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Introduction The TROPHIES observational study enrolled patients with type 2 diabetes mellitus (T2DM) initiating their first injectable treatment with the glucagon-like peptide 1 receptor agonists (GLP-1 RAs) dulaglutide or liraglutide. This manuscript focuses on the study design, baseline characteristics of the enrolled population, and factors associated with GLP-1 RA choice. Methods TROPHIES is a prospective, observational, 24-month study conducted in France, Germany, and Italy. Inclusion criteria include adult patients with T2DM, naïve to injectable antihyperglycemic treatments, initiating dulaglutide or liraglutide per routine clinical practice. The primary outcome is the duration of treatment on dulaglutide or liraglutide without a significant treatment change. Results The analysis included 2181 patients (dulaglutide, 1130; liraglutide, 1051) (cutoff date May 15, 2019). The population was 56% male with mean [standard deviation (SD)] patient characteristics at baseline as follows: age, 59.2 (11.0) years; body mass index (BMI), 33.9 (6.6) kg/m2; T2DM duration, 8.5 (6.9) years; and glycated hemoglobin (HbA1c), 8.2 (1.3)%. Between-cohort demographic and clinical characteristics were balanced. The mean (SD) HbA1c and BMI values for French, German, and Italian patients were, respectively, 8.6 (1.4)%, 8.2 (1.4)%, 8.0 (0.8)%; 33.3 (6.1) kg/m2, 36.0 (7.2) kg/m2, and 32.6 (5.9) kg/m2. Conclusion This study analysis at baseline provides an opportunity to evaluate between-country differences in baseline HbA1c, weight, macrovascular complications, and factors driving GLP-1 RA selection for patients with T2DM in daily practice. Supplementary Information The online version contains supplementary material available at 10.1007/s13300-021-01076-0., Plain Language Summary Dulaglutide and liraglutide are medications that can help people with type 2 diabetes mellitus (T2DM) to control their blood sugar levels. These medications may also reduce body weight and reduce the risk of major cardiovascular disease. Given these treatment effects, it is essential to know how they are used in everyday clinical practice. Therefore, a study is being performed in three countries (France, Germany, and Italy) in people with T2DM who had a first-ever injectable therapy for T2DM with dulaglutide or liraglutide. Here, we present the study design, the patient characteristics at the start of treatment, and the factors driving the choice of one or the other medication. We analyzed data from 2181 people with T2DM. On average, it was shown that they were middle-aged and obese. On average, these people were diagnosed with T2DM 8.5 years before the start of dulaglutide or liraglutide and had high blood sugar levels when these medications were started. The patient characteristics were slightly different between the three countries. Country-specific factors driving the choice of either medication were also identified. Supplementary Information The online version contains supplementary material available at 10.1007/s13300-021-01076-0.

Introduction: This exploratory post hoc analysis investigated the relative changes in glycated haemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM) treated with dulaglutide versus active comparators across a continuous range of baseline HbA1c values using data from three phase III randomised controlled trials. Methods: Data from patients receiving once-weekly dulaglutide 0.75 and 1.5 mg, once-daily sitagliptin 100 mg, once-daily liraglutide 1.8 mg or twice-daily exenatide 10 ?g in the intent-to-treat populations in the AWARD-5, AWARD-6 and AWARD-1 trials were analysed using last observation carried forward analysis of covariance. Starting with the predefined statistical model from each study, the type of association between HbA1c baseline and change at 26 weeks was modelled. Consistency of treatment effect was assessed via treatment-by-baseline HbA1c interaction terms. Results: Improvements in HbA1c occurred in all treatment groups across the entire baseline HbA1c range. The relationship between HbA1c baseline and magnitude of change was linear in all treatment groups, with greater reductions in patients with higher baseline HbA1c values. Across the continuum of baseline HbA1c values, patients treated with dulaglutide 1.5 mg achieved a similar mean HbA1c reduction to patients receiving liraglutide 1.8 mg and a greater reduction than patients receiving twice-daily exenatide or sitagliptin. In AWARD-5, the treatment-by-baseline HbA1c interaction P value (0.001) demonstrated progressively greater HbA1c reduction in dulaglutide-treated compared with sitagliptin-treated patients as baseline HbA1c increased. Conclusion: Our results suggest that dulaglutide is an appropriate therapeutic option for patients with T2DM across a wide range of baseline HbA1c values, including those with poor metabolic control.

Despite the importance of individualised strategies for patients with type 2 diabetes mellitus (T2DM) and the availability of alternative treatments, including glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs), sulphonylureas are still widely used in practice. Clinical evidence shows that GLP‐1 RAs may provide better and more durable glycaemic control than sulphonylureas, with lower risk of hypoglycaemia. Other reported benefits of GLP‐1 RAs include weight loss rather than weight gain (as observed with sulphonylureas), blood pressure reduction and improvement in lipid profiles. In general, the main adverse events with GLP‐1 RAs are gastrointestinal in nature. The respective modes of action of GLP‐1 RAs and sulphonylureas contribute to differences in the durability of glycaemic control (related to effects on beta‐cells) and effects on body weight. Moreover, the glucose‐dependent mode of action of GLP‐1 RAs, which favours a low incidence of hypoglycaemia, contrasts with the glucose‐independent mode of action of sulphonylureas. Evidence from cardiovascular outcomes trials indicates a consistent finding of cardiovascular safety across the GLP‐1 RAs and suggests a class benefit for the long‐acting GLP‐1 RAs in reducing three‐point major adverse cardiovascular events, cardiovascular mortality and all‐cause mortality. In contrast, potential concerns relating to an increased incidence of adverse cardiovascular events with sulphonylureas have yet to be fully resolved. Recent updates to management guidelines recommend that treatment selection for patients with T2DM should consider clinical trial evidence of cardiovascular safety. Available evidence suggests that this selection should give preference to GLP‐1 RAs over sulphonylureas, especially for patients at high cardiovascular risk.

Aims. To determine the early benefit:risk balance of dulaglutide versus insulin glargine in patients with type 2 diabetes mellitus (T2DM). Methods. This post hoc analysis used data from a randomized, open-label study (AWARD-2; modified intention-to-treat group) in which suboptimally controlled metformin + glimepiride-treated patients received dulaglutide 1.5 mg (n = 273) or insulin glargine (n = 262). Two composite endpoints were used: for weeks 2–20, fasting serum glucose (FSG)

Many people with type 2 diabetes mellitus (T2DM) fail to achieve glycaemic control promptly after diagnosis and do not receive timely treatment intensification. This may be in part due to 'clinical inertia', defined as the failure of healthcare providers to initiate or intensify therapy when indicated. Physician-, patient- and healthcare-system-related factors all contribute to clinical inertia. However, decisions that appear to be clinical inertia may, in fact, be only 'apparent' clinical inertia and may reflect good clinical practice on behalf of the physician for a specific patient. Delay in treatment intensification can happen at all stages of treatment for people with T2DM, including prescription of lifestyle changes after diagnosis, introduction of pharmacological therapy, use of combination therapy where needed and initiation of insulin. Clinical inertia may contribute to people with T2DM living with suboptimal glycaemic control for many years, with dramatic consequences for the patient in terms of quality of life, morbidity and mortality, and for public health because of the huge costs associated with uncontrolled T2DM. Because multiple factors can lead to clinical inertia, potential solutions most likely require a combination of approaches involving fundamental changes in medical care. These could include the adoption of a person-centred model of care to account for the complex considerations influencing treatment decisions by patients and physicians. Better patient education about the progressive nature of T2DM and the risks inherent in long-term poor glycaemic control may also reinforce the need for regular treatment reviews, with intensification when required.

AIM To assess the relationship between baseline body mass index (BMI) and glycaemic control in dulaglutide-treated patients, a post hoc analysis was conducted on HbA1c and baseline BMI data from eight AWARD studies, with a total of 5770 patients. MATERIALS AND METHODS Changes from baseline in HbA1c data from patients treated with 1.5 mg or 0.75 mg dulaglutide, active comparator or placebo, were analyzed in each study (AWARD-1 to -6, -8 and - 9) at approximately 6 months (26, 24 and 28 weeks, respectively). Within each study, data were analyzed by the following baseline BMI categories

Aims: Several glucagon like peptide-1 (GLP-1) receptor agonists are available as weekly injections for treatment of type 2 diabetes. These medications vary in their injection devices, and these differences could impact quality-of-life and patient preference. The purpose of this study was to examine patient preferences and estimate health state utilities associated with injection devices for two weekly GLP-1 therapies. Materials and methods: Participants with type 2 diabetes in Italy (Milan, Rome) valued three health state vignettes in time trade-off interviews. The health states had identical descriptions of type 2 diabetes, but differed in description of the treatment process: (1) oral treatment regimen, (2) oral plus weekly dulaglutide injection, and (3) oral plus weekly semaglutide injection. Results: A total of 216 participants completed interviews (57.9% male; mean age = 60.5). Almost all patients (99.5%) preferred the oral health state over either injection health state. Comparing between the two injections, 88.4% preferred the dulaglutide health state, while 11.6% preferred the semaglutide state. Mean (SD) utilities were 0.907 (0.076) for oral, 0.894 (0.085) for dulaglutide, and 0.887 (0.087) for semaglutide. The mean (SD) utility difference between the injection device health states was 0.007 (0.019). Limitations: Although the health states were designed to match the injection device instructions for use as closely as possible, vignette-based methods are inherently limited because results are based on perceptions of the health states rather than actual patient experience with the devices. Conclusions: Results provide insight into patient preferences associated with injection devices for weekly GLP-1 receptor agonists. The majority of patients preferred the dulaglutide device over the semaglutide device, and for some patients, this difference had an impact on utility valuations. Patient preferences for injection devices could be an important factor to consider when selecting treatments for type 2 diabetes.

Many patients with type 2 diabetes mellitus (T2DM) require insulin therapy. If basal insulin fails to achieve glycemic control, insulin intensification is one possible treatment intensification strategy. We summarized clinical data from randomized clinical trials designed to compare the efficacy and safety of basal-bolus and premixed insulin intensification regimens. We defined a between-group difference of ≥0.3% in end-of-study glycated hemoglobin (HbA1c) as clinically meaningful. A PubMed database search supplemented by author-identified papers yielded 15 trials which met selection criteria: randomized design, patients with T2DM receiving basal-bolus (bolus injection ≤3 times/day) vs. premixed (≤3 injections/day) insulin regimens, primary/major endpoint(s) HbA1c- and/or hypoglycemia-related, and trial duration ≥12 weeks. Glycemic control improved with both basal-bolus and premixed insulin regimens with - in most cases - acceptable levels of weight gain and hypoglycemia. A clinically meaningful difference between regimens in glycemic control was recorded in only four comparisons, all of which favored basal-bolus therapy. The incidence of hypoglycemia was significantly different between regimens in only three comparisons, one of which favored premixed insulin and two basal-bolus therapy. Of the four trials that reported a significant difference between regimens in bodyweight change, two favored basal-bolus therapy and two favored premixed insulin. Thus, on a population level, neither basal-bolus therapy nor premixed insulin showed a consistent advantage in terms of glycemic control, hypoglycemic risk, or bodyweight gain. It is therefore recommended that clinicians should adopt an individualized approach to insulin intensification - taking into account the benefits and risks of each treatment approach and the attitude and preferences of each patient - in the knowledge that both basal-bolus and premixed regimens may be successful.

Louis S Matza,1 Kristina S Boye,2 Jessica B Jordan,1 Kirsi Norrbacka,3 Raffaella Gentilella,4 Amara R Tiebout,1 Chantelle Browne,5 Marco Orsini Federici,4 Giovanni Biricolti,4 Katie D Stewart1 1Patient-Centered Research, Evidera, Bethesda, MD, USA; 2Eli Lilly and Company, Indianapolis, IN, USA; 3Eli Lilly and Company, Helsinki, Finland; 4Eli Lilly and Company, Florence, Italy; 5Modeling and Simulation, Evidera, London, UK Objectives: Several glucagon-like peptide-1 receptor agonists are administered as weekly injections for treatment of type 2 diabetes (T2D). These medications vary in their injection processes, and a recent study in the UK found that these differences had an impact on patient preference and health state utilities. The purpose of this study was to replicate the UK study in Italy to examine preferences of an Italian patient sample, while allowing for comparison between utilities in the UK and Italy.Materials and methods: Participants with T2D in Italy valued health states in time trade-off interviews. All health states had the same description of T2D, but differed in description of the treatment process. As in the original UK study, the first health state described an oral treatment regimen, while additional health states added a weekly injection. The injection health states differed in three injection-related attributes: requirements for reconstituting the medication, waiting during medication preparation, and needle handling.Results: Interviews were completed by 238 patients (58.8% male; mean age = 60.2 years; 118 from Milan, 120 from Rome). The oral treatment health state had a mean (SD) utility of 0.90 (0.10). The injection health states had significantly (p < 0.0001) lower utilities, which ranged from 0.87 (requirements for reconstitution, waiting, and handling) to 0.89 (weekly injection with none of these requirements). Differences in health state utility scores suggest that each administration requirement was associated with a disutility (ie, negative utility difference): -0.006 (reconstitution), -0.006 (needle handling), -0.011 (reconstitution, needle handling), and -0.022 (reconstitution, waiting, needle handling).Conclusion: Disutilities associated with the injection device characteristics were similar to those reported with the UK sample. Results suggest that injection device attributes may be important to some patients with T2D, and it may be useful for clinicians to consider these attributes when choosing medication for patients initiating these weekly treatments. Keywords: utility, type 2 diabetes, injection process, GLP-1 receptor agonist, time trade-off, weekly injection, Italy, injection device&nbsp

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an important class of drugs with a well-established efficacy and safety profile in patients with type 2 diabetes mellitus. Agents in this class are derived from either exendin-4 (a compound present in Gila monster venom) or modifications of human GLP-1 active fragment. Differences among these drugs in duration of action (ie, short-acting vs long-acting), effects on glycaemic control and weight loss, immunogenicity, tolerability profiles, and administration routes offer physicians several options when selecting the most appropriate agent for individual patients. Patient preference is also an important consideration. The aim of this review is to discuss the differences between and similarities of GLP-1 RAs currently approved for clinical use, focusing particularly on the properties characterising the single short-acting and long-acting GLP-1 RAs rather than on their individual efficacy and safety profiles. The primary pharmacodynamic difference between short-acting (ie, exenatide twice daily and lixisenatide) and long-acting (ie, albiglutide, dulaglutide, exenatide once weekly, liraglutide, and semaglutide) GLP-1 RAs is that short-acting agents primarily delay gastric emptying (lowering postprandial glucose) and long-acting agents affect both fasting glucose (via enhanced glucose-dependent insulin secretion and reduced glucagon secretion in the fasting state) and postprandial glucose (via enhanced postprandial insulin secretion and inhibition of glucagon secretion). Other advantages of long-acting GLP-1 RAs include smaller fluctuations in plasma drug concentrations, improved gastrointestinal tolerability profiles, and simpler, more convenient administration schedules (once daily for liraglutide and once weekly for albiglutide, dulaglutide, the long-acting exenatide formulation, and semaglutide), which might improve treatment adherence and persistence.

Background: Exenatide is an incretin mimetic that activates glucagon-like-peptide-1 receptors. It blunts the postprandial rise of plasma glucose by increasing glucose-dependent insulin secretion, suppressing inappropriately high glucagon secretion and delaying gastric emptying. Methods: In seven clinical trials performed in 2845 adult patients with type 2 diabetes mellitus who were inadequately controlled by a sulphonylurea and/or metformin (glycosylated haemoglobin, HbA1c ≤11%), or by thiazolidinediones (with or without metformin) and treated for periods from 16 weeks to 3 years, exenatide (5 μg b.i.d. s.c. for the first 4 weeks of treatment and 10 μg b.i.d. s.c. thereafter) reduced HbA1c, fasting and postprandial glucose, and body weight dose dependently, and was similar to insulin glargine and biphasic insulin aspart in reducing HbA1c. Body weight diminished with exenatide, whereas it increased with both insulin preparations. Positive effects on the lipid profile and a reduction in C-reactive protein were also recorded with exenatide. Treatment extensions up to 3 years showed that benefits were maintained in the long term. Adverse events were usually mild to moderate in intensity, and generally the frequency decreased with continued therapy. The most common was nausea (whose incidence may be reduced by gradual dose escalation from 5 μg b.i.d. to 10 μg b.i.d.), vomiting, diarrhoea, headache and hypoglycaemia (almost exclusively in patients treated with a sulphonylurea). Results and conclusions: Exenatide is a new, promising therapeutic option for type 2 diabetic patients inadequately controlled by oral agents, before insulin therapy, offering the added benefits of body weight reduction and tight postprandial glucose control.

Secondary failure is defined as a deterioration of glucose control in patients with Type 2 diabetes on oral antidiabetic drugs (OAD), mainly due to the progressive decline in beta-cell function and reduction in insulin secretion. The consequent hyperglycemia is the most important determinant for the development of microvascular and macrovascular complications, so that an early recognition of this phenomenon can improve long-term outcomes. The recent lowering of target glycosylated hemoglobin (HbA1c) levels by international guidelines not only emphasises the importance of tight glycemic control, but also means that secondary failure to OAD will occur much sooner and is almost unavoidable. Accordingly, in the last years, new different therapeutic strategies were explored to improve the treatment of this condition. The aim of this review is to examine current approaches for treating patients with secondary failure, barriers to achieving and maintaining glycemic control, and recent evidence for emerging therapies which may represent a valid therapeutic option in subjects failing on oral hypoglycemic agents by acting mainly, but not only, at a beta-cell level. In particular, we will focus on the co-administration of OAD plus a novel drug class known as incretin mimetics (e.g. exenatide and liraglutide), which target insulin secretion, and on thiazolidinediones, which act on insulin resistance. Only incretin-mimetics have a lowering HbA1c action, due to the improvement in beta-cell function, which is coupled to significant weight loss. Even if these new options seem to improve the outcome of secondary failure, further investigation is needed to confirm positive results in the long term.

BACKGROUND Obesity is characterised by growth hormone (GH) abnormalities, including a blunted response to stimulation and a 'paradoxical' increase after meals. The blunted GH release is reversed by a surgical intestinal bypass procedure. However, this does not mean that normal GH dynamics have been restored. The present study assessed whether post-surgical weight reduction in obese patients normalised the modulation of GH release produced by metabolic fuels. SUBJECTS Ten obese female subjects, aged 23-54 y, were studied before and after biliopancreatic diversion (BPD). All patients, after surgery, had experienced a significant reduction in body weight (mean body mass index (BMI) 25.78 +/- 1.01 kg/m2 vs 44.68 +/- 1.73 kg/m2). Two groups were also studied as controls: Ten normal body weight female subjects and ten patients suffering from anorexia nervosa (AN, mean BMI 17.46 +/- 1.12 kg/m2). MEASUREMENTS We have studied the GH response to a GH releasing hormone (GHRH) bolus (1 microg/kg i.v., at 13.00 h) before and after a standard meal. RESULTS In post-BPD subjects, the GH response to GHRH in the fasting state, was clearly augmented in comparison with the pre-BPD values (peak values 18.06 +/- 4.56 vs 3.24 +/- 0.68 microg/L). In post-BPD subjects the postprandial GH response was further augmented in comparison with the fasting test (peak 30.12 +/- 4.99 microg/L, P < 0.05). This pattern was similar to that observed in anorexic patients. CONCLUSION The surgical procedure restores a normal GH response to GHRH in the fasting state, but the 'paradoxical' GH response after meals remains present, suggesting a persistent GH derangement in such patients, which is not related to body weight per se. The surgical procedure makes obese patients similar to anorexics, in the relationships between metabolic fuels and GH secretion. The persistence of the GH postprandial response to GHRH in post-BPD subjects suggests a role for metabolic fuels in the regulation of somatostatin (SRIF) secretion.

Studies performed in animals and humans have suggested a functional interaction between opioid and cholinergic systems in the control of growth hormone (GH) secretion. Moreover, the sex-dependent modulation of GH secretion in humans is well established. To investigate the role of sex and food intake in the regulation of the reciprocal influences of opioids and acetylcholine in the modulation of GH secretion, we studied the GH response to pyridostigmine (PYR) alone and during a naloxone (NAL) infusion in a group of normal men and women before a meal (at 1:00 PM) and postprandially. In women, the response of GH to PYR alone before the meal was significantly lower than in the men (area under the curve [AUC], mean +/- SEM, 320.18 +/- 87.16 v 1,031.06 +/- 333.21 micrograms/L/90 min, P < .01). Before the meal, NAL completely abolished the response of GH to PYR in men (AUC, 1,031.06 +/- 333.21 v 16.50 +/- 7.50 micrograms/L/90 min, P < .01), whereas infusion of NAL did not significantly modify the GH response to PYR in women. Consumption of the meal significantly decreased PYR-induced GH release in both women (AUC, 21.75 +/- 12.75 v 320.18 +/- 87.16 micrograms/L/90 min, P < .05) and men (AUC, 45.75 +/- 18.75 v 1,031.06 +/- 333.21 micrograms/L/90 min, P < .01). Conversely, food intake did not change the effects of NAL infusion on the GH response to PYR either in women or in men. We conclude that the sex-dependent opioid modulation of PYR-induced GH secretion is observed before a meal but not in the postprandial state. Food intake may be hypothesized to influence the cholinergic regulation of GH secretion and the sex-dependent opioid modulation of central cholinergic tone.

Objectifs Evaluer selon leur âge, les preferences des patients diabetiques de type 2 (DT2) pour les caracteristiques des GLP-1RAs au Royaume-Uni. Methodes C’etait un modele de choix discret (MDC) chez des patients DT2 adultes naifs de traitement injectable. Les parametres du MDC comprenaient : frequence d’administration, variation de l’HbA1c, variation du poids, type de dispositif d’administration, frequence des nausees et frequence des hypoglycemies. Les utilites partielles ont ete estimees par un modele logit a effets aleatoires et utilisees pour calculer l’importance relative (IR) de chaque parametre. Des tests du Chi 2 ont ete utilises pour tester les differences d’IR pour chaque parametre par groupe d’âge ( 65 ans). Resultats Un total de 243 participants ont termine l’etude ( n = 68 ; 55–65 ans, n = 95 ; > 65 ans, n = 80). Dans tous les groupes, frequence d’administration, type de dispositif d’administration et frequence des nausees etaient les trois parametres les plus importants par ordre de preference. Des differences d’IR ont ete observees entre les groupes pour le type de dispositif d’administration ( 65 ans, IR = 37,9 % ; p = 0,0477) et la frequence des hypoglycemies ( 65 ans, IR = 7,6 % ; p = 0,0384). Discussion Dans cette etude, quel que soit l’âge, l’ordre d’IR des caracteristiques des GLP-1RA est globalement similaire, avec la frequence d’administration classee en tete de maniere constante. Lorsque des differences etaient observees, le type de dispositif d’administration et la frequence des hypoglycemies etaient plus importants pour les patients plus âges.

Insulin lispro protamine suspension (ILPS) is a protamine-based insulin lispro formulation that allows 24-h coverage while limiting the number of daily injections. ILPS was developed to be the basal insulin component of premixed biphasic formulations with insulin lispro, i.e., the lispro/ILPS 25/75 and 50/50 mixed compounds, but has recently also been marketed as a basal insulin analog formulation, with an indication for the therapy of diabetic patients.This article reviews the available literature on pharmacokinetics/pharmacodynamics (PK/PD), efficacy and safety of ILPS administered as basal insulin, or in premixed biphasic formulations, in patients with type 1 and type 2 diabetes mellitus.The results of this review suggest that ILPS may be associated with a favorable time-action profile, basal and postprandial glycemic control, and efficacy in terms of rates of patients reaching glycosylated hemoglobin targets; an increased risk of hypoglycemic episodes, compared to other basal insulins, seems to be related to the percentage of patients upgrading from once- to twice-daily injections. This increased risk might be linked with the concomitant use of insulin secretagogues in patients on higher daily dosages and is generally not observed in patients using one injection of ILPS a day. Thus, ILPS can be considered a valid option both as basal insulin and as basal component of the actual premixed formulations of lispro for the therapy of diabetic patients.

This observational study examined the effects of insulin lispro protamine suspension (ILPS) given as basal insulin in intensive insulin regimens in patients with type 1 and type 2 diabetes mellitus who attended a reference outpatient centre for the treatment of diabetes due to poor glycaemic control, frequent hypoglycaemia or intolerance to previous therapy.The study population included 64 patients, 33 male and 31 female, mean age 59.6 years; 50 patients were receiving an insulin regimen, while 14 had previously been treated with oral antidiabetic drugs (OADs). The starting insulin dose for patients receiving OADs was 0.5-0.8 IU/kg which was titrated according to a standard algorithm. Patients also received an individualised programme for diet adjustment and physical activity. Fasting plasma glucose (FPG), glycosylated haemoglobin (HbA(1c)), hypoglycaemic events, lipid profile, body weight and blood pressure were measured at baseline and thereafter.The mean duration of therapy was 229.3 days. Total insulin daily dosage did not change statistically in the observation period. FPG and HbA(1c) levels decreased significantly (p0.001) in this period, with no increase in hypoglycaemic episodes. Univariate analysis has shown that patients having higher HbA(1c) and FPG levels at baseline have higher improvement in HbA(1c) and FPG than those having better glycaemic control at baseline. Patients with concomitant pathologies at baseline had a significantly lower improvement in HbA(1c) and FPG, while females had a significantly higher improvement in HbA(1c). Frequency of hypoglycaemic episodes was significantly lower in those patients who had previously experienced hypoglycaemia, had previously used insulin therapy, had concomitant pathologies, had HbA(1c) above 6.5% at baseline and required higher total daily insulin doses. A significant improvement in total cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride levels, together with a significant decrease in the cardiovascular risk index, were also observed, with no significant variation in body weight and blood pressure.This study shows that the use of ILPS as basal insulin in intensive insulin therapy, improved glycaemic control with no significant increase in hypoglycaemic episodes in the 64 patients observed undergoing treatment at the Potenza outpatient clinic. Because of the nature of this study, these results have to be confirmed in further randomised, controlled clinical trials.

Some studies have shown that fetal outcome observed in patients using insulin lispro is much the same as in pregnant women using regular insulin. This study aims to analyze the Italian data emerging from a multinational, multicenter, retrospective study on mothers with type 1 diabetes mellitus before pregnancy, comparing those treated with insulin lispro for at least 3 months before and 3 months after conception with those treated with regular insulin. The data collected on pregnant women with diabetes attending 15 Italian centers from 1998 to 2001 included: HbA1c at conception and during the first and third trimesters, frequency of severe hypoglycemic episodes, spontaneous abortions, mode and time of delivery, fetal malformations and mortality. Seventy-two diabetic pregnancies treated with lispro and 298 treated with regular insulin were analyzed, revealing a trend towards fewer hypoglycemic episodes in the former, who also had a significantly greater reduction in HbA1c during the first trimester. The rate of congenital malformations was similar in the offspring of the two groups of women treated with insulin lispro or regular insulin. These findings suggest that insulin lispro could be useful for the treatment of hyperglycemia in type 1 diabetic pregnant women.

Objectifs DU, agoniste hebdomadaire du recepteur du GLP-1 (glucagon-like peptide-1) etait superieur a l’EX BID et non inferieur au LIR OD sur la reduction de l’HbA1c dans deux essais AWARD, dont nous presentons ici des donnees supplementaires d’auto-surveillance glycemique (ASG). Patients et methodes Des patients DT2 ont recu aleatoirement DU1,5 mg, DU0,75 mg, EX BID, ou placebo, associes avec metformine et pioglitazone (AWARD-1, n = 976), et DU1,5 mg ou LIR1,8 mg, associes avec metformine (AWARD-6, n = 599) (populations en intention de traiter). Dans les deux etudes, les variations de la glycemie plasmatique (GP) par ASG a la semaine 26 ont ete analysees selon un modele mixte de mesures repetees. Resultats DU a entraine une reduction des moyennes des moindres carres (MMC) de toutes les GP mesurees. Dans AWARD-1, les variations de la MMC de la totalite des 8 points de la GP etaient respectivement de -46,8, -42,1 et -37,5 mg/dL pour DU1,5 mg, DU0,75 mg et EX (p Discussion DU en prise hebdomadaire entraine une amelioration des profils d’ASG plus importante qu’EX en prise biquotidienne et comparable au LIR1,8 mg en prise quotidienne. DU est efficace sur la reduction de la GP pre et post-prandiale.

Objectifs Analyse post-hoc des resultats d’efficacite du dulaglutide (DU) vs comparateurs actifs chez des patients DT2 selon leur IMC initial dans les etudes de phase III randomisees, AWARD (Assessment of Weekly AdministRation of dulaglutide in Diabetes)–1 a–5. Patients et methodes Des patients DT2 ont recu du DU (1,5 mg, n = 1420 ; 0,75 mg, n = 1417), de l’exenatide ( n = 276), de l’insuline glargine ( n = 558), de la metformine ( n = 268) ou de la sitagliptine ( n = 315) en complement d’autres traitements antidiabetiques. L’analyse de covariance incluant des tests d’interaction a permis d’estimer, par etude, les effets du traitement sur l’HbA 1c et le poids a 52 semaines et de comparer le DU aux comparateurs chez des patients avec un IMC initial 2 (population en intention de traiter). Resultats Les IMC moyens initiaux de tous les groupes de traitement (toutes etudes combinees, n = 4572) variaient de 32,3 a 32,4 kg/m 2 . Dans toutes les etudes, une reduction du taux d’HbA 1c par rapport a la valeur initial a ete observee, dans tous les sous-groupes d’IMC. Aucune interaction statistiquement significative traitement/sous-groupe d’IMC n’a ete observee pour les diminutions de l’HbA 1c ( p = 0,159–0,871). Pour le controle du poids, l’effet du DU 1,5 mg apparait meilleur ou similaire aux comparateurs dans tous les sous-groupes d’IMC ; les interactions n’etaient pas statistiquement significatives ( p = 0,215–0,885), quelle que soit l’etude. Conclusions L’absence d’interaction traitement/sous-groupe d’IMC sur les variations de l’HbA 1c et du poids, suggere une absence d’effet de l’IMC initial sur l’efficacite relative glycemique et ponderale du dulaglutide versus comparateurs.

Objectif Determiner l'impact de l'IMC initial sur le traitement par dulaglutide hebdomadaire et comparateurs chez des patients DT2 avec un taux d'HbA1c ≥ 7,5 % (AWARD 1-5), valeur recommandee par le National Institute for Health and Care Excellence (NICE) pour initier un traitement par GLP-1RA. Materiels et methodes Analyses post-hoc, par etude, de la variation de l'HbA1c et du poids a 26 semaines de traitement par dulaglutide hebdomadaire 1,5mg ( n =954) ou 0,75mg ( n =943), exenatide ( n =165), insuline glargine ( n =432), metformine ( n =126) ou sitagliptine ( n =224). Resultats Dans les 5 etudes, les moyennes des moindres carres (erreur type) [MMC (ET)] des reductions d'HbA1c chez les patients avec IMC p 35kg/m², AWARD-2. Les resultats etaient similaires pour le dulaglutide 0,75mg vs comparateurs. Dans toutes les etudes, les MMC (ET) des variations ponderales etaient: dulaglutide 1,5mg: 0,12 (0,45) a 2,68 (0,32)kg ( p d'interaction traitement-sous-groupe d'IMC pour les variations d'HbA1c et de poids allaient de 0,214 a 0,856. Conclusion Ces donnees suggerent une efficacite constante avec les deux doses de dulaglutide vs comparateurs actifs. Declaration d’interet Les auteurs declarent avoir un interet avec un organisme prive, industriel ou commercial en relation avec le sujet presente. Michael Cummings: recieved educational grants and honoraria from Eli Lilly. Omolara Adetunji, Claudia Nicolay and Raffaella: Employees of Eli Lilly.

Current strategies for the treatment of osteoporosis rely almost exclusively on agents whose pharmacological actions are primarily antiresorptive. There is, therefore, growing interest in developing agents able to stimulate bone formation, such as GH and IGF-I, which play an important role in bone metabolism, being essential for the development and growth of the skeleton and for the maintenance of bone mass. Furthermore, the decline in GH/IGF-I axis with aging, is correlated with the increased risk of osteoporosis and fragility fractures in elderly population. Several studies investigated the potential of GH and/or IGF-I as therapeutic agents in osteoporotic patients (post-menopausal women and idiopathic osteoporotic men), showing a clear correlation between the used GH dosage (and the obtained IGF-I plasmatic levels) and the increase in bone turnover markers and/or bone mineral density (BMD) at different skeletal sites. In particular, the use of IGF-I/IGFBP-3 complex seems to be very useful and safe in older women with recent hip fracture. Also the possibility of combining GH/IGF-I treatment with antiresorptive drugs (such as calcitonin and alendronate) has been explored, showing controversial results on BMD at different skeletal sites. In summary, based on the current evidence, it is clear that circulating GH and IGF-I are critical for skeletal modeling, bone acquisition and age related bone loss. Nevertheless, controlled studies with fracture incidence as endpoints are needed to fully assess the potential of these bone anabolic agents in the treatment of osteoporosis.

Obesity is characterized by increased leptin levels and insulin resistance, whereas blunted GH secretion is paired with normal, low, or high plasma IGF-I levels. To investigate body composition in human obesity and the interactions among the GH-IGF-I axis, leptin, and insulin resistance [measured with the homeostasis model assessment (HOMA) score], we studied 15 obese females, aged 23-54 yr (mean age, 42.7 +/- 2.6), with a body mass index (BMI) of 44.02 +/- 1.45 kg/m(2), who underwent treatment by biliopancreatic diversion (BPD), before and after surgery (16-24 months; BMI, 28.29 +/- 0.89 kg/m(2)). Our controls were 15 normal females, aged 28-54 yr (mean age, 40.8 +/- 2.3 yr), with a BMI of 27.52 +/- 0.53 kg/m(2). Insulin and leptin levels and HOMA scores were higher pre-BPD than in the controls. The GH response to GHRH was blunted, with a GH peak and GH area under the curve (AUC) significantly lower than those in controls. IGF-I and IGF-binding protein-3 (IGFBP-3) were also lower than control values. After surgery, BMI, fat mass, lean body mass, HOMA, insulin, and leptin significantly decreased. Furthermore, the GH response to GHRH severely increased; IGF-I and IGFBP-3 levels did not significantly vary. Considering all subjects, correlation analysis showed a strong positive correlation between insulin and leptin, and a negative correlation between insulin and GH peak and between insulin and GH AUC. Regression analysis performed grouping pre- and post-BPD indicated that leptin and GH peak or AUC could best be predicted from insulin levels. The surgical treatment of severe obesity after stabilization of body weight decreases BMI and fat mass while preserving normal lean body mass as well as positively influencing insulin sensitivity and thus aiding the normalization of leptin levels. The insulin reduction may be mainly involved in the increase in the GH response to GHRH through various possible central and peripheral mechanisms while decreasing the peripheral sensitivity to GH itself, as shown by the stable nature of the IGF-I and IGFBP-3 values. Our findings suggest that the changes in insulin levels are the starting point for changes in both leptin levels and the somatotrope axis after BPD.

The objective of this study was to investigate the relationship between growth hormone (GH) dynamic tests (thyrotropin-releasing hormone [TRH] test and oral glucose tolerance test [OGTT]), insulin-like growth factor-I (IGF-I) plasma values, tumor size, and clinical outcome in patients with GH-secreting pituitary adenomas. Furthermore, we investigated the potential prognostic utility of the above biochemical parameters in the follow-up of patients with acromegaly. We studied 50 acromegalic patients (18 males and 32 females; mean age, 40 years; range, 16 to 69) who underwent trans-sphenoidal removal of a GH-secreting pituitary adenoma from 1990 to 1994. Preoperatively, we evaluated (1) GH plasmatic levels after an oral glucose load (OGTT) (blood samples were drawn at -15, 0, 30, 60, 90, 120, 150, and 180 minutes after oral administration of 0.75 g/kg body weight [BW] of glucose), (2) GH plasma levels after a TRH test (200 microg as an intravenous [IV] bolus), and (3) basal IGF-I plasma levels after an overnight fast. From 3 to 12 months after surgery we evaluated (1) GH plasma values after an OGTT, and (2) basal plasma IGF-I, free triiodothyronine (FT(3)), free thyroxine (FT(4)), thyroid-stimulating hormone (TSH), and urinary free cortisol. The same tests were performed every year for 5 years. All of the patients were classified into 4 subgroups according to the system of Hardy and Vezina. Preoperatively, "controlled" patients (n = 29) had a GH paradoxical response to TRH (n = 28) and an unresponsiveness to OGTT (n = 29); 23 of them belonged to the I and II classes. Only 5 poorly controlled patients (n = 21) showed a preoperative paradoxical response to TRH and 9 had a preoperative GH partial inhibition after OGTT; 19 of them belonged to the III and IV classes. Our data suggest that in the preoperative period in acromegalic patients the simultaneous presence of a GH paradoxical response to TRH and lack of GH inhibition after OGTT is inversely related to the tumor size and therefore more likely to be restored to normal by surgical treatment.

Previously, we have shown that in the opposite extremes of nutritional status (obesity and anorexia nervosa [AN]), the growth hormone (GH) response to GH-releasing hormone (GHRH) is not inhibited by the ingestion of a normal 800-kcal meal at noon. In obese subjects, GHRH-induced GH release is significantly increased (known as the "paradoxical response"). An opiate antagonist infusion (naloxone [NAL]) inhibited this postprandial meal-induced augmenting effect in obese subjects, suggesting opioid involvement in the paradoxical response. The paradoxical postprandial GH release persisted in obese subjects, who after biliopancreatic diversion (BPD) experienced a reduction in body weight, despite the elevation of fasting GH levels. We therefore tested a group of patients, before and after BPD, composed of 10 females, aged 23 to 54 years, who after surgery had experienced a significant reduction in body weight (mean body mass index [BMI], 25.78 +/- 1.01 kg/mg v 44.68 +/- 1.73 kg/mg). The subjects were studied 16 to 24 months after operation, in a phase of stabilized body weight. They underwent, in randomized order, the following tests: GHRH (1 microg/kg as an intravenous [IV] bolus) at 1:00 PM, in the fasting state; GHRH (1 microg/kg) at 1:00 PM, 45 minutes after a standard 800-kcal meal consumed between noon and 12:15 PM; and fasting state and postprandial GHRH (1 microg/kg) during NAL infusion (1.6 mg/h x 2.5 h, starting at noon). We found that NAL inhibited the paradoxical postprandial GH increase only in pre-BPD subjects (GH area under the concentration time curve [AUC] in microg/L/90 min)-before meal: after GHRH 237.54 +/- 62.28, after NAL + GHRH 699.2 +/- 271.57; after meal: after GHRH 575.46 +/- 109.68, after NAL + GHRH 156.17 +/- 24.96. On the other hand, NAL failed to have significant effects in post-BPD subjects (GH AUC in microg/L/90 min)-before meal: after GHRH 871.11 +/- 256.38, after NAL + GHRH 449.19 +/- 119.13; after meal: after GHRH 1,981.54 +/- 319.92, after NAL + GHRH 1,665.91 +/- 315.4. It could be hypothesized that the opioid system is radically modified by the surgical procedure, and that opioids are not the only mediators in the paradoxical response, which persists after BPD, despite the reversion of the hyposecretory GH state, which is a characteristic of obese subjects.

Hexarelin (HEX) is a new synthetic analog of the Growth Hormone releasing peptides and is stronger than GHRH in releasing GH in vivo. No information is available on the effect of food ingestion on HEX-induced GH secretion. On the other hand, we have previously demonstrated that food intake at lunchtime in normal subjects has an inhibitory effect on the GH response to GHRH. The aim of the present study was to investigate the effect of food ingestion on GH secretion induced by HEX as compared to GHRH in six normal men (aged 23-29 years) and six normal women (aged 24-29 years). The body weights for all subjects were within 120% of their ideal body weight, according to their sex and age. Our data confirm that HEX is much more powerful than GHRH in inducing GH release in humans, both in the fasting state (GH-AUC: 3010 +/- 695 after HEX, vs. 1339 +/- 281 after GHRH, microg/L/120 min; p

Galanin (GAL) elicits growth hormone (GH) release in normal subjects through interaction with hypothalamic somatostatin. GAL also stimulates GH-releasing hormone (GHRH) secretion in vitro. In rats, GAL is able to stimulate prolactin (PRL) release, but this effect is not clear in humans. We have thus investigated GAL effects on GH and PRL release in patients with anorexia nervosa (AN), known to have altered regulation of the GH-insulin-like growth factor axis and PRL dynamics, and compared the effects of GHRH and GAL on GH and PRL secretion in AN and normal healthy subjects. Eight women with AN (15 to 27 years; body mass index [BMI], 17 to 19.5 kg/m2) were treated with (1) GHRH 50 microg intravenous (IV) injection, (2) porcine GAL 500 microg infusion from -10 to +30 minutes, and (3) 135-minutes saline infusion as a control, respectively. Both peptides induced a significant increase in plasma GH in AN patients (peak level, 27.41 +/- 5.50 microg/L after GAL and 18.97 +/- 2.67 microg/L after GHRH). When data for AN patients and the control group were compared, GH peak levels after GAL were significantly higher in AN patients (27.41 +/- 5.50 v 13.64 +/- 2.32 microg/L), while GH peak levels after GHRH were not different between the 2 groups (18.97 +/- 2.67 v 15.98 +/- 3.88 microg/L). PRL levels significantly increased after both GHRH (peak, 11.70 +/- 2.80 microg/L) and GAL (peak, 18.02 +/- 5.10 microg/L) treatment in AN patients, but not in normal subjects. We conclude that GAL stimulates exaggerated GH release in AN patients as compared with normal controls, suggesting a dual hypothalamic interaction via both an increase in endogenous GHRH and a decrease in somatostatin secretion. Finally, GAL may act as a PRL secretagogue in AN patients.

To study the impact of severe head injury on both basal pituitary hormone secretion and the response to exogenous synthetic hypothalamic releasing factors (TRH and GHRH) in order to evaluate sequential changes in the central control of hypophyseal secretion in the days following head injury.Prospective clinical study21 comatose male patients with head injuries, each intubated and ventilated, intensively monitored and having no previous endocrine problems.AND RESULTS The GH and PRL responses to TRH (200 microg iv), and the GH and PRL responses to GHRH (50 microg iv) were evaluated, respectively, on the days 1 and 16 and on days 2, 7and 15 after admission. Daily blood samples were also collected for GH, PRL, TSH, T3 and T4 evaluation. In the basal samples taken on days 2, 7 and 15, IGF-I and cortisol were also determined. Nitrogen balance was assessed daily. On the day 1, TRH increased GH levels from 9.8 +/- 2.2 to 22.4 +/- 6.5 mU/l but failed to induce GH release on day 16. The PRL response to TRH was normal. The GH peak response to GHRH was normal on the day 2 (35.7 +/- 13.9 mU/l), but was increased on days 7 and 15 (68.3 +/- 10.7 mU/l on day 7; 73.8 +/- 9.2 mU/l on day 15, P0.01 vs. day 2). We found a significant PRL response to GHRH during the whole period of observation. In the daily evaluation, nitrogen balance was negative in all patients from the day 1 to 5. On average, all patients reached a positive nitrogen balance on the day 8. Compared to the day 2, a statistical increase in IGF-I concentration was observed on days 7 and 15.The evaluation of pituitary dynamics in the acute phase of a severe injury demonstrates an alteration of GH and PRL secretion, which correlate with the aminergic and/or peptidergic derangements. Taken together, our data suggest augmented tone of both GHRH and somatostatin in the very acute phase, while an imbalance of releasing factors is hypothesized in the following days. The metabolic consequences of this neuroendocrine pattern could be advantageous in the rapid recovery from the cascade of events produced by the trauma, as documented by the increase in IGF-1 levels and the positive nitrogen balance.