Assessment of potential transthyretin amyloid cardiomyopathy cases in the Brazilian public health system using a machine learning mode

OBJECTIVES: To identify and describe the profile of potential transthyretin cardiac amyloidosis (ATTR-CM) cases in the Brazilian public health system (SUS), using a predictive machine learning (ML) model. METHODS: This was a retrospective descriptive database study that aimed to estimate the frequency of potential ATTR-CM cases in the Brazilian public health system using a supervised ML model, from January 2015 to December 2021. To build the model, a list of ICD-10 codes and procedures potentially related with ATTR-CM was created based on literature review and validated by experts. RESULTS: From 2015 to 2021, the ML model classified 262 hereditary ATTR-CM (hATTR-CM) and 1,581 wild-type ATTR-CM (wtATTR-CM) potential cases. Overall, the median age of hATTR-CM and wtATTR-CM patients was 66.8 and 59.9 years, respectively. The ICD-10 codes most presented as hATTR-CM and wtATTR-CM were related to heart failure and arrythmias. Regarding the therapeutic itinerary, 13% and 5% of hATTR-CM and wtATTR-CM received treatment with tafamidis meglumine, respectively, while 0% and 29% of hATTR-CM and wtATTR-CM were referred to heart transplant. CONCLUSION: Our findings may be useful to support the development of health guidelines and policies to improve diagnosis, treatment, and to cover unmet medical needs of patients with ATTR-CM in Brazil.

Assessment of potential transthyretin amyloid cardiomyopathy cases in the Brazilian public health system using a machine learning model.

OBJECTIVES: To identify and describe the profile of potential transthyretin cardiac amyloidosis (ATTR-CM) cases in the Brazilian public health system (SUS), using a predictive machine learning (ML) model. METHODS: This was a retrospective descriptive database study that aimed to estimate the frequency of potential ATTR-CM cases in the Brazilian public health system using a supervised ML model, from January 2015 to December 2021. To build the model, a list of ICD-10 codes and procedures potentially related with ATTR-CM was created based on literature review and validated by experts. RESULTS: From 2015 to 2021, the ML model classified 262 hereditary ATTR-CM (hATTR-CM) and 1,581 wild-type ATTR-CM (wtATTR-CM) potential cases. Overall, the median age of hATTR-CM and wtATTR-CM patients was 66.8 and 59.9 years, respectively. The ICD-10 codes most presented as hATTR-CM and wtATTR-CM were related to heart failure and arrythmias. Regarding the therapeutic itinerary, 13% and 5% of hATTR-CM and wtATTR-CM received treatment with tafamidis meglumine, respectively, while 0% and 29% of hATTR-CM and wtATTR-CM were referred to heart transplant. CONCLUSION: Our findings may be useful to support the development of health guidelines and policies to improve diagnosis, treatment, and to cover unmet medical needs of patients with ATTR-CM in Brazil.

Using machine learning to assess potential cases of transthyretin cardiac amyloidosis in Brazil: a retrospective database approach

INTRODUCTION: Amyloidosis is a group of protein misfolding disorders leading to organ damage due to insoluble amyloid fibril deposits • The two primary types of cardiac amyloidosis are light-chain amyloid (AL) and transthyretin (TTR) cardiac amyloidosis • TTR amyloidosis can be hereditary (hATTR) or age-related (wtATTR). It is an often-overlooked cause of heart failure in older adults • Recent studies reveal its prevalence in various patient groups: up to 13% in HFpEF, 16% in aortic stenosis patients undergoing valve replacement, 7-8% in carpal tunnel release surgery, and 17% in some other contexts • ATTR-CM is significant in the context of cardiovascular diseases, a leading global cause of death. OBJECTIVE: This study aimed to identify and describe the profile of potential transthyretin cardiac amyloidosis (ATTR-CM) cases in the Brazilian public health system (SUS), using a predictive machine learning (ML) model. MATERIALS AND METHODS: This was a retrospective descriptive database study that aimed to estimate the frequency of potential ATTR-CM cases in the Brazilian public health system (Figure 1) using a supervised machine learning (Figure 2) model, with data extracted from DATASUS outpatient and inpatient datasets from January 2015 to December 2021 • To build the model, a list of ICD-10 codes and procedures potentially related with ATTR-CM was created based on literature review and validated by experts (Figure 3). RESULTS: From 2015 to 2021, the ML model classified 262 hATTR-CM (213 reference hATTR-CIM and 49 hATTR-CM-like) and 1,581 wtATTR-CM (203 reference wtATTR-CM and 1,378 wtATTR-CM-like). Overall, the median age of hATTR-CM and wtATTR-CM patients was 66.8 and 59.9 years, respectively • The ICD-10 codes most presented as hATTR-CM and wtATTR-CM were related to heart failure and arrythmias, with similar procedures performed (Figure 4). Regarding healthcare utilization, hATTR-CM and hATTR-CM-like had similar profiles on proportion of patients with outpatient visits (hATTR-CM 98.0% vs. 92.0% hATTR-CM-like) and different profile related to proportion of hospitalized patients (hATTR-CM 94.4% vs. 32.7% hATTR-CM-like) (Figure 5) • In wtATTR-CM groups, although both proportions on outpatient visits and hospitalizations were similar, the length of stay (LOS) on hospitalizations was different in wtATTR-CM-like (wtATTR-CM median LOS 5.0 (IQR:2.0 - 10.0] vs. median LOS 7.0 [IQR:3.0 - 14.0]). CONCLUSIONS: Our findings may be useful to support decreasing the uncertainties on ATTR-CM population size in Health Technology Assessment appraisals and in the development of healthcare guidelines and policies to address patients' unmet needs and to improve early diagnosis and access to treatment for patients with ATTR-CM in Brazil This study puts a spotlight on the ATTR-CM underdiagnosis in Brazil using a machine learning approach, which can be used as an important tool to support diagnosis improvement.

Pituitary function and the response to GH therapy in patients with Langerhans cell histiocytosis: analysis of the KIMS database.

Objective: To analyze the effectiveness and safety of growth hormone (GH) replacement treatment in adult patients with Langerhans cell histiocytosis (LCH) and GH deficiency (GHD) enrolled in KIMS (Pfizer International Metabolic Database). Patients and methods: Patients with LCH and GHD were studied at baseline and some of them after 1 year of GH treatment. The effectiveness of GH is presented as change after 1 year of treatment (mean, 95% CI). The LCH population was compared to two other groups of patients enrolled in KIMS, granulomatous and lymphocytic hypophysitis. Results: At baseline, 81 adults with LCH (27 with childhood onset, 56% females), mean age at GHD onset of 29 (15) years were studied. Diabetes insipidus was diagnosed in 86% of patients. Analysis of 1 year of GH treatment was possible in 37 patients. One-year cross-sectional values for the GH dose were 0.39 (s.d.± 0.21) mg and -0.5 (-1.2 to 0.2) for insulin-like growth factor-1 s.d. Total cholesterol decreased 0.9 (-1.5 to -0.3 (mmol/L); P < 0.05); AGHDA-QoL-score (n = 20) was improved by 2.8 points (-5.6 to 0.0; P < 0.05), while mean BMI increased 0.6 ± 3 kg/m2 (95% CI: -0.2 to 1.4). All these effects did not differ from the two other groups after adjusting for age, gender, and baseline values. In 20 of 77 patients included in the safety analysis, 36 serious adverse events were reported during 435 patient-years (82.8/1000); no new safety signals were reported. Conclusion: After 1 year of GH treatment in patients with LCH, metabolic variables and quality of life improved, with no new safety signals.

More than a decade of real-world experience of pegvisomant for acromegaly: ACROSTUDY.

OBJECTIVE: To report the final long-term safety and efficacy analyses of patients with acromegaly treated with pegvisomant from the ACROSTUDY. DESIGN: Global (15 countries), multicentre, non-interventional study (2004-2017). METHODS: The complete ACROSTUDY cohort comprised patients with acromegaly, who were being treated with pegvisomant (PEGV) prior to the study or at enrolment. The main endpoints were long-term safety (comorbidities, adverse events (AEs), pituitary tumour volumes, liver tests) and efficacy (IGF1 changes). RESULTS: Patients (n = 2221) were treated with PEGV for a median of 9.3 years (range, 0-20.8 years) and followed up for a median of 7.4 years (range, 0-13.9 years). Before PEGV, 96.3% had received other acromegaly treatments (surgery/radiotherapy/medications). Before PEGV treatment, 87.2% of patients reported comorbidities. During ACROSTUDY, 5567 AEs were reported in 56.5% of patients and of these 613 were considered treatment-related (in 16.5% of patients) and led to drug withdrawal in 1.3%. Pituitary imaging showed a tumour size increase in 7.1% of patients; the majority (71.1%) reported no changes. Abnormal AST or ALT liver tests occurred in 3.2% of patients. IGF1 normalization rate improved over time, increasing from 11.4% at PEGV start to 53.7% at year 1, and reaching 75.4% at year 10 with the use of ≥30 mg PEGV/day in an increasing proportion of patients. CONCLUSION: This comprehensive review of the complete cohort in ACROSTUDY confirmed the overall favourable benefit-to-risk profile and high efficacy of PEGV as mono- and combination therapy in patients with an aggressive course/uncontrolled/active acromegaly requiring long-term medical therapy for control.

Response to GH Treatment After Radiation Therapy Depends on Location of Irradiation.

OBJECTIVES: Cancer survivors with GH deficiency (GHD) receive GH therapy (GHT) after 1+ year observation to ensure stable tumor status/resolution. HYPOTHESIS: Radiation therapy (RT) to brain, spine, or extremities alters growth response to GHT. AIM: Identify differences in growth response to GHT according to type/location of RT. METHODS: The Pfizer International Growth Database was searched for cancer survivors on GHT for ≥5 years. Patient data, grouped by tumor type, were analyzed for therapy (surgery, chemotherapy, RT of the focal central nervous system, cranial, craniospinal, or total body irradiation [TBI] as part of bone marrow transplantation), sex, peak stimulated GH, age at GHT start, and duration from RT to GHT start. Kruskal-Wallis test and quantile regression modeling were performed. RESULTS: Of 1149 GHD survivors on GHT for ≥5 years (male 733; median age 8.4 years; GH peak 2.8 ng/mL), 431 had craniopharyngioma (251, cranial RT), 224 medulloblastoma (craniospinal RT), 134 leukemia (72 TBI), and 360 other tumors. Median age differed by tumor group (P < 0.001). Five-year delta height SD score (SDS) (5-year ∆HtSDS; median [10th-90th percentile]) was greatest for craniopharyngioma, 1.6 (0.3-3.0); for medulloblastoma, 5-year ∆HtSDS 0.9 (0.0-1.9); for leukemia 5-year ∆HtSDS, after TBI (0.3, 0-0.7) versus without RT (0.5, 0-0.9), direct comparison P < 0.001. Adverse events included 40 treatment-related, but none unexpected. CONCLUSIONS: TBI for leukemia had significant impact on growth response to GHT. Medulloblastoma survivors had intermediate GHT response, whereas craniopharyngioma cranial RT did not alter GHT response. Both craniospinal and epiphyseal irradiation negatively affect growth response to GH therapy compared with only cranial RT or no RT.

A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness.

CONTEXT: Individual patients vary in their response to growth hormone (GH). No large-scale genome-wide studies have looked for genetic predictors of GH responsiveness. OBJECTIVE: To identify genetic variants associated with GH responsiveness. DESIGN: Genome-wide association study (GWAS). SETTING: Cohorts from multiple academic centers and a clinical trial. PATIENTS: A total of 614 individuals from 5 short stature cohorts receiving GH: 297 with idiopathic short stature, 276 with isolated GH deficiency, and 65 born small for gestational age. INTERVENTION: Association of more than 2 million variants was tested. MAIN OUTCOME MEASURES: Primary analysis: individual single nucleotide polymorphism (SNP) association with first-year change in height standard deviation scores. Secondary analyses: SNP associations in clinical subgroups adjusted for clinical variables; association of polygenic score calculated from 697 genome-wide significant height SNPs with GH responsiveness. RESULTS: No common variant associations reached genome-wide significance in the primary analysis. The strongest suggestive signals were found near the B4GALT4 and TBCE genes. After meta-analysis including replication data, signals at several loci reached or retained genome-wide significance in secondary analyses, including variants near ST3GAL6. There was no significant association with variants previously reported to be associated with GH response nor with a polygenic predicted height score. CONCLUSIONS: We performed the largest GWAS of GH responsiveness to date. We identified 2 loci with a suggestive effect on GH responsiveness in our primary analysis and several genome-wide significant associations in secondary analyses that require further replication. Our results are consistent with a polygenic component to GH responsiveness, likely distinct from the genetic regulators of adult height.

Near-Adult Height After Growth Hormone Treatment in Children Born Prematurely-Data From KIGS.

CONTEXT: Children born prematurely have been treated with growth hormone (GH), and a significant improvement in height during the first years of treatment has been described. OBJECTIVE: To evaluate the influence of prematurity on near-adult height (NAH) after GH treatment. DESIGN: KIGS (Pfizer International Growth Database) was queried for children born preterm treated with GH. SETTING: KIGS database. PATIENTS: A total of 586 children short in stature born preterm with various GH status and with available gestational age (GA), birth weight, and NAH, all treated with GH. INTERVENTION: GH treatment. MAIN OUTCOME MEASURE: NAH. RESULTS: Values were expressed as median. From the 586 children included, 482 born appropriate for GA (AGA; median age 8.26 years) and 104 born small for gestational age (SGA) (median age 8.54 years); 66.6% of preterm AGA had GH peak < 7 µg/L during a provocation test, whereas only 8.6% of preterm SGA. Change in height standard deviation scores (SDS) from GH start to NAH after 8.04 years of GH treatment was 1.82 in preterm AGA. Respective values were 7.08 years and 1.08 SDS for preterm SGA (P < 0.001); 57% of the variability of the growth response to NAH could be explained, and the distance to parental height was the strongest predictor. No significant changes in height SDS were observed from puberty start to NAH. No correlation was found with GA. GH treatment was well tolerated. CONCLUSION: GH treatment resulted in significant improvement in height in children born preterm, particularly during prepubertal years and for those with GH deficiency. The degree of prematurity did not influence the growth response.

Adult height prediction by bone age determination in children with isolated growth hormone deficiency.

BACKGROUND: The precision of adult height prediction by bone age determination in children with idiopathic growth hormone deficiency (IGHD) is unknown. METHODS: The near adult height (NAH) of patients with IGHD in the KIGS database was compared retrospectively to adult height prediction calculated by the Bayley-Pinneau (BP) prediction based on bone age by Greulich-Pyle (GP) in 315 children and based on the Tanner-Whitehouse 2 (TW2) method in 121 children. Multiple linear regression analyses adjusted for age at GH start, age at puberty, mean dose and years of of GH treatment, and maximum GH peak in stimulation test were calculated. RESULTS: The mean underestimation of adult height based on the BP method was at baseline 4.1 ± 0.7 cm in girls and 6.1 ± 0.6 cm in boys, at 1 year of GH treatment 2.5 ± 0.5 cm in girls and 0.9 ± 0.4 cm in boys, while at last bone age determination adult height was overestimated in mean by 0.4 ± 0.6 cm in girls and 3.8 ± 0.5 cm in boys. The mean underestimation of adult height based on the TW2 method was at baseline 5.3 ± 2.0 cm in girls and 7.9 ± 0.8 cm in boys, at 1 year of GH treatment adult height was overestimated in girls 0.1 ± 0.6 cm in girls and underestimated 4.1 ± 0.4 cm in boys, while at last bone age determination adult height was overestimated in mean by 3.1 ± 1.5 cm in girls and 3.6 ± 0.8 cm in boys. CONCLUSIONS: Height prediction by BP and TW2 at onset of GH treatment underestimates adult height in prepubertal IGHD children, while in mean 6 years after onset of GH treatment these prediction methods overestimated adult height.

Change in baseline characteristics over 20 years of adults with growth hormone (GH) deficiency on GH replacement therapy.

OBJECTIVE: Clinical observations over time of adults with growth hormone (GH) deficiency (GHD) have indicated a shift in patient characteristics at diagnosis. The objective of this study was to compare baseline characteristics of patients diagnosed with adult-onset GHD naive to GH replacement during three study periods (1994-1999 (P1), 2000-2004 (P2), and 2005-2012 (P3)) using the KIMS (Pfizer's International Metabolic) database. METHODS: Data were retrieved for a total of 6069 patients with adult-onset GHD from six countries (Belgium, Germany, Netherlands, Spain, Sweden, and UK): P1 (n = 1705), P2 (n = 2397), and P3 (n = 1967). RESULTS: The proportions of patients with pituitary/hypothalamic tumors and patients with multiple pituitary hormone deficiencies decreased per entry year period, while the proportions with hypertension and diabetes increased. The lag time from diagnosis of pituitary disease to start of GH treatment decreased by 2.9 years over the entry year periods. IGF-1 increased by 0.1 standard deviation score per entry year period. Maximum GH following various stimulation tests, BMI, and waist circumference increased. The use of radiotherapy, glucocorticoid replacement doses, and the proportion of women >50 years on estrogen replacement therapy decreased. The effects of 1 year of GH replacement were similar over the entry year periods despite changes in the patients' baseline characteristics. An expected increase in fasting blood glucose was seen after 1 year of GH treatment. CONCLUSIONS: The degree of confirmed GHD became less pronounced and more patients with co-morbidities and diabetes were considered for GH replacement therapy, possibly reflecting increased knowledge and confidence in GH therapy gained with time.

Near Adult Height in Girls with Turner Syndrome Treated with Growth Hormone Following Either Induced or Spontaneous Puberty.

OBJECTIVE: To understand whether spontaneous vs induced puberty and the type and route of estrogen influence the height of girls with Turner syndrome on growth hormone (GH). STUDY DESIGN: Search of an international database of children treated with GH revealed 772 girls with Turner syndrome followed from GH initiation to near adult height. Data from girls with sustained spontaneous puberty (n = 145) were compared with those requiring estrogens for induction or maintenance of puberty (n = 627). RESULTS: At GH start, mean age (7.5 vs 7.9 years), weight (-1.7 vs -1.7 SDS), and body mass index (0.2 SDS vs 0.1 SDS) were similar for girls with spontaneous puberty and with induced puberty. Although those girls with spontaneous puberty were shorter than those with induced puberty, when midparental height was taken into consideration, starting heights in both groups averaged -2.8 SDS. Both groups received approximately 0.3 mg/kg/week of GH. Girls with spontaneous puberty initiated puberty and reached near adult height earlier than girls with induced puberty (12.6 ± 1.8 years vs 13.4 ± 1.4 years and 16.0 ± 1.3 years vs 16.9 ± 1.4 years, respectively). Although girls with spontaneous puberty grew more in the first year of GH therapy and between the onset of puberty and near adult height (11.0 cm vs 9.3 cm), height SDS at near adult height and the length of time in puberty before reaching near adult height were comparable. A 45,X karyotype was detected in 22.1% of girls with spontaneous puberty and in 58.4% of girls with induced puberty. Patients receiving transdermal estrogens did not grow better than those on oral estrogens. Adverse event reporting was comparable between groups. CONCLUSIONS: Girls with Turner syndrome with spontaneous puberty tended to grow better in response to GH than girls with induced puberty, but not enough to produce a difference in height SDS at near adult height.

Treatment with Growth Hormone in Noonan Syndrome Observed during 25 Years of KIGS: Near Adult Height and Outcome Prediction.

BACKGROUND/AIMS: There is little information how rhGH treatment affects height in NS. This study aims to analyze data from the NS patients assembled in KIGS over 25 years. PATIENTS/METHODS: Of 613 (389 m/224 f) NS patients documented, 476 (302 m/174 f) were treated for 1 year, 237 (160 m/77 f) of which served to develop a 1st year height velocity (HV) prediction algorithm. One-hundred and forty (74 m/66 f) had reached near adult height (NAH). Factors affecting NAH on rhGH were determined. RESULTS: At the start of rhGH, the NAH groups were (median, m, f) 11.0 and 10.3 years, with a height SDS of -3.2 and -3.8 SDS (Prader), respectively. The total gain after 6.3 and 5.6 years on rhGH (0.27 and 0.30 mg/kg/week) was 1.2 and 1.3 SDS. Age at the start of rhGH (negative), height at the start of rhGH, rhGH dose, number of rhGH injections/wk and birth weight (all positive) explained 36% of the variability of 1st year HV. Height at the start of rhGH, 1st year growth on rhGH, birth weight, and gender explained 74% of the variability of NAH. Causes for rhGH treatment discontinuation and adverse events were also analyzed. CONCLUSION: rhGH treatment increases NAH in NS. Prediction algorithms may optimize treatment in the future.

Improvements in Body Composition after 4 Years of Growth Hormone Treatment in Adult-Onset Hypopituitarism Compared to Age-Matched Controls.

BACKGROUND/AIMS: It is unknown whether long-term growth hormone replacement therapy (GHRT) affects body composition in an age- or sex-dependent manner. We aimed to study the effects of 4 years of GHRT on body composition in a large cohort of patients with hypopituitarism compared to a reference population matched by age and sex. METHODS: A total of 964 GH-deficient adults from KIMS (Pfizer International Metabolic Database) with adult-onset hypopituitarism, adequately replaced with all pituitary hormones except for GH at baseline were included. A random sample of the general population (2,301 subjects) from a similar time period was used as reference. Patients and controls were grouped by sex in 5 age cohorts of 10 years. Main outcome measures were changes in BMI and waist circumference after 4 years of GHRT. RESULTS: In younger patients (28-47 years), 4 years of GHRT resulted in a BMI increase similar to that observed in the reference population, but older patients (48-67 years) had significantly less BMI increase than age-matched healthy controls. Significant differences were seen in waist circumference in patients of all age cohorts who showed virtually no change after 4 years of GHRT compared to approximately 4 cm of increase in the reference population. CONCLUSION: Four years of GHRT resulted in improvements in BMI and waist circumference in patients with adult-onset hypopituitarism compared to age-matched controls observed during the same follow-up time. Despite these beneficial effects on body composition, BMI and waist circumference remained higher in patients on GHRT compared to healthy controls.

Targeted literature review of the humanistic and economic burden of adult growth hormone deficiency.

BACKGROUND: Quality of life (QoL) and health economic data are becoming increasingly important factors in healthcare decision making. While there is a wealth of information establishing the benefit of growth hormone (GH) replacement therapy in adults with growth hormone deficiency (aGHD), recent reviews on the QoL and health economic impact of aGHD and the effect of treatment on these factors is limited. OBJECTIVE: The aim of this article is to summarize the impact of early and sustained treatment on the QoL and economic burden of aGHD by conducting a targeted literature review. METHODS: Standard electronic databases, including PubMed and the Cochrane collaboration website, were searched for publications between January 2006 and July 2016 for evidence of the humanistic and economic burden of aGHD. Search terms included growth hormone deficiency, health-related quality of life, HRQoL, patient-reported outcomes, outcome assessment, well-being and adherence. RESULTS: The literature search identified 732 initial hits and a final 14 publications were included. The analysis showed that the economic burden of aGHD is largely driven by the productivity losses associated with the disease. This is because most patients with aGHD are of working age and the QoL domains (memory & concentration and energy & vitality) most commonly affected by aGHD severely impair a person's ability to work and may limit their contribution to society. CONCLUSION: Untreated aGHD can seriously affect patients' functioning. Early and continued treatment with GH replacement therapy could potentially improve the QoL and reduce the economic burden associated with aGHD. This review has limitations: only English language articles published since January 2006 were included and many of the studies were conducted in the Nordic countries; it is unclear how representative these studies are of the population as a whole. This was a literature review and not a systematic review, as it was thought to be unlikely that, in this rare disease, any additional publications would have been identified. Overall, this review reveals a paucity of data in this underserved population and points to research gaps which could be addressed with new studies.

Diabetes in patients with acromegaly treated with pegvisomant: observations from acrostudy.

PURPOSE: To explore the effects of pegvisomant (PEGV) on glucose metabolism in patients with acromegaly within ACROSTUDY, an international, observational, prospective safety surveillance study. METHODS: Patients were retrospectively divided into two cohorts, with (DM group) or without diabetes mellitus (no-DM). Parameters of glucose metabolism and IGF-I values were analyzed yearly both cross-sectionally for 4 years (yrs) and longitudinally at 1 and 4-5 yrs of PEGV treatment. RESULTS: Among 1762 patients, 510 (28.9%) had DM before PEGV start. At cross-sectional analyses, in the DM group mean blood glucose was 140.0 ± 58.7 mg/dl at baseline, 116.4 ± 44.8 mg/dl at year 1 and 120.0 ± 44.3 mg/dl at yr 4. Mean HbA1c was 6.6 ± 1.2 % at yr 1 vs. 7.0 ± 1.4 % at baseline. HbA1c was above 6.5% in 61.9% at baseline and ranged from 45.4 to 53.8% at subsequent yearly time points. At the 4-yr longitudinal analysis, in the DM group (n = 109), mean blood glucose decreased by 20.2 mg/dl at yr 4, mean HbA1c was 7.0 ± 1.5% at baseline vs. 6.8 ± 1.4%. Patients achieved IGF-I normalization in 52.1% and 57.4% of cases in the DM and no-DM groups, respectively at 1 year. The mean daily PEGV dose (mg/day) was higher in the DM group (18.2 vs. 15.3) while the absolute change of IGF-I values from baseline was similar in both groups. PEGV was well tolerated in both groups without any unexpected AEs. CONCLUSIONS: Patients with DM had a moderate decrease in mean fasting glucose values during PEGV treatment.

Long-term treatment with pegvisomant: observations from 2090 acromegaly patients in ACROSTUDY.

Objectives ACROSTUDY is an international, non-interventional study of acromegaly patients treated with pegvisomant (PEGV), a growth hormone receptor antagonist and has been conducted since 2004 in 15 countries to study the long-term safety and efficacy of PEGV. This report comprises the second interim analysis of 2090 patients as of May 12, 2016. Methods Descriptive analyses of safety, pituitary imaging and outcomes on PEGV treatment up to 12 years were performed. Results Prior to starting PEGV, 96% of patients had reported surgery, radiation, medical therapy or any combinations of those. At start of PEGV, 89% of patients had IGFI levels above the upper limit of normal (ULN). The percentage of patients with normal IGFI levels increased from 53% at year 1 to 73% at year 10, and the average daily dose of PEGV increased from 12.8 mg (year 1) to 18.9 mg (year 10). A total of 4832 adverse events (AEs) were reported in 1137 patients (54.4%), of which 570 were considered treatment related in 337 patients (16.1%). Serious AEs were reported in 22% of patients, of which 2.3% were considered treatment related. Locally reported MRIs showed most patients (72.2%) had no change in tumor size relative to the prior scan; 16.8% had a decrease, 6.8% an increase and 4.3% both. In patients with normal liver tests at PEGV start, an ALT or AST elevation of >3× ULN at any time point during their follow-up was reported in 3%. Conclusions This second interim analysis confirms that long-term use of PEGV is an effective and safe treatment in patients with acromegaly.

Racial/Ethnic Disparities in US Pediatric Growth Hormone Treatment.

BACKGROUND/AIMS: To compare racial/ethnic proportions of subjects receiving growth hormone (GH) treatment to the expected proportions, and secondarily, to assess racial/ethnic differences in subject characteristics at GH treatment initiation. METHODS: Race/ethnicity-based expected frequencies of height <-2.25 SD were determined by applying relative risks for short stature, calculated from a regional population of 189,280 pediatric primary care patients, to US census data, and compared to racial/ethnic proportions of US subjects enrolled in the Pfizer International Growth Study (KIGS) using the χ2 test. Characteristics of white and black subjects at GH treatment initiation were presented as medians and compared by the Wilcoxon rank sum test (significant p < 0.01). RESULTS: White subjects exceeded the expected frequency (63%) for all indications (83%) and each separately, ranging from 73% for congenital GH deficiency (GHD) to 85% for idiopathic short stature (p < 0.001). Compared to white subjects, black subjects treated for idiopathic GHD had greater height deficits relative both to the population (-2.97 vs. -2.56 SD) and to their mid-parental heights (-2.47 vs. -1.89 SD), lower stimulated GH peak levels (4.9 vs. 6.0 ng/mL), and lower birth weights (-0.86 vs. -0.48 SD). Black subjects with congenital GHD had lower stimulated GH peaks (2.1 vs. 3.2 ng/mL) and started GH treatment at younger ages (2.9 vs. 4.8 years), while those with acquired GHD had lower birth weights (-1.12 vs. -0.08 SD). Male predominance did not differ by race for any or all indications. CONCLUSION: Overrepresentation of white children among those receiving GH treatment in the US KIGS registry reflects racial/ethnic treatment biases, not just differences in growth rates.

The prevalence of the metabolic syndrome and associated cardiovascular complications in adult-onset GHD during GH replacement: a KIMS analysis.

BACKGROUND: Adult-onset growth hormone deficiency (AO-GHD) is associated with an increased prevalence of the metabolic syndrome (MetS). AIM: To determine the effect of GH replacement on the prevalence of MetS in AO-GHD and to study the impact of MetS on the incidence of cardiovascular events during GH replacement. PATIENTS AND METHODS: 1449 AO-GHD patients (males 48.9%; mean age 48.9 ± 12.8 year) were retrieved from KIMS (Pfizer International Metabolic Database). The prevalence of MetS (using International Diabetes Federation criteria) and its components were calculated at baseline and after one year of GH replacement. The relative risk to develop cardiovascular events according to the presence of MetS at baseline was assessed in another group of 3282 patients after prolonged GH replacement. RESULTS: The prevalence of MetS was 46.9% at baseline and 48.2% after one year of GH replacement (P = NS). The percentage of patients with abnormal waist circumference decreased significantly (80.3 vs 77.4%; P < 0.001), but impaired glucose metabolism (17.1 vs 23.3%; P < 0.001) increased and HDL cholesterol (48.2 vs 50.9%; P = 0.011) decreased. Switch from MetS to NoMS (18.5%) and from NoMS to MetS (18.8%) occurred. All patients showed a significant and comparable amelioration of quality of life. During seven years of GH replacement patients with MetS had a 66% higher risk (P = 0.0016) to develop a new coronary disease compared to NoMS. CONCLUSION: MetS prevalence remains unchanged in AO-GHD during one year of GH replacement whereas its components are differentially affected. Besides GH replacement, consequent pharmacotherapy of all risk factors and endorsement of lifestyle intervention appears to be of uttermost importance together with early GHD diagnosis to prevent cardiovascular disease during prolonged treatment.

Efficacy of Growth Hormone Treatment in Children with Type 1 Diabetes Mellitus and Growth Hormone Deficiency-An Analysis of KIGS Data.

OBJECTIVE: To analyze first-year treatment growth response and growth hormone (GH) dosage in prepubertal patients with the combination of type 1 diabetes mellitus (T1DM) and growth hormone deficiency (GHD). STUDY DESIGN: A total of 69 patients with T1DM and GHD treated with GH have been enrolled in KIGS (Pfizer International Growth Database). Of these, 24 prepubertal patients had developed T1DM before GHD and were included in this analysis. Of 30 570 patients with GHD without T1DM, 15 024 were prepubertal and served as controls. Values are expressed as mean ± SD. RESULTS: Patients with T1DM and GHD had similar characteristics compared with the GHD-alone group. Neither age (10.2 ± 3.13 vs 8.42 ± 3.46 years, P = .14), height SDS corrected for midparental height SDS at start of treatment (-1.62 ± 1.38 vs -1.61 ± 1.51, P = .80), nor GH dosage (0.24 ± 0.08 mg/kg/wk vs 0.20 ± 0.04 mg/kg/wk, P = .09) were different between those with and without T1DM. First-year catch-up growth was comparable between the 2 patient groups (first treatment year height velocity 7.54 ± 3.11 cm/year compared with 8.35 ± 2.54 cm/year in control patients, P = .38). Height SDS of children with T1DM and GHD improved from -2.62 ± 1.04 to -1.88 ± 1.11 over 1 year of GH treatment. CONCLUSION: Short-term response to GH therapy appeared similar in subjects with T1DM who then developed GHD and in those with GHD alone. Thus, T1DM does not appear to compromise GH response in children with GHD and should not exclude GH treatment in these children. GH treatment was safe in both subgroups of patients.