Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial

Background: Oral semaglutide is the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes. We aimed to compare the efficacy and safety of flexible dose adjustments of oral semaglutide with sitagliptin 100 mg. Methods: In this 52-week, multicentre, randomised, open-label, phase 3a trial, we recruited patients with type 2 diabetes from 81 sites in ten countries. Patients were eligible if they were aged 18 years or older (19 years or older in South Korea), had type 2 diabetes (diagnosed ≥90 days before screening), HbA1c of 7·5–9·5% (58–80 mmol/mol), and were inadequately controlled on stable daily doses of one or two oral glucose-lowering drugs (for 90 days or more before screening). Participants were randomly assigned (1:1) by use of an interactive web-response system, stratified by background glucose-lowering medication at screening, to oral semaglutide with flexible dose adjustments to 3, 7, or 14 mg once daily or sitagliptin 100 mg once daily. To approximate treatment individualisation in clinical practice, oral semaglutide dose could be adjusted on the basis of prespecified HbA1c and tolerability criteria. Two efficacy-related estimands were prespecified: treatment policy (regardless of treatment discontinuation or use of rescue medication) and trial product (on treatment and without use of rescue medication) for participants randomly assigned to treatment. The primary endpoint was achievement of HbA1c of less than 7% (53 mmol/mol) at week 52 and the confirmatory secondary efficacy endpoint was change in bodyweight from baseline to week 52. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02849080, and European Clinical Trials Database, EudraCT number 2015-005593-38, and an open-label extension is ongoing. Findings: Between Sept 20, 2016, and Feb 7, 2017, of 804 patients assessed for eligibility, 504 were eligible and randomly assigned to oral semaglutide (n=253) or sitagliptin (n=251). Most participants were male (285 [57%] of 504) with a mean age of 57·4 years (SD 9·9). All participants were given at least one dose of their allocated study drug except for one participant in the sitagliptin group. From a mean baseline HbA1c of 8·3% (SD 0·6%; 67 mmol/mol [SD 6·4]), a greater proportion of participants achieved an HbA1c of less than 7% with oral semaglutide than did with sitagliptin (treatment policy estimand: 58% [134 of 230] vs 25% [60 of 238]; and trial product estimand: 63% [123 of 196] vs 28% [52 of 184]). The odds of achieving an HbA1c of less than 7% was significantly better with oral semaglutide than sitagliptin (treatment policy estimand: odds ratio [OR] 4·40, 95% CI 2·89–6·70, p<0·0001; and trial product estimand: 5·54, 3·54–8·68, p<0·0001). The odds of decreasing mean bodyweight from baseline to week 52 were higher with oral semaglutide than with sitagliptin (estimated mean change in bodyweight, treatment policy estimand: −2·6 kg [SE 0·3] vs −0·7 kg [SE 0·2], estimated treatment difference [ETD] −1·9 kg, 95% CI −2·6 to −1·2; p<0·0001; and trial product estimand: −2·9 kg [SE 0·3] vs −0·8 kg [SE 0·3], ETD −2·2 kg, −2·9 to −1·5; p<0·0001). Adverse events occurred in 197 (78%) of 253 participants in the oral semaglutide group versus 172 (69%) of 250 in the sitagliptin group, and nausea was the most common adverse event with oral semaglutide (53 [21%]). Two deaths occurred in the sitagliptin group during the trial. Interpretation: Oral semaglutide, with flexible dose adjustment, based on efficacy and tolerability, provided superior glycaemic control and weight loss compared with sitagliptin, and with a safety profile consistent with subcutaneous GLP-1 receptor agonists. Funding: Novo Nordisk A/S

Effects of Alloying Elements on Martensitic Transformation Behavior and Damping Capacity in Fe-17Mn Alloy

Effect of carbon and Ti on γ ←→ εmartensitic transformation behavior and damping capacity has been investigated in an Fe-17Mn alloy. The suppressive force of carbon against γ ←→ ε transformation increases linearly with an increase in carbon content, lowering Ms temperature and volume fraction of ε martensite. Carbon deteriorates damping capacity by reducing the area of γ/ε interfaces and by decreasing the mobility of the interfaces operated as damping source. The reduction in the mobility of the interfaces is accelerated when carbon-containing alloy is aged at high temperatures. The effect of Ti on the damping capacity is found to be beneficial in carbon-containing alloy, because the Ti contributes to depletion of carbon solute by the formation of TiC

Transformation Behavior and its Effect on Damping Capacity in Fe-Mn Based Alloys

γ→ε transformation behavior in a Fe-21Mn alloy with different grain size and a Fe-32Mn-6Si alloy with various degrees of cold rolling is investigated and correlated with damping capacity. Effect of microstructure on damping capacity is discussed on the assumption that the capacity is proportional to volume swept by γ/ε boundaries

Anisotropy of Several Properties in a Polycrystalline Fe-Mn-Si Based Shape Memory Alloy

The tensile properties, γ ←→ ε transformation and shape recovery have been related to the orientation of tensile axes i.e., along rolling direction(specimen 'A') and toward 45° to the rolling direction(specimen 'B') in a cold-rolled and then annealed Fe-15Mn-10Co-5Cr-3Si alloy. It is revealed that the deformation modes of the specimens 'A' and 'B' with respect to tensile axes are not the same ; tensile deformation of the specimen 'A' is mainly achieved by slip, while that of the specimen 'B' is mainly governed by γ → ε transformation. The yield strengths of the specimens 'A' and 'B' are 569MPa and 745MPa, respectively. The reverse transformation temperature of the specimen 'A' is much higher than that of the specimen 'B', and the shape recovery of the specimen 'B' is much larger than that of the specimen 'A'. The differences between those properties with tensile axes are discussed in association with texture developed in a cold-rolled and then annealed Fe-15Mn-10Co-5Cr-3Si alloy

Éducation des diabétiques de type 2: impact sur les soins, la consommation des ressources et les conditions de travail. Données de l’International Diabetes Management Practices Study (IDMPS)

Aim: To evaluate the impact of diabetes education provided to patients with type 2 diabetes mellitus (T2DM) in non-controlled studies (" real-world conditions" ) on quality of care, resource consumption and conditions of employment. Methods: This cross-sectional study and longitudinal follow-up describe the data (demographic and socioeconomic profiles, clinical characteristics, treatment of hyperglycaemia and associated cardiovascular risk factors, resource consumption) collected during the second phase (2006) of the International Diabetes Management Practices Study (IDMPS). Patients received diabetes education directly from the practice nurse, dietitian or educator, or were referred to ad hoc group-education programmes; all programmes emphasized healthy lifestyle changes, self-care and active participation in disease control and treatment. Educated vs non-educated T2DM patients (n=5692 in each group), paired by age, gender and diabetes duration, were randomly recruited for the IDMPS by participating primary-care physicians from 27 countries in Eastern Europe, Asia, Latin America and Africa. Outcome measures included clinical (body weight, height, waist circumference, blood pressure, foot evaluation), metabolic (HbA 1c levels, blood lipid profile) and biochemical control measures. Treatment goals were defined according to American Diabetes Association guidelines. Results: T2DM patients' education significantly improved the percentage of patients achieving target values set by international guidelines. Educated patients increased their insulin use and self-care performance, had a lower rate of chronic complications and a modest increase in cost of care, and probably higher salaries and slightly better productivity. Conclusion: Diabetes education is an efficient tool for improving care outcomes without having a major impact on healthcare costs.Objectif: Évaluer l’impact de l’éducation prodiguée aux patients atteints de diabète de type 2 à partir de l’étude observationnelle (dans les conditions réelles de suivi des patients) de la qualité des soins et de leurs coûts, exprimés en dépenses de soins et en journées de travail perdues. Méthodes: Étude transversale et longitudinale ayant pour but de recueillir des données des patients concernant leur profil socioéconomique, le traitement du diabète et de ses complications et les coûts. Cette étude appartient à la seconde vague de l’International Diabetes Management Practices Study (IDMPS) (2006). Les patients ont reçu des informations relatives au diabète d’une infirmière, d’un diététicien, d’un éducateur spécialisé ou grâce à un programme d’éducation spécifique. Chaque programme mettait l’accent sur les modifications hygiéno-diététiques et la prise en charge active de la maladie et de son traitement par le patient lui-même. Les diabétiques de type 2 qui avaient reçu on non cette éducation (n = 592 dans chaque groupe) étaient appariés selon l’âge, le sexe, et la durée de diabète. Les patients avaient été recrutés par randomisation par les médecins traitants de 27 pays de l’Europe de l’Est, de l’Asie, de l’Amérique Latine et d’Afrique. Les données recueillies étaient cliniques (poids, taille, périmètre adominal, pression artérielle, examen des pieds), métabolique (HbA1c, profil lipidique) et biologiques. Les objectifs de traitement étaient ceux définis par les recommendations de l’American Diabetes Association. Résultats: L’éducation diabétique apportée aux diabétiques de type 2 augmente significativement le pourcentage de patients atteignant les objectifs de traitement définis par les recommandations internationales. Les patients qui avaient reçu une éducation diabétologique utilisaient davantage l’insuline et se prenaient mieux en charge. Ils présentaient un plus faible pourcentage de complications chroniques. Une augmentation modérée des coûts de traitement fut notée, associée probablement à des salaires plus élevés et à une productivité légèrement plus élevée. Conclusion: L’éducation diabétique est efficace et améliore le devenir des patients sans élévation importante des coûts de traitement.Fil: Gagliardino, Juan Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Centro de Endocrinología Experimental y Aplicada (i); Argentina. Organizacion Mundial de la Salud; ArgentinaFil: Aschner, P.. Universidad Javeriana; ColombiaFil: Baik, S.H.. Korea University Guro Hospital; Corea del SurFil: Chan, J.. Chinese University of Hong Kong; ChinaFil: Chantelot, J.M.. Sanofi-Aventis. Department of Intercontinental Medical Affairs; FranciaFil: Ilkova, H.. Istanbul University Cerrahpasa Medical Faculty; TurquíaFil: Ramachandran, A.. Dr. A. Ramachandran’s Diabetes Hospitals. India Diabetes Research Foundation; Indi