Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Trends in diagnostic and therapeutic criteria in Graves' disease in the last 10 years

A questionnaire describing a typical clinical case of Graves' disease and 10 variations on it was mailed to 70 Spanish units of endocrinology with the aim of assessing the new diagnostic and therapeutic trends for hyperthyroidism caused by Graves' disease in Spain and to compare the results obtained from previous studies carried out in Europe and Spain 10 years previously.
  Responses indicated that thyrotrophin (98%) and free thyroxine (88%) were the most used tests in the in vitro diagnosis of Graves' disease with a significant decrease in the use of total thyroxine, total triiodothyronine, and thyroglobulin in comparison with the surveys conducted 10 years previously in Europe and Spain. The presence of antibodies against the thyrotrophin receptor was the most frequently used immune marker in the diagnosis (78%) and the new use of antithyroperoxidase antibodies (36%) in diagnosis is noteworthy. Antithyroid drugs remain the treatment of choice (98%). Surgery was used mainly for large size goitres (33%) and radioiodine for recurrences after medical (61%) or surgical (80%) treatment.
  In conclusion, the responses obtained from this questionnaire provide insight into current specialist diagnostic and therapeutic practices with respect to Graves' disease and which could be of value to non-specialist units of endocrinology.


Keywords: Graves' disease; antithyroid drugs; radioiodine; surger

T1DiabetesGranada: a longitudinal multi-modal dataset of type 1 diabetes mellitus

Type 1 diabetes mellitus (T1D) patients face daily difficulties in keeping their blood glucose levels within appropriate ranges. Several techniques and devices, such as flash glucose meters, have been developed to help T1D patients improve their quality of life. Most recently, the data collected via these devices is being used to train advanced artificial intelligence models to characterize the evolution of the disease and support its management. Data scarcity is the main challenge for generating these models, as most works use private or artificially generated datasets. For this reason, this work presents T1DiabetesGranada, an open under specific permission longitudinal dataset that not only provides continuous glucose levels, but also patient demographic and clinical information. The dataset includes 257 780 days of measurements spanning four years from 736 T1D patients from the province of Granada, Spain. This dataset advances beyond the state of the art as one the longest and largest open datasets of continuous glucose measurements, thus boosting the development of new artificial intelligence models for glucose level characterization and prediction.University of Granada within the framework of the Development Cooperation FundAndalusian Ministry of Economic Transformation, Industry, Knowledge and Universities under grant P20_00163Instituto de Salud Carlos III grants (PI18–01235), co-funded by the European Regional Development Fund (FEDER

Cambios en marcadores del metabolismo óseo y parámetros ultrasónicos en mujeres postmenopáusicas inducidos por isoflavonas de soja

Introducción: Los resultados de los trabajos publicados sobre el papel de las isoflavonas en la prevención de la osteoporosis postmenopáusica son contradictorios. El objetivo de nuestro estudio es evaluar los efectos de la intervención nutricional con un producto lácteo enriquecido con isoflavonas de soja sobre el metabolismo óseo en mujeres postmenopáusicas españolas. Sujetos y método: Estudio aleatorizado, controlado y a doble ciego, realizado en 99 mujeres postmenopáusicas que fueron distribuidas en dos grupos: el grupo S (n=48), con consumo de un producto lácteo enriquecido con isoflavonas de soja (50 mg/día), y el grupo C (n=51), con consumo de un producto lácteo control durante 12 meses. Se evaluaron basalmente y al año parámetros hormonales y marcadores del metabolismo óseo. Se utilizó ultrasonido del calcáneo (QUS, Hologic Sahara®, Carolina del Norte, EE.UU.) como técnica de evaluación de masa ósea. Resultados: A los 12 meses, se produjo un descenso en los niveles séricos de fosfatasa ácida tartrato resistente y osteoprotegerina (2,18 ± 0,8 vs. 1,76 ± 0,54 U/l, p<0,001, y 5,21 ± 3,36 vs. 3,89 ± 1,47 pmol/L, p=0,007, respectivamente) y un aumento de 25-OH-vitamina D (24,48 ± 9,85 vs. 28,18 ± 10,45 ng/ml, p<0,001), sin diferencias entre ambos grupos. No hubo cambios significativos en los parámetros hormonales y el resto de marcadores óseos. En cuanto al QUS, en la muestra total hubo un aumento de velocidad del sonido [SOS] (1517,86 ± 38,13 vs. 1525,11 ± 35,6 m/s, p=0,036), QUI (76,37 ± 19,87 vs. 80,82 ± 18,26, p=0,012), densidad mineral ósea estimada [Est. DMO] (0,408 ± 0,13 vs. 0,435 ± 0,12 g/cm², p=0,013) y T-score (-1,55 ± 1.12 vs. -1,31 ± 1,03, p=0,019). En el grupo S se produjeron cambios positivos en QUI (74,37 ± 18,87 vs. 78,83 ± 13,68, p=0,032) y Est. DMO (0,397 ± 0,12 vs. 0,423 ± 0,09 g/cm², p=0,04), mientras que el grupo C no hubo diferencias significativas. Conclusiones: El consumo diario de estos productos lácteos aumenta los niveles de 25-OH-vitamina D y supone un descenso de los marcadores del metabolismo óseo. La dieta rica en isoflavonas de soja puede ser una opción como medida preventiva de los efectos óseos de la menopausia

Lixisenatide in patients with type 2 diabetes and obesity: Beyond glycaemic control

To evaluate tolerance to lixisenatide and its effects on weight and metabolic control in type2 diabetes and obese patients. DESIGN: Prospective study. SETTING: Endocrinology clinics in Almeria, Granada and Malaga. PARTICIPANTS: Patients with type2 diabetes and obesity. INTERVENTIONS: Response and tolerance to lixisenatide treatment. MAIN MEASUREMENTS: Clinical and analytical data of the subjects were evaluated at baseline and after treatment. RESULTS: The study included 104 patients (51% women) with type2 diabetes and obesity (Almeria 18.3%; Granada 40.4%; Malaga 41.3%). The mean age was 58.4±10.5years, and the mean duration of diabetes was 11.2±6.7years. The patients were re-evaluated at 3.8±1.6months after treatment with lixisenatide. Significant improvements were found in weight (P<.001), body mass index (P<.001), waist circumference (P=.002), systolic blood pressure (P<.001), diastolic blood pressure (P=.001), fasting glucose (P<.001), HbA1c (P=.022), Total cholesterol (P<.001), LDL-cholesterol (P=.046), triglycerides (P=.020), hypertension drugs (P<.001), and lipids drugs (P<.001). No changes were observed in levels of amylase related to lixisenatide treatment, and 7.9% of patients did not tolerate it. CONCLUSIONS: Lixisenatide achieved significant improvements in anthropometric parameters, glycaemic control (fasting glucose and HbA1c), blood pressure and lipids. It was safe and well tolerated in most patients. In addition, there was a significant increase in the use of antihypertensive and lipid-lowering therapy.Este trabajo ha sido financiado, en parte, con ayudas del Instituto de Salud Carlos III (PI15/01114) y de la Consejería de Innovación, Ciencia y Empresa de la Junta de Andalucía (PI11-CTS-8181). Este estudio ha sido cofinanciado con fondos FEDER.YesObjetivo: Evaluar la tolerancia a lixisenatida y sus efectos sobre el peso y el control metabólico de pacientes con diabetes tipo 2 y obesidad. Diseño: ˜Estudio prospectivo. Emplazamiento: Consultas de atención especializada de Endocrinología y Nutrición en Almería, Granada y Málaga. Participantes: Pacientes con diabetes tipo 2 y obesidad. Intervenciones: Respuesta y tolerancia al tratamiento con lixisenatida. Mediciones principales: Se analizaron datos clínicos y analíticos con medidas de cambio intrasujeto antes-después del tratamiento. Resultados: Evaluamos 104 pacientes (51% mujeres) con diabetes tipo 2 y obesidad (Almería 18,3%; Granada 40,4%; Málaga 41,3%). Edad media 58,4 ± 10,5 anos ˜ y duración media de diabetes 11,2 ± 6,7 anos. ˜ El tiempo medio desde la visita basal a la revisión tras inicio de tratamiento con lixisenatida fue de 3,8 ± 1,6 meses. Encontramos mejoría significativa del peso (p < 0,001)índice de masa corporal (p < 0,001), circunferencia de cintura (p = 0,002), presión arterial sistólica (p < 0,001) y diastólica (p = 0,001), glucemia en ayunas (p < 0,001), HbA1c (p = 0,022), colesterol total (p < 0,001), colesterol LDL (p = 0,046) y triglicéridos (p = 0,020). No se observó alteración de cifras de amilasa en relación con el tratamiento con lixisenatida, y el 7,9% no lo toleraron. Conclusiones: Lixisenatida consigue: 1) mejoría significativa de parámetros antropométricos ycontrol glucémico (glucemia basal y HbA1c); 2) descenso significativo de la presión arterial y del perfil lipídico, y 3) seguridad y buena tolerancia en la mayoría de los pacientes. Además, encontramos una significativa intensificación del tratamiento antihipertensivo e hipolipemiante

MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma

Item does not contain fulltextPURPOSE: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. Design: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. RESULTS: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. CONCLUSIONS: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients

Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial

Background: We aimed to assess efficacy and safety, with a special focus on cardiovascular safety, of the novel dual GIP and GLP-1 receptor agonist tirzepatide versus insulin glargine in adults with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications. Methods: This open-label, parallel-group, phase 3 study was done in 187 sites in 14 countries on five continents. Eligible participants, aged 18 years or older, had type 2 diabetes treated with any combination of metformin, sulfonylurea, or sodium-glucose co-transporter-2 inhibitor, a baseline glycated haemoglobin (HbA1c) of 7·5–10·5% (58–91 mmol/mol), body-mass index of 25 kg/m2 or greater, and established cardiovascular disease or a high risk of cardiovascular events. Participants were randomly assigned (1:1:1:3) via an interactive web-response system to subcutaneous injection of either once-per-week tirzepatide (5 mg, 10 mg, or 15 mg) or glargine (100 U/mL), titrated to reach fasting blood glucose of less than 100 mg/dL. The primary endpoint was non-inferiority (0·3% non-inferiority boundary) of tirzepatide 10 mg or 15 mg, or both, versus glargine in HbA1c change from baseline to 52 weeks. All participants were treated for at least 52 weeks, with treatment continued for a maximum of 104 weeks or until study completion to collect and adjudicate major adverse cardiovascular events (MACE). Safety measures were assessed over the full study period. This study was registered with ClinicalTrials.gov, NCT03730662. Findings: Patients were recruited between Nov 20, 2018, and Dec 30, 2019. 3045 participants were screened, with 2002 participants randomly assigned to tirzepatide or glargine. 1995 received at least one dose of tirzepatide 5 mg (n=329, 17%), 10 mg (n=328, 16%), or 15 mg (n=338, 17%), or glargine (n=1000, 50%), and were included in the modified intention-to-treat population. At 52 weeks, mean HbA1c changes with tirzepatide were −2·43% (SD 0·05) with 10 mg and −2·58% (0·05) with 15 mg, versus −1·44% (0·03) with glargine. The estimated treatment difference versus glargine was −0·99% (multiplicity adjusted 97·5% CI −1·13 to −0·86) for tirzepatide 10 mg and −1·14% (−1·28 to −1·00) for 15 mg, and the non-inferiority margin of 0·3% was met for both doses. Nausea (12–23%), diarrhoea (13–22%), decreased appetite (9–11%), and vomiting (5–9%) were more frequent with tirzepatide than glargine (nausea 2%, diarrhoea 4%, decreased appetite &lt;1%, and vomiting 2%, respectively); most cases were mild to moderate and occurred during the dose-escalation phase. The percentage of participants with hypoglycaemia (glucose &lt;54 mg/dL or severe) was lower with tirzepatide (6–9%) versus glargine (19%), particularly in participants not on sulfonylureas (tirzepatide 1–3% vs glargine 16%). Adjudicated MACE-4 events (cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina) occurred in 109 participants and were not increased on tirzepatide compared with glargine (hazard ratio 0·74, 95% CI 0·51–1·08). 60 deaths (n=25 [3%] tirzepatide; n=35 [4%] glargine) occurred during the study. Interpretation: In people with type 2 diabetes and elevated cardiovascular risk, tirzepatide, compared with glargine, demonstrated greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycaemia at week 52. Tirzepatide treatment was not associated with excess cardiovascular risk. Funding: Eli Lilly and Company

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke