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    Default Hgh Study on glucose

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    The effect of growth hormone (GH) replacement on blood glucose homeostasis in adult nondiabetic patients with GH deficiency: real-life data from the NordiNetâ International Outcome Study
    Matthias M. Weber*, Beverly M.K. Biller†, Birgitte Tønnes Pedersen‡, Effie Pournara§, Jens Sandahl Christiansen¶ and Charlotte H€oybye**
    *Department of Endocrinology and Metabolism, Medical Clinic, University of Mainz, Mainz, Germany, †Neuroendocrine Unit, Massachusetts General Hospital, Boston, MA, USA, ‡Epidemiology, Novo Nordisk A/S, Søborg, Denmark, §Novo Nordisk Health Care AG, Zurich, Switzerland, ¶Department of Endocrinology and Diabetes, MEA, Aarhus University Hospital, NBG, Aarhus, Denmark and **Department of Endocrinology, Metabolism and Diabetology, Department of Molecular Medicine and Surgery, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
    Summary
    Objective To assess the effect of 4 years’ growth hormone (GH) replacement on glucose homeostasis and evaluate factors affecting glycosylated haemoglobin (HbA1c) in adults with growth hormone deficiency (GHD).
    Design NordiNetâ International Outcome Study, a noninter- ventional study, monitors long-term effectiveness and safety of GH replacement [Norditropinâ (somatropin), Novo Nordisk A/S] in real-life clinical practice.
    Patients Nondiabetic patients (n = 245) with adult-onset GHD (age ≥20 years at GH start), ≥4 years’ GH replacement and HbA1c values at baseline and 4 years were included in the analysis. Measurements Changes from baseline (Δ) to 4 years in HbA1c, fasting plasma glucose (FPG), IGF-I, lipids (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides), waist circumference, glycaemic (HbA1c <5Á7%; HbA1c, 5Á7–6Á5%; HbA1c, ≥6Á5%) and metabolic health status were evaluated. Effects of baseline HbA1c, gender, baseline age, average GH dose and baseline body mass index (BMI) on DHbA1c were investigated. The models were adjusted for con- comitant medication use.
    Results Mean (standard deviation) baseline HbA1c was 5Á13 (0Á65)% and remained at the same level at 4 years. Age at treat- ment start (P = 0Á0094) and BMI (P = 0Á0008) had a significant impact on ΔHbA1c. At 4 years, 85% of patients with HbA1c <5Á7% (normal levels) at baseline and 55% of patients with HbA1c 5Á7–6Á5% (impaired glucose tolerance) at baseline
    Correspondence: Matthias M. Weber, Department of Endocrinology and Metabolism, Medical Clinic, University of Mainz, Germany. Tel.: +49 06131/ 39-23209; Fax: +49 06131 17-5608; E-mail: MMWeber@uni- mainz.de
    remained in the same glycaemic health category. Nineteen patients improved from impaired glucose tolerance to normal HbA1c. Seven patients developed diabetes.
    Conclusions These data demonstrate that 4 years’ GH replace- ment therapy did not adversely affect glucose homeostasis in the majority of adults with GHD.
    (Received 22 December 2015; returned for revision 5 October 2016; finally revised 31 August 2016; accepted 10 October 2016)
    Introduction
    Growth hormone (GH) plays an important role in regulating glucose homeostasis, and impaired glucose homeostasis and increased risk for diabetes have been reported in association with both GH insufficiency and GH excess.1–3 In addition to impaired quality of life, reduced physical activity, decreased bone mineral density and adverse changes in body composition notably increased visceral fat mass, and growth hormone defi- ciency (GHD) in adults is characterized by an adverse metabolic profile and elevated cardiovascular risk markers.4 Furthermore, risk factors associated with diabetes in the general population,5 as a family history of diabetes mellitus or compromised beta-cell function and high body mass index (BMI), have been proposed to increase the risk for adverse changes in carbohydrate metabo- lism during GH replacement in patients with GHD.1
    Metabolic syndrome is a complex clinical condition character- ized by the presence of multiple metabolic and cardiovascular risk factors in the same individual, including high blood pressure, abdominal obesity, lipid abnormalities [low levels of high-density lipoprotein (HDL) cholesterol and high levels of triglycerides], insulin resistance and impaired fasting glucose.6 In the general population, metabolic syndrome is accompanied by
    192 Hgh Study on glucose 2016 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.
    This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

    an almost four- to fivefold increase in the incidence of diabetes mellitus.7 A similar increased risk has been reported in patients with metabolic syndrome and GHD,8 due in part to the con- comitant visceral adiposity.9
    Because GHD in adults is associated with disturbances of car- bohydrate metabolism,9 special attention has been paid to changes in glucose, glycosylated haemoglobin (HbA1c) levels and other parameters of glucose metabolism during GH replacement. It has been speculated that the favourable effects of GH replace- ment on body composition, including reduced adiposity, may counteract the potential adverse effects of GH replacement, resulting in insulin resistance and hyperglycaemia.10
    Although a transient increase in fasting plasma glucose (FPG) was reported in some studies after initiating GH replacement,10,11 others report equivocal effects of GH replacement on insulin sen- sitivity.12,13 However, these studies involved small patient num- bers and a higher GH dose than currently recommended. Indeed, low-dose (0Á1 mg/day) GH replacement enhanced insulin sensi- tivity during a 12-month period, but a standard dose (0Á5 mg/ day) did not.14 Duration of treatment may represent a confound- ing factor with a deterioration of glucose metabolism during the initial phase, which may be followed by improved glycaemia and insulin levels as body composition improves with long-term GH replacement.15,16 Furthermore, previous findings from observa- tional studies are inconsistent, with both increased risk1 and no increased risk reported.15,17–19 No association between diabetes incidence and GH dose has been described.1,18 While these con- flicting data may be due in part to different study methods and design,12,13,20 the effects of GH replacement on glucose home- ostasis in adults with GHD remain unclear.
    This study evaluates the effect of 4 years’ continuous GH replacement on HbA1c, FPG and parameters of cardiovascular risk in nondiabetic adults with GHD receiving GH replacement enrolled in the observational NordiNetâ International Outcome Study (IOS) (Novo Nordisk A/S, Bagsvaerd, Denmark).
    Patients and methods
    Patients
    Nondiabetic patients who fulfilled the criteria for the diagnosis of adult GHD,21 aged ≥20 years at GH treatment start (adult- onset GHD), enrolled in NordiNetâ IOS with at least 4 years’ GH replacement with Norditropinâ, and HbA1c values at base- line and 4 years were eligible for inclusion in the analyses (n = 272). Patients with a pre-existing diagnosis of diabetes or receiving antidiabetic treatment at the start of GH replacement [n = 19; type 1 diabetes, n = 3 (female, n = 2; age 37–57 years); type 2 diabetes, n = 16 [female, n = 6; age 22–68 years)] or HbA1c values above 6Á5% at both baseline and at 4-year follow- up [n = 8; (female, n = 8; age 27–74 years)] were excluded, leaving a total of 245 eligible patients.
    All patients provided written informed consent prior to enrol- ment in NordiNetâ IOS. NordiNetâ IOS is conducted in accor- dance with the Declaration of Helsinki,22 was approved by the local institutional ethics committee/institutional review board
    GH and glucose homeostasis in adults with GHD 193
    and the local regulatory authorities at each study centre and data privacy agencies as required, and complies with Good Pharma- coepidemiology Practice guidelines. The study registration num- ber is NCT00960128 (Home - ClinicalTrials.gov).
    Study design
    The primary objective of NordiNetâ IOS, an international, non- interventional, multicentre study,23 is to determine the long-term safety and effectiveness of GH [Norditropinâ (somatropin), Novo Nordisk A/S] in clinical practice. This report evaluates data from eligible patients in the Czech Republic, Denmark, France, Germany, Hungary, Montenegro, Serbia and Sweden.
    Anthropometric parameters (weight, waist circumference and body height), blood pressure (systolic and diastolic), IGF-I, lipids [HDL cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol and triglycerides], FPG levels, fasting blood glu- cose (FBG) levels and HbA1c data were collected at baseline and at regular clinic visits according to normal clinical practice at each centre. FPG, HbA1c, lipid and IGF-I concentrations were measured in local laboratories. IGF-I standard deviation scores (SDS) were calculated using an age- and sex-specific reference by Brabant et al., 2003.24,25 All data, including concomitant medica- tions (antidiabetics, glucocorticoids and lipid-lowering therapy) and comorbidity, were entered in the clinic via NordiNetâ, an electronic Good Clinical Practice-certified platform.
    Statistical analyses
    Descriptive statistics were applied for all parameters and are pre- sented as mean [standard deviation (SD)] or median (range) where appropriate.
    A multiple regression model, including baseline HbA1c, gen- der, age at treatment start, BMI at baseline, average GH dose, antidiabetic treatment, treatment with glucocorticoids and GH treatment duration (year), was used to investigate factors influ- encing change in HbA1c from baseline (DHbA1c). Age and GH dose were included as continuous variables and BMI was strati- fied as normal (<25 kg/m2; overweight, ≥25–<30 kg/m2; obese, ≥30 kg/m2). Gender was included in the model to adjust for a potential confounding effect; however, because gender differ- ences are not the focus of this report, limited data are presented on the effect of gender.
    Patients were categorized as developing diabetes during the 4-year follow-up period based on HbA1c levels according to current guidelines26 and/or when reported as an additional diag- nosis and/or when antidiabetic medication was prescribed. Fur- thermore, the glycaemic status of each patient was assessed by HbA1c levels as normal (<5Á7%), impaired glucose tolerance (5Á7–6Á4%) or diabetes (≥6Á5%).26
    A paired t-test was used to analyse the individual DHbA1c to year of treatment. A chi-square test was applied to test the asso- ciation between GH dose during the 4th year of treatment (low, ≤0Á2 mg/day; standard >0Á2 mg/day) and a clinically relevant DHbA1c (≥0Á3% increase or decrease) or unchanged HbA1c after 4 years of GH treatment. The distinction between ‘low’ and

    ‘standard’ dose of GH was set at 0Á2 mg/day, based on the authors’ clinical experience.
    The model used for DHbA1c was also used to analyse the change in FPG from baseline (DFPG) to year of treatment. If FPG values were unavailable, blood glucose values were converted to FPG.27
    A multiple regression model, including gender, age at GH treat- ment start, average GH dose and treatment duration (year), was used to analyse change from baseline in secondary outcome parameters, IGF-SDS, waist circumference and lipids. The analysis of HDL cholesterol, LDL cholesterol, total cholesterol and triglyc- erides was also corrected for lipid-lowering therapy. The baseline level of each outcome parameter was included in the model.
    The proportions of patients meeting the criteria for metabolic syndrome were calculated at baseline and 4 years. The metabolic syndrome criteria were defined as presence of at least three of five risk factors: triglycerides ≥1Á7 mmol/l or on drug treatment for elevated triglycerides; HDL cholesterol <1Á03 mmol/l (male)/ <1Á30 mmol/l (female) or on drug treatment for reduced HDL cholesterol; waist circumference ≥102 cm (male)/≥88 cm (female); systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or antihypertensive therapy in a patient with a history of hypertension; and elevated fasting glucose ≥5Á6 mmol/l or on drug treatment for elevated glucose.6
    Results
    Baseline characteristics, GH dose and IGF-I SDS
    Baseline characteristics and 4-year data for the 245 (43% female) patients included in the analysis are presented in Table 1. Median (range) age at treatment start was 50 (21–85) years and median GH dose was 0Á17 (0Á05–1Á20) mg/day. During year 4, most (72%; 177/245) patients received a standard GH dose (>0Á2 mg/day). Median BMI of 28 (17–55) kg/m2 indicated that most patients
    were overweight (BMI 25–30 kg/m2) at baseline; 10 patients had obesity (BMI ≥30 kg/m2) at treatment start. Reported medical conditions at baseline with nonpituitary pathology are shown in Table S1 (Supporting Information) for all patients and in Table 3 for patients with cardiovascular events within the 4-year GH treat- ment period. At 4 years of GH replacement, the mean GH dose was increased by 68% from baseline (Table 1).
    In the total cohort, mean (SD) IGF-I SDS increased from <0 at baseline to >0 after 4 years of GH replacement (Table 1). Gender (estimated effect (EE; female), À0Á3215; P < 0Á0001] and age at treatment start (EE, 0Á009434; P = 0Á0009), but not mean dose at relevant year (EE, 0Á1751; P = NS), had a significant impact on the change in IGF-I SDS from baseline to year 4, with older patients experiencing a greater mean change in IGF-I SDS than younger patients.
    Concomitant medications
    Overall, 114 (46Á5%) patients were prescribed glucocorticoids [mean (range) dose 19Á3 (5Á0–40Á3) mg/day (n = 80)], with most (91Á2%) starting treatment prior to or on starting GH replacement. Lipid-lowering (statin) treatment was prescribed for nine patients, of whom seven started treatment after starting GH replacement.
    Glucose homeostasis
    Patients developing diabetes during the 4-year follow-up period. Overall, seven patients developed diabetes during the first 4 years of GH replacement (Table 1). These patients tended to be older, receiving a lower GH dose and had a greater BMI at baseline compared with the total cohort, and all but one received concomitant treatment with glucocorticoids. At baseline, three of these patients had normal HbA1c and four had impaired glucose

    TABLE 1 BELOW REFER TO PHOTO FOR TABLES

    Table 1. Demographic and clinical characteristics of patients at baseline and after 4 years of GH replacement
    All patients Patients who developed diabetes
    Baseline 4 years of GH
    Age at GH treatment start (years)
    Change from
    baseline (D) Baseline 4 years of GH
    Change from baseline (Δ)
    N Mean (SD) N Mean (SD) N Mean (SD) N Mean (SD) N Mean (SD) N Mean (SD) 245 48Á83 (14Á31) – – – – 7 52Á23 (11Á45) – – – –
    GH dose (mg/day) 245 0Á22 (0Á18) 245 0Á37 (0Á21) 245 0Á16 (0Á20) 7 0Á14 (0Á09) 7 0Á25 (0Á13) 7 0Á11 (0Á14) HbA1c (%) 245 5Á13 (0Á65) 245 5Á16 (0Á71) 245 0Á03 (0Á49) 7 5Á61 (0Á56) 7 6Á40 (1Á27) 7 0Á79 (1Á23) FPG (mmol/l) 187 5Á08 (0Á87) 167 5Á36 (0Á89) 150 0Á33 (0Á95) 7 6Á07 (1Á31) 7 6Á88 (1Á84) 7 0Á80 (1Á87) IGF-I (lg/l) 237 108Á89 (66Á79) 236 189Á76 (83Á72) 229 80Á62 (86Á57) 7 120Á00 (46Á36) 7 174Á29 (74Á82) 7 54Á29 (60Á55) IGF-I SDS 237 À0Á94 (1Á22) 236 0Á69 (1Á16) 236 1Á64 (1Á40) 7 À0Á40 (1Á08) 7 0Á61 (1Á06) 7 1Á01 (1Á14) Weight (kg) 229 85Á71 (21Á09) 230 85Á73 (20Á68) 222 À0Á13 (11Á47) 7 97Á40 (29Á69) 7 106Á17 (36Á96) 7 8Á77 (1Á82) BMI (kg/m2) 227 28Á64 (5Á72) 230 28Á83 (6Á07) 220 0Á18 (2Á87) 7 34Á74 (11Á16) 7


    tolerance. Type 2 diabetes was diagnosed in three patients between 9 and 29 months of starting GH replacement.
    HbA1c. At baseline, median (range) HbA1c was 5Á20% [3Á20– 6Á80%; normal range <5Á7% (39 mmol/mol)] and remained at the same level at 4 years (Table 1). Regression analyses showed that age at treatment start had a small but statistically significant impact [estimated effect (EE), 0Á0027; P = 0Á0094] on the mean DHbA1c at 4 years (Table 2). BMI (P = 0Á0008) also had a significant impact on DHbA1c; a significantly greater increase in HbA1c was shown in patients with obesity (BMI ≥30 kg/m2) than in patients with normal BMI (<25 kg/m2; EE, 0Á1280; P = 0Á0005), but DHbA1c was similar between patients with normal BMI and those with overweight (Table 2). No significant effect of gender, GH dose or treatment with glucocorticoids on DHbA1c was observed. Antidiabetic treatment did not have a statistically significant influence on the results due to the low number of patients with reported antidiabetic treatment (n = 2). The model adjustment for baseline HbA1c was significant (P < 0Á0001). Overall, >50% of patients in each GH dose group experienced no change in HbA1c status during 4 years of GH replacement and similar proportions of patients in both dose groups experienced a decrease in HbA1c, while proportionally more patients in the low- versus the standard-dose group exhibited an increase in HbA1c (Fig. 1); however, no significant association was found between GH dose group and clinically relevant DHbA1c atyear 4 (P = 0Á2419).
    Fasting plasma glucose. A small increase in mean FPG (n = 187) levels from baseline to 4 years was observed (Table 1). Age at treatment start (EE, 0Á0066; P = 0Á0106) and GH dose (EE, À0Á4475; P = 0Á0267) had a significant effect on ΔFPG from baseline to 4 years; older patients at baseline had a greater increase in FPG than younger patients, and patients with higher GH doses had a greater reduction in FPG. No effect of BMI, gender or glucocorticoid treatment was observed.

    TABLE 2 REFER TO PHOTO BELOW

    Table 2. Estimated effects and P-values from the multiple regression analysis examining the impact of different parameters on the change in HbA1c from baseline and up to year 4
    Parameter Estimated effect Standard error P-value
    Baseline HbA1c À0Á1536 0Á0218 <0Á0001 Age at treatment start 0Á0027 0Á0011 0Á0094 GH dose À0Á1283 0Á0809 0Á1131 Gender* À0Á0151 0Á0289 0Á6022 Glucocorticoid treatment 0Á0537 0Á0284 0Á0590 Antidiabetic treatment À0Á1539 0Á1617 0Á3415 BMI† 0Á0008 Normal (<25 kg/m2) 0 – – Overweight (25–30 kg/m2) 0Á0348 0Á0359 0Á3319 Obese (≥30 kg/m2) 0Á1280 0Á0364 0Á0005
    BMI, body mass index; GH, growth hormone; HbA1c, glycosylated hae- moglobin. The estimated effect indicates the magnitude of the explana- tory value of each variable in the model.
    *Female patients were compared with male patients as reference. †Patients with obese BMI or overweight BMI were compared with patients with normal BMI.
    GH and glucose homeostasis in adults with GHD 195
    100 GH dose during year 4 ≤0·2 mg/day
    Proportion of patients (%) 403020100 Decreasing
    GH dose during year 4 >0·2 mg/day
    9080706050
    18·1% 17·6% (32/177)
    (12/68)
    61·0% 51·5% (108/177) (35/68)
    30·9% (21/68) 20·9% (37/177)
    Increasing
    No change
    Fig. 1 Distribution of patients by change in HbA1c from baseline to 4 years of growth hormone (GH) replacement by GH dose group (GH dose during year 4). HbA1c was considered to be increasing or decreasing if the change was ≥0Á3%. GH, growth hormone; HbA1c, glycosylated haemoglobin.
    Glycaemic health status according to HbA1c. At baseline, the majority of patients (78Á4%, n = 192) had normal HbA1c levels, 51 (20Á8%) patients had impaired glucose tolerance and two (0Á8%) patients had HbA1c ≥6Á5%. The majority (84Á9%) of those with normal baseline HbA1c remained within this range at 4 years, 27 (14%) progressed to impaired glucose tolerance and two (1Á1%) had HbA1c levels ≥6Á5% at 4 years. Although 28 (54Á9%) patients with impaired glucose tolerance at baseline remained in this category at 4 years, 19 (37Á3%) patients in this group improved to normal HbA1c levels and four (7Á8%) progressed to HbA1c levels ≥6Á5%. The two patients with HbA1c ≥6Á5% at baseline improved to normal or impaired glucose tolerance at 4 years.
    Metabolic syndrome index. Among the 125 (51%) patients with data on the metabolic syndrome at baseline, 36% (45/125) of patients fulfilled the criteria for metabolic syndrome at baseline and 40% (40/101) fulfilled these criteria at 4 years.
    Cardiovascular risk markers
    Adiposity (waist circumference). After 4 years’ GH replacement, mean (SD) waist circumference was similar to baseline [baseline, 99Á9 (14Á2) cm (n = 140); 4 years, 99Á3 (15Á0) cm, (n = 137); mean change from baseline, À0Á69 (6Á2) cm (n = 108)]; however, a higher GH dose was associated with a greater reduction in waist circumference (EE, À5Á2418; P = 0Á0002). No effect of gender or age at treatment start was observed.
    Blood pressure. Mean (SD) blood pressure (systolic/diastolic) was 128 (18)/80 (11) mmHg (n = 191) at baseline and 130 (18)/ 80 (10) mmHg (n = 163) following 4 years of GH replacement. This did not exceed the upper normal range for patients aged approximately 50 years (systolic/diastolic: 140/80 mmHg).28
    Lipids
    High-density lipoprotein cholesterol. A small increase in mean (SD) HDL cholesterol levels from baseline [1Á33 (0Á44) mmol/l (n = 216)] to 4 years [1Á35 (0Á43) mmol/l (n = 189)] was

    observed [mean (SD) change from baseline, 0Á02 (0Á33) mmol/l (n = 173)]. Age at treatment start (EE, 0Á0018; P = 0Á0276) and gender (EE, 0Á0711; P = 0Á0021), but not antilipid treatment, had a significant impact on the change in HDL cholesterol from baseline, with older patients having a greater increase in HDL cholesterol than younger patients.
    Low-density lipoprotein cholesterol. Mean (SD) LDL cholesterol levels decreased from 3Á57 (1Á13) mmol/l (n = 178) at baseline to 3Á36 (0Á93) mmol/l (n = 164) at 4 years. Of the parameters tested, only antilipid therapy had a significant effect on change in LDL cholesterol from baseline (EE, À0Á4417; P = 0Á0092).
    Total cholesterol. Mean (SD) total cholesterol levels decreased from 5Á79 (1Á27) mmol/l (n = 217) at baseline to 5Á42 (1Á09) mmol/l (n = 192) at 4 years [mean change from baseline À0Á38 (1Á20) mmol/l (n = 175)]. Gender (EE, 0Á3341; P < 0Á0001) and antilipid treatment (EE, À0Á5829; P = 0Á0006) had a significant impact on the change from baseline; neither age at treatment start nor GH dose had an observed effect.
    Triglycerides. Mean (SD) triglyceride levels increased slightly from baseline [1Á73 (1Á21) mmol/l (n = 119)] at 1 year [1Á93 (1Á30) mmol/l (n = 79)] and then decreased during subsequent years [2 years, 1Á92 (1Á20) mmol/l (n = 96); 3 years, 1Á92 (1Á33) mmol/l (n = 73); 4 years, 1Á89 (1Á20) mmol/l (n = 75)]; overall mean (SD) change from baseline was À0Á01 (1Á09) mmol/l (n = 50). Age at baseline had a significant impact on the change in triglycerides; patients who were older at baseline had a greater reduction in triglyceride levels during the 4-year period (EE, À0Á0076; P = 0Á0422) than younger patients.
    Cardiovascular events reported during the follow-up period. Six patients [2Á4%; female n = 4; median age at event, 66Á5 (range 40–75) years] experienced seven cardiovascular events during the 4-year period after starting GH replacement [median duration of treatment, 1Á1 (0Á4–4Á2) years; Table 3]. Obesity, reported in three patients at baseline, and weight gain in one patient after starting GH, may have been predisposing factors. The most common event, hypertension, was reported in four patients; stroke was reported in two patients (one of whom later also
    developed hypertension), and ischaemic heart disease was reported in one elderly male patient (age, 74Á5 years) approximately 1 year after starting GH replacement.
    Discussion
    This international study with data from real-life clinical practice demonstrates that 4 years of GH replacement therapy in non- diabetic patients with adult-onset GHD does not adversely impact glucose metabolism in most patients. Mean HbA1c remained at the same levels from baseline and a small increase in FPG was observed. Very few patients showed any deteriora- tion in glycaemic health status; indeed, more than one-third of patients with impaired glucose tolerance at baseline showed improvement to normal HbA1c levels at 4 years. Moreover, the proportion of patients with metabolic syndrome was similar at baseline and following 4 years of GH replacement.
    Notwithstanding the increased risk of progression to diabetes associated with age29 and presence of GHD,3 19 patients in our cohort of 245 patients improved from impaired glucose toler- ance to normal glucose HbA1c levels, and only seven patients developed diabetes during 4 years of GH treatment. Two other postmarketing surveillance databases have reported on diabetes during GH treatment. Although an increased risk for diabetes was reported in 5143 patients in KIMS followed for a mean of 3Á9 (range 0Á01–13) years compared with a reference popula- tion,1 a report from HypoCCS concluded there was no signifi- cant increase in the incidence of diabetes compared with several reference populations, among 6672 patients from the USA and Europe followed for a mean of 4Á1 years.18 Using a proportional hazard model, age and BMI were shown to be associated with increased risk for diabetes.
    In our study, an increase in triglyceride levels from baseline was observed at 1 year, after which a small decrease was observed so that at 4 years mean triglyceride levels were unchanged from baseline. Although insulin sensitivity was not measured directly, as fasting insulin levels are not routinely assessed in clinical practice, this suggests that any decrease in insulin sensitivity during GH replacement may be transient. In an 18-month randomized placebo-controlled trial involving 40 men with GHD, Sesmilo et al. reported short-term increases in

    REFER TO PHOTO FOR TABLE 3
    Table 3. Details of cardiovascular events diagnosed after starting GH replacement during 4 years of GH therapy. Information on comorbid conditions and time of diagnosis (years), relative to start of GH treatment, is also shown
    Gender
    Age at GH
    treatment start (years)
    Cardiovascular event (years between
    diagnosis and start of GH replacement) Comorbidity (years between diagnosis and start of GH replacement)
    Male 74Á5 Ischaemic heart disease (1Á1) None
    Male 50Á2 Hypertension (4Á2) Weight gain; reduced vitality and energy; reduced libido (all –12Á4) Female 51Á9 Hypertension (0Á4) Hyperlipidaemia; Hypercholesterinaemia (both 3Á3)
    Female 65Á5 Stroke (1Á1), Hypertension (2Á9) Barrett’s oesophagus (À2Á4); obesity/hyperlipidaemia (both 0);
    depressive episode (3Á1)3 Female 74Á7 Stroke (1Á2) Obesity (0) Female 40 Hypertension (0Á6) Obesity (0)

    glucose and insulin levels as well as the glucose/insulin ratio of which only the elevated glucose levels were sustained, together with transient reductions in lipids.30 Moreover, long-term GH replacement in adults may even help to slow the age-related decline in insulin sensitivity.12
    Some evidence suggests that low-dose GH may have positive effects on insulin sensitivity and FPG independently of GH- induced improvements in body composition.14 In the present study, change in HbA1c was independent of GH dose. Indeed, a similar proportion of patients on low- and standard-dose GH experienced a decrease in HbA1c from baseline to 4 years. Although a mean decrease in waist circumference was observed in the standard-dose group versus a small increase in the low- dose group, it is not possible to draw an inference regarding the potential benefits of low-dose versus standard-dose GH replace- ment because the focus of this study was to assess the overall effects of GH replacement on glucose homeostasis.
    The classical risk factors associated with the development of type 2 diabetes in the general population are typically the same characteristics observed in untreated patients with GHD.1,2,18 In our study, although the majority of patients with normal base- line HbA1c levels maintained their normal glycaemic status, those with obesity had a greater increase in HbA1c than those with a normal BMI. Together, these findings suggest that GH replacement does not adversely impact glucose metabolism in adults with GHD without additional risk factors. Monitoring glucose parameters is advisable in all patients taking GH replace- ment, especially in those with additional risk factors for develop- ing hyperglycaemia.
    Use of glucocorticoids may influence the development of dia- betes.31 Even though we found no effect of glucocorticoids on HbA1c or FPG, the lack of clinical details of glucocorticoid ther- apy, including glucocorticoid type, dose, changes in dose and time of initiation for a proportion of patients, represents a limi- tation in our study.
    In the present study, cardiovascular events were reported in 2Á4% (6/245) of patients during GH replacement, with hyperten- sion reported in four patients. Changes in HDL cholesterol, LDL cholesterol and total cholesterol during GH replacement were also observed; treatment with statins had a significant impact on the observed changes in LDL cholesterol and total cholesterol that should be considered when interpreting these data. It is also noteworthy that adverse cardiovascular outcomes are more prevalent in nondiabetic, GH-treated adult patients with GHD and conventional risk factors than in those with no known risk factors,32 and may also be exacerbated by glucocorticoid therapy started following initiation of GH replacement33; in our study, 46% of patients received glucocorticoid replacement.
    A considerable strength of this study is that it reports longitu- dinal changes in HbA1c levels in GH-treated adult patients with GHD over a period of 4 years in a real-world multinational set- ting. The limitations of this study, as with all observational stud- ies, include the lack of control group and selection and information biases introduced by the selection of patients, the variety of methods used to analyse blood samples and different treatment practices across countries.
    GH and glucose homeostasis in adults with GHD 197
    Conclusions
    These data collected in a real-life clinical setting demonstrate that 4 years of growth hormone replacement therapy in adults with growth hormone deficiency had no adverse impact on glu- cose homeostasis in the majority of patients. Monitoring glucose parameters is advisable in all patients taking growth hormone replacement, perhaps more frequently in those at higher risk of developing hyperglycaemia.
    Funding and declaration of interest
    This study was sponsored by Novo Nordisk. M Weber and C H€oybye are members of NordiNetâ IOS International Study Committee; E Pournara and B Tønnes Pedersen are employees of Novo Nordisk. BMK Biller is the PI of research grants to Massachusetts General Hospital from Novo Nordisk, Opko and Versartis and has received consulting honoraria from Novo Nor- disk, Pfizer and Versartis. JS Christiansen was a member of the NordiNetâ IOS International Study Committee.
    Acknowledgments
    The authors take full responsibility for the content of the manu- script but are grateful to Watermeadow Medical (supported by Novo Nordisk) for writing assistance. Statistical support was provided by Anita Iwona Chudecka, an employee of Novo Nor- disk. The authors wish to pay tribute to Professor Jens Sandahl Christensen for his significant contributions in the field of endocrinology, and notably as a pioneer in the study of adult growth hormone deficiency and its treatment. His positive atti- tude, enthusiasm and kindness will be remembered by all those who were fortunate enough to have had the opportunity to work with him.
    References
    1 Luger, A., Mattsson, A.F., Koltowska-Haggstrom, M. et al. (2012) Incidence of diabetes mellitus and evolution of glucose parameters in growth hormone-deficient subjects during growth hormone replace- ment: a long-term observational study. Diabetes Care,35,57–62.
    2 Møller, N. & Jørgensen, J.O. (2009) Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocrine Reviews, 30, 152–177.
    3 Abs, R., Mattsson, A.F., Thunander, M. et al. (2013) Prevalence of diabetes mellitus in 6050 hypopituitary patients with adult- onset GH deficiency before GH replacement: a KIMS analysis. European Journal of Endocrinology, 168, 297–305.
    4 Molitch, M.E., Clemmons, D.R., Malozowski, S. et al. (2011) Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. Journal of Clini- cal Endocrinology and Metabolism, 96, 1587–1609.
    5 Bonora, E., Kiechl, S., Willeit, J. et al. (2004) Population-based incidence rates and risk factors for type 2 diabetes in white indi- viduals: the Bruneck study. Diabetes, 53, 1782–1789.
    6 Grundy, S.M., Cleeman, J.I., Daniels, S.R. et al. (2005) Diagnosis and management of the metabolic syndrome: an American Heart
    Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation, 112, 2735–2752.
    7 Ford, E.S., Li, C. & Sattar, N. (2008) Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care, 31, 1898–1904.
    8 Verhelst, J., Mattsson, A.F., Luger, A. et al. (2011) Prevalence and characteristics of the metabolic syndrome in 2479 hypopituitary patients with adult-onset GH deficiency before GH replacement: a KIMS analysis. European Journal of Endocrinology, 165, 881–889. 9 Murray, R.D. & Shalet, S.M. (2005) Insulin sensitivity is impaired in adults with varying degrees of GH deficiency. Clini- cal Endocrinology, 62, 182–188.
    10 Fowelin, J., Attvall, S., Lager, I. et al. (1993) Effects of treatment with recombinant human growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone defi- ciency. Metabolism, 42, 1443–1447.
    11 Florakis, D., Hung, V., Kaltsas, G. et al. (2000) Sustained reduc- tion in circulating cholesterol in adult hypopituitary patients given low dose titrated growth hormone replacement therapy: a two year study. Clinical Endocrinology, 53, 453–459.
    12 Svensson, J., Fowelin, J., Landin, K. et al. (2002) Effects of seven years of GH-replacement therapy on insulin sensitivity in GH- deficient adults. Journal of Clinical Endocrinology and Metabolism, 87, 2121–2127.
    13 Rosenfalck, A.M., Maghsoudi, S., Fisker, S. et al. (2000) The effect of 30 months of low-dose replacement therapy with recombinant human growth hormone (rhGH) on insulin and C- peptide kinetics, insulin secretion, insulin sensitivity, glucose effectiveness, and body composition in GH-deficient adults. Jour- nal of Clinical Endocrinology and Metabolism, 85, 4173–4181.
    14 Yuen, K.C. & Dunger, D.B. (2006) Persisting effects on fasting glucose levels and insulin sensitivity after 6 months of discontin- uation of a very low-dose GH therapy in adults with severe GH deficiency. Clinical Endocrinology, 64, 549–555.
    15 Woodmansee, W.W., Hartman, M.L., Lamberts, S.W. et al.
    (2010) Occurrence of impaired fasting glucose in GH-deficient adults receiving GH replacement compared with untreated sub- jects. Clinical Endocrinology, 72, 59–69.
    16 Elbornsson, M., G€otherstrom, G., Bosæus, I. et al. (2013) Fifteen years of GH replacement improves body composition and car- diovascular risk factors. European Journal of Endocrinology, 168, 745–753.
    17 Hartman, M.L., Xu, R., Crowe, B.J. et al. (2013) Prospective safety surveillance of GH-deficient adults: comparison of GH- treated vs untreated patients. Journal of Clinical Endocrinology and Metabolism, 98, 980–988.
    18 Attanasio, A.F., Jung, H., Mo, D. et al. (2011) Prevalence and incidence of diabetes mellitus in adult patients on growth hor- mone replacement for growth hormone deficiency: a surveillance database analysis. Journal of Clinical Endocrinology and Metabo- lism, 96, 2255–2261.
    19 Shimatsu, A., Tai, S., Imori, M. et al. (2013) Efficacy and safety of growth hormone replacement therapy in Japanese adults with growth hormone deficiency: a post-marketing observational study. Endocrine Journal, 60, 1131–1144.
    20 B€ulow, B., Agardh, D.C., Eckert, B. et al. (1999) Individualized low-dose growth hormone (GH) treatment in GH-deficient adults with childhood-onset disease: metabolic effects during fasting and hypoglycemia. Metabolism, 48, 1003–1010.
    21 Ho, K.K. (2007) GH Deficiency Consensus Workshop Partici- pants (2007) Consensus guidelines for the diagnosis and
    treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endo- crine Society of Australia. European Journal of Endocrinology, 157, 695–700.
    22 World Medical Association (2013) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA, 310, 2191–2194.
    23 H€oybye, C., S€avendahl, L., Christesen, H.T. et al. (2013) The NordiNetâ International Outcome Study and NovoNetâ ANSWER Programâ: rationale, design, and methodology of two international pharmacoepidemiological registry-based studies monitoring long-term clinical and safety outcomes of growth hor- mone therapy (Norditropinâ). Clinical Epidemiology,26, 119–127. 24 Brabant, G., von zur M€ulhen, A., W€uster, C. et al. (2003) Serum insulin-like growth factor I reference values for an automated chemiluminescence immunoassay system: results from a multi- centre study. Hormone Research, 60, 53–60.
    25 Blankenstein, O., Pedersen, B.T., Schlumpf, M. et al. (2015) Management and interpretation of heterogeneous observational data: using insulin-like growth factor-I data from the NordiNetâ International Outcome Study. Growth Hormone & IGF Research, 25, 41–46.
    26 American Diabetes Association (2013) Diagnosis and classifica-
    tion of diabetes mellitus. Diabetes Care, 36(Suppl 1), S67–S74. 27 D’Orazio, P., Burnett, R.W., Fogh-Andersen, N. et al. (2006) Approved IFCC recommendation on reporting results for blood glucose: International Federation of Clinical Chemistry and Labo- ratory Medicine Scientific Division, Working Group on Selective Electrodes and Point-of-Care Testing (IFCC-SD-WG-SEPOCT). Clinical Chemistry and Laboratory Medicine,44, 1486–1490.
    28 James, P.A., Oparil, S., Carter, B.L. et al. (2014) Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA, 311, 507–520.
    29 Meigs, J.B., Muller, D.C., Nathan, D.N. et al. (2003) The natural history of progression from normal glucose tolerance to type 2 diabetes in the Baltimore Longitudinal Study of Aging. Diabetes, 52, 1475–1484.
    30 Sesmilo, G., Biller, B.M., Llevadot, J. et al. (2000) Effects of growth hormone administration on inflammatory and other car- diovascular risk markers in men with growth hormone defi- ciency. A randomized, controlled clinical trial. Annals of Internal Medicine, 133, 111–122.
    31 Di Dalmazi, G., Pagotto, U., Pasquali, R. et al. (2012) Glucocor- ticoids and Type 2 diabetes: from physiology to pathology. Jour- nal of Nutrition and Metabolism, 2012, 525093.
    32 de Gregorio, C., Ando, G., Cannavo, S. et al. (2015) Cardiovas- cular outcomes and conventional risk factors in non-diabetic adult patients with GH deficiency: a long-term retrospective cohort study. European Journal of Internal Medicine, 26, 813–818. 33 Giavoli, C. (2007) Unmasking other pituitary deficits during growth hormone replacement therapy. Annals of Endocrinology, 68, 237–240.
    Supporting Information
    Additional supporting information may be found in the online version of this article at the publisher’s web site.

    Table 1 below then table 2 then graph
    Then table 3

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    MuscleChemistry Registered Member Board Certified MD
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    It's not working not allowing copy and paste on whole thing.
    Tried seperate post will get it tomorrow
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    Ok it went thru. Gotta see about computer. Only use my private computer and it has issues getting new just been swamped. Came home took nap all after noon..
    Hope it's that i am growing.
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    Wow, great information. Being Type 2 diabetic it has some real world implications for me.
    Get It Done!

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    Quote Originally Posted by drtbear1967 View Post
    Wow, great information. Being Type 2 diabetic it has some real world implications for me.
    IGF alot better for helping diabeties

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    People need to know about all of this.
    Get It Done!

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