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

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

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

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. Obesity Surgery, 26(3), 672-678. doi:10.1007/s11695-015-1889-yMuñoz, R., Dominguez, A., Muñoz, F., Muñoz, C., Slako, M., Turiel, D., … Escalona, A. (2013). Baseline glycated hemoglobin levels are associated with duodenal-jejunal bypass liner-induced weight loss in obese patients. Surgical Endoscopy, 28(4), 1056-1062. doi:10.1007/s00464-013-3283-yOgata, H., Tokuyama, K., Nagasaka, S., Ando, A., Kusaka, I., Sato, N., … Yamamoto, Y. (2007). Long-range Correlated Glucose Fluctuations in Diabetes. Methods of Information in Medicine, 46(02), 222-226. doi:10.1055/s-0038-1625411Rodríguez de Castro, C., Vigil, L., Vargas, B., García Delgado, E., García Carretero, R., Ruiz-Galiana, J., & Varela, M. (2016). Glucose time series complexity as a predictor of type 2 diabetes. Diabetes/Metabolism Research and Reviews, 33(2), e2831. doi:10.1002/dmrr.2831DeFronzo, R. A. (2004). Pathogenesis of type 2 diabetes mellitus. Medical Clinics of North America, 88(4), 787-835. doi:10.1016/j.mcna.2004.04.013Zhang, X.-S., Roy, R. J., & Jensen, E. W. (2001). EEG complexity as a measure of depth of anesthesia for patients. IEEE Transactions on Biomedical Engineering, 48(12), 1424-1433. doi:10.1109/10.966601Bandt, C., & Pompe, B. (2002). Permutation Entropy: A Natural Complexity Measure for Time Series. Physical Review Letters, 88(17). doi:10.1103/physrevlett.88.174102Bian, C., Qin, C., Ma, Q. D. Y., & Shen, Q. (2012). Modified permutation-entropy analysis of heartbeat dynamics. Physical Review E, 85(2). doi:10.1103/physreve.85.021906Zhao, L., Wei, S., Zhang, C., Zhang, Y., Jiang, X., Liu, F., & Liu, C. (2015). Determination of Sample Entropy and Fuzzy Measure Entropy Parameters for Distinguishing Congestive Heart Failure from Normal Sinus Rhythm Subjects. Entropy, 17(12), 6270-6288. doi:10.3390/e17096270Weinstein, R. L., Schwartz, S. L., Brazg, R. L., Bugler, J. R., Peyser, T. A., & McGarraugh, G. V. (2007). Accuracy of the 5-Day FreeStyle Navigator Continuous Glucose Monitoring System: Comparison with frequent laboratory reference measurements. Diabetes Care, 30(5), 1125-1130. doi:10.2337/dc06-1602Weber, C., & Schnell, O. (2009). The Assessment of Glycemic Variability and Its Impact on Diabetes-Related Complications: An Overview. Diabetes Technology & Therapeutics, 11(10), 623-633. doi:10.1089/dia.2009.0043Cuesta-Frau, D., Miró-Martínez, P., Oltra-Crespo, S., Jordán-Núñez, J., Vargas, B., González, P., & Varela-Entrecanales, M. (2018). Model Selection for Body Temperature Signal Classification Using Both Amplitude and Ordinality-Based Entropy Measures. Entropy, 20(11), 853. doi:10.3390/e20110853Cuesta–Frau, D., Miró–Martínez, P., Oltra–Crespo, S., Jordán–Núñez, J., Vargas, B., & Vigil, L. (2018). Classification of glucose records from patients at diabetes risk using a combined permutation entropy algorithm. Computer Methods and Programs in Biomedicine, 165, 197-204. doi:10.1016/j.cmpb.2018.08.018Cuesta–Frau, D., Varela–Entrecanales, M., Molina–Picó, A., & Vargas, B. (2018). Patterns with Equal Values in Permutation Entropy: Do They Really Matter for Biosignal Classification? Complexity, 2018, 1-15. doi:10.1155/2018/1324696Mayer, C. C., Bachler, M., Hörtenhuber, M., Stocker, C., Holzinger, A., & Wassertheurer, S. (2014). Selection of entropy-measure parameters for knowledge discovery in heart rate variability data. BMC Bioinformatics, 15(S6). doi:10.1186/1471-2105-15-s6-s2Sheng Lu, Xinnian Chen, Kanters, J. K., Solomon, I. C., & Chon, K. H. (2008). Automatic Selection of the Threshold Value $r$ for Approximate Entropy. IEEE Transactions on Biomedical Engineering, 55(8), 1966-1972. doi:10.1109/tbme.2008.919870Crenier, L., Lytrivi, M., Van Dalem, A., Keymeulen, B., & Corvilain, B. (2016). Glucose Complexity Estimates Insulin Resistance in Either Nondiabetic Individuals or in Type 1 Diabetes. The Journal of Clinical Endocrinology & Metabolism, 101(4), 1490-1497. doi:10.1210/jc.2015-4035Cuesta, D., Varela, M., Miró, P., Galdós, P., Abásolo, D., Hornero, R., & Aboy, M. (2007). Predicting survival in critical patients by use of body temperature regularity measurement based on approximate entropy. Medical & Biological Engineering & Computing, 45(7), 671-678. doi:10.1007/s11517-007-0200-3Chen, W., Zhuang, J., Yu, W., & Wang, Z. (2009). Measuring complexity using FuzzyEn, ApEn, and SampEn. Medical Engineering & Physics, 31(1), 61-68. doi:10.1016/j.medengphy.2008.04.005Xiao-Feng, L., & Yue, W. (2009). Fine-grained permutation entropy as a measure of natural complexity for time series. Chinese Physics B, 18(7), 2690-2695. doi:10.1088/1674-1056/18/7/011Fadlallah, B., Chen, B., Keil, A., & Príncipe, J. (2013). 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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/)

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

Modulacni vliv scavengeru kyslikovych radikalu methylenove modri na endokrinni system

Available from STL Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi

A Plant-Based Meal Stimulates Incretin and Insulin Secretion More Than an Energy- and Macronutrient-Matched Standard Meal in Type 2 Diabetes: A Randomized Crossover Study

Diminished postprandial secretion of incretins and insulin represents one of the key pathophysiological mechanisms behind type 2 diabetes (T2D). We tested the effects of two energy- and macronutrient-matched meals: A standard meat (M-meal) and a vegan (V-meal) on postprandial incretin and insulin secretion in participants with T2D. A randomized crossover design was used in 20 participants with T2D. Plasma concentrations of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), amylin, and gastric inhibitory peptide (GIP) were determined at 0, 30, 60, 120, and 180 min. Beta-cell function was assessed with a mathematical model, using C-peptide deconvolution. Repeated-measures ANOVA was used for statistical analysis. Postprandial plasma glucose responses were similar after both test meals (p = 0.64). An increase in the stimulated secretion of insulin (by 30.5%; 95% CI 21.2 to 40.7%; p &lt; 0.001), C-peptide (by 7.1%; 95% CI 4.1 to 9.9%; p &lt; 0.001), and amylin (by 15.7%; 95% CI 11.8 to 19.7%; p &lt; 0.001) was observed following consumption of the V-meal. An increase in stimulated secretion of GLP-1 (by 19.2%; 95% CI 12.4 to 26.7%; p &lt; 0.001) and a decrease in GIP (by &#8722;9.4%; 95% CI &#8722;17.3 to &#8722;0.7%; p = 0.02) were observed after the V-meal. Several parameters of beta-cell function increased after the V-meal, particularly insulin secretion at a fixed glucose value 5 mmol/L, rate sensitivity, and the potentiation factor. Our results showed an increase in postprandial incretin and insulin secretion, after consumption of a V-meal, suggesting a therapeutic potential of plant-based meals for improving beta-cell function in T2D