Cancer risks of anti-hyperglycemic drugs for type 2 diabetes treatment - a clinical appraisal

AIM: A clinical appraisal of existing scientific literature sought to assess the need for long-term prospective epidemiological studies to investigate an increased cancer risk of anti-hyperglycemic medication in type 2 diabetes. METHOD: A focus statement was formulated as: "With a higher risk of cancers in patients with type 2 diabetes, all anti-hyperglycemic drugs should undergo long-term, prospective epidemiological studies for cancer risks." Field surveys were sent to practicing physicians and endocrinologists to identify the currently prevalent level of acceptance of this statement. Subsequently, a meeting with a six-member panel of key opinion leaders was held to discuss published evidence in support and against the statement. This publication reviews the publications and discussion points brought forth in this meeting and their effect on statement acceptance by the panel. RESULTS: Whereas the majority of field survey responders primarily agreed with the statement, panel members were divided in their statement support. This division remained intact after review of the literature. CONCLUSIONS: While there was evidence that type 2 diabetes is associated with an increased risk of cancer, existing studies seemed insufficient to definitively demonstrate a link between cancer risk and use of specific anti-hyperglycemic therapies

Fixed-ratio combination of insulin degludec and liraglutide (IDegLira) improves cardiovascular risk markers in patients with type 2 diabetes uncontrolled on basal insulin

In this post hoc analysis we investigated the effects of insulin degludec/liraglutide fixed-ratio combination (IDegLira) versus comparators on cardiovascular (CV) risk markers in participants in the DUAL II (vs. insulin degludec), DUAL V (vs. insulin glargine 100 units/mL) and DUAL VII (vs. basal-bolus therapy) trials, grouped by sex, age (<65 years, ≥65 years) and diabetes duration (<10 years, ≥10 years). Treatment contrasts were in favour of IDegLira in many subgroups for changes from baseline in glycated haemoblogin (DUAL II, DUAL V), body weight (all three trials), systolic blood pressure (BP; all three trials), HDL cholesterol (DUAL VII) and LDL cholesterol (DUAL II, DUAL V). Higher heart rates were seen with IDegLira versus comparators (all three trials) plus significantly higher diastolic BP in men (DUAL V). Differences in treatment effect were seen between sexes in waist circumference (DUAL II), systolic BP (DUAL II, DUAL V) and triglycerides (DUAL VII), and between diabetes durations in LDL cholesterol (DUAL V). In conclusion, IDegLira is associated with a general improvement in CV risk markers compared with basal insulin or basal-bolus therapy after 26 weeks of treatment

Applying the SRL vs. ERL Theory to the Knowledge of Achievement Emotions in Undergraduate University Students

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpsyg. 2019.02070/full#supplementary-materialThe SRL vs.ERL Theory predicts that a student's own self-regulation and the regulatory nature of the context are factors that jointly determine the student's level of motivational-affective variables. However, this principle has not yet been verified in the case of achievement emotions. The aim of this research was to test this prediction, with the hypothesis that students' level of self-regulation (low-medium-high), in interaction with the regulatory nature of the teaching (low-medium-high), would determine positive or negative emotions as well as the degree of burnout/engagement. A total of 440 university students completed validated questionnaires on self-regulation; regulatory teaching; achievement emotions in class, in study and in testing situations; and on burnout/engagement. Using a quasi-experimental design by selection, ANOVAs and MANOVAs (3 × 3; 5 × 1) were carried out. The results confirmed that the level of self-regulation and the level of external regulation jointly determined university students' level of achievement emotions, as well as their level of burnout/engagement. Based on these results, a five-level progressive scale was configured. We conclude that this scale may be useful and adequate as a heuristic technique or model for understanding and analyzing the type of student-teacher interaction that is taking place in the university classroom, and thereby learn the probability of stressful effects and the students' level of emotional health.R&D Project PGC2018-094672-B-I00 (Ministry of Science and Education, Spain), and UAL18-SEJ-DO31-A-FEDER (University of Almería, Spain), and the European Social Fund

Hypoxia and Hypoglycemia synergistically regulate mRNA stability

Ischemic events, common in many diseases, result from decreased blood flow and impaired delivery of oxygen and glucose to tissues of the body. While much is known about the cellular transcriptional response to ischemia, much less is known about the posttranscriptional response to oxygen and glucose deprivation. The goal of this project was to investigate one such posttranscriptional response, the regulation of mRNA stability. To that end, we have identified several novel ischemia-related mRNAs that are synergistically stabilized by oxygen and glucose deprivation including VEGF, MYC, MDM2, and CYR61. This increase in mRNA half-life requires the synergistic effects of both low oxygen (1%) as well as low glucose ( 1 g/L) conditions. Oxygen or glucose deprivation alone fails to initiate the response, as exposure to either high glucose (4 g/L) or normoxic conditions inhibits the response. Furthermore, in response to hypoxia/hypoglycemia, the identified mRNAs are released from the RNA binding protein KHSRP which likely contributes to their stabilization

Efficacy and Safety of Alirocumab in Individuals with Diabetes Mellitus:Pooled Analyses from Five Placebo-Controlled Phase 3 Studies

Introduction: Diabetes mellitus (DM) carries an elevated risk for cardiovascular disease. Here, we assessed alirocumab efficacy and safety in people with/without DM from five placebo-controlled phase 3 studies. Methods: Data from up to 78 weeks were analyzed in individuals on maximally tolerated background statin. In three studies, alirocumab 75 mg every 2 weeks (Q2W) was increased to 150 mg Q2W at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was ≥ 70 mg/dL; two studies used alirocumab 150 mg Q2W throughout. The primary endpoint was percentage change in LDL-C from baseline to week 24. Results: In the alirocumab 150 mg pool (n = 2416), baseline LDL-C levels were 117.4 mg/dL (DM) and 130.6 mg/dL (without DM), and in the 75/150 mg pool (n = 1043) 112.8 mg/dL (DM) and 133.0 mg/dL (without DM). In the 150 mg Q2W group, week 24 LDL-C reductions from baseline were observed in persons with DM (− 59.9%; placebo, − 1.4%) and without DM (− 60.6%; placebo, + 1.5%); 77.7% (DM) and 76.8% (without DM) of subjects achieved LDL-C < 70 mg/dL. In the alirocumab 75/150 mg group, 26% (DM) and 36% (without DM) of subjects received dose increase. In this group, week 24 LDL-C levels changed from baseline by − 43.8% (DM; placebo, + 0.3%) and − 49.7% (without DM; placebo, + 5.1%); LDL-C < 70 mg/dL was achieved by 68.3% and 65.8% of individuals, respectively. At week 24, alirocumab was also associated with improved levels of other lipids. Adverse event rates were generally comparable in all groups (79.8–82.0%). Conclusions: Regardless of DM status, alirocumab significantly reduced LDL-C levels; safety was generally similar. Funding Sanofi and Regeneron Pharmaceuticals, Inc. Plain Language Summary Plain language summary available for this article. Electronic supplementary material The online version of this article (10.1007/s13300-018-0439-8) contains supplementary material, which is available to authorized users

Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes : the randomised, head-to-head CONCLUDE trial

Aims/hypothesis A head-to-head randomised trial was conducted to evaluate hypoglycaemia safety with insulin degludec 200 U/ml (degludec U200) and insulin glargine 300 U/ml (glargine U300) in individuals with type 2 diabetes treated with basal insulin. Methods This randomised (1:1), open-label, treat-to-target, multinational trial included individuals with type 2 diabetes, aged ≥18 years with HbA1c ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m2. Participants were previously treated with basal insulin with or without oral glucose-lowering drugs (excluding insulin secretagogues) and had to fulfil at least one predefined criterion for hypoglycaemia risk. Both degludec U200 and glargine U300 were similarly titrated to a fasting blood glucose target of 4.0–5.0 mmol/l. Endpoints were assessed during a 36 week maintenance period and a total treatment period up to 88 weeks. There were three hypoglycaemia endpoints: (1) overall symptomatic hypoglycaemia (either severe, an event requiring third-party assistance, or confirmed by blood glucose [<3.1 mmol/l] with symptoms); (2) nocturnal symptomatic hypoglycaemia (severe or confirmed by blood glucose with symptoms, between 00:01 and 05:59 h); and (3) severe hypoglycaemia. The primary endpoint was the number of overall symptomatic hypoglycaemic events in the maintenance period. Secondary hypoglycaemia endpoints included the number of nocturnal symptomatic events and number of severe hypoglycaemic events during the maintenance period. Results Of the 1609 randomised participants, 733 of 805 (91.1%) in the degludec U200 arm and 734 of 804 (91.3%) in the glargine U300 arm completed the trial (87.3% and 87.8% completed on treatment, respectively). Baseline characteristics were comparable between the two treatment arms. For the primary endpoint, the rate of overall symptomatic hypoglycaemia was not significantly lower with degludec U200 vs glargine U300 (rate ratio [RR] 0.88 [95% CI 0.73, 1.06]). As there was no significant difference between treatments for the primary endpoint, the confirmatory testing procedure for superiority was stopped. The pre-specified confirmatory secondary hypoglycaemia endpoints were analysed using pre-specified statistical models but were now considered exploratory. These endpoints showed a lower rate of nocturnal symptomatic hypoglycaemia (RR 0.63 [95% CI 0.48, 0.84]) and severe hypoglycaemia (RR 0.20 [95% CI 0.07, 0.57]) with degludec U200 vs glargine U300. Conclusions/interpretation There was no significant difference in the rate of overall symptomatic hypoglycaemia with degludec U200 vs glargine U300 in the maintenance period. The rates of nocturnal symptomatic and severe hypoglycaemia were nominally significantly lower with degludec U200 during the maintenance period compared with glargine U300

Gad65 is recognized by t-cells, but not by antibodies from nod-mice

Since the 64kDa-protein glutamic acid decarboxylase (GAD) is one of the major autoantigens in T-cell mediated Type 1 diabetes, its relevance as a T-cell antigen needs to be clarified. After isolation of splenic T-cells from non-obese diabetic (NOD) mice, a useful model for human Type 1 diabetes, we found that these T-cells proliferate spontaneously when incubated with human GAD65, but only marginally after incubation with GAD67, both recombinated in the baculovirus system. No effect was observed with non-diabetic NOD mice or with T-cells from H-2 identical NON-NOD-H-2g7 control mice. It has been published previously that NOD mice develop autoantibodies against a 64kDa protein detected with mouse beta cells. In immunoprecipitation experiments with sera from the same NOD mice and 33S-methionine-labelled GAD, no autoantibody binding could be detected. We conclude firstly that GAD65 is an important T-cell antigen which is relevant early in the development of Type 1 diabetes and secondly that there is an antigenic epitope in the human GAD65 molecule recognized by NOD T-cells, but not by NOD autoantibodies precipitating conformational epitopes. Our results therefore provide further evidence that GAD65 is a T-cell antigen in NOD mice, being possibly also involved in very early processes leading to the development of human Type 1 diabetes

Hacia un nuevo modelo económico

El Seminario Nacional sobre Alternativas para la Economía Mexicana desarrolló un análisis integral de la situación y perspectivas de la economía mexicana bajo el actual entorno mundial, con el propósito de determinar las alternativas viables de política económica que permitan a México lograr un crecimiento económico sostenido con menor vulnerabilidad externa y mejor distribución del ingreso en el marco de un desarrollo ambientalmente sustentable. Convocado por centros de investigación y docencia de la UNAM, UAM, U de G., IPN, UIA, UAP, UPN, UACH, UAS, UNISON, UAEM, UAZ, UADY, UAJ, UNACH y COLSON, el Seminario contó con la participación de más de trescientos científicos sociales de importantes instituciones académicas del país (además de las mencionadas, UANI, COLMEX, ITESM, ITAM, COLEF, COLMICH, CIAD, U. la Salle, etc.) y se celebró en dos grandes fases: seminarios modulares por bloques temáticos, realizados en diversas sedes del país en el curso de octubre de 1993, y un seminario general, realizado en noviembre, que abordó el conjunto de la problemática económica y social de México y las alternativas viables de desarrollo económico con equidad. El análisis interdisciplinario y multidisciplinario de la economía mexicana y de su entorno internacional arrojó resultados altamente relevantes en tres grandes direcciones: 1) la determinación de los márgenes de libertad que el entorno económico mundial otorga a México para el diseño e instrumentación de una nueva estrategia de desarrollo económico; 2) la evaluación objetiva, basada en las evidencias empíricas, de los principios, instrumentos y resultados de las políticas neoliberales de ajuste económico y estabilización instrumentadas en México a partir de 1983; 3) la delineación de los principios e instrumentos fundamentales de una estrategia alternativa de desarrollo incluyente de la mayoría de los mexicanos y asentada en equilibrios macroeconómicos sólidos derivados del fortalecimiento de nuestra economía real y del bienestar mexicanos. Este volumen incluye versiones revisadas de trabajos presentados en el Seminario, así como contribuciones especiales elaboradas por sus autores en 1997

Hypoglycaemia in Type 2 diabetes

The primary cause of hypoglycaemia in Type 2 diabetes is diabetes medication—in particular, those which raise insulin levels independently of blood glucose, such as sulphonylureas (SUs) and exogenous insulin. The risk of hypoglycaemia is increased in older patients, those with longer diabetes duration, lesser insulin reserve and perhaps in the drive for strict glycaemic control. Differing definitions, data collection methods, drug type/regimen and patient populations make comparing rates of hypoglycaemia difficult. It is clear that patients taking insulin have the highest rates of self-reported severe hypoglycaemia (25% in patients who have been taking insulin for > 5 years). SUs are associated with significantly lower rates of severe hypoglycaemia. However, large numbers of patients take SUs in the UK, and it is estimated that each year > 5000 patients will experience a severe event caused by their SU therapy which will require emergency intervention. Hypoglycaemia has substantial clinical impact, in terms of mortality, morbidity and quality of life. The cost implications of severe episodes—both direct hospital costs and indirect costs—are considerable: it is estimated that each hospital admission for severe hypoglycaemia costs around £1000. Hypoglycaemia and fear of hypoglycaemia limit the ability of current diabetes medications to achieve and maintain optimal levels of glycaemic control. Newer therapies, which focus on the incretin axis, may carry a lower risk of hypoglycaemia. Their use, and more prudent use of older therapies with low risk of hypoglycaemia, may help patients achieve improved glucose control for longer, and reduce the risk of diabetic complications

Effects of semaglutide on stroke subtypes in type 2 diabetes: post hoc analysis of the randomised SUSTAIN 6 & PIONEER 6

This is the final version. Available on open access from Lippincott, Williams & Wilkins via the DOI in this record Background: Glucagon-like peptide-1 receptor agonists, including semaglutide, may reduce stroke risk in people with type 2 diabetes (T2D). This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with T2D at high cardiovascular (CV) risk. Methods: SUSTAIN 6 and PIONEER 6 were randomised CV outcome trials of subcutaneous and oral semaglutide in people with T2D at high CV risk, respectively. Time to first stroke and stroke subtypes were analysed using a Cox proportional hazards model stratified by trial with pooled treatment as a factor. The impact of prior stroke, prior myocardial infarction or stroke, age, sex, systolic blood pressure, estimated glomerular filtration rate, and prior atrial fibrillation on treatment effects was assessed using interaction p-values. Risk of major adverse CV event (MACE) was analysed according to prior stroke. Results: 106/6480 participants had a stroke (1.0 event/100 patient-years of observation [PYO]). Semaglutide reduced incidence of any stroke versus placebo (0.8 vs 1.1 events/100 PYO; HR 0.68, 95%CI 0.46–1.00;p=0.048), driven by significant reductions in risk of small-vessel occlusion (0.3 vs 0.7 events/100 PYO; HR 0.51, 95%CI 0.29–0.89;p=0.017). HRs for risk of any stroke with semaglutide versus placebo were 0.60 (95%CI 0.37–0.99; 0.5 vs 0.9 events/100 PYO) and 0.89 (95%CI 0.47–1.69; 2.7 vs 3.0 events/100 PYO) in those without and with prior stroke, respectively. Except for prior atrial fibrillation (pinteraction=0.025), no significant interactions were observed between treatment effects on risk of any stroke and subgroups investigated, or between treatment effects on risk of MACE and prior stroke (pinteraction>0.05 for all). Conclusions: Semaglutide reduced incidence of any first stroke during the trials versus placebo in people with T2D at high CV risk, primarily driven by small-vessel occlusion prevention. Semaglutide treatment, versus placebo, lowered the risk of stroke irrespective of prior stroke at baseline. Clinical Trial Registration Information: SUSTAIN 6: NCT01720446 (https://clinicaltrials.gov/ct2/show/NCT01720446); PIONEER 6: NCT02692716 (https://clinicaltrials.gov/ct2/show/NCT02692716).Novo Nordisk A/S (Søborg, Denmark