary to exclude the diagnosis in 2.5%
of normal population who have an elevated
IGF-I
Correlates with degree of improvement
after surgery
Predicts long term mortality outcome
Summary of Criteria for
Selecting IGF-I Assays
1. Adequate age-adjusted normative data
2. Interassay variability is stated
3. Method is adequate to eliminate binding
protein interference
4. Assay results show proven GH
dependence
5. Reference values are available that allow
comparison of results to other commercial
assays
IGF-I Age Adjusted Reference
Ranges
Bidlingmaier M, et al. J Clin Endocrinol Metab. 2014;99:1712.
Summary of Criteria for
Selecting IGF-I Assays
1. Adequate age-adjusted normative data
2. Interassay variability is stated
3. Method is adequate to eliminate binding
protein interference
4. Assay results show proven GH
dependence
5. Reference values are available that allow
comparison of results to other commercial
assays
Interlaboratory Agreement of Insulin-like Growth
Factor 1 Concentrations Measured by Mass
Spectrometry
Mean
concentration,
ng/mL
Central calibrator,
CV, %a
1
85
4.0
16.4
2
90
5.6
19.3
3
210
6.1
10.6
4
356
6.9
5.5
5
179
3.5
11.8
5.2
12.8
Sample
Mean CV, %c
Local calibrator,
CV, %b
Comparison of a central calibrator vs a local calibrator.
•↵a One laboratory generated a single calibration curve and distributed it.
•↵b Each laboratory generated its own calibration curve using rat plasma and reference material.
•↵c Average CV was calculated from the CV of all 4 samples.
Cox HD, et al. Clin Chem. 2014;60:541-548.
Results from a HGH Recovery Study
Recovery value, %
Background
matrix
PBS
hGHdepleted
serum
Charcoalstripped
serum
SRM 971
male
Sheep serum
hGH, μg/ml
5.05
Immulite
Cobas e411
hGHsensitive
ELISA
DiaSorin
<1
0.60
<1
<1
<1
IDS
5.18
38
38
32
28
31
5.09
28
28
23
21
23
5.03
25
22
17
16
20
5.12
28
24
20
15
18
4.94
145
135
103
89
106
5.01
107
98
88
81
89
5.03
103
94
81
82
88
4.91
106
90
83
80
92
4.97
122
100
90
77
90
Reconstitutio
n in PBSBSA
PBS-BSA
hGHdepleted
serum
Charcoalstripped
serum
Boulo S et al. Clin Chem.
2013;59:1074-1082.
SRM 971
male
Sheep serum
Comparison of LC-MS and Immunoassay
Techniques with Respect to hGH Quantification
Sample
A
B
C
[hGH] by LC-MS,
μg/L
Peptide
T12
Peptide
T6
[GHBP], μg/L
7.250 (0.023)
5.205 (0.010)
4.365 (0.019)
6.348 (0.005)
4.458 (0.017)
3.675 (0.012)
42.2 (1.8)
21.2 (1.6)
24.7 (1.4)
10.6
14.8
Decrease in [hGH]
upon addition of
9.7
10 μg/L GHBP, %
[hGH] by
immunoassay,
μg/L
Siemens
9.78 (0.31)
7.14 (0.44)
4.21 (0.18)
Roche
9.29 (0.21)
7.26 (0.12)
4.10 (0.11)
7.91 (0.17)
5.62 (0.06)
3.14 (0.07)
DiaSorin
6.90 (0.87)
5.60 (0.30)
2.87 (0.15)
IDS
7.99 (0.76)
6.18 (0.25)
3.25 (0.13)
Mediagnost
Boulo S et al. Clin Chem. 2013;59:1074-1082.
Surgical Cure Rates for Acromegaly According
to Tumor Size and Criteria Used
% Cured
Series
Micros
Macros
Abosch (n=254)
75
71
Swearingen (n=149)
91
48
Freda (n=99)
88
53
Beauregard (n=103)
82
47
Shimon (n=98)
84
64
Krieger (n=181)
80
31
Abosch A, et al. J Clin Endocrinol Metab. 1998;83:3411-3418. Beauregard C, et al. Clin Endocrinol. 2003;58:86-91.
Swearingen B, et al. J Clin Endocrinol Metab.1998;83:3419-3426. Freda PU, et al. J Neurosurg. 1998;89:353-358.
Shimon I, et al. Neurosurgery. 2001;48:1239-1243. Krieger MD, et al. J Neurosurg. 2003;98:719-724.
Correlation Between Tumor Size and
Remission Rate After Surgery
Microadenoma
Macroadenoma
Giant adenoma
N
142 (27%)
Diameter (mm)
2-9
Avg. Diameter (mm) 7.6±1.75
378 (70.7%)
10-37
16.7 ± 5.6
12 (2.2%)
41-60
50.9±9.5
GH level (µg/l)
1-142
Average GH
16.4±15.2
level (µg/l)
Remission rate N= 107 (75.3%)
4-357
42.6±38.4
10-398
102.4±64.3
186 (48.6%)
1(8.3%)
Nomikos P et al. Eur J Endocrinol. 2005;152:379-387.
Odds Ratio for Presence of Left Ventricular Hypertrophy, Diastolic and
Systolic Dysfunction in Patients with Estimated Duration of Acromegaly ≥10
Years Compared with Those with Estimated Disease Duration <10 Years
Colao A et al. Eur J Endocrinol 2011;165:713-721.
© 2011 European Society of Endocrinology
IGF-I at Diagnosis Predicts OA Severity
Biermasz NR, et al. J Clin Endocrinol Metab. 2005;90:2731-2739.
Physician vs Computer Model
Sensitivity
Specificity
Positive
predictive
value
Accuracy
Physicians
Average
46
96
85
26
Worst
33
100
100
16
Best
83
96
95
90
Computer
71
100
100
86
Ten physicians, internists, or family practitioners, examined 49 8 × 10 color
photographs and decided which represented patients with acromegaly or normal
subjects. The same photographs were analyzed by the computer model. The
computer was more accurate (86%) than all but one of the physicians (90%).
Miller RE, et al. Clin Endo. 2011;75:226-231.
Case 1
• 46-year-old man referred for evaluation of
•
•
•
•
enlarged thyroid
Noted to have osteoarthritis
Recalled hand and foot enlargement,
sweaty palms, and change in facial features
Sleep apnea, hypertension, and impaired
fasting glucose
GH 1.6 ng/ml IGF-I 609 ng/mL (87-267)
MRI and Histology
Case 2
• 44-year-old woman presented for
evaluation of new onset diabetes
• BMI 26 kg/mm2 and no family history of
diabetes
• Reported changing ring size twice and shoe
size once, modest increase in sweating
• IGF-I 804 ng/mL (110-368) GH suppression
nadir 2.2 ng/mL
MRI: Microadenoma
Case 3
• 36-year-old man presented with clicking jaw
symptoms of TMJ
• History revealed joint pain and weight gain
• Occupation: Barber, had to enlarge his
scissors because fingers didn’t fit
• IGF-I 1600 ng/mL GH 13.9 ng/mL
Consensus Guidelines: Initial
Evaluation
• Screening: There are no consensus guidelines for
screening
• Diagnostic testing: Consensus recommendation is to
measure IGF-I and growth hormone after glucose
• Initial evaluation should include: MRI, visuals field (if large
tumor), prolactin, testosterone/LH (males), FSH estrogen
(females)
• Comorbidity evaluation: Fasting glucose; calcium
assessment of arthritis; sleep study, if symptomatic ECG,
followed by echocardiogram, if LVH is present;
colonoscopy; dexa scan and radiographs of spine and hip
films, if history of fracture or if hypogonadism is present;
genetic analysis, if family is positive for pituitary tumors
Summary
•
Confirmation of the diagnosis of acromegaly is straightforward the major
problem is early detection.
•
IGF-I measurements provide an index of disease severity and are useful for
diagnosis and monitoring the response to treatment.
•
GH suppression testing is useful for confirming that an elevated IGF-I is due to a
GH secreting tumor.
•
Assays for both IGF-I an GH have improved and further steps to improve the
comparability of results among different reference labs are being undertaken.
•
Abnormal enlargement of the hands and feet are the most common presenting
symptoms of acromegaly and merit investigation.
•
Early diagnosis predicts a much higher rate of surgical cure.
•
Consensus guidelines recommend both GH and IGF-I measurements at
diagnosis and proactive use of these tests to determine the need for further
therapy.
Therapeutic Approaches to
Acromegaly Management
Shlomo Melmed, MD
Cedars-Sinai Medical Center
Los Angeles, CA
Disclosure
• Consultant: Chiasma, Genentech
• Principal Investigator: Ipsen, Pfizer,
Novartis
Acromegaly: Approach to
Management
Governor Pio Pico
1847
Treatment Outcomes
Unchanged
GH
BP
Improved, with
disease persistence
DM
Recurrence
SA
OA
QOL
Spontaneous
resolution
…..etc
Long-term
normalization
Hours Days Weeks Months
Melmed 2014
Years
Acromegaly Treatment
Goals:
•
Eliminate morbidity
•
Reduce mortality to expected rates
Strategy:
•
Safe treatments
•
Remove tumor or control growth
•
Normalize GH secretion and action
•
Preserve pituitary function
Assessment:
•
Age-adjusted IGFI
•
Nadir GH <1 mg/L after OGTT
Giustina A, et al. J Clin Endocrinol Metab. 2010;95:3141-3148.
Acromegaly Treatment Outcomes
Uncontrolled
8.0
IGF-1 Z-SCORE
Partial
IGF-1 (mg/L)
6.0
High IGF-1
24%
4.0
Active
Disease
35%
2.0
0.0
Controlled
-2.0
High GH
11%
Controlled
30%
-4.0
0.1
0.11
1.0
3.3
GH (mg/L)
If IGF-1 nl ... probably controlled!
If GH elevated … likely sign of early relapse!
Adapted from: Alexopoulou O, et al. J Clin Endocrinol Metab. 2008;93:1324-1330.
10
33
100
n=229
GH as a Postoperative
Remission Biomarker
100
10
8
Nonremission
6
Remission
4
2
0
2
6
12
18
24
Time (hr)
48
72
Probability of remission (%)
GH (mg/liter)
12
24-hour postop GH <1 µg/L has 98% predictive value
80
60
40
20
0
Caveats:
IGF-1 normalization might be delayed after surgery
Medication effects might be delayed and progressive
Adapted from: Kim EH, et al. Neurosurgery. 2012;70:1106-1113.
0
2
4
Nadir GH (mg/L)
6
GH-secreting Adenoma:
Remission Predictors
Densely granulated
Sparsely granulated
Predictors for postsurgical disease persistence
Macroadenoma
Parasellar extension
Young age
High GH/IGF1
Osamura RY, et al. Histochem Cell Biol. 2008;130:495-507.
Fougner SL, et al. Clin Endocrinol (Oxf). 2012;76:96-102.
Kiseljak-Vassiliades K, et al. Endocrine. 2012;42:18-28.
Arita H, et al. J Clin Endocrinol Metab. 2012;97:2741-2747.
Larkin s, et al. Eur J Endocrinol. 2013;168:491-499.
Melmed S, et al. Endocr Rev. 1983;4:271-290.
…………Choice of surgeon
Hospital and Surgeon Volume
Determine Outcome
% Post-op GH<2.5 ng/mL
100
86
8 Surgeons
SINGLE Surgeon
80
60
408 hospitals
140
1.5
Mortality (%)
66
54
52
1.0
30
40
68
33
20
`
0.5
Micro
Macro
20
Overall
Lissett CA, et al. Clin Endocrinol (Oxf). 1998;49:653-657.
1-4
5-9
10-24
25+
Admissions/yr
534 surgeons
2.5
Mortality (%)
305
2.0
95
1.5
36
1.0
0.5
1
2-3
4-7
8+
Adapted from: Barker FG 2nd, et al. J
Clin Endocrinol Metab. 2003;88:47094719.
Surgery
•
Advantages
– Rapid GH decrease
– One-time cost
– Potential cure
– Debulking may enhance
adjuvant therapy
•
Disadvantages
– Tumor persistence
– Hypopituitarism
– Not all appropriate
candidates
Risks
%
Temporary vs permanent
• Overall complications
25
• Diabetes insipidus
10
• Electrolyte abnormalities 9
• Neurologic deficit
5
• CSF rhinorrhea
1.5
• Mortality
1
• More complications:
– Low-volume surgeon
– Comorbidity
Melmed 2014
Radiotherapy
Glucose-suppressed GH (<1 mcg/L)
% of Patients (N=47)
80
Normal IGF-I
Hypopituitarism
60
40
20
0
2 years Post RT
5 years Post RT
10 years Post RT
MORTALITY
RT
SMR (O/E)
95% CI
All
No
Yes
1.4
2.1
1.7, 2.6
0.006
Cancer
No
Yes
1.1
2.4
0.8, 2.2
0.442
CV
No
Yes
1.7
2.2
1.6, 3.1
0.247
Cerebrovascular
No
Yes
1.7
4.1
0.8, 3.3
2.3, 6.6
0.034
Adapted from: Minniti G, et al. J Clin Endocrinol Metab. 2005;90:800-804.
Adapted from: Sherlock M, et al. J Clin Endocrinol Metab. 2009;94:4216-4223.
P
Radiotherapy
•
Advantages
– Permanent
– No long-term therapy
– No drug-related
adverse events
•
Disadvantages
– Ineffective and slow
onset
– IGF-I not normalized
– Hypopituitarism
– One-time cost
– CVA
– Patient compliance
– Cost of interim
medical therapy
– Visual problems
– Secondary brain
malignancies
– CNS damage
Tumor Shrinkage in 55 Patients
Receiving Primary Octreotide Therapy
•
Mean tumor volume reduction
• Reduction to empty sella
• Cavernous sinus resolution
• Tumor disappeared
62%
11 patients
Tumor shrinkage: Progressive
%
Before hormone normalization
45
Without GH control
35
None, with GH control
Cozzi R, et al. J Clin Endocrinol Metab. 2006;91:1397-1403.
3
Primary Medical Treatment
• Poor likelihood of surgical cure
• Frailty
• Patient declines surgery
• Unacceptable anesthetic risk
Advantages
• Avoid noncurative surgery and
radiation with attendant side effects
• Medications can be personalized
SRL Therapy
Adverse effects
•
Gallbladder
–
•
•
Gastrointestinal
–
Diarrhea
–
Nausea
–
Abdominal discomfort
Glucose
–
•
Advantages
•
Rapid GH and/or IGF-I control and symptom relief
•
No hypopituitarism
•
Tumor mass control
Doppman The Endocrinologist 1998
Hypo/hyperglycemia
Cardiac
–
•
Gallstones or sludge
Sinus bradycardia
Other
–
Injection site pain
–
Headache
–
Alopecia
Disadvantages
–
Cure not permanent
–
Long-term treatment
–
Cost
–
Patient compliance required
GH Receptor Antagonist
•
Goals
– Normalize IGF-I
– Control symptoms
•
Efficacy Biomarker (nl IGF-I)
– >60% at 20-40 mg/day
•
Disadvantages
– Elevated liver enzymes
– Lipodystrophy
– Very rare increase in tumor
volume; uncertain if due to drug
or natural history
van der Lely AJ, et al. Lancet. 2001;358:1754-1759.
Trainer PJ, et al. N Engl J Med. 2000;342:1171-1177.
Melmed S. J Clin Invest. 2009;119:3189-3202.
ACROSTUDY: Pegvisomant
Biomarkers
100
Proportion of patients (%)
IGF-I normalized
80
Mean dose ( 18 mg/day)
63%
60
40
20
0
1
2
3
4
Years on Rx
n 435
426
339
5
257
160
Diabetes Biomarkers
Baseline
6 Mos
24 Mos
Glucose Fasting
(mg/dL)
141 ± 61
N=58
126 ± 56
N=51
102* ± 24
N=28
HbA1c (%)
7.0 ± 1.4
N=71
6.5* ± 1.2
N=65
6.5 ± 1.3
N=41
*P<0.05.
Adapted from: Van der Lely AJ, et al. J Clin Endocrinol Metab. 2012;97:1589-1597.
Combined SRL and Pegvisomant
= monthly SRL
105
= +pegvisomant
IGF-I (nmol/L)
125
85
65
45
25
30
40
50
Age (yrs)
60
70
Morbidity
IGF-I
Pituitary function
Tumor size
Adverse effects
Improved
Controlled ~80%
Uncompromised
Shrinkage ~50%
Similar to adjuvant Rx
Avoiding other less safe Rx
Patient choice
Adapted from: Neggers SJ, et al. J Clin Endocrinol Metab. 2007;92:4598-4601.
Pasireotide* Control of Acromegaly
octreotide SOM230
100mg
Ratio OCT/SOM
250mg
0
GH inhibition %
-25
SSTR1
30
SSTR2
SSTR3
SSTR4
SSTR5
5
-
35
0.4
-50
Weckbecker Endocrinol 2003
n=8
-75
-100
%
Pasireotide mg (bid)
0
-25
n=3
-50
-75
200 (n=21)
400 (n=17)
600(n=20)
70
*
P = 0.019
60
Adapted from: Van der
Hoek J, et al. J Clin
Endocrinol Metab.
2004;89:638-645.
Patients (%)
-100
50
Adverse events (%)
Gastro-intestinal
BS
HbA1c
Diabetes
25
6
5
5
Octreotide 100 mg tid (n=58)
40
30
20
10
0
GH 2.5 mg/L + normal IGF-I
GH 2.5 mg/L
Adapted from: Petersenn S, et al. J Clin Endocrinol Metab. 2010;95:2781-2789.
Normal IGF-I
*Not FDA approved
Comparing Treatment with Pasireotide* LAR
and Octreotide LAR
• Overall, the number of patients with GH
<2.5 µg/L and normal IGF-1 was
significantly greater with pasireotide LAR
compared to octreotide LAR (p=.007)
• Safety profile of pasireotide similar to
octreotide, except for hyperglycemiarelated AEs (57% vs 22%)
Colao A, et al. J Clin Endocrinol Metab. 2014;99:791-799.
*Not FDA approved
Effect of Octreolin* on Basal GH in
18 Healthy Subjects
4.0
Control
3.5
Octreolin
Serum GH µg/mL
3.0
2.5
2.0
1.5
0
83% inhibition of
basal GH
0.5
0.0
-1.0
-0.5
Pre dose
0.0
0.5
1.0
1.5
2.0
2.5
Basal Secretion
Octreolin
Adapted from: Tuvia S, et al. J Clin Endocrinol Metab. 2012;97:2362-2369.
*Not FDA approved
Effect of Oral Octreotide on GH
Surge in 18 Healthy Subjects
Serum GH ng/mL
70
Control
60
79% inhibition of
GHRH-induced GH
OOA
50
40
30
Octreolin
20
GHRH-Arg
10
0
-1.0
0.0
1.0
2.0
3.0
4.0
5.0
Hours of Study
Pre dose
Basal Secretion
GHRH-Stimulated
Adapted from: Tuvia S, et al. J Clin Endocrinol Metab. 2012;97:2362-2369.
Medical Management of Acromegaly
Somatostatin Receptor Ligand
Well controlled
Partial response
No response
Consider reducing
SRL dose
or increasing
dose interval
Increase SRL
dose or decrease
dose interval
SRL + pegv
Switch to
pegv
Well controlled
No response
No response
Well controlled
Monitor
IGF-I
SRL + pegv
Pegv + cabergoline
SRL + dopamine agonist
Increase pegv dose
and/or add
cabergoline
Consider reducing
pegv dose and/or
increasing dose interval
Adapted from: Giustina A, et al. Nat Rev Endocrinol. 2014;10:243-248.
Challenges for Improved
Treatment Efficacy
• Delivery modes
• Targeted Rx
• Safety
• Surgical technology
• Cost