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Patrick Wilton

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Patrick Wilton

We gratefully acknowledge the work of the Guest Editors Beverly MK Biller, Hugo Fideleff, Vera Popovic and Felipe Casanueva on the EJE special issue 15 years of KIMS® and 5 years of ACROSTUDY™ Their contribution to the management of adult patients with growth hormone disorders. This acknowledgement was omitted by mistake from EJE 161 (Suppl 1) S1–S2.

Open access

Christian J Strasburger, Anders Mattsson, Patrick Wilton, Ferah Aydin, Judith Hey-Hadavi and Beverly M K Biller

Pegvisomant monotherapy is effective and safe in treatment of acromegaly. However, some clinicians combine pegvisomant with somatostatin analogues (SSA) or dopamine agonist (DA). In this analysis of ACROSTUDY, a long-term non-interventional study, the use of combination regimens was evaluated. Based on their baseline treatment, 2043 patients were retrospectively categorized as: long-acting SSA combined with pegvisomant, ‘Combo SSA’ 768 patients (38%); DA combined with pegvisomant, ‘Combo DA’ 123 (6%); pegvisomant monotherapy, ‘Peg mono’ 1128 (55%). Treatment patterns changed over the 10-year period, with recent patients more likely to receive any combination (20% in 2003 vs 54% in 2012). Combo SSA use varied widely among countries from 22% to 78%. Exposure periods of the three treatment modalities were defined from pegvisomant start until the last visit in ACROSTUDY; patients could switch treatment categories. At year 4, IGF-I was normal in 62% of Combo SSA, 63% of Combo DA and 65% of Peg mono groups. Pegvisomant was initiated as daily injections in 94% of patients in the Peg mono group, 66% of Combo SSA and 91% of Combo DA patients. During 6169 years of treatment exposure, 3424 adverse events (AEs) were reported in 946 (51%) patients, of which 617 (18%) were serious and 401 (12%) were considered treatment related. The reported incidence of serious AEs and treatment-related non-serious AEs were similar among the three treatment modalities. This analysis describes real-world clinical care and shows favorable efficacy and safety for Peg mono and combinations. Novel findings include an increased use of combination therapy over time and variability in treatment modalities between countries.

Free access

Aart Jan van der Lely, Peter Jönsson, Patrick Wilton, Ann-Charlotte Åkerblad, José Cara and Ezio Ghigo

Objective

To investigate the characteristics of patients who need more or less pegvisomant (PEGV) to normalize serum IGF-I.

Design

ACROSTUDY is a global noninterventional safety surveillance study of long-term treatment outcomes in patients treated with PEGV. As of June, 2014, ACROSTUDY included data on 2016 patients. All patients treated for at least 6weeks at a dose above 30mg/day and who had two consecutive normal serum IGF-I values were included in the ‘high’-dose group (H; n=56; mean daily dose 44±12.5; median dose 40, 35–60 (10–90%)). Patients with two consecutive normal IGF-I values and who never received a PEGV dose above 10mg/day were included in the ‘low’-dose group (L; n=368; mean daily dose 7.5±2.5; median dose 8.6, 4.3–10 (10–90%)).

Results

Patients in the H group were significantly younger (median 47 vs 52years) and had a significantly higher BMI (median 31.8 vs 26.5kg/m2). They had more diabetes (55% vs 21%), sleep apnea (25% vs 14 %) and more hypertension (61% vs 43%). The incidence of (serious) adverse events was low and was not different between the groups.

Conclusions

Patients who need more PEGV to normalize IGF-I have more aggressive disease, as they are younger, have higher baseline IGF-I levels, more hypertension, more sleep apnea and diabetes and are more overweight. A better understanding of this dose-efficacy relationship of PEGV might avoid inappropriate dosing and prevent serum IGF-I levels from remaining unnecessarily uncontrolled.

Free access

Pascale Abrams, Hugo Boquete, Hugo Fideleff , Ulla Feldt-Rasmussen, Peter J Jönsson, Maria Koltowska-Häggström, Patrick Wilton and Roger Abs

Objective

GH deficiency (GHD) in adults is characterized by elevated body mass index (BMI), increased waist girth (WG) and increased fat mass (FM). Information about how these indicators of obesity affect the lipid profile and quality of life (QoL) of GHD subjects is scarce. It is also unclear how changes in these indicators brought about by GH replacement influence lipids and QoL.

Design and methods

Adult GHD subjects from the Pfizer International Metabolic Database were grouped according to BMI (n=291 with BMI <25 kg/m2, n=372 with BMI 25–30 kg/m2, n=279 with BMI >30 kg/m2), WG (n=508 with normal WG, n=434 with increased WG) and FM (n=357) and according to changes in these variables after 1 year of GH replacement. Serum IGF-I concentrations, lipid concentrations and QoL using the QoL Assessment of GHD in Adults questionnaire were assessed at baseline and after 1 year of treatment.

Results

At baseline, total and low-density lipoprotein (LDL) cholesterol were similarly elevated in the BMI and WG groups, but high-density lipoprotein (HDL) cholesterol decreased and triglycerides increased with increasing BMI and WG. QoL was progressively poorer with increasing BMI and WG. After 1 year of GH replacement, total and LDL cholesterol and QoL improved in all BMI, WG and FM groups.

Conclusions

Variables of obesity adversely affect the already unfavourable lipid profile in GHD subjects by decreasing HDL cholesterol, but do not counteract the positive effect of GH replacement on LDL cholesterol. Similarly, QoL is influenced by obesity, but responds equally well to GH treatment independent of BMI, WG and FM.

Free access

Roger Abs, Anders F Mattsson, Maria Thunander, Johan Verhelst, Miklós I Góth, Patrick Wilton, Maria Kołtowska-Häggström and Anton Luger

Objective

GH deficiency (GHD) in adults is characterized by a tendency toward obesity and an adverse body composition with visceral fat deposit and may thus predispose to the development of type 2 diabetes mellitus. The aim of this study was to assess the observed prevalence proportion (PP) and observed PP over expected PP ratio (standardized prevalence proportion ratio, SPR) of diabetes according to International Diabetes Federation criteria in a large cohort of GH-untreated adult-onset GHD patients.

Design and methods

Associations between baseline variables and diabetes prevalence in 6050 GHD patients from KIMS (Pfizer International Metabolic Database) were studied and robust Poisson-regression analyses were performed. Comparisons between baseline status and HbA1c categories in the nondiabetic patients were done with covariance analysis. P values <0.05 were considered statistically significant.

Results

PP was 9.3% compared with the expected 8.2%. SPR was 1.13 (95% confidence intervals (95% CIs), 1.04–1.23), which was significantly increased in females (1.23; 95% CI, 1.09–1.38%) but not in males (SPR 1.04; 95% CI, 0.92–1.17%). PP increased significantly by age, familial diabetes, country selection, BMI, waist circumference, number of pituitary deficiencies, and GHD etiology. SPR decreased significantly by age and increased significantly by BMI, waist circumference, and IGF1 SDS. Multiple regression model showed that the most important impact on SPR was from age and BMI. HbA1c values of 6.0–6.5% were found in 9.5% of nondiabetic patients and were associated with higher BMI and waist circumference.

Conclusions

GHD is associated with an increased prevalence of diabetes, largely to be explained by the adverse body composition. These data urge toward early initiation of lifestyle modification measures.

Free access

Roger Abs, Ulla Feldt-Rasmussen, Anders F Mattsson, John P Monson, Bengt-Åke Bengtsson, Miklós I Góth, Patrick Wilton and Maria Koltowska-Häggström

Objective: The aim of the present study was to clarify the relationship between GH deficiency (GHD) and some cardiovascular risk factors and to analyse the effect of GH replacement therapy in a large number of patients over a prolonged period of time.

Design: Data for analysis were retrieved from KIMS (Pfizer International Metabolic Database). Serum concentrations of total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides were obtained from 2589 patients at baseline and from 1206 patients after 1 and 2 years of GH replacement therapy. Body mass index (BMI), waist and hip, resting blood pressure and body composition were also measured.

Results: At baseline, the unfavourable effects of GHD were most obvious in the lipid profile demonstrating elevated mean total and LDL-cholesterol, in the increased waist circumference and the elevated BMI. The cholesterol concentration, BMI and body composition were significantly adversely affected by a number of factors, including age, sex and the use of anti-epileptic drugs. The therapeutic effect of GH was essentially uniform across the whole population. GH replacement reduced significantly the mean total and LDL-cholesterol, the waist circumference and the fat mass and was maintained during 2 years.

Conclusions: This analysis of a large number of patients confirmed that GHD adults present with an increased cardiovascular risk. The sustained improvement of the adverse lipid profile and body composition suggests that GH replacement therapy may reduce the risk of cardiovascular disease and the premature mortality seen in hypopituitary patients with untreated GHD.

Free access

Rolf C Gaillard, Anders F Mattsson, Ann-Charlotte Åkerblad, Bengt-Åke Bengtsson, José Cara, Ulla Feldt-Rasmussen, Maria Kołtowska-Häggström, John P Monson, Bernhard Saller, Patrick Wilton and Roger Abs

Objective

Hypopituitarism is associated with an increased mortality rate but the reasons underlying this have not been fully elucidated. The purpose of this study was to evaluate mortality and associated factors within a large GH-replaced population of hypopituitary patients.

Design

In KIMS (Pfizer International Metabolic Database) 13 983 GH-deficient patients with 69 056 patient-years of follow-up were available.

Methods

This study analysed standardised mortality ratios (SMRs) by Poisson regression. IGF1 SDS was used as an indicator of adequacy of GH replacement. Statistical significance was set to P<0.05.

Results

All-cause mortality was 13% higher compared with normal population rates (SMR, 1.13; 95% confidence interval, 1.04–1.24). Significant associations were female gender, younger age at follow-up, underlying diagnosis of Cushing's disease, craniopharyngioma and aggressive tumour and presence of diabetes insipidus. After controlling for confounding factors, there were statistically significant negative associations between IGF1 SDS after 1, 2 and 3 years of GH replacement and SMR. For cause-specific mortality there was a negative association between 1-year IGF1 SDS and SMR for deaths from cardiovascular diseases (P=0.017) and malignancies (P=0.044).

Conclusions

GH-replaced patients with hypopituitarism demonstrated a modest increase in mortality rate; this appears lower than that previously published in GH-deficient patients. Factors associated with increased mortality included female gender, younger attained age, aetiology and lower IGF1 SDS during therapy. These data indicate that GH replacement in hypopituitary adults with GH deficiency may be considered a safe treatment.