Abstract
Adult growth hormone deficiency (AGHD) is a rare disease with both physiological and psychological effects for untreated patients. AGHD symptoms can improve over time with GH treatment. Here we have analyzed the long-term effectiveness and safety of short-acting GH replacement therapy (GHRT) in treatment naïve and nonnaïve patients with AGHD using real-world data from the NordiNet® International Outcome Study and American Norditropin® Studies: Web Enabled Research Program. Outcomes were compared between 3 age groups, comprised of patients aged 18 to 29 years, 30 to 39 years, and 40 to 59 years. The safety outcome was the incidence of nonserious and serious adverse reactions and serious adverse events by age group. Efficacy outcomes included mean GH exposure by age group alone, by sex and age group, or based on estrogen usage in female patients; IGF-I SD score (SDS) levels by sex and age group; mean glycated hemoglobin by sex and age group; and mean non-high-density lipoprotein cholesterol by sex and age group. The incidence rates of adverse events and reactions did not statistically differ between the 3 groups. Mean IGF-I SDS levels reached a normal range (−2 to 2) in ≥80% of patients from all groups in the effectiveness analysis set by year 2. Together with previous reports of older patients, these results support the real-world safety and efficacy of short-acting GHRT among all ages of patients with AGHD.
Keywords: adult GH deficiency, GH replacement therapy, registry data, age groups
Adult GH deficiency (AGHD) is a rare disease characterized by body composition changes in reduced muscle mass, osteoporosis, and increased body fat [1], as well as cognitive impairment and altered mood [2-4]. AGHD is additionally associated with the impairment of various quality of life measures, including emotional lability, social isolation, and energy levels [5]. The incidence rate of AGHD is estimated to be 6000 new cases per year, with more than 50 000 diagnosed adults in the United States [6].
Importantly, previous studies have suggested that GH treatment is effective in mitigating these health impacts [7, 8]. Furthermore, withdrawal of treatment can lead to increased negative effects [9, 10]. The benefits of GH replacement therapy (GHRT) may include improvements in cardiovascular risk markers, cardiac function, bone mineral density, and overall enhanced quality of life. However, common adverse effects associated with GHRT include peripheral edema, arthralgias, carpal tunnel syndrome, and paresthesia. There are data to suggest that the risk for such adverse effects increases with age and dosage [11].
The large-scale, noninterventional NordiNet® International Outcome Study (IOS) and American Norditropin® Studies: Web Enabled Research (ANSWER) Program collected real-world data on the long-term effectiveness and safety of short-acting GHRT [12]. The objective of the current study was to compare the safety and clinical outcomes of short-acting GHRT in adults with AGHD across 3 age groups, including the incidence of nonserious (NSARs) and serious adverse reactions (SARs) and serious adverse events (SAEs) by age group, and mean GH exposure, IGF-I SD score (SDS) level, glycated hemoglobin (HbA1c) level, and non-high-density lipoprotein (HDL) cholesterol level by age group and sex.
Methods
The methods used in this study were adapted from those of a prior study with several key differences [13]. The analyzed population includes patients with AGHD aged 18 to 59 years, while the prior study included patients aged ≥60 years. Additionally, the effectiveness analysis set (EAS) included naïve patients from both the ANSWER and NordiNet IOS programs, while the prior study included only patients from NordiNet IOS.
Real-world data from NordiNet IOS and ANSWER were used to analyze short-acting GHRT safety and clinical outcomes in adults with AGHD. Patients were divided into 3 age groups, including group 1, with patients aged 18 to 29 years; group 2, with patients aged 30 to 39 years; and group 3, with patients aged 40 to 59 years. The primary safety outcome was the incidence of NSARs, SARs, and SAEs by age group. The primary efficacy outcome was mean GH exposure by age group. Secondary efficacy outcomes were assessed by sex and age group and included GH exposure or based on estrogen usage in female patients, IGF-I SDS levels, mean HbA1c, and mean non-HDL cholesterol.
Safety was assessed in the full analysis set (FAS), including all GH-naïve and -nonnaïve patients with a GH deficiency diagnosis who initiated GH replacement after the age of 18 years and continued beyond the age of 20 years. Adverse events (AEs) describe any undesired medical occurrence experienced by a participant during the time of the study and can be classified as serious or nonserious based on severity, as determined by both the investigator and the sponsor. Adverse reactions were defined as an AE or SAE with a suspected causal (possibly or probably) relationship to short-acting GHRT, as determined by either the investigator or the sponsor. SARs, NSARs, and SAEs are presented as incidence rates per 1000 patient years. NSARs, SARs, and AEs were analyzed descriptively.
Clinical outcomes were assessed in the EAS, including patients who were GH naïve at baseline with valid baseline body mass index, age, and GH dosing information. Clinical outcomes were assessed yearly for ≤10 years of follow-up, and clinical outcome differences between groups were compared at 2 years. This time period was selected because it was considered sufficient for changes to be observed, and, after 2 years, the number of patients steadily decreased.
Baseline characteristics were analyzed descriptively. Continuous variables were statistically compared using ANOVA F-tests for overall 3-group differences with pairwise comparisons using t-tests and the Scheffe familywise adjustment. Statistical comparisons of incidence rates were performed using Poisson regression. P-values <.05 were considered significant.
Results
Clinical and Baseline Characteristics
Pooled analyses from NordiNet IOS and ANSWER included 2469 patients from the FAS and 1006 patients from the EAS. Select baseline characteristics, including average follow-up times, are described in Table 1 for both the EAS and FAS. In the EAS, the largest age group was group 3 (n = 649), the second largest age group was group 2 (n = 209), and the smallest age group was group 1 (n = 148). Similarly, most patients in the FAS fell within the group 3 age group (n = 1417). Group 1 (n = 558) and group 2 (n = 494) of the FAS were similar in size. Most patients in both analysis sets had a diagnosis of multiple pituitary hormone deficiencies. Consistent with the known impact of age on IGF-I levels in adults, baseline IGF-I levels decreased with increasing age [14].
Table 1.
Baseline characteristics of adult patients in the EAS and FAS from NordiNet IOS and the ANSWER Program stratified by age group
| EASa | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Group 1 Aged 18-29 y |
Group 2 Aged 30-39 y |
Group 3 Aged 40-59 y |
Total | |||||||
| Female n = 68 |
Male n = 80 |
Total n = 148 |
Female n = 125 |
Male n = 84 |
Total n = 209 |
Female n = 337 |
Male n = 312 |
Total n = 649 |
Total n = 1006 |
|
| Sex, n (%) | ||||||||||
| Female | 68 (45.9) | 125 (59.8) | 337 (51.9) | 530 (52.7) | ||||||
| Male | 80 (54.1) | 84 (40.2) | 312 (48.1) | 476 (47.3) | ||||||
| IGHD, n (%) | 47 (31.8) | 85 (40.7) | 281 (43.3) | 413 (41.1) | ||||||
| MPHD, n (%) | 101 (68.2) | 124 (59.3) | 368 (56.7) | 593 (58.9) | ||||||
| Age at treatment start, y (SD) | ||||||||||
| n | 68 | 80 | 148 | 125 | 84 | 209 | 337 | 312 | 649 | 1006 |
| Mean (SD) | 25.31 (3.02) | 24.62 (2.99) | 25 (3.0) | 35.49 (2.79) | 34.99 (2.93) | 35 (2.9) | 50.17 (5.60) | 51.06 (5.37) | 51 (5.5) | 44 (11.0) |
| GH dose at baseline (mg/day) | ||||||||||
| n | 68 | 80 | 148 | 125 | 84 | 209 | 337 | 312 | 649 | 1006 |
| Mean (SD) | 0.34 (0.21) | 0.36 (0.33) | 0.35 (0.28) | 0.32 (0.21) | 0.33 (0.24) | 0.32 (0.22) | 0.32 (0.24) | 0.27 (0.24) | 0.29 (0.24) | 0.31 (0.24) |
| IGF-I SDS (Brabant) | ||||||||||
| n | 56 | 68 | 124 | 106 | 63 | 169 | 286 | 253 | 539 | 832 |
| Mean (SD) | −2.03 (1.48) | −1.66 (2.14) | −1.83 (1.87) | −0.85 (1.40) | −1.17 (2.05) | −0.97 (1.67) | −0.56 (1.54) | −0.84 (1.48) | −0.69 (1.51) | −0.92 (1.65) |
| BMI, kg/m2 | ||||||||||
| n | 68 | 80 | 148 | 125 | 84 | 209 | 337 | 312 | 649 | 1006 |
| Mean (SD) | 28.8 (9.7) | 27.7 (6.5) | 28.2 (8.1) | 30.7 (8.2) | 29.3 (7.0) | 30.1 (7.7) | 30.9 (8.6) | 30.2 (5.9) | 30.6 (7.4) | 30.1 (7.6) |
| Waist circumference, cm | ||||||||||
| n | 30 | 38 | 68 | 52 | 41 | 93 | 129 | 144 | 273 | 434 |
| Mean (SD) | 93.6 (23.0) | 97.2 (15.7) | 95.6 (19.2) | 96.3(18.5) | 101.1 (17.1) | 98.4 (18.0) | 96.4 (16.0) |
103.5 (12.9) | 100.2 (14.8) | 99.1 (16.3) |
| HbA1c, % | ||||||||||
| n | 36 | 31 | 67 | 38 | 31 | 69 | 103 | 147 | 250 | 386 |
| Mean (SD) | 5.3 (0.89) | 5.0 (0.8) | 5.2 (0.9) | 5.2 (0.8) | 5.3 (1.5) |
5.2 (1.2) | 5.3 (0.7) |
5.4 (0.8) | 5.4 (0.8) | 5.3 (0.9) |
| Non-HDL cholesterol, mmol/L | ||||||||||
| n | 34 | 37 | 71 | 38 | 34 | 72 | 111 | 148 | 259 | 402 |
| Mean (SD) | 4.08 (1.20) | 3.95 (1.18) | 4.01 (1.19) | 4.06 (1.37) | 4.11 (1.2) | 4.09 (1.28) | 4.38 (1.12) | 4.63 (1.34) | 4.52 (1.25) | 4.35 (1.27) |
| Duration of follow-up, y | ||||||||||
| n | 67 | 79 | 146 | 123 | 82 | 205 | 334 | 307 | 641 | 992 |
| Mean (SD) | 5.04 (4.40) | 4.51 (3.73) | 4.75 (4.04) | 4.59 (3.87) | 4.44 (4.24) | 4.53 (4.01) | 5.04 (4.05) | 5.34 (4.14) | 5.19 (4.09) | 4.99 (4.07) |
| Etiology, n (%) | ||||||||||
| Pituitary tumorsb | 46 (31.2) | 84 (40.3) | 305 (47.0) | 435 (43.3) | ||||||
| Pituitary adenoma | 40 (27.0) | 67 (32.1) | 267 (41.1) | 374 (37.2) | ||||||
| Prolactin-secreting tumor | 2 (1.4) | 8 (3.8) | 20 (3.1) | 30 (3.0) | ||||||
| Acromegaly | 1 (0.7) | 1 (0.5) | 10 (1.5) | 12 (1.2) | ||||||
| Cushing's syndrome | 2 (1.4) | 7 (3.4) | 7 (1.1) | 16 (1.6) | ||||||
| TSH-secreting tumor | 1 (0.7) | — | 1 (0.2) | 2 (0.2) | ||||||
| Pituitary apoplexy | — | 1 (0.5) | — | 1 (0.1) | ||||||
| Cranial tumorsb | 38 (25.6) | 32 (15.3) | 64 (9.8) | 134 (13.4) | ||||||
| Postprocedural hypopituitarism | 9 (6.1) | 12 (5.7) | 34 (5.2) | 55 (5.5) | ||||||
| Craniopharyngioma | 15 (10.1) | 12 (5.7) | 23 (3.5) | 50 (5.0) | ||||||
| Irradiation | 8 (5.4) | 4 (1.9) | 4 (0.6) | 16 (1.6) | ||||||
| Medulloblastoma | — | — | — | — | ||||||
| Meningioma | — | — | 2 (0.3) | 2 (0.2) | ||||||
| Astrocytoma | 2 (1.3) | 2 (1.0) | 1 (0.2) | 5 (0.5) | ||||||
| Germinoma | 3 (2.0) | 2 (1.0) | — | 5 (0.5) | ||||||
| Glioma | 1 (0.7) | — | — | 1 (0.1) | ||||||
| Vascular | 3 (2.0) | 8 (3.8) | 10 (1.6) | 21 (2.1) | ||||||
| Sheehan syndrome | 3 (2.0) | 8 (3.8) | 9 (1.4) | 20 (2.0) | ||||||
| Subarachnoid hemorrhage | — | — | 1 (0.2) | 1 (0.1) | ||||||
| Infiltrative/inflammatory disease | 2 (1.4) | — | 2 (0.3) | 4 (0.4) | ||||||
| Granulomatous | 1 (0.7) | — | 2 (0.3) | 3 (0.3) | ||||||
| Neurofibromatosis | 1 (0.7) | — | — | 1 (0.1) | ||||||
| Langerhans cell histiocytosis | — | — | — | — | ||||||
| Isolated/idiopathic GHD | 12 (8.1) | 39 (18.7) | 148 (22.8) | 199 (19.8) | ||||||
| Congenital GHD | 13 (8.8) | 10 (4.8) | 16 (2.5) | 39 (3.9) | ||||||
| Acquired GHD (unspecified) | 7 (4.7) | 4 (1.9) | 14 (2.2) | 25 (2.5) | ||||||
| Traumatic brain injury | 4 (2.7) | 7 (3.4) | 16 (2.5) | 27 (2.7) | ||||||
| Empty sella syndrome | 1 (0.7) | — | 1 (0.2) | 2 (0.2) | ||||||
| Hypothalamic dysfunctionc | 1 (0.7) | 1 (0.5) | 9 (1.4) | 11 (1.1) | ||||||
| Not reported or missing | 21 (14.2) | 24 (11.5) | 64 (9.9) | 109 (10.8) | ||||||
| FASd | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Group 1 Aged 18-29 y |
Group 2 Aged 30-39 y |
Group 3 Aged 40-59 y |
Total | |||||||
| Female n = 246 |
Male n = 312 |
Total n = 558 |
Female n = 272 |
Male n = 222 |
Total n = 494 |
Female n = 729 |
Male n = 688 |
Total n = 1417 |
Total n = 2469 |
|
| Sex, n (%) | ||||||||||
| Female | 246 (44.1) | 272 (55.1) | 729 (51.4) | 1247 (50.5) | ||||||
| Male | 312 (55.9) | 222 (44.9) | 688 (48.6) | 1222 (49.5) | ||||||
| IGHD, n (%) | 211 (37.8) | 186 (37.7) | 550 (38.8) | 947 (38.4) | ||||||
| MPHD, n (%) | 347 (62.2) | 308 (62.3) | 867 (61.2) | 1522 (61.6) | ||||||
| Age at treatment start, y (SD) | ||||||||||
| n | 246 | 312 | 558 | 272 | 222 | 494 | 729 | 688 | 1417 | 2469 |
| Mean (SD) | 23.56 (3.50) | 23.17 (3.58) | 23 (3.6) | 35.49 (2.83) | 35.11 (2.90) | 35 (2.9) | 50.36 (5.63) | 50.83 (5.49) | 51 (5.6) | 41 (12.3) |
| GH dose at baseline (mg/day) | ||||||||||
| n | 234 | 297 | 531 | 257 | 211 | 468 | 695 | 646 | 1341 | 2340 |
| Mean (SD) | 0.48 (0.45) | 0.52 (0.53) | 0.51 (0.49) | 0.40 (0.31) |
0.37 (0.29) | 0.38 (0.30) | 0.34 (0.25) | 0.29 (0.22) | 0.31 (0.24) | 0.37 (0.33) |
| IGF-I SDS (Brabant) | ||||||||||
| n | 142 | 197 | 339 | 175 | 129 | 304 | 495 | 438 | 933 | 1576 |
| Mean (SD) | −1.93 (1.72) | −1.79 (2.37) | −1.85 (2.12) | −0.90 (1.46) | −0.94 (1.79) | −0.92 (1.61) | −0.493 (1.47) | −0.58 (1.60) | −0.53 (1.53) | −0.89 (1.77) |
| BMI, kg/m2 | ||||||||||
| n | 177 | 226 | 403 | 199 | 148 | 347 | 556 | 504 | 1060 | 1810 |
| Mean (SD) | 27.3 (8.5) | 25.7 (5.9) | 26.4 (7.2) | 30.2 (8.5) |
29.5 (6.8) | 29.9 (7.8) | 30.5(8.2) | 30.5 (5.8) | 30.5 (7.2) | 29.5 (7.5) |
| Waist circumference, cm | ||||||||||
| n | 69 | 100 | 169 | 95 | 73 | 168 | 238 | 244 | 482 | 819 |
| Mean (SD) | 88.8 (19.5) | 92.1 (12.9) | 90.73 (15.95) | 90.8 (17.7) |
99.5 (15.4) | 94.55 (17.25) | 95.9 (17.9) | 103.6 (13.4) | 99.78 (16.26) | 96.84 (16.80) |
| HbA1c, % | ||||||||||
| n | 78 | 92 | 170 | 69 | 59 | 128 | 184 | 224 | 408 | 706 |
| Mean (SD) | 5.1 (0.8) | 5.1 (0.8) |
5.1 (0.8) | 5.3 (1.0) |
5.3(1.3) | 5.3 (1.1) | 5.4 (0.9) | 5.4 (0.8) | 5.4 (0.8) | 5.3 (0.9) |
| Non-HDL cholesterol, mmol/L | ||||||||||
| n | 83 | 92 | 175 | 73 | 61 | 134 | 197 | 226 | 423 | 732 |
| Mean (SD) | 3.88 (1.19) | 3.67 (1.07) | 3.77 (1.13) | 4.23 (1.35) |
4.25 (1.40) | 4.24 (1.37) | 4.24 (1.05) | 4.54 (1.30) | 4.40 (1.20) | 4.22 (1.24) |
| Duration of follow-up, y | ||||||||||
| n | 245 | 309 | 554 | 268 | 220 | 488 | 725 | 682 | 1407 | 2449 |
| Mean (SD) | 5.04 (4.45) | 4.85 (4.38) | 3.77 (1.13) | 4.68 (4.15) |
5.46 (5.12) | 4.24 (1.37) | 4.86 (4.22) | 5.51 (4.73) | 4.40 (1.20) | 4.22 (1.24) |
| Etiology, n (%) | ||||||||||
| Pituitary tumorsb | 126 (22.7) | 183 (37.0) | 657 (46.4) | 966 (39.1) | ||||||
| Pituitary adenoma | 112 (20.1) | 154 (31.2) | 579 (40.9) | 845 (34.2) | ||||||
| Prolactin-secreting tumor | 5 (0.9) | 17 (3.4) | 46 (3.3) | 68 (2.8) | ||||||
| Acromegaly | 2 (0.4) | 1 (0.2) | 11 (0.78) | 14 (0.6) | ||||||
| Cushing's syndrome | 6 (1.1) | 10 (2.0) | 19 (1.3) | 35 (1.4) | ||||||
| TSH-secreting tumor | 1 (0.2) | — | 2 (0.1) | 3 (0.1) | ||||||
| Pituitary apoplexy | — | 1 (0.2) | — | 1 (0.0) | ||||||
| Cranial tumorsb | 147 (26.4) | 76 (15.4) | 142 (10.1) | 365 (14.9) | ||||||
| Postprocedural hypopituitarism | 37 (6.6) | 29 (5.9) | 71 (5.0) | 137 (5.6) | ||||||
| Craniopharyngioma | 43 (7.7) | 28 (5.7) | 58 (4.1) | 129 (5.2) | ||||||
| Irradiation | 40 (7.2) | 9 (1.8) | 5 (0.4) | 54 (2.2) | ||||||
| Medulloblastoma | 2 (0.4) | — | — | 2 (0.1) | ||||||
| Meningioma | 1 (0.2) | 1 (0.2) | 3 (0.2) | 5 (0.2) | ||||||
| Astrocytoma | 10 (1.8) | 3 (0.6) | 3 (0.2) | 16 (0.7) | ||||||
| Germinoma | 9 (1.6) | 6 (1.2) | 1 (0.1) | 16 (0.7) | ||||||
| Glioma | 5 (0.9) | — | 1 (0.1) | 6 (0.2) | ||||||
| Vascular | 5 (0.9) | 18 (3.6) | 34 (2.4) | 57 (2.4) | ||||||
| Sheehan syndrome | 5 (0.9) | 18 (3.6) | 32 (2.3) | 55 (2.3) | ||||||
| Subarachnoid hemorrhage | — | — | 2 (0.1) | 2 (0.1) | ||||||
| Infiltrative/inflammatory disease | 4 (0.8) | 1 (0.2) | 3 (0.2) | 8 (0.4) | ||||||
| Granulomatous | 2 (0.4) | — | 2 (0.1) | 4 (0.2) | ||||||
| Neurofibromatosis | 1 (0.2) | — | 1 (0.1) | 2 (0.1) | ||||||
| Langerhans' cell histiocytosis | 1 (0.2) | 1 (0.2) | — | 2 (0.1) | ||||||
| Isolated/idiopathic GHD | 76 (13.6) | 79 (16.0) | 249 (17.6) | 404 (16.4) | ||||||
| Congenital GHD | 68 (12.2) | 27 (5.5) | 31 (2.2) | 126 (5.1) | ||||||
| Acquired GHD (unspecified) | 19 (3.4) | 16 (3.2) | 48 (3.4) | 83 (3.4) | ||||||
| Traumatic brain injury | 10 (1.8) | 23 (4.7) | 38 (2.7) | 71 (2.9) | ||||||
| Empty sella syndrome | 1 (0.2) | 1 (0.2) | 4 (0.3) | 6 (0.2) | ||||||
| Hypothalamic dysfunctionc | 8 (1.4) | 6 (1.2) | 24 (1.7) | 38 (1.5) | ||||||
| Not reported or missing | 94 (16.9) | 64 (13.0) | 187 (13.2) | 345 (14.0) | ||||||
Abbreviations: ANSWER, American Norditropin Studies: Web Enabled Research; BMI, body mass index; EAS, effectiveness analysis set; FAS, full analysis set; GHD, GH deficiency; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; IGHD, isolated GH deficiency; IOS, International Outcome Study; MPHD, multiple pituitary hormone deficiency; SDS, SD score.
aFemale, group 1 vs 2, P < .05: IGF-I. Female, group 1 vs 3, P < .05: IGF-I. Male, group 1 vs 3, P < .05: GH dose at baseline, IGF-I, BMI, non-HDL cholesterol. All other comparisons of groups stratified by sex were not significant (P > .05). Age at treatment start was not tested for significance.
bStated etiology and/or its respective treatment.
cNot elsewhere classified.
dFemale, group 1 vs 2, P < .05: GH dose at baseline, IGF-I, BMI. Male, group 1 vs 2, P < .05: GH dose at baseline, IGF-I, BMI, HbA1c, non-HDL cholesterol. Female, group 1 vs 3, P < .05: GH dose at baseline, IGF-I, BMI, waist circumference. Male, group 1 vs 3, P < .05: GH dose at baseline, IGF-I, BMI, waist circumference, non-HDL cholesterol. Female, group 2 vs 3, P < .05: IGF-I. Male, group 2 vs 3, P < .05: GH dose at baseline, HbA1c. All other comparisons of groups stratified by sex were not significant (P > .05). Age at treatment start was not tested for significance.
Reported etiologies for AGHD are summarized in Table 1. The most common etiologies in the EAS included pituitary tumors (group 1, 31.2%; group 2, 40.3%; group 3, 47.0%), cranial tumors (group 1, 25.6%; group 2, 15.3%; group 3, 9.8%), and isolated/idiopathic GH deficiency (group 1, 8.1%; group 2, 18.7%; group 3, 22.8%). The most common etiologies in the FAS also included pituitary tumors (group 1, 22.7%; group 2, 37.0%; group 3, 46.4%), cranial tumors (group 1, 26.4%; group 2, 15.4%; group 3, 10.1%), and isolated/idiopathic GH deficiency (group 1, 13.6%; group 2, 16.0%; group 3, 17.6%).
Baseline characteristics for the EAS and FAS were also analyzed by age group and sex (Table 1). Age at the start of treatment did not notably differ by sex within each age group. In group 1 of the EAS, IGF-I levels were lower in women; however, IGF-I levels were higher in women vs men in groups 2 and 3. Notably, group 1 had a higher proportion of female patients taking oral estrogen compared with the other age groups. In the EAS, the proportion of women with IGF-1 SDS recorded at baseline who were on oral estrogen was 23.2%, 7.6%, and 8.4% in groups 1, 2, and 3, respectively. In the FAS, the proportion of women with IGF-1 SDS recorded at baseline who were on oral estrogen was 16.2%, 6.9%, and 7.3% in groups 1, 2, and 3, respectively. Mean duration of follow-up was similar between male and female patients of all groups, ranging from 4.44 years to 5.34 years in the EAS and 4.68 years to 5.51 years in the FAS.
Safety Analyses
NSARs, SARs, and SAEs were analyzed and compared between age groups (Table 2). SAR and SAE events were mutually exclusive. No statistically significant differences in the incidence rates of NSARs, SARs, or SAEs were observed between the 3 groups. In the FAS, “neoplasms benign, malignant, and unspecified” and “nervous system disorders” were among the most common SARs in all groups (Table 3). The most common NSARs in all groups included “musculoskeletal and connective tissue disorders,” “nervous system disorders,” and “general disorders and administration site conditions.” The most common AEs (Table 4) in all groups included “nervous system disorders,” “musculoskeletal and connective tissue disorders,” and “neoplasms benign, malignant, and unspecified.” The most common SAEs included “neoplasms benign, malignant, and unspecified” (group 1, 0.54%; group 2, 0.61%; group 3, 1.34%), “nervous system disorders” (group 1, 0.90%; group 2, 0.61%; group 3, 0.64%), and “infections and infestations” (group 1, 0.18%; group 2, 1.42%; group 3, 0.42%). Notably, the “neoplasms benign, malignant, and unspecified” incidence was numerically higher in the oldest age group (group 3) compared to groups 1 and 2 when reported as an SAR, AE, or SAE. Of the 10 total deaths recorded, 2 cases (1 due to metastatic colon cancer and 1 due to anaplastic astrocytoma) were deemed possibly related to treatment.
Table 2.
Adverse reactions and events from the FAS by age groupa
| Patient-years | Patients with events | Rate/1000 patient-years | Comparison vs 40-59 y, IRRb (95% CI) | P-value | Comparison vs 30-39 y, IRR (95% CI) | P-value | |
|---|---|---|---|---|---|---|---|
| NSARs | |||||||
| Group 1: 18-29 yc | 2733 | 9 | 3.29 | 0.61 (0.30-1.27) | .19 | 0.62 (0.27-1.46) | .27 |
| Group 2: 30-39 yd | 2456 | 13 | 5.29 | 0.99 (0.53-1.85) | .97 | ||
| Group 3: 40-59 ye | 7282 | 39 | 5.36 | ||||
| SARs | |||||||
| Group 1: 18-29 yc | 2733 | 2 | 0.73 | 0.28 (0.07-1.20) | .09 | 0.30 (0.06-1.48) | .14 |
| Group 2: 30-39 yd | 2456 | 6 | 2.44 | 0.94 (0.37-2.34) | .89 | ||
| Group 3: 40-59 ye | 7282 | 19 | 2.61 | ||||
| SAEs | |||||||
| Group 1: 18-29 yc | 2733 | 14 | 5.12 | 0.58 (0.33-1.04) | .07 | 0.63 (0.32-1.25) | .19 |
| Group 2: 30-39 yd | 2456 | 20 | 8.14 | 0.93 (0.56-1.53) | .77 | ||
| Group 3: 40-59 ye | 7282 | 64 | 8.79 | ||||
Abbreviations: AE, adverse event; FAS, full analysis set; GHRT, GH replacement therapy; IRR, incidence rate ratio; NSAR, nonserious adverse reaction; SAE, serious adverse event; SAR, serious adverse reaction.
aSARs and NSARs were defined as an AE or SAE with a suspected causal (possibly or probably) relationship to short-acting GHRT, as determined by either the investigator or the sponsor. Other SAEs not considered related to short-acting GHRT are also presented.
bIncidence rates are per 1000 patient-years.
cn = 554.
dn = 488.
en = 1407.
Table 3.
Summary of nonserious and serious adverse reactions for adult patients with AGHD in the FAS from NordiNet IOS and the ANSWER Program stratified by age group
| Group 1 Aged 18-29 y n = 558 |
Group 2 Aged 30-39 y n = 494 |
Group 3 Aged 40-59 y n = 1417 |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| SOC | PT | E | n | (%) | E | n | (%) | E | n | (%) |
| Total | ||||||||||
| NSAR | All | 14 | 9 | 1.613 | 33 | 13 | 2.632 | 53 | 39 | 2.752 |
| SAR | All | 2 | 2 | 0.358 | 8 | 6 | 1.215 | 26 | 19 | 1.341 |
| Endocrine disorders | ||||||||||
| SAR | All | — | — | — | — | — | — | 1 | 1 | 0.071 |
| Pituitary hemorrhage | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Gastrointestinal disorders | ||||||||||
| NSAR | All | 3 | 1 | 0.179 | — | — | — | 1 | 1 | 0.071 |
| Abdominal pain | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Abdominal pain upper | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Diarrhea | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Nausea | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| General disorders and administration site conditions | ||||||||||
| NSAR | All | 2 | 2 | 0.358 | 6 | 4 | 0.81 | 8 | 8 | 0.565 |
| Fatigue | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Injection site reaction | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Edema | — | — | — | 5 | 3 | 0.607 | 6 | 6 | 0.423 | |
| Edema peripheral | 1 | 1 | 0.179 | — | — | — | 1 | 1 | 0.071 | |
| Peripheral swelling | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| SAR | All | — | — | — | 1 | 1 | 0.202 | — | — | — |
| Condition aggravated | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Immune system disorders | ||||||||||
| NSAR | All | — | — | — | — | — | — | 1 | 1 | 0.071 |
| Hypersensitivity | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Infections and infestations | ||||||||||
| NSAR | All | — | — | — | 1 | 1 | 0.202 | — | — | — |
| Gastroenteritis | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| SAR | All | — | — | — | — | — | — | 1 | 1 | 0.071 |
| Respiratory tract infection | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Injury, poisoning, and procedural complications | ||||||||||
| NSAR | All | 1 | 1 | 0.179 | — | — | — | — | — | — |
| Off-label use | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| SAR | All | — | — | — | — | — | — | 2 | 2 | 0.141 |
| Fracture | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Meniscus injury | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Investigations | ||||||||||
| NSAR | All | — | — | — | — | — | — | 1 | 1 | 0.071 |
| Weight increased | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| SAR | All | — | — | — | — | — | — | 1 | 1 | 0.071 |
| Cortisol abnormal | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Metabolism and nutrition disorders | ||||||||||
| NSAR | All | 1 | 1 | 0.179 | 1 | 1 | 0.202 | 6 | 6 | 0.423 |
| Abnormal loss of weight | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Hyperglycemia | — | — | — | 1 | 1 | 0.202 | 4 | 4 | 0.283 | |
| Type 2 diabetes mellitus | — | — | — | — | — | — | 2 | 2 | 0.141 | |
| SAR | All | — | — | — | — | — | — | 2 | 2 | 0.141 |
| Type 2 diabetes mellitus | — | — | — | — | — | — | 2 | 2 | 0.141 | |
| Musculoskeletal and connective tissue disorders | ||||||||||
| NSAR | All | 3 | 3 | 0.538 | 13 | 6 | 1.215 | 19 | 16 | 1.129 |
| Arthralgia | 2 | 2 | 0.358 | 6 | 5 | 1.012 | 11 | 11 | 0.776 | |
| Joint stiffness | — | — | — | 2 | 2 | 0.405 | 4 | 4 | 0.282 | |
| Myalgia | 1 | 1 | 0.179 | 5 | 4 | 0.81 | 4 | 4 | 0.282 | |
| SAR | All | — | — | — | 1 | 1 | 0.202 | — | — | — |
| Myalgia | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Neoplasms benign, malignant, and unspecified (including cysts and polyps) | ||||||||||
| NSAR | All | — | — | — | — | — | — | 1 | 1 | 0.071 |
| Glioma | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| SAR | All | — | — | — | 3 | 3 | 0.607 | 14 | 12 | 0.847 |
| Anaplastic astrocytoma | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Bronchial carcinoma | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Colon cancer metastatic | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Enchondromatosis | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Nasal sinus cancer | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Neoplasm | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Neoplasm malignant | — | — | — | — | — | — | 3 | 3 | 0.212 | |
| Neoplasm progression | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Nonsecretory adenoma of pituitary | — | — | — | 1 | 1 | 0.202 | 1 | 1 | 0.071 | |
| Papillary renal cell carcinoma | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Pituitary cancer metastatic | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Pituitary neoplasm malignant recurrent | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Pituitary tumor benign | — | — | — | — | — | — | 2 | 2 | 0.141 | |
| Nervous system disorders | ||||||||||
| NSAR | All | 2 | 2 | 0.358 | 10 | 7 | 1.417 | 12 | 10 | 0.706 |
| Carpal tunnel syndrome | — | — | — | — | — | — | 3 | 3 | 0.212 | |
| Dizziness | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Headache | 1 | 1 | 0.179 | 10 | 7 | 1.417 | 8 | 6 | 0.423 | |
| Paresthesia | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| SAR | All | 2 | 2 | 0.358 | 3 | 2 | 0.405 | 2 | 2 | 0.141 |
| Carpal tunnel syndrome | — | — | — | — | — | — | 2 | 2 | 0.141 | |
| Headache | — | — | — | 2 | 1 | 0.202 | — | — | — | |
| Seizure | 1 | 1 | 0.179 | 1 | 1 | 0.202 | — | — | — | |
| Syncope | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Psychiatric disorders | ||||||||||
| NSAR | All | — | — | — | — | — | — | 1 | 1 | 0.071 |
| Mood swings | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Respiratory, thoracic, and mediastinal disorders | ||||||||||
| SAR | All | — | — | — | — | — | — | 1 | 1 | 0.071 |
| Pulmonary embolism | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Skin and subcutaneous tissue disorders | ||||||||||
| NSAR | All | 2 | 2 | 0.358 | 2 | 2 | 0.405 | 3 | 3 | 0.212 |
| Acne | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Hair disorder | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Pruritus | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Rash | 2 | 2 | 0.358 | 1 | 1 | 0.202 | 1 | 1 | 0.071 | |
| Surgical and medical procedures | ||||||||||
| SAR | All | — | — | — | — | — | — | 1 | 1 | 0.071 |
| Hospitalization | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Vascular disorders | ||||||||||
| SAR | All | — | — | — | — | — | — | 1 | 1 | 0.071 |
| Venous thrombosis | — | — | — | — | — | — | 1 | 1 | 0.071 | |
Abbreviations: ANSWER, American Norditropin Studies: Web Enabled Research; E, events; IOS, International Outcome Study; n, number of patients in each group; NSAR, nonserious adverse reaction; PT, preferred term; SAR, serious adverse reaction; SOC, system organ class.
Table 4.
Summary of adverse events for adult patients with AGHD in the FAS from NordiNet IOS and the ANSWER Program stratified by age group
| Group 1 Aged 18-29 y n = 558 |
Group 2 Aged 30-39 y n = 494 |
Group 3 Aged 40-59 y n = 1417 |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| SOC | PT | E | n | (%) | E | n | (%) | E | n | (%) |
| Total | Total | 40 | 23 | 4.122 | 82 | 32 | 6.478 | 183 | 114 | 8.045 |
| Blood and lymphatic system disorders | All | 1 | 1 | 0.179 | 1 | 1 | 0.202 | — | — | — |
| Immune thrombocytopenic purpura | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Iron deficiency anemia | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Cardiac disorders | All | 2 | 1 | 0.179 | 2 | 2 | 0.405 | 5 | 5 | 0.353 |
| Arrhythmia | 1 | 1 | 0.179 | 1 | 1 | 0.202 | 2 | 2 | 0.141 | |
| Cardiac failure | — | — | — | 1 | 1 | 0.202 | 1 | 1 | 0.071 | |
| Myocardial ischemia | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Myocarditis | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Tachycardia | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Congenital, familial, and genetic disorders | All | — | — | — | — | — | — | 1 | 1 | 0.071 |
| Type V hyperlipidemia | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Ear and labyrinth disorders | All | — | — | — | — | — | — | 1 | 1 | 0.071 |
| Vertigo | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Endocrine disorders | All | 1 | 1 | 0.179 | 1 | 1 | 0.202 | 4 | 4 | 0.282 |
| Adrenal insufficiency | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Adrenocortical insufficiency acute | 1 | 1 | 0.179 | 1 | 1 | 0.202 | 1 | 1 | 0.071 | |
| Glucocorticoid deficiency | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Pituitary hemorrhage | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Gastrointestinal disorders | All | 3 | 1 | 0.179 | 2 | 2 | 0.405 | 7 | 6 | 0.423 |
| Abdominal pain | 1 | 1 | 0.179 | — | — | — | 1 | 1 | 0.071 | |
| Abdominal pain upper | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Diarrhea | — | — | — | — | — | — | 2 | 2 | 0.141 | |
| Gastric ulcer hemorrhage | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Inflammatory bowel disease | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Nausea | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Esophageal spasm | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Pancreatitis | — | — | — | — | — | — | 2 | 2 | 0.141 | |
| Vomiting | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| General disorders and administration site conditions | All | 2 | 2 | 0.358 | 10 | 8 | 1.619 | 14 | 14 | 0.988 |
| Chest pain | — | — | — | 1 | 1 | 0.202 | 1 | 1 | 0.071 | |
| Condition aggravated | — | — | — | 1 | 1 | 0.202 | 2 | 2 | 0.141 | |
| Death | — | — | — | 1 | 1 | 0.202 | 1 | 1 | 0.071 | |
| Fatigue | — | — | — | — | — | — | 2 | 2 | 0.141 | |
| General physical health deterioration | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Injection site reaction | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Edema | — | — | — | 5 | 3 | 0.607 | 6 | 6 | 0.423 | |
| Edema peripheral | 1 | 1 | 0.179 | — | — | — | 1 | 1 | 0.071 | |
| Peripheral swelling | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Pyrexia | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Hepatobiliary disorders | All | — | — | — | — | — | — | 4 | 3 | 0.212 |
| Biliary colic | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Cholelithiasis | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Hepatorenal syndrome | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Liver disorder | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Immune system disorders | All | — | — | — | — | — | — | 1 | 1 | 0.071 |
| Hypersensitivity | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Infections and infestations | All | 1 | 1 | 0.179 | 11 | 8 | 1.619 | 8 | 7 | 0.494 |
| Appendicitis | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Cellulitis | — | — | — | 1 | 1 | 0.202 | 1 | 1 | 0.071 | |
| Chronic sinusitis | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Cystitis | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Endocarditis | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Gastroenteritis | — | — | — | 3 | 3 | 0.607 | — | — | — | |
| Gastroenteritis norovirus | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Hemorrhagic fever with renal syndrome | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Hepatitis C | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Influenza | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Pyelonephritis | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Respiratory tract infection | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Sepsis | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Sinusitis | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Tonsillitis | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Urinary tract infection | — | — | — | 2 | 1 | 0.202 | — | — | — | |
| Injury, poisoning and procedural complications | All | 3 | 3 | 0.538 | 2 | 2 | 0.405 | 7 | 6 | 0.423 |
| Accident at work | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Contusion | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Fracture | — | — | — | — | — | — | 3 | 3 | 0.212 | |
| Lower limb fracture | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Meniscus injury | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Off-label use | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Postprocedural hemorrhage | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Spinal compression fracture | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Stab wound | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Toxicity to various agents | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Investigations | All | — | — | — | — | — | — | 5 | 5 | 0.353 |
| Cortisol abnormal | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Cortisol decreased | — | — | — | — | — | — | 3 | 3 | 0.212 | |
| Weight increased | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Metabolism and nutrition disorders | All | 2 | 2 | 0.358 | 3 | 2 | 0.405 | 9 | 9 | 0.635 |
| Abnormal loss of weight | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Hyperglycemia | — | — | — | 1 | 1 | 0.202 | 4 | 4 | 0.283 | |
| Hypokalemia | — | — | — | 2 | 2 | 0.405 | — | — | — | |
| Hyponatremia | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Type 2 diabetes mellitus | — | — | — | — | — | — | 4 | 4 | 0.282 | |
| Vitamin D deficiency | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Musculoskeletal and connective tissue disorders | All | 4 | 3 | 0.538 | 15 | 8 | 1.619 | 30 | 23 | 1.623 |
| Arthralgia | 2 | 2 | 0.358 | 6 | 5 | 1.012 | 11 | 11 | 0.776 | |
| Arthritis | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Fibromyalgia | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Intervertebral disc protrusion | — | — | — | — | — | — | 4 | 4 | 0.282 | |
| Joint stiffness | — | — | — | 2 | 2 | 0.405 | 4 | 4 | 0.282 | |
| Lumbar spinal stenosis | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Myalgia | 1 | 1 | 0.179 | 6 | 5 | 1.012 | 4 | 4 | 0.282 | |
| Osteoarthritis | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Psoriatic arthropathy | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Rhabdomyolysis | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Scoliosis | 1 | 1 | 0.179 | — | — | — | 1 | 1 | 0.071 | |
| Spinal column stenosis | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Neoplasms benign, malignant, and unspecified (including cysts and polyps) | All | 3 | 3 | 0.538 | 6 | 6 | 1.215 | 38 | 32 | 2.258 |
| Acute myeloid leukemia | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Anaplastic astrocytoma | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Astrocytoma malignant | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| B-cell lymphoma stage IV | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Bronchial carcinoma | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Colon cancer metastatic | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Craniopharyngioma | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Enchondromatosis | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Follicle center lymphoma, follicular grade I, II, III | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Gastric cancer stage 0 | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Glioma | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Intraductal papillary mucinous neoplasm | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Lipoma | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Lung adenocarcinoma | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Malignant melanoma | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Nasal sinus cancer | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Neoplasm | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Neoplasm malignant | — | — | — | — | — | — | 12 | 11 | 0.776 | |
| Neoplasm progression | — | — | — | — | — | — | 2 | 2 | 0.141 | |
| Neoplasm recurrence | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Nonsecretory adenoma of pituitary | — | — | — | 1 | 1 | 0.202 | 1 | 1 | 0.071 | |
| Esophageal cancer metastatic | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Papillary renal cell carcinoma | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Pituitary cancer metastatic | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Pituitary neoplasm malignant recurrent | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Pituitary tumor | — | — | — | 1 | 1 | 0.202 | 2 | 2 | 0.141 | |
| Pituitary tumor benign | — | — | — | — | — | — | 3 | 3 | 0.212 | |
| Prostate cancer | — | — | — | — | — | — | 2 | 2 | 0.141 | |
| Renal cancer | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Nervous system disorders | All | 11 | 8 | 1.434 | 24 | 10 | 2.024 | 24 | 20 | 1.411 |
| Aphasia | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Ataxia | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Carpal tunnel syndrome | — | — | — | — | — | — | 5 | 5 | 0.353 | |
| Cerebral infarction | 1 | 1 | 0.179 | — | — | — | 1 | 1 | 0.071 | |
| Cerebrospinal fluid leakage | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Cerebrovascular accident | 1 | 1 | 0.179 | — | — | — | 1 | 1 | 0.071 | |
| Dizziness | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Facial paresis | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Generalized tonic-clonic seizure | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Headache | 1 | 1 | 0.179 | 12 | 8 | 1.619 | 8 | 6 | 0.423 | |
| Ischemic stroke | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Loss of consciousness | — | — | — | 1 | 1 | 0.202 | 1 | 1 | 0.071 | |
| Migraine | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Multiple sclerosis | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Paresthesia | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Presyncope | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Sciatica | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Seizure | 3 | 2 | 0.358 | 3 | 2 | 0.405 | — | — | — | |
| Syncope | 2 | 2 | 0.358 | 3 | 2 | 0.405 | 1 | 1 | 0.071 | |
| Toxic encephalopathy | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Transient ischemic attack | — | — | — | — | — | — | 2 | 1 | 0.071 | |
| Pregnancy, puerperium, and perinatal conditions | All | 1 | 1 | 0.179 | — | — | — | — | — | — |
| Preeclampsia | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Psychiatric disorders | All | 3 | 1 | 0.179 | — | — | — | 7 | 4 | 0.282 |
| Bipolar disorder | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Completed suicide | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Depression | 1 | 1 | 0.179 | — | — | — | 2 | 2 | 0.141 | |
| Mental disorder | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Mood swings | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Stress | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Suicide attempt | 2 | 1 | 0.179 | — | — | — | — | — | — | |
| Renal and urinary disorders | All | — | — | — | 1 | 1 | 0.202 | 2 | 2 | 0.141 |
| Nephrolithiasis | — | — | — | 1 | 1 | 0.202 | 1 | 1 | 0.071 | |
| Renal failure | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Reproductive system and breast disorders | All | — | — | — | 1 | 1 | 0.202 | — | — | — |
| Uterine hemorrhage | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Respiratory, thoracic, and mediastinal disorders | All | — | — | — | — | — | — | 3 | 2 | 0.141 |
| Pulmonary embolism | — | — | — | — | — | — | 3 | 2 | 0.141 | |
| Skin and subcutaneous tissue disorders | All | 2 | 2 | 0.358 | 2 | 2 | 0.405 | 3 | 3 | 0.212 |
| Acne | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Hair disorder | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Pruritus | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Rash | 2 | 2 | 0.358 | 1 | 1 | 0.202 | 1 | 1 | 0.071 | |
| Surgical and medical procedures | All | 1 | 1 | 0.179 | — | — | — | 5 | 5 | 0.353 |
| Cholecystectomy | — | — | — | — | — | — | 2 | 2 | 0.141 | |
| Cholecystostomy | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Hospitalization | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Pituitary tumor removal | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Wisdom teeth removal | 1 | 1 | 0.179 | — | — | — | — | — | — | |
| Vascular disorders | All | — | — | — | 1 | 1 | 0.202 | 5 | 4 | 0.282 |
| Deep vein thrombosis | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Hypertension | — | — | — | — | — | — | 2 | 2 | 0.141 | |
| Thrombosis | — | — | — | 1 | 1 | 0.202 | — | — | — | |
| Venous thrombosis | — | — | — | — | — | — | 1 | 1 | 0.071 | |
| Venous thrombosis limb | — | — | — | — | — | — | 1 | 1 | 0.071 | |
Abbreviations: ANSWER, American Norditropin Studies: Web Enabled Research; E, events; IOS, International Outcome Study; n, number of patients in each group; PT, preferred term; SOC, system organ class.
Efficacy Analyses
Mean GH dose for patients in the EAS (Fig. 1) and FAS (Fig. 2) was analyzed by age group and sex. In female patients of all groups, the mean GH dose was higher for patients who were treated for a longer duration. Mean GH doses were similar between male patients aged 18 to 29 years and 40 to 59 years with different treatment durations, whereas mean GH dose was lower for males aged 18 to 29 years who were treated for a longer duration. No differences were observed in mean GH dose between male patients in the FAS with different treatment durations, regardless of age group.
Figure 1.
Mean GH exposure for (A) female and (B) male patients with AGHD in the EAS from NordiNet® IOS and the ANSWER Program stratified by age and sex. Error bars represent ± SE.
Abbreviations: AGHD, adult GH deficiency; ANSWER, American Norditropin Studies: Web Enabled Research; EAS, effectiveness analysis set.
Figure 2.
Mean GH exposure for (A) female and (B) male patients with AGHD in the FAS from NordiNet IOS and the ANSWER Program stratified by age and sex. Error bars represent ± SE.
Abbreviations: AGHD, adult GH deficiency; ANSWER, American Norditropin Studies: Web Enabled Research; FAS, full analysis set.
Mean GH dose was also analyzed by estrogen use for female patients in the EAS (Fig. 3) and FAS (Fig. 4). In the EAS and FAS, the mean GH dose was higher for female patients who were treated for a longer duration, regardless of estrogen use. In group 3 of both cohorts, there was no noticeable difference in mean GH dose between patients with different treatment durations.
Figure 3.
Mean GH exposure for female patients with AGHD in the EAS from NordiNet International Outcome Study and the ANSWER Program either (A) using any form of estrogen (oral, vaginal, or patch) or (B) not using any form of estrogen. Error bars represent ± SE.
Abbreviations: AGHD, adult GH deficiency; ANSWER, American Norditropin Studies: Web Enabled Research; EAS, effectiveness analysis set.
Figure 4.
Mean GH exposure for female patients with AGHD in the FAS from NordiNet International Outcome Study and the ANSWER Program either (A) using any form of estrogen (oral, vaginal, or patch) or (B) not using any form of estrogen. Error bars represent ± SE.
Abbreviations: AGHD, adult GH deficiency; ANSWER, American Norditropin Studies: Web Enabled Research; EAS, effectiveness analysis set.
Mean IGF-I SDS levels were determined for adult patients in the EAS and stratified by both age group and sex (Fig. 5). By year 2, the proportion of patients within the normal range (−2 to +2) of IGF-I SDS had increased in all groups to ≥80% and remained >80% over most of the follow-up years and up to year 10.
Figure 5.
IGF-I SDS levels for (A) female, (B) male, and (C) all adult patients with AGHD in the NordiNet International Outcome Study and the ANSWER Program stratified by age and sex.
Abbreviations: AGHD, adult GH deficiency; ANSWER, American Norditropin Studies: Web Enabled Research; EAS, effectiveness analysis set; SDS, SD score.
Mean (SD) HbA1c levels were analyzed from year 0 to 2 for adult patients in the EAS and FAS by age group and sex (Table 5). No notable change was observed within this time frame for female or male patients in either the EAS or the FAS, regardless of age group.
Table 5.
Mean HbA1c of adult patients in the EAS and FAS from NordiNet IOS and the ANSWER Program stratified by age group and sex
| Group 1 Aged 18-29 y |
Group 2 Aged 30-39 y |
Group 3 Aged 40-59 y |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Female | Male | Female | Male | Female | Male | |||||||
| n | Mean (SD) | n | Mean (SD) | n | Mean (SD) | n | Mean (SD) | n | Mean (SD) | n | Mean (SD) | |
| EAS | ||||||||||||
| HbA1c, % | ||||||||||||
| Year 0 | 36 | 5.3 (0.9) | 31 | 5.0 (0.8) | 38 | 5.2 (0.8) | 31 | 5.3 (1.5) | 103 | 5.3 (0.7) | 147 | 5.4 (0.8) |
| Year 2 | 17 | 5.5 (1.0) | 22 | 5.1 (0.6) | 32 | 5.2 (0.7) | 23 | 5.3 (1.0) | 72 | 5.4 (1.0) | 92 | 5.3 (0.8) |
| FAS | ||||||||||||
| HbA1c, % | ||||||||||||
| Year 0 | 78 | 5.1 (0.8) | 92 | 5.1 (0.8) | 69 | 5.3 (1.0) | 59 | 5.3 (1.3) | 184 | 5.4 (0.9) | 224 | 5.4 (0.8) |
| Year 2 | 47 | 5.2 (0.9) | 56 | 5.3 (1.0) | 48 | 5.3 (0.7) | 51 | 5.2 (0.8) | 142 | 5.4 (1.0) | 153 | 5.3 (1.0) |
Abbreviations: ANSWER, American Norditropin Studies: Web Enabled Research; EAS, effectiveness analysis set; FAS, full analysis set; HbA1c, glycated hemoglobin; IOS, International Outcome Study.
Mean non-HDL cholesterol was analyzed from year 0 to 2 for adult patients in the EAS and FAS by age group and sex (Table 6). In both female and male patients in all age groups of the FAS, a decrease was observed between 0 and 2 years. No notable change was observed for female or male patients in the EAS.
Table 6.
Mean non-HDL cholesterol of adult patients in the EAS and FAS from NordiNet IOS and the ANSWER Program stratified by age group and sex
| Group 1 Aged 18-29 y |
Group 2 Aged 30-39 y |
Group 3 Aged 40-59 y |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Female | Male | Female | Male | Female | Male | |||||||
| n | Mean (SD) | n | Mean (SD) | n | Mean (SD) | n | Mean (SD) | n | Mean (SD) | n | Mean (SD) | |
| EAS | ||||||||||||
| Non-HDL cholesterol, mmol/L | ||||||||||||
| Year 0 | 34 | 4.08 (1.20) | 37 | 3.95 (1.18) | 38 | 4.06 (1.37) | 34 | 4.11 (1.20) | 111 | 4.38 (1.12) | 148 | 4.63 (1.34) |
| Year 2 | 17 | 3.89 (1.12) | 18 | 3.26 (0.97) | 28 | 3.95 (1.23) | 20 | 4.22 (1.43) | 67 | 4.27 (1.10) | 93 | 4.13 (1.20) |
| FAS | ||||||||||||
| Non-HDL cholesterol, mmol/L | ||||||||||||
| Year 0 | 83 | 3.88 (1.19) | 92 | 3.67 (1.07) | 73 | 4.23 (1.35) | 61 | 4.25 (1.40) | 197 | 4.24 (1.05) | 226 | 4.54 (1.30) |
| Year 2 | 51 | 3.74 (0.99) | 50 | 3.58 (1.08) | 45 | 4.06 (1.18) | 46 | 3.94 (1.25) | 130 | 4.08 (1.07) | 151 | 4.26 (1.21) |
Abbreviations: ANSWER, American Norditropin Studies: Web Enabled Research; EAS, effectiveness analysis set; FAS, full analysis set; HDL, high-density lipoprotein; IOS, International Outcome Study.
Discussion
Evaluation of the safety of short-acting GHRT in adult patients with AGHD aged 18 to 59 years revealed no significant differences in the incidence of NSARs and SARs or SAEs between age groups. The most common SAE reported was “neoplasms benign, malignant, and unspecified” with a rate of 0.54%, 0.61%, and 1.34% across groups of increasing age (groups 1, 2, and 3, respectively). This is consistent with an observational study of patients treated with GH, aged 6 to 91 years, from 1994 to 2012 [15]. The most common treatment-related SAE was tumor/neoplasm recurrence, observed at a rate of 1.3%. This is supported by a previous report establishing greater risk of myeloid neoplasm occurrence with increasing age [16], as well as a higher overall incidence of cancer with older age groups and an increase in the incidence of cancer in younger age groups over time [17].
It is important to note that recent evidence-based guidance released by the American Association of Clinical Endocrinologists and the American College of Endocrinology on the use of recombinant human GHRT acknowledge that there are no data to support an increased risk of cancer or recurrence of tumors in the hypothalamic-pituitary region of adults taking GHRT. However, it is recommended to continue long-term monitoring and cancer screening in these patients for the purpose of safety surveillance [18]. Additionally, a previous study has shown that tumor progression within the hypothalamic–pituitary region did not differ between patients treated with or without GHRT, and recurrence risk was similar between these 2 groups. Independent predictors of recurrence included the use of radiotherapy and residual tumor [19]. Family history and increasing age may also be predictors of cancer recurrence in patients with AGHD [20, 21]. A previous study examining registry data for patients with AGHD has also demonstrated that mortality due to malignancies was not elevated in patients receiving GHRT [22]. Similarly, a study examining the Hypopituitary Control and Complications Study registry safety data in patients with AGHD treated with or without GHRT showed no significant difference in the overall rate of cancer incidence between these two groups [23, 24]. Similar to the safety events reported here, the Hypopituitary Control and Complications Study registry reported additional safety events including arthralgia, peripheral edema, and myalgia [25].
No notable changes were observed for any of the age groups in HbA1c levels from year 0 to 2. This observation is supported by previous analyses establishing no change in HbA1c levels from baseline over the course of 1 to 2 years [26, 27]. Additionally, a decrease in mean non-HDL cholesterol levels was observed in all groups of the FAS from year 0 to 2. Previous studies have similarly established a significant decrease in total and low-density lipoprotein cholesterol with GH treatment in adult patients over the course of 6 months [28, 29].
Limitations
Registry data is a helpful tool to establish general ideas of safety and efficacy but may be in part limited by patient dropout and missing data. Limitations of the current analyses include decreasing n values over time, and therefore, patient dropout and missing information may limit the longitudinal scope of the data. The cause for patient dropout may be attributed to not only a preference to stop or switch GH treatment but also to the limitations of insurance coverage. In this context, registries lose impact due to the method in which the health system imposes changes on patient treatment plans. Additionally, registry data input is not a mandatory task and therefore not standardized. Consequently, some variables of this dataset may remain incomplete. Nonserious AEs were not systematically collected, introducing a further limitation to the dataset.
Conclusions
This study aimed to establish the real-world safety and efficacy of short-acting GHRT in adult patients with AGHD among different age groups. No significant differences in the risk of short-acting GHRT–related adverse reactions were observed across age groups. By year 2, ≥ 80% of patients across all groups had a normal IGF-I SDS. Together, these results indicate the safety and efficacy of short-acting GHRT for the treatment of AGHD, regardless of age.
Acknowledgments
The authors acknowledge the medical writing assistance of Amy Ryan, PhD, of Precision AQ, which was supported financially by Novo Nordisk Inc. (Plainsboro, NJ), in compliance with international Good Publication Practice guidelines.
Contributor Information
John D Carmichael, Email: john.carmichael@med.usc.edu, Endocrinology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Atil Y Kargi, Neurosurgery, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Laura Dichtel, Neuroendocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Nicky Kelepouris, US Medical Affairs, Rare Endocrine Disorders, Novo Nordisk Inc., Plainsboro, NJ 08536, USA.
Navid Nedjatian, Global Medical Affairs, Rare Endocrine Disorders, Novo Nordisk Health Care AG, 8050 Zurich, Switzerland.
Moshe Fridman, Scientific Analytics, Novo Nordisk Inc., Plainsboro, NJ 08536, USA.
Matthias M Weber, Unit of Endocrinology, Medical Department, University Hospital, Universitätsmedizin Mainz, der Johannes Gutenberg Universität, 55131 Mainz, Germany.
Funding
This study was funded by Novo Nordisk Inc.
Disclosures
J.D.C. has consulted for Novo Nordisk Inc., Camurus, and Xeris Biopharma. A.Y.K. has consulted for Corcept Therapeutics, Novo Nordisk Inc., Ascendis Pharma, Recordati, Camurus, and Xeris Biopharma. L.D. has received study medication and/or research support from Pfizer, Perspectum Ltd., Lumos Pharma, Recordati, and Novo Nordisk Inc. She is a consultant for Lumos Pharma, Marea Therapeutics, and Merida Biosciences. She has equity in Marea Therapeutics and Merida Biosciences. She is a fellow at Third Rock Ventures through the Mass General Brigham's Innovation Fellows Program but remained a full-time employee of Mass General Brigham during the course of this educational program (October 1, 2022-September 30, 2024). N.K. is an employee of Novo Nordisk Inc. N.N. is an employee of Novo Nordisk Health Care AG. M.F. is a contingent/contract employee of Novo Nordisk Inc. M.W. received honoraria as a speaker or board member from Ipsen, Eli Lilly, and Novo Nordisk Inc.
Data Availability
Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.