Adult Growth Hormone Deficiency: How to Incorporate Guidelines into - - PDF document

1/25/20 1

UCSF CME Pituitary Disorders: Advances in Diagnosis and Management San Francisco, CA Saturday January 25, 2020

Adult Growth Hormone Deficiency: How to Incorporate Guidelines into Clinical Practice

Kevin C.J. Yuen, MD, FRCP(UK), FACE

Professor of Medicine and Medical Director Barrow Neurological Institute Pituitary Center

• St. Joseph’s Hospital and Medical Center

University of Arizona College of Medicine and Creighton School of Medicine Phoenix, AZ 1

Disclosures

• Received research grants to Barrow Neurological Institute from Ionis,

Crinetics, Millendo, Corcept and Novartis

• Served on Advisory Boards for Pfizer, Novo Nordisk, Ipsen, and Corcept

2

1/25/20 2

What are Clinical Practice Guidelines (CPG)?

“Systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances.” (Institute of Medicine, 1990)

• Most of the content are derived from extensive literature reviews
• Reflects the state of the field at time of publication, and because changes in this

area are expected, periodic updates may be implemented

• Some recommendations may not be appropriate in certain situations

Bottomline: use CPG in conjunction with best clinical judgment

3

GRS Workshop in Australia April 14-17, 1997

4

1/25/20 3

2007 Consensus Guidelines for the Diagnosis and Treatment

• f adults with GHD:

GRS, ESPE, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society and Endocrine Society of Australia

5

2009 Medical Guidelines for Clinical Practice for GH Use in GH-Deficient Adults and Transition Patients: AACE

6

1/25/20 4

2011 Evaluation and Treatment of Adult GH Deficiency Clinical Practice Guideline: Endocrine Society

7

2016 Hormone Replacement in Hypopituitarism in Adults Clinical Practice Guideline: Endocrine Society

8

1/25/20 5

2019 Guidelines for Management of GH Deficiency in Adults and Patients Transitioning from Pediatric to Adult Care: AACE

9

Why another CPG in 2019?

• Summarize current knowledge of GH stimulation tests
• Summarize the increasing evidence of beneficial effects and long-term safety of GH replacement
• Address skepticism about GH use:
• high cost of therapy and its true benefits
• difficulty conducting GH stimulation tests in the office
• concerns about safety of long-term therapy
• still a misconception of true adult GHD vs physiological decline in GH
• Highlight several sub-populations of patients described to be “at risk” for adult GHD
• how to test?
• when and how to treat?
• Review the literature of GH use for conception and pregnancy
• Dispel the myth of using GH for sports and aging
• New developments

10

1/25/20 6

Outline summary of the new AACE 2019 CPG

• 58 numbered recommendations:
• 12 Grade A (21%), 19 Grade B (33%), 21 Grade C (36%), and 6 Grade D (10%)
• 13 question-based sub-sections
• 357 references:
• 51 (14%) EL 1 (strong)
• 168 (47%) EL 2 (intermediate)
• 61 (17%) EL 3 (weak)
• 77 (22%) EL 4 (no clinical evidence)

11

Case 1: 57 y/o male with NFPA

• TSS 3 years ago and SRS 2 years ago
• Now has TSH and ACTH deficiencies (on stable doses of

Levothyroxine and Hydrocortisone)

• IGF-I SDS -1.5
• Healthy, except for possible childhood febrile seizures
• Presents with a 10 lb (4.5 kg) weight gain over 6 months,

and persistent fatigue

• Family history of osteoporosis, hyperlipidemia and cancer

Read on the internet and would like to be considered for GH

12

1/25/20 7

• Why treat adult GHD?
• Who to test for adult GHD?
• Use of appropriate GH stimulation tests and cut-points
• Interactions between GH and concurrent GCs and thyroid hormone
• Safety concerns associated with long-term GH replacement
• Use of GH for anti-aging

Case 1 discussion points

13

Why treat adult GHD?

Body composition

• ­ lean body mass
• ¯ fat mass

Bone

• ­ total body bone mass
• ­ BMD
• Effects require >18–24 months treatment

Aerobic exercise capacity

• ­ VO2 max (most studies)

Quality of life (QoL)

• ­ in some aspects of QoL (proportional to degree of baseline impairment)

Improved surrogate CV risk markers ?Decreased mortality risk

BMD, bone mineral density; QoL, quality of life. Simpson H et al. Growth Horm IGF Res 2002;12:1–33.

14

1/25/20 8

Potential impact of untreated GHD vs benefits of GH replacement on CV risk

CRP, C-reactive protein; CV, cardiovascular; GH, growth hormone; GHD, growth hormone disorder; LDL, low-density lipoprotein; TG, triglyceride; TNF, tumor necrosis factor.

UNTREATED ADULT GHD CV RISK FACTORS CONVENTIONAL Lipids (total cholesterol, LDL, TG) ­ Glucose intolerance/hyperglycemia β-cell function ¯ Insulin resistance ­ Metabolic syndrome ­ SURROGATE CV RISK MARKERS CRP ­ Pro-inflammatory cytokines (IL-6, TNF-a) ­ Adipokines (adiponectin ­, leptin ­/«) Pregnancy-associated plasma protein A ­ Coagulation system (pro-coagulation ­) Endothelial dysfunction ­ INCREASED INDIVIDUAL CV RISK REPLACEMENT ¯ ­ ­ ¯ ¯ ¯ ¯ ¯ ¯ ¯ « ¯ IMPROVED

15

Life expectancy in adults with NFPA receiving GH replacement therapy

CI, confidence interval; GH, growth hormone; GHRT, growth hormone replacement therapy; NFPA, non-functioning pituitary adenoma Olsson DS et al. Eur J Endocrinol 2017;176:67–75.

16

1/25/20 9

17

Who to test for adult GHD?

Acquired Skull-based lesions Pituitary adenoma, craniopharyngioma, Rathke’s cleft cyst, meningioma, glioma/astrocytoma, hamartoma, chordoma, lymphoma, metastases Brain injury TBI, sports-related head trauma, blast injury, perinatal insults Infiltrative/granulomatous disease Langerhans cell histiocytosis, autoimmune hypophysitis, sarcoidosis, TB, amyloidosis Surgery to sella, suprasellar and parasellar region Cranial irradiation CNS infections Bacterial, viral, fungal, parasital Infarction/hemorrhage Apoplexy, Sheehan’s syndrome, SAH, stroke, snake bite Empty sella Hydrocephalus Idiopathic Congenital Genetic Transcription factor defects (PIT-1, PROP-1, LHX3/4, HESX-1, PITX-2) GHRH receptor gene defects GH gene defects GH receptor/post-receptor defects Associated with brain structural defects Single central incisor Cleft lip/palate

Yuen KCJ, et al. Endocr Pract. 2019;25(11):1191-1232.

18

1/25/20 10

Pulsatile pattern of 24-hr GH secretion in a 30 y/o vs 60 y/o healthy adult vs an adult with GHD

GH (µg/L) 25 20 15 10 05 Clock time 09:00 21:00 09:00

Sleep

GH, growth hormone; GHD, growth hormone disorder.

Random points of

• verlap with GH levels

in healthy adults

30 yo healthy adult 60 yo healthy adult Adult with GHD

19

Serum IGF-I levels throughout life

IGF, insulin-like growth factor. Hilding A et al. J Clin Endocrinol Metab 1999; 84:2013–9

Men (n = 81)

20 40 160 640 10 320 80 10 20 100 90 80 70 60 50 40 30

Age (years) IGF-I (µg/L)

Women (n = 71)

Normal range IGF-I more reliable for screening for diagnosis in young adults

20

1/25/20 11

AACE 2019 CPG algorithm for testing adult patients with clinical suspicion of GHD

Yuen KCJ, et al. Endocr Pract. 2019;25(11):1191-1232. Adult patient with clinical suspicion of GHD Organic GHD 0, 1 or 2 hormone deficiencies Low IGF-I (<0 SDS) Further testing required History of hypothalamic-pituitary tumors, surgery, cranial irradiation, empty sella, pituitary apoplexy, traumatic brain injury, subarachnoid hemorrhage, autoimmune hypophysitis

• r Rathke’s cleft cyst

Low suspicion Normal IGF-I (≥0 SDS) Observe High suspicion Low IGF-I (<0 SDS) Organic GHD ≥3 hormone deficiencies Low IGF-I (<−2.0 SDS) No further testing required Treat Further testing required Macimorelin Peak GH ≤2.8 µg/L Treat GST (see Legend) ITT Peak GH ≤ 5.0 µg/L Treat

Legend for GST Treat if:

• peak GH ≤ 3.0 µg/L in normal-weight (BMI < 25 kg/m2) patients
• peak GH ≤ 3.0 µg/L in overweight (BMI 25-30 kg/m2) patients

with a high pre-test probability

• peak GH ≤ 1.0 µg/L in overweight (BMI 25-30 kg/m2) patients

with a low pre-test probability

• peak GH ≤ 1.0 µg/L in obese (BMI > 30 kg/m2) patients

21

Lower GH cut-point recommended for the GST

ROC curve analysis to determine the GH cut-point for the GST

GH, growth hormone; GST, glucagon stimulation test; ROC, receiver operating characteristics. Gomez JM et al. Clin Endocrinol (Oxf) 2002;56:329–34.

Specificity Sensitivity 22

1/25/20 12

Previous GST studies suggesting the effects of central adiposity and glucose intolerance in decreasing peak GH levels

GH, growth hormone; GST, glucagon stimulation test.

Yuen et al. Pituitary 2013 Jun;16:220–30 Dichtel et al. J Clin Endocrinol Metab 2014 Dec;19:4712–9 Diri et al. Pituitary 2015 Dec;18:884–92 Wilson et al. Growth Horm IGF Res 2016 Feb;26:24–31 Hamrahian et al. Pituitary 2016 Jun;19:332–41 Retrospective Prospective

23

Mechanism of action of macimorelin

GH, growth hormone; GHRH, growth hormone-releasing hormone; IGF, insulin-like growth factor. Camina JP et al. Endocrine 2003 Oct;22(1):5-12.

Macimorelin acetate Pituitary gland GH Ghrelin Stomach GHRH

SRIF

Liver IGF Hypothalamus

+

–

+ +

–

–

24

1/25/20 13

Features of the macimorelin test

Garcia JM et al. J Clin Endocrinol Metab 2013;98:2422–9.

Only 1.5 hours No hospitalization 4 blood draws

Non- parenteral administration Less time consuming Fewer blood draws No contra- indications Well- tolerated

Oral administration

25

Macimorelin dosage and administration

EMA Macimorelin Aeterna Zentaris SmPC. Available at: https://www.ema.europa.eu/en/documents/product-information/macimorelin-aeterna-zentaris-epar-product-information_en.pdf, Accessed 11 June 2019; FDA Macrilen Highlights of Prescribing Information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/205598Orig1s000LBL.pdf Accessed 11 June 2019

Quick Guide to Administration

1

≤120 kg=1 pouch >120 kg=2 pouches Weigh your patient

Quick Guide to Administration

2

1 pouch=120 ml water 2 pouches=240 ml water

3

(a small amount of undissolved particles will remain)

4

Example: A patient weighing 70 kg will need 70 ml of reconstituted Macrilen solution. Calculate volume Dissolve in water Stir gently (for 2-3 minutes)

Quick Guide to Administration

5

Use a syringe (without a needle) with graduations in mL to measure the exact volume

• f solution.

Measure exact volume

6

Transfer the exact required volume of Macrilen solution into drinking glass.

Quick Guide to Administration

7 8

Draw venous blood samples for GH determination at 30, 45, 60, and 90 minutes. Draw blood samples Transfer exact volume Administer solution Have patient drink the entire volume of Macrilen solution in drinking glass within 30 seconds.

X kg = X mL solution

(Patient weight) (Macrilen solution) 30 min 45 min 60 min 90 min

26

1/25/20 14

Oral macimorelin GH test

Diagnostic accuracy and correlation analysis compared to the GHRH-arginine test

AUC, area under the curve; GH, growth hormone; GHRH, growth hormone-releasing hormone; ROC, receiver operator characteristics. Garcia JM et al. J Clin Endocrinol Metab 2013;98:2422–9.

20 40 60 80 100 20 40 60 80 100 100-specificity (false positive rate) Sensitivity (true positive rate) ROC AUC=0.923 4.5 ng/ml: 90% sens; 79% spec; 15% misclass 2.7 ng/ml: 82% sens; 92% spec; 13% misclass

27

• Greater pituitary GH secretion than the ITT
• Sensitivity (87%) and specificity (96%) with cut-point of 2.8 ng/ml vs ITT cutpoint of 5.1 ng/ml
• Highly reproducible and good safety profile

Now approved by the FDA and EMA*

High risk Intermediate risk Low risk Controls

Peak GH concentrations in macimorelin and ITT stratified by likelihood of having adult GHD

Validation Phase 3 study comparing with the ITT

*Not commercialized yet in the EU. ITT, insulin tolerance test. Garcia JM et al. J Clin Endocrinol Metab 2018;103:3083–99.

GH level (ng/ml)

MAC evaluable at first try 99% MAC not evaluable at first try, evaluable on repeat 1% ITT evaluable at first try 82% ITT not repeated 6% ITT evaluable

• n request

9% ITT not evaluable twice 3%

ITT (N=157) Macimorelin (N=154)

28

1/25/20 15

Estimated specificities and sensitivities of macimorelin and ITT

ITT, insulin tolerance test. Garcia JR, et al. Presented at ENDO 2019, New Orleans, March 24, 2019

A cut-off point of 5.1 ng/ml instead of 2.8 ng/ml, increases sensitivity without decreasing specificity

29

Accepted GH cut-points (µg/L) for GH stimulation tests used in the US by different consensus guidelines to diagnose adult GHD

GRS 2007 AACE 2009 Endocrine Society 2011 (Molitch et al.) Endocrine Society 2016 (Fleseriu et al.) AACE 2019 ITT < 3.0 ≤ 5.0 < 3.0 to 5.0 ≤ 3.0 to 5.0 ≤ 5.0 GHRH-arginine

• BMI < 25 kg/m2
• BMI 25-30 kg/m2
• BMI ≥ 30 kg/m2

< 11.0 < 8.0 < 4.0 ≤ 11.0 ≤ 8.0 ≤ 4.0 < 11.0 < 8.0 < 4.0 < 11.0 < 8.0 < 4.0 No recommendation (not commercially available since 2008) Glucagon

• BMI < 25 kg/m2
• BMI 25-30 kg/m2
• BMI ≥ 30 kg/m2

All patients < 3.0 regardless of BMI All patients < 3.0 regardless of BMI All patients < 3.0 regardless of BMI All patients < 3.0 regardless of BMI ≤ 3.0 ≤ 3.0 or ≤ 1.0 ≤ 1.0 Macimorelin Not commercially available Not commercially available Not commercially available Not commercially available ≤ 2.8* Arginine Not recommendations ≤ 0.4 No recommendations No recommendations No longer recommended to be used

*5.1 µg/L may be considered in patients with high pre-test probability

30

1/25/20 16

0.4–0.5 mg/day (higher for transition and younger patients) 0.2–0.3 mg/day

Recommendations for starting GH doses in adults with GHD

• Use lower GH doses (0.1–0.2 mg/day) in

patients with DM, obesity, and previous GDM

• Target IGF-I SDS between -2 and +2

Age < 30 years Age 30 - 60 years

AACE 2009 and 2019

0.1–0.2 mg/day Age > 60 years

GRS 2007:

• young men and women, start at 0.2-0.3 mg/day
• older individuals, start at 0.1 mg/day
• target IGF-I SDS < +2

Endo Society 2011:

• age 30 – 60 years, start at 0.2-0.3 mg/day
• target IGF-I SDS between 0 and +2

Endo Society 2016:

• age < 60 years, start at 0.2-0.4 mg/day
• age > 60 years, start at 0.1-0.2 mg/day
• target IGF-I SDS to the mid-range

31

Interactions between GH therapy and concurrent GCs and thyroid hormone

GRS 2007, AACE 2009, Endo Society 2011, Endo Society 2016 and AACE 2019 GH therapy may unmask clinical central hypothyroidism and hypoadrenalism ­levothyroxine and ­hydrocortisone doses

32

1/25/20 17

Safety concerns associated with long-term GH replacement

• DM and glucose intolerance – use low GH doses
• History of active malignancy and proliferative diabetic retinopathy -

contraindicated

• Strong family history of cancer – careful consideration
• Previous history of cancer – careful consideration, discuss with oncologist,

initiate > 5 years after cancer remission, and use low GH doses

• History of CVD – GH replacement exerts positive effects on some CV risk

markers

• Recurrence of pituitary adenoma – no increase in relative risk
• Cancer risk – no increased risk (possibly even reduced risk)
• Mortality risk – no increased risk (possibly even reduced risk)

Yuen KCJ, et al. Endocr Pract. 2019;25(11):1191-1232.

33

Use of GH for anti-aging

• No studies have assessed long-term (> 6 months) efficacy or safety of GH

for anti-aging purposes

• Meta-analysis of 31 studies in healthy elderly subjects reported small

changes in body composition but increased AEs (Liu et al. Ann Intern Med

2007;146:104-115), while animal studies have shown reduced life spans and

premature onset of age-related cognitive changes (Bartke A. World J Mens

• Health. 2019;37:19-30)

Use of GH for marketing, distributing, or administration for any reason other than the well-defined approved uses of the drug is illegal and strongly discouraged

Yuen KCJ, et al. Endocr Pract. 2019;25(11):1191-1232.

34

1/25/20 18

Case 2: 21 y/o male with panhypopituitarism due to suprasellar germinoma

• S/p chemotherapy and cranial DXT
• On DDAVP, Hydrocortisone, and Levothyroxine
• IGF-I SDS -0.1
• Underwent Macimorelin test: serum GH levels

0.06, 3.22, 3.27, 2.84 and 1.29 µg/L

• Amenable to resume GH therapy
• Childhood GH dose was 2.0 mg/day

35

• When to retest and which test to use?
• To treat or not to treat? If treat, what dose to resume GH therapy?
• Safety concerns regarding long-term GH replacement
• Fertility and pregnancy
• Use of GH for sports
• Long-term adherence

Case 2 discussion points

36

1/25/20 19

AACE 2019 CPG algorithm for testing transition patients with clinical suspicion of GHD

Adult patient with clinical suspicion of GHD

Organic GHD 0, 1 or 2 hormone deficiencies Low IGF-I (<0 SDS) Further testing required Idiopathic isolated childhood GHD or suspected hypothalamic GHD Low suspicion Normal IGF-I (≥0 SDS) Observe High suspicion Low IGF-I (<0 SDS) Congenital defects Genetic defects Organic disease ≥ 3 hormone deficiencies Low IGF-I (<-2.0 SDS) No further testing required Treat Further testing required Macimorelin Peak GH ≤2.8 µg/L Treat GST (see Legend) ITT Peak GH ≤ 5.0 µg/L Treat

Legend for GST Treat if:

• peak GH ≤ 3.0 µg/L in normal-weight (BMI < 25 kg/m2) patients
• peak GH ≤ 3.0 µg/L in overweight (BMI 25-30 kg/m2) patients

with a high pre-test probability

• peak GH ≤ 1.0 µg/L in overweight (BMI 25-30 kg/m2) patients

with a low pre-test probability

• peak GH ≤ 1.0 µg/L in obese (BMI > 30 kg/m2) patients

Yuen KCJ, et al. Endocr Pract. 2019;25(11):1191-1232.

37

How to resume GH therapy in transition patients?

GRS 2007: intermediate doses between the pediatric doses required during the growth years and the adult dose Endo Society 2011: younger pts (< 30 yrs) may benefit from higher initial doses (0.4-0.5 mg/day); for patients transitioning from pediatric doses, even higher doses may be appropriate Endo Society 2016: no recommendation AACE 2009 and AACE 2019: restart at ~50% of the pediatric dose

38

1/25/20 20

Safety concerns regarding long-term GH replacement

• Risk of secondary neoplasms in childhood cancer survivors
• increased risk more likely related to previous exposure to cranial irradiation

2018 Endo Society CPG (Sklar CA, et al. JCEM 2018) and 2019 AACE CPG recommend carefully considering GH to childhood cancer survivors with confirmed GHD

39

• Not approved by the FDA
• Several studies support use of GH while seeking fertility, and continuing

GH during pregnancy does not appear to impact mother or fetus

• Giampietro A, et al. Fertil Steril. 2009
• Vila G, et al. Fertil Steril. 2015
• Bassiouny YA, et al. Fertil Steril. 2016
• Correa FA, et al. J Endocr Soc. 2017

More data still needed on safety of GH use in women with GHD to assist conception and during pregnancy before it can be routinely recommended

AACE 2019 CPG recommendations on GH use during conception and pregnancy

Yuen KCJ, et al. Endocr Pract. 2019;25(11):1191-1232.

40

1/25/20 21

Use of GH for sports

• GH improves body composition but may not improve strength, worsen

exercise capacity and increase AEs (Hermansen K, et al. Growth Horm IGF

• Res. 2017;34:38-44)
• Detecting GH abuse is challenging
• short t1/2 of exogenous GH
• urine sampling of GH not viable
• what biomarkers to test for?

Use of GH for marketing, distributing, or administration for any reason other than the well-defined approved uses of the drug is illegal and strongly discouraged

Yuen KCJ, et al. Endocr Pract. 2019;25(11):1191-1232.

41

Improving long-term adherence

• See some patients more frequently (“individualized care”)
• Provide electronic resources (cater to “the millennials”)
• Have an open and non-judgmental conversation with patient (ask “open-

ended” questions about adherence barriers)

• Review the risks of untreated GHD with the patient
• Review the benefits and safety of long-term GH replacement therapy
• RN to spend time reviewing the patient’s injection technique
• Medication reminder systems and longer duration of GH prescriptions
• Regular educational and motivational support

Bozzola M, et al. HormRes Paediatr. 2014; 81(5):331-335. Mohseni S, et al. J Pedistr Endocrinol Metab. 2018;3:13-20.

42

1/25/20 22

Problems with daily GH injections

• Inconvenient, painful and distressing
• Non-adherence increases over time
• Life circumstances can interfere with adherence

By decreasing injection frequency, long-acting GH preparations may improve adherence and thereby potentially improve clinical outcomes

Why consider LAGH preparations?

43

Overview of LAGH preparations currently under development

Yuen KC, et al. Expert Rev Endocrinol Metab. 2019 Nov 13:1-18. Technology used Product (Company) Modification to the GH molecule Frequency of administration Current status Depot LB03002 (LG Life Sciences, Ltd) Microparticles containing GH incorporated into sodium hyaluronate and dispersed in an oil base of medium-chain TG 7 days Approved and marketed in S Korea for childhood GHD. Approved but not marketed in Europe. Depot CP016 (Critical Pharmaceuticals) Supercritical carbon dioxide, formed when carbon dioxide exceeds its thermodynamic critical point, used to create the depot 14 days (planned) Pre-clinical studies PEGylated BBT-031 (Bolder Biotechnology) Site-specific PEGylated GH analog 7 days (planned) Pre-clinical studies PEGylated Jintrolong (GeneScience Pharmaceuticals, Ltd) 40-kDa PEG linked to GH 7 days Approved in China for childhood GHD Prodrug TransCon ACP-001 (Ascendis) GH transiently linked to carrier molecule via a self- cleaving linker, and releases GH unmodified 7 days Phase 3 in children completed and presented, phase 3 in adults in planning stages GH molecule bound to albumin Somapacitan NNC0195-0092 (Novo Nordisk) Single point mutation in GH, with non-covalent albumin binding moiety attached 7 days Phase 3 in children, phase 3 and extension study in adults GH molecule bound to Fab Ab AG-B1512 (Ahngook Pharmaceutical Co., Ltd.) Recombinant human GH genetically fused to a polypeptide linker and an anti-HSA Fab antibody 14-28 days (planned) Pre-clinical studies GH fusion protein ProFuse GH (Asterion) GH-binding protein 1 month (planned) Pre-clinical studies GH fusion protein GX-H9 (Genexine, Inc. and Handok, Inc.) Hybridization of non-cytolytic immunoglobulin Fc portion of IgD and IgG4 7-14 days Phase 2 in children and adults, pending phase 3 trial in adults GH fusion protein LAPSrhGH/HM10560A (Hanmi Pharmaceutical Co., Ltd.) Homodimeric aglycosylated IgG4 Fc fragment 7-14 days Phase 2 in children and adults GH fusion protein MOD-4023 (Pfizer, Inc.) Carboxyl-terminal peptide of hCG β-subunit 7 days Phase 3 in children, phase 3 in adults failed primary end-point and further studies planned for pen devices

44

1/25/20 23

Questions regarding LAGH preparations

• Where is the place of LAGH in relation to naïve GH-deficient patients and patients

already on daily GH?

• Are all the LAGH preparations the same?
• Will the effects of LAGH preparations be durable with long-term use?
• Any prolonged metabolic consequences and side effects?
• Can LAGH preparations with large molecular sizes penetrate all tissues equally?
• When to measure IGF-I levels and is it the same for all LAGH preparations?
• Are LAGH cost-effective?
• Will LAGH receive regulatory approval if convenience not accepted as an added

value?

• Will LAGH truly improve adherence and outcomes?
• Will the safety profile of LAGH be different to daily GH?

45

Summary of changes of AACE 2019 CPG compared to previous CPG

• Recently described non-tumoral causes of adult GHD
• More emphasis on clinical suspicion when ordering and interpreting GH stimulation

tests

• More emphasis on re-testing, how to re-test, and recommendations on re-initiation

and benefits of continuing GH therapy in transition patients

• Recommendations of BMI-specific cut-points for the GST and deleted the prior

recommendation of using arginine test for assessing adult GHD

• Recommendation regarding the place of macimorelin when testing for adult GHD,

and interpretation of its results

46

1/25/20 24

Summary of changes of AACE 2019 CPG compared to previous CPG

• Emphasizing the importance of standardized GH and IGF-I assays for diagnosis and

guiding GH dosing

• More detailed recommendations on initiation and monitoring of GH replacement
• Insufficient data to recommend routine GH use for conception and pregnancy
• Increasing data supporting the safety of long-term GH use
• Strong emphasis of NOT using GH for sports and aging
• Discussion of current status of LAGH preparations

47

Outstanding knowledge and treatment gaps

• Are the currently available GH stimulation tests reliable and accurate when

used in different types of GHD?

• Is there a better biomarker than IGF-I?
• What is the optimal IGF-I target to titrate GH doses to?
• How long to treat with GH?
• Safety data of GH > 20 yr follow-up
• Safety data of GH for fertility (male and female) and pregnancy
• Safety data of GH in the elderly (> 80 yrs)
• Optimal interval between completion of cancer treatment and initiation of

GH therapy

• Reliable diagnostic methodology in assessing GH misuse for unapproved

conditions

48

1/25/20 25

THANK YOU FOR YOUR ATTENTION!

49