A greater proportion of participants with type 2 diabetes achieve treatment targets with insulin degludec/liraglutide versus insulin glargine 100 units/mL at 26 weeks. DUAL VIII, a randomized trial designed to resemble clinical practice

This report presents the efficacy and safety of insulin degludec/liraglutide (IDegLira) versus insulin glargine 100 units/mL (IGlar U100) as initial injectable therapy at 26 weeks in the 104-week DUAL VIII durability trial (NCT02501161). Participants (N = 1012) with type 2 diabetes (T2D) uncontrolled on oral antidiabetic drugs (OADs) were randomized 1:1 to open-label IDegLira or IGlar U100. Visits were scheduled at weeks 1, 2, 4 and 12, and every 3 months thereafter. After 26 weeks, glycated haemoglobin (HbA1c) reductions were greater with IDegLira versus IGlar U100 (−21.5 vs. –16.4 mmol/mol [−2.0 vs. –1.5%]), as was the percentage of participants achieving HbA1c <53 mmol/mol (78.7% vs. 55.7%) and HbA1c targets without weight gain and/or hypoglycaemia. Estimated treatment differences for insulin dose (−13.01 U) and body weight change (−1.57 kg) significantly favoured IDegLira. The hypoglycaemia rate was 44% lower with IDegLira versus IGlar U100. Safety results were similar. In a trial resembling clinical practice, more participants receiving IDegLira than IGlar U100 met treatment targets, supporting use of IDegLira as an initial injectable therapy for people with T2D uncontrolled on OADs and eligible for insulin initiation

Effectiveness and Safety of iGlarLixi (Insulin Glargine 100 U/mL Plus Lixisenatide) in Type 2 Diabetes According to the Timing of Daily Administration: Data from the REALI Pooled Analysis

INTRODUCTION: iGlarLixi (insulin glargine 100 U/mL plus lixisenatide) has demonstrated glycaemic efficacy and safety in adults with inadequately controlled type 2 diabetes mellitus (T2DM). Per the European Medicines Agency's product label, iGlarLixi should be injected once a day within 1 h prior to a meal, preferably the same meal every day when the most convenient meal has been chosen. It is however unknown whether iGlarLixi administration timing affects glycaemic control and safety, as clinical trial evidence is mainly based on pre-breakfast iGlarLixi administration. Therefore, we assessed the effectiveness and safety of iGlarLixi in clinical practice, according to its administration timing. METHODS: Data were pooled from two prospective observational studies including 1303 European participants with T2DM inadequately controlled on oral antidiabetic drugs with or without basal insulin who initiated iGlarLixi therapy for 24 weeks. Participants were classified into four subgroups based on daily timing of iGlarLixi injection: pre-breakfast (N = 436), pre-lunch (N = 262), pre-dinner (N = 399), and those who switched iGlarLixi injection time during the study (N = 206). RESULTS: No meaningful differences in baseline characteristics were observed between the study groups. Least-squares mean reductions in haemoglobin A1c (HbA1c) from baseline to week 24 were substantial in all groups, with the numerically largest decrease observed in the pre-breakfast group (1.57%) compared with the pre-lunch (1.27%), pre-dinner (1.42%), or changed injection time (1.33%) groups. Pre-breakfast iGlarLixi injection also resulted in a numerically greater proportion of participants achieving HbA1c < 7.0% at week 24 (33.7% versus 19.0% for pre-lunch, 25.6% pre-dinner, and 23.2% changed injection time). iGlarLixi was well tolerated across all groups, with low rates of gastrointestinal disorders and hypoglycaemia. Mean body weight decreased similarly in all groups (by 1.3-2.3 kg). CONCLUSION: iGlarLixi was effective and safe regardless of its daily administration time. However, pre-breakfast iGlarLixi injection resulted in a more effective glycaemic control

iGlarLixi (insulin glargine 100 U/ml plus lixisenatide) is effective and well tolerated in people with uncontrolled type 2 diabetes regardless of age: A REALI pooled analysis of prospective real-world data

AIM: To evaluate the effectiveness and safety in routine clinical practice of insulin glargine/lixisenatide (iGlarLixi) in people with type 2 diabetes (T2D) according to age. METHODS: Patient-level data were pooled from 1316 adults with T2D inadequately controlled on oral antidiabetic drugs with or without basal insulin who initiated iGlarLixi for 24 weeks. Participants were classified into age subgroups of younger than 65 years (N = 806) and 65 years or older (N = 510). RESULTS: Compared with participants aged younger than 65 years, those aged 65 years or older had a numerically lower mean body mass index (31.6 vs. 32.6 kg/m2 ), a longer median diabetes duration (11.0 vs. 8.0 years), were more likely to receive prior basal insulin (48.4% vs. 43.5%) and had a lower mean HbA1c (8.93% [74.10 mmol/mol] vs. 9.22% [77.28 mmol/mol]). Similar and clinically relevant reductions in HbA1c and fasting plasma glucose from baseline to week 24 of iGlarLixi therapy were observed regardless of age. At 24 weeks, least-squares adjusted mean (95% confidence interval [CI]) change in HbA1c from baseline was -1.55% (-1.65% to -1.44%) in those aged 65 years or older and -1.42% (-1.50% to -1.33%) in those aged younger than 65 years (95% CI: -0.26% to 0.00%; P = .058 between subgroups). Low incidences of gastrointestinal adverse events and hypoglycaemic episodes were reported in both age subgroups. iGlarLixi decreased mean body weight from baseline to week 24 in both subgroups (-1.6 kg in those aged ≥ 65 years and -2.0 kg in those aged < 65 years). CONCLUSIONS: iGlarLixi is effective and well tolerated in both younger and older people with uncontrolled T2D

Characterization of Artifact Influence on the Classification of Glucose Time Series Using Sample Entropy Statistics

[EN] This paper analyses the performance of SampEn and one of its derivatives, Fuzzy Entropy (FuzzyEn), in the context of artifacted blood glucose time series classification. This is a difficult and practically unexplored framework, where the availability of more sensitive and reliable measures could be of great clinical impact. Although the advent of new blood glucose monitoring technologies may reduce the incidence of the problems stated above, incorrect device or sensor manipulation, patient adherence, sensor detachment, time constraints, adoption barriers or affordability can still result in relatively short and artifacted records, as the ones analyzed in this paper or in other similar works. This study is aimed at characterizing the changes induced by such artifacts, enabling the arrangement of countermeasures in advance when possible. Despite the presence of these disturbances, results demonstrate that SampEn and FuzzyEn are sufficiently robust to achieve a significant classification performance, using records obtained from patients with duodenal-jejunal exclusion. The classification results, in terms of area under the ROC of up to 0.9, with several tests yielding AUC values also greater than 0.8, and in terms of a leave-one-out average classification accuracy of 80%, confirm the potential of these measures in this context despite the presence of artifacts, with SampEn having slightly better performance than FuzzyEn.The Czech partners were supported by DROIKEM000023001 and RVOVFN64165. No funding was received to support this research work by the Spanish partners.Cuesta Frau, D.; Novák, D.; Burda, V.; Molina Picó, A.; Vargas-Rojo, B.; Mraz, M.; Kavalkova, P.... (2018). Characterization of Artifact Influence on the Classification of Glucose Time Series Using Sample Entropy Statistics. Entropy. 20(11):1-18. https://doi.org/10.3390/e20110871S118201

Clinical Evaluation of Subcutaneous Lactate Measurement in Patients after Major Cardiac Surgery

Minimally invasive techniques to access subcutaneous adipose tissue for glucose monitoring are successfully applied in type1 diabetic and critically ill patients. During critical illness, the addition of a lactate sensor might enhance prognosis and early intervention. Our objective was to evaluate SAT as a site for lactate measurement in critically ill patients. In 40 patients after major cardiac surgery, arterial blood and SAT microdialysis samples were taken in hourly intervals. Lactate concentrations from SAT were prospectively calibrated to arterial blood. Analysis was based on comparison of absolute lactate concentrations (arterial blood vs. SAT) and on a 6-hour lactate trend analysis, to test whether changes of arterial lactate can be described by SAT lactate. Correlation between lactate readings from arterial blood vs. SAT was highly significant (r2 = 0.71, P < .001). Nevertheless, 42% of SAT lactate readings and 35% of the SAT lactate trends were not comparable to arterial blood. When a 6-hour stabilization period after catheter insertion was introduced, 5.5% of SAT readings and 41.6% of the SAT lactate trends remained incomparable to arterial blood. In conclusion, replacement of arterial blood lactate measurements by readings from SAT is associated with a substantial shortcoming in clinical predictability in patients after major cardiac surgery

Influence of Duodenal-Jejunal Implantation on Glucose Dynamics: A Pilot Study Using Different Nonlinear Methods

[EN] Diabetes is a disease of great and rising prevalence, with the obesity epidemic being a significant contributing risk factor. Duodenal¿jejunal bypass liner (DJBL) is a reversible implant that mimics the effects of more aggressive surgical procedures, such as gastric bypass, to induce weight loss. We hypothesized that DJBL also influences the glucose dynamics in type II diabetes, based on the induced changes already demonstrated in other physiological characteristics and parameters. In order to assess the validity of this assumption, we conducted a quantitative analysis based on several nonlinear algorithms (Lempel¿Ziv Complexity, Sample Entropy, Permutation Entropy, and modified Permutation Entropy), well suited to the characterization of biomedical time series. We applied them to glucose records drawn from two extreme cases available of DJBL implantation: before and after 10 months. The results confirmed the hypothesis and an accuracy of 86.4% was achieved with modified Permutation Entropy. Other metrics also yielded significant classification accuracy results, all above 70%, provided a suitable parameter configuration was chosen. With the Leave¿One¿Out method, the results were very similar, between 72% and 82% classification accuracy. There was also a decrease in entropy of glycaemia records during the time interval studied. These findings provide a solid foundation to assess how glucose metabolism may be influenced by DJBL implantation and opens a new line of research in this field.The Czech clinical partners were supported by DRO IKEM 000023001 and RVO VFN 64165. The Czech technical partners were supported by Research Centre for Informatics grant numbers CZ.02.1.01/0.0/16 - 019/0000765 and SGS16/231/OHK3/3T/13-Support of interactive approaches to biomedical data acquisition and processing. No funding was received to support this research work by the Spanish and British partnersCuesta Frau, D.; Novák, D.; Burda, V.; Abasolo, D.; Adjei, T.; Varela, M.; Vargas, B.... (2019). Influence of Duodenal-Jejunal Implantation on Glucose Dynamics: A Pilot Study Using Different Nonlinear Methods. Complexity. 2019. https://doi.org/10.1155/2019/6070518S2019Kassirer, J. P., & Angell, M. (1998). Losing Weight — An Ill-Fated New Year’s Resolution. New England Journal of Medicine, 338(1), 52-54. doi:10.1056/nejm199801013380109Van Gaal, L., & Dirinck, E. (2016). Pharmacological Approaches in the Treatment and Maintenance of Weight Loss. Diabetes Care, 39(Supplement 2), S260-S267. doi:10.2337/dcs15-3016De Jonge, C., Rensen, S. S., Verdam, F. J., Vincent, R. P., Bloom, S. R., Buurman, W. A., … Greve, J. W. M. (2015). Impact of Duodenal-Jejunal Exclusion on Satiety Hormones. 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Differential Mammary Gland Development in FVB and C57Bl/6 Mice: Implications for Breast Cancer Research

A growing body of research suggests a linkage between pubertal mammary gland development and environmental factors such as diet as modifiers of long term breast cancer risk. Much of this research is dependent upon mouse models, which may vary between studies. However, effects may be strain dependent and further modified by diet, which has not been previously examined. Therefore, the objective of the present study was to determine whether mammary gland development differs between FVB and C57Bl/6 strains on diets containing either n-6 or n-3 polyunsaturated fats. Developmental measures related to onset of puberty and mammary gland development differed between strains. Mice fed the n-3 polyunsaturated fatty acids (PUFA) diet were shown to have lower numbers of terminal end buds, a marker of mammary gland development. This study helps to further clarify differences in development and dietary response between FVB and C57Bl/6 mice in order to more appropriately relate mammary gland research to human populations

Adoption of the ADA/EASD guidelines in 10 Eastern and Southern European countries: Physician survey and good clinical practice recommendations from an international expert panel

Aims: Evidence from cardiovascular outcomes trials (CVOTs) of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors was reflected in the most recent guidelines from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). The aim of the present study was to assess the adoption of the ADA/EASD guidelines in a convenience sample of physicians from Eastern and Southern Europe, the barriers to the implementation of these guidelines and the measures needed to facilitate their implementation. Methods: Attendees at two international diabetes conferences could volunteer to respond to a fully anonymous survey. Responses were analysed descriptively and a panel of experts from around the region was consulted to interpret the survey results. Results: Responses (n = 96) from 10 countries were analysed. Most participants (63.4%) considered the ADA/EASD guidelines fundamental to their practice. All respondents saw the value of the CVOT-based ADA/EASD recommendations and 77-80% generally implemented them. Measures suggested to improve adherence to the ADA/EASD guidelines included aligning reimbursement policy with the guidelines (54.4%), publishing guidelines in a simple and concise form (42.4%) and translating guidelines into local languages (33.3%). Conclusions: Aligning reimbursement with recent evidence and providing short summaries of the ADA/EASD guidelines in local languages could facilitate physician adherence.(c) 2020 The Author. Published by Elsevier B.V. This is an open access article under the CC BY NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Dysregulation of epicardial adipose tissue in cachexia due to heart failure. the role of natriuretic peptides and cardiolipin

Background: Cachexia worsens long-term prognosis of patients with heart failure (HF). Effective treatment of cachexia is missing. We seek to characterize mechanisms of cachexia in adipose tissue, which could serve as novel targets for the treatment. Methods: The study was conducted in advanced HF patients (n&nbsp;=&nbsp;52; 83% male patients) undergoing heart transplantation. Patients with ≥7.5% non-intentional body weight (BW) loss during the last 6&nbsp;months were rated cachectic. Clinical characteristics and circulating markers were compared between cachectic (n&nbsp;=&nbsp;17) and the remaining, BW-stable patients. In epicardial adipose tissue (EAT), expression of selected genes was evaluated, and a combined metabolomic/lipidomic analysis was performed to assess (i) the role of adipose tissue metabolism in the development of cachexia and (ii) potential impact of cachexia-associated changes on EAT-myocardium environment. Results: Cachectic vs. BW-stable patients had higher plasma levels of natriuretic peptide B (BNP; 2007&nbsp;±&nbsp;1229 vs. 1411&nbsp;±&nbsp;1272&nbsp;pg/mL; P&nbsp;=&nbsp;0.010) and lower EAT thickness (2.1&nbsp;±&nbsp;0.8 vs. 2.9&nbsp;±&nbsp;1.4&nbsp;mm; P&nbsp;=&nbsp;0.010), and they were treated with ~2.5-fold lower dose of both β-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACE/ARB-inhibitors). The overall pattern of EAT gene expression suggested simultaneous activation of lipolysis and lipogenesis in cachexia. Lower ratio between expression levels of natriuretic peptide receptors C and A was observed in cachectic vs. BW-stable patients (0.47 vs. 1.30), supporting activation of EAT lipolysis by natriuretic peptides. Fundamental differences in metabolome/lipidome between BW-stable and cachectic patients were found. Mitochondrial phospholipid cardiolipin (CL), specifically the least abundant CL 70:6 species (containing C16:1, C18:1, and C18:2 acyls), was the most discriminating analyte (partial least squares discriminant analysis; variable importance in projection score&nbsp;=&nbsp;4). Its EAT levels were higher in cachectic as compared with BW-stable patients and correlated with the degree of BW loss during the last 6&nbsp;months (r&nbsp;=&nbsp;−0.94; P&nbsp;=&nbsp;0.036). Conclusions: Our results suggest that (i) BNP signalling contributes to changes in EAT metabolism in cardiac cachexia and (ii) maintenance of stable BW and ‘healthy’ EAT-myocardium microenvironment depends on the ability to tolerate higher doses of both ACE/ARB inhibitors and β-adrenergic blockers. In line with preclinical studies, we show for the first time in humans the association of cachexia with increased adipose tissue levels of CL. Specifically, CL 70:6 could precipitate wasting of adipose tissue, and thus, it could represent a therapeutic target to ameliorate cachexia