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Journal Cover Diabetes, Obesity and Metabolism
  [SJR: 2.729]   [H-I: 87]   [314 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1462-8902 - ISSN (Online) 1463-1326
   Published by John Wiley and Sons Homepage  [1592 journals]
  • Efficacy and safety of canagliflozin as add-on therapy to a glucagon-like
           peptide-1 receptor agonist in Japanese patients with type 2 diabetes
           mellitus: a 52-week, open-label, phase IV study
    • Authors: Shin-ichi Harashima; Nobuya Inagaki, Kazuoki Kondo, Nobuko Maruyama, Makiko Otsuka, Yutaka Kawaguchi, Yumi Watanabe
      Abstract: Sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are antihyperglycaemic agents with weight-lowering effects. The efficacy and safety of the SGLT2 inhibitor canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control with a GLP-1RA (≥12 weeks) were evaluated in this phase IV study. Patients received canagliflozin 100 mg once daily for 52 weeks. Efficacy endpoints included the change in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), bodyweight, systolic blood pressure (SBP), and high-density lipoprotein cholesterol (HDL-C) from baseline to Week 52. Safety endpoints included adverse events (AEs), hypoglycaemia and laboratory tests. Of the 71 patients treated with canagliflozin, 63 patients completed the study. At 52 weeks, HbA1c was significantly reduced from baseline (−0.70%; paired t-test, p
      PubDate: 2018-02-23T05:31:39.33447-05:0
      DOI: 10.1111/dom.13267
  • Effect of exenatide QW or placebo, both added to titrated insulin
           glargine, in uncontrolled type 2 diabetes: the DURATION-7 randomized study
    • Authors: Cristian Guja; Juan P. Frías, Aniko Somogyi, Serge Jabbour, Hui Wang, Elise Hardy, Julio Rosenstock
      Abstract: AimsTo compare the efficacy and safety of adding the glucagon-like peptide-1 receptor agonist exenatide once weekly (QW) 2 mg or placebo among patients with type 2 diabetes inadequately controlled despite titrated insulin glargine (IG) ± metformin.MethodsThis multicentre, double-blind study randomized (1:1) patients with persistent hyperglycaemia after 8-week IG titration (glycated haemoglobin [HbA1c] 7.0–10.5% [53–91 mmol/mol]) to exenatide QW or placebo. The primary endpoint was HbA1c change from baseline to week 28. Secondary endpoints included body weight, 2-hour postprandial glucose, and mean daily IG dose.ResultsOf 464 randomized patients (mean: age 58 years; HbA1c 8.5% [69 mmol/mol]; diabetes duration 11.3 years), 91% completed 28 weeks. Exenatide QW+IG versus placebo+IG significantly reduced HbA1c (least-squares mean difference, −0.73% [−8.0 mmol/mol]; 95% confidence interval, −0.93%, −0.53% [−10.2, −5.8 mmol/mol]; P
      PubDate: 2018-02-23T05:27:25.338724-05:
      DOI: 10.1111/dom.13266
  • Increased Mortality in Patients With Heart Failure Who Are Taking Commonly
           Prescribed Antidiabetic Medications and Achieve Recommended Levels of
           Glycemic Control
    • Authors: Milton Packer
      Abstract: Current guidelines for diabetes recommend that physicians attain a glycated hemoglobin (HbA1c) ≤ 7.0%, but this target may not be applicable to those with heart failure. Fourteen studies of patients with chronic heart failure that examined the relationship between the level of glycated hemoglobin and the risk of death specified whether the HbA1c was influenced by treatment with antidiabetic medications. In patients with heart failure not receiving glucose-lowering drugs, mortality was not increased if the HbA1c was 7.0%. These studies suggest that patients with both heart failure and diabetes are at increased risk of death if they are prescribed certain glucose-lowering drugs to achieve levels of HbA1c < 7.0%.
      PubDate: 2018-02-22T05:05:26.917971-05:
      DOI: 10.1111/dom.13265
  • Specific synbiotics in early life protect against diet-induced obesity in
           adult mice
    • Authors: Mona Mischke; Tulika Arora, Sebastian Tims, Eefje Engels, Nina Sommer, Kees van Limpt, Annemarie Baars, Raish Oozeer, Annemarie Oosting, Fredrik Bäckhed, Jan Knol
      Abstract: AimsThe metabolic state of human adults is associated with their gut microbiome. The symbiosis between host and microbiome is initiated at birth, and early life microbiome perturbation can disturb health long-lastingly. Here, we determined how beneficial microbiome interventions in early life affect metabolic health in adulthood.MethodsPostnatal diets were supplemented with either prebiotics (scGOS/lcFOS) or synbiotics (scGOS/lcFOS with Bifidobacterium breve M-16V) until post-natal (PN) day 42 in a well-established rodent model for nutritional programming. Mice were subsequently challenged with high-fat Western-style diet (WSD) for eight weeks. Body weight and composition were monitored, as was gut microbiota composition at PN21, 42 and 98. Markers of glucose homeostasis, lipid metabolism and host transcriptomics of six target tissues were determined in adulthood (PN98).ResultsEarly life synbiotics protected mice against WSD-induced excessive fat accumulation throughout life, replicable in two independent European animal facilities. Adult insulin sensitivity and dyslipidemia were improved and most pronounced gene expression changes were observed in the ileum. We observed subtle changes in fecal microbiota composition, both in early life and in adulthood, including increased Bifidobacterium abundance. Microbiota transplantation using samples collected from synbiotics-supplemented adolescent mice at PN42 to age-matched germ-free recipients did not transfer the beneficial phenotype, indicating that synbiotics-modified microbiota at PN42 is not sufficient to transfer the long-lasting protection of the metabolic health status.ConclusionTogether, these findings show the potential and importance of timing of synbiotic interventions in early life during crucial microbiota development as preventive measure to ameliorate obesity risk and improve metabolic health throughout life.
      PubDate: 2018-02-20T03:55:25.734382-05:
      DOI: 10.1111/dom.13240
  • 5-Years Long-term Clinical Outcome after Bariatric Surgery – A
           Multi-ethnic Asian Population in Singapore
    • Authors: BC Toh; WH Chan, AKH Eng, EKW Lim, CH Lim, KW Tham, S Fook-Chong, JTH Tan
      Abstract: Bariatric surgery is an effective treatment for morbid obesity and its metabolic related comorbidities – Type II Diabetes, Hypertension and Hyperlipidaemia.1 However, the literature is scarce regarding the long-term outcome after bariatric surgery especially among multi-ethnic Asian populations. Considering the growing number of bariatric metabolic operations in Asia, we have attempted to provide a regional perspective on 5-year long-term clinical outcomes post bariatric surgery in Singapore. Between years 2010 to 2016, all bariatric operative cases consisted of 393 Laparoscopic Sleeve Gastrectomy (LSG), 125 Laparoscopic Roux-En-Y Gastric Bypass (RYGB) and 43 Laparoscopic Mini-gastric Bypass (MGB) were included. Primary outcome measure was the percentage of excess weight loss (% EWL) at 6-month, 1-year, 2-years, 3-years, 4-years and 5-years with % remission of Type-II diabetes mellitus (T2DM) at 1-year for LSG (49.7%, 61.2%, 56.1%, 47.8%, 40.8% and 47.3%; 82.2%), RYGB (60.2%, 62.1%, 57.6%, 50.1%, 48.7% and 47.7%; 86.9%) and MGB (58%, 68.1%, 62.7%, 66.2%, 64.0%, 65.2%; 71.9%). In conclusion, MGB and RYGB showed the greatest %EWL at 5-years and is recommended for moderate T2DM. LSG is an effective bariatric operation with high %EWL up to 2 years and high remission rate of mild T2DM. The remission rate of T2DM was equally high in all 3 surgical groups despite ethnic differences.
      PubDate: 2018-02-20T00:00:35.213331-05:
      DOI: 10.1111/dom.13263
  • Pharmacokinetics of metformin in patients with gastrointestinal
    • Authors: L McCreight; TB Stage, P Connelly, M Lonergan, F Nielsen, C Prehn, J Adamski, K Brosen, ER Pearson
      Abstract: AimsMetformin intolerance symptoms are gastrointestinal in nature, but the underlying mechanism is poorly understood. The aim of this study was to assess potential causes of metformin intolerance including: altered metformin uptake from the intestine; increased anaerobic glucose utilisation and subsequent lactate production; altered serotonin uptake; and altered bile acid pool.MethodsThis pharmacokinetic study recruited ten severely intolerant and ten tolerant individuals matched for age, sex and BMI. A single 500mg dose of metformin was administered, with blood sampling at eleven time points over 24 hours. Blood samples were analysed for metformin, lactate, serotonin, and bile acid concentrations and compared across the phenotypes.ResultsThe intolerant individuals were severely intolerant to 500mg metformin. No significant difference was identified between tolerant and intolerant cohorts in metformin pharmacokinetics: median Cmax 2.1 (IQR 1.7 – 2.3) and 2.0 (IQR 1.8 – 2.2) mg/L respectively (p = 0.76); tmax 2.5 hours; median AUC0-24 16.9 (IQR 13.9 – 18.6) and 13.9 (IQR 12.9 – 16.8) (mg/L)*h respectively (p = 0.72). Lactate concentration peaked at 3.5 hours, with mean peak concentration of 2.4 mmol/L in both cohorts (95% CIs 2.0 – 2.8, and 1.8 – 3.0 mmol/L respectively), and comparable iAUC0-24: tolerant 6.98 (3.03 –10.93) and intolerant 4.47 (-3.12 – 12.06) mmol/L*h, (p=0.55). Neither serotonin nor bile acid concentrations were significantly different.ConclusionsDespite evidence of severe intolerance in our cohort, there was no significant difference in metformin pharmacokinetics or systemic measures of lactate, serotonin or bile acids. This suggests that metformin intolerance may be due to local factors within the lumen or enterocyte.
      PubDate: 2018-02-19T09:15:24.280061-05:
      DOI: 10.1111/dom.13264
  • Epigenetic effects of metformin: from molecular mechanisms to clinical
    • Authors: SC Bridgeman; GC Ellison, PE Melton, P Newsholme, CDS Mamotte
      Abstract: There is a growing body of evidence that links epigenetic modifications to type 2 diabetes. Researchers have more recently investigated effects of commonly used medications, including those prescribed for diabetes, on epigenetic processes. This work reviews the influence of the widely used antidiabetic drug metformin on epigenomics, microRNA levels and subsequent gene expression and potential clinical implications. Metformin may influence the activity of numerous epigenetic modifying enzymes, mostly via modulating the activation of AMP-activated protein kinase (AMPK). Activated AMPK can phosphorylate numerous substrates, including epigenetic enzymes such as histone acetyltransferases (HATs), class II histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), generally resulting in their inhibition, although HAT1 activity may be increased. Metformin has also been reported to decrease expression of multiple histone methyltransferases, increase the activity of the class III HDAC SIRT1 and to decrease the influence of DNMT inhibitors. There is evidence that these alterations influence the epigenome and gene expression, and may contribute to the antidiabetic properties of metformin and potentially protect against cancer, cardiovascular disease, cognitive decline and aging. The expression levels of numerous microRNAs are also reportedly influenced by metformin treatment and may confer antidiabetic and anticancer activities. However, as the reported effects of metformin on epigenetic enzymes act to both increase and decrease histone acetylation, histone and DNA methylation, and gene expression, a significant degree of uncertainty exists on the overall effect of metformin on the epigenome, gene expression and subsequent effect on the health of metformin users.
      PubDate: 2018-02-19T09:01:30.119219-05:
      DOI: 10.1111/dom.13262
  • Insulin degludec/insulin aspart lowers fasting plasma glucose and rates of
           confirmed and nocturnal hypoglycaemia independent of baseline HbA1c
           levels, disease duration or BMI: A pooled meta-analysis of phase 3 studies
           in patients with type 2 diabetes
    • Authors: Martin Haluzík; Greg Fulcher, Thomas R. Pieber, Lars Bardtrum, Deniz Tutkunkardas, Helena W. Rodbard
      Abstract: AimsPrevious studies demonstrated the co-formulation of insulin degludec (IDeg)/insulin aspart (IAsp) ‘IDegAsp’ offers lower rates of hypoglycaemia with smaller changes in weight compared with basal–bolus (IDeg once daily [OD] + IAsp [2–4 injections]) and premix insulin (BIAsp 30 twice daily [BID]) comparators. This study aimed to investigate whether the benefits of IDegAsp, given twice daily, extend across a wide spectrum of patients with diabetes.Materials and MethodsThis was a post hoc pooled analysis of five phase 3 randomised, 26-week, open-label, BID, treat-to-target trials comparing IDegAsp BID (n = 1111) with one of two ‘comparators’ – BIAsp 30 BID (n = 561) or IDeg OD + IAsp (n = 136). Patient data were stratified according to baseline HbA1c or fasting plasma glucose (FPG) categories, as well as by baseline duration of diabetes or BMI categories.ResultsEnd-of-trial results were broadly consistent with differences between IDegAsp and comparators observed in phase 3 trials. HbA1c was comparable between IDegAsp and comparators among all baseline characteristics (HbA1c, duration of diabetes or BMI) and category groups. Significantly lower FPG was observed with IDegAsp versus comparators among all baseline characteristics and most categories (excluding FPG
      PubDate: 2018-02-16T10:00:25.917848-05:
      DOI: 10.1111/dom.13261
  • Sodium-glucose co-transporter 2 (SGLT2) inhibitors as add-on therapy to
           insulin for type 1 diabetes mellitus: Systematic review and meta-analysis
           of randomized controlled trials
    • Authors: Tomohide Yamada; Nobuhiro Shojima, Hisashi Noma, Toshimasa Yamauchi, Takashi Kadowaki
      Abstract: New treatments for type 1 diabetes are an unmet need. We investigated the efficacy and safety of adding SGLT-2is to insulin for type 1 diabetes by meta-analysis of prospective randomized, placebo-controlled trials. Searching electronic databases up to October 2017 identified 1361 studies, among which 14 were investigated (N=4,591). Meta-analysis revealed that SGLT-2i therapy significantly reduced HbA1c by 0.4% (95% confidence interval [CI]: 0.35, 0.46; P
      PubDate: 2018-02-16T09:20:25.138884-05:
      DOI: 10.1111/dom.13260
  • Impact of Cigarette Smoking on the Relationship between BMI and Insulin:
           Longitudinal Observation from the Bogalusa Heart Study
    • Authors: Ying Li; Tao Zhang, Tianshu Han, Shengxu Li, Lydia Bazzano, Jiang He, Wei Chen
      Abstract: BackgroundDespite the inverse association between cigarette smoking and body mass index (BMI), it is unknown about whether the effect of smoking on insulin is mediated through decreased BMI. This study aims to examine the temporal relationship between BMI and insulin, the impact of smoking on this relationship and mediation effect of BMI on the association between smoking and insulin levels.MethodsThe longitudinal cohort consisted of 1,121 adults (807 whites and 314 blacks, mean age=42.0 years at follow-up) who had BMI and fasting insulin measured twice, with an average follow-up period of 17.1 years. Cross-lagged panel and mediation analysis models were used to examine the temporal relations between BMI and insulin, and mediation effect of BMI on the smoking-insulin association.ResultsSmoking was inversely associated with insulin (regression coefficient=-0.073, p=0.015 at baseline and -0.121, p
      PubDate: 2018-02-15T06:45:23.588741-05:
      DOI: 10.1111/dom.13259
  • Safety and tolerability of dapagliflozin, saxagliptin and metformin in
           combination: post hoc analysis of concomitant add-on versus sequential
           add-on to metformin and of triple versus dual therapy with metformin
    • Authors: Stefano Del Prato; Julio Rosenstock, Ricardo Garcia-Sanchez, Nayyar Iqbal, Lars Hansen, Eva Johnsson, Hungta Chen, Chantal Mathieu
      Abstract: The safety of triple oral therapy with dapagliflozin plus saxagliptin plus metformin, versus dual therapy with dapagliflozin or saxagliptin plus metformin, was compared in a post hoc analysis of three randomized trials of sequential or concomitant add-on of dapagliflozin and saxagliptin to metformin. In the concomitant add-on trial, patients with type 2 diabetes on stable metformin received dapagliflozin 10 mg/day plus saxagliptin 5 mg/day. In sequential add-on trials, patients on metformin plus either saxagliptin 5 mg/day or dapagliflozin 10 mg/day received add-on dapagliflozin 10 mg/day or saxagliptin 5 mg/day, respectively. After 24 weeks, incidences of adverse events and serious adverse events were similar between triple and dual therapy and between concomitant and sequential add-on regimens. Urinary tract infections were more common with sequential than with concomitant add-on therapy; genital infections were reported only with sequential add-on of dapagliflozin to saxagliptin plus metformin. Hypoglycaemia incidence was
      PubDate: 2018-02-15T06:40:22.71348-05:0
      DOI: 10.1111/dom.13258
  • Cover Image, Volume 20, Issue 3
    • Authors: Zara J. Franklin; Anastasia Tsakmaki, Patricia Fonseca Pedro, Aileen J. King, Guo Cai Huang, Sakeena Amjad, Shanta J. Persaud, Gavin A. Bewick
      Abstract: The cover image, by Zara J. Franklin et al., is based on the Original Article Islet neuropeptide Y receptors are functionally conserved and novel targets for the preservation of beta-cell mass,
      DOI : 10.1111/dom.13119.The cover image, by Zara J. Franklin et al., is based on the Original Article Islet neuropeptide Y receptors are functionally conserved and novel targets for the preservation of beta-cell mass,
      DOI : 10.1111/dom.13119.
      PubDate: 2018-02-13T23:36:35.493856-05:
  • Alirocumab versus usual lipid-lowering care as add-on to statin therapy in
           individuals with type 2 diabetes and mixed dyslipidaemia: The ODYSSEY
           DM-DYSLIPIDEMIA randomized trial
    • Authors: Kausik K. Ray; Lawrence A. Leiter, Dirk Müller-Wieland, Bertrand Cariou, Helen M. Colhoun, Robert R. Henry, Francisco J. Tinahones, Maja Bujas-Bobanovic, Catherine Domenger, Alexia Letierce, Rita Samuel, Stefano Del Prato
      Abstract: AimsIndividuals with type 2 diabetes (T2DM) and mixed dyslipidaemia represent a high-risk and difficult-to-treat population. ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) compared alirocumab, a proprotein convertase subtilisin-kexin type 9 inhibitor, with usual care (UC) in individuals with T2DM and mixed dyslipidaemia not optimally managed by maximally-tolerated statins.Materials and MethodsUC options (no additional lipid-lowering therapy; fenofibrate; ezetimibe; omega-3 fatty acid; nicotinic acid) were selected prior to stratified randomization to open-label alirocumab 75 mg every 2 weeks (Q2W; with increase to 150 mg Q2W at Week [W]12 if W8 non-high-density lipoprotein cholesterol [non-HDL-C] was ≥2.59 mmol/L [100 mg/dL]) or UC for 24 weeks. Primary efficacy endpoint was percentage change in non-HDL-C from baseline to W24.ResultsThe randomized population comprised 413 individuals (409 intention-to-treat; 412 safety). At W24, mean non-HDL-C reductions were superior with alirocumab (-32.5% difference vs UC; 97.5% confidence interval: -38.1 to -27.0; P
      PubDate: 2018-02-13T06:40:27.42114-05:0
      DOI: 10.1111/dom.13257
  • A 52-week extension study of switching from gemigliptin vs. sitagliptin to
           gemigliptin only as an add-on to patients with type 2 diabetes
           inadequately controlled on metformin alone
    • Authors: Chan-Hee Jung; Eun-Jung Rhee, Won-Young Lee, Kyung Wan Min, Vyankatesh K. Shivane, Aravind R Sosale, Hak Chul Jang, Choon Hee Chung, Il Seong Nam-Goong,
      Abstract: We investigated the long-term efficacy and safety of gemigliptin and the efficacy and safety of gemigliptin treatment after once daily treatment with sitagliptin 100 mg, in patient with type 2 diabetes. This study was a 28-week, extension of a 24-week, randomized, double-blind, parallel study of gemigliptin or sitagliptin, added to ongoing metformin therapy. After randomized to sitagliptin 100 mg qd(S), gemigliptin 25 mg bid (G1), or gemigliptin 50 mg qd(G2) groups and completing treatment of 24 weeks, 118 patients switched from gemigliptin 25 mg bid to 50 mg qd(G1/G2), 111 patients continued gemigliptin 50 mg qd(G2/G2), and 106 patients switched from sitagliptin 100 mg qd to gemigliptin 50 mg qd(S/G2). All three treatments reduced glycated hemoglobin (HbA1c) (S/G2:-0.99% (95% CI [-1.25%, -0.73%]), G1/G2:-1.11% (95% CI [-1.33%, -0.89%]), G2/G2:-1.06% (95% CI [-1.28%, -0.85%])). The percentage of patients achieving HbA1c
      PubDate: 2018-02-13T06:25:22.838612-05:
      DOI: 10.1111/dom.13256
  • Prolonged Uninterrupted Sitting Elevates Postprandial Hyperglycaemia
           Proportional to Degree of Insulin Resistance
    • Authors: Paddy C. Dempsey; Robyn N. Larsen, Elisabeth A.H. Winkler, Neville Owen, Bronwyn A. Kingwell, David W. Dunstan
      Abstract: Prolonged uninterrupted sitting is related adversely to cardiometabolic risk markers and postprandial hyperglycaemia, relative to sitting interrupted by regular brief activity breaks. However, whether the magnitude of hyperglycaemic responses to prolonged sitting is dependent upon the underlying degree of insulin resistance remains unclear. Data were pooled from three randomised cross-over laboratory-based trials (n=62) that examined the postprandial blood glucose- and insulin-lowering effects of prolonged sitting versus sitting interrupted by regular brief activity breaks in overweight/obese adults who had normal or impaired glucose metabolism (two trials), or type 2 diabetes not treated by insulin (one trial). Corrected for study effects, the magnitude of differences in postprandial glucose and insulin responses between the two conditions was significantly exacerbated with poorer baseline levels of fasting glucose, insulin and/or surrogate markers of β-cell function and insulin resistance. This suggests that those with higher underlying levels of insulin resistance may derive greater metabolic benefits from regularly interrupting prolonged sitting than their counterparts. If these findings can be replicated, they will have implications for future targeting and optimisation of physical activity/sedentary behaviour interventions in the prevention and management of type 2 diabetes.
      PubDate: 2018-02-12T06:55:34.479522-05:
      DOI: 10.1111/dom.13254
  • SGLT-2 inhibitors and the risk of lower-limb amputation: is this a class
    • Authors: Charles Khouri; Jean-Luc Cracowski, Matthieu Roustit
      Abstract: ObjectiveInhibitors of the sodium-glucose co-transporter-2 (SGLT-2) are a novel class of glucose lowering agents showing promising results. However, the use of canagliflozin has been associated with an increased risk of lower-limb amputation. Whether this risk concerns other SGLT-2 inhibitors is unclear.MethodsWe performed a disproportionality analysis using the WHO global database of individual case safety reports (VigiBase®) to address this issue.ResultsAmong the 8,293,886 reports available between January 2013 and December 2017, we identified 79 reports of lower-limb amputations associated with SGLT-2 inhibitors. Among all blood glucose lowering drugs, the proportional reporting ratio (PRR) was increased only for SGLT-2 inhibitors [5.55 (4.23, 7.29)]. While we observed an expected signal for canagliflozin [7.09 (5.25, 9.57)], the PRR was also high for empagliflozin [4.96 (2.89, 8.50)] and, for toe amputations only, for dapagliflozin [2.62 (1.33, 5.14)].ConclusionIn conclusion, our results reveal a positive disproportionality signal for canagliflozin, and also for empagliflozin, and, for toe amputations only, for dapagliflozin. However, our analysis relies on a limited number of cases and is exposed to the biases inherent to pharmacovigilance studies. Further prospective data are therefore needed to better characterize the risk of amputations with the different SGLT-2 inhibitors.
      PubDate: 2018-02-12T04:20:21.336052-05:
      DOI: 10.1111/dom.13255
  • Direct medical costs of diabetes mellitus in the year of mortality and
           year before mortality
    • Authors: Carlos King Ho Wong; Fangfang Jiao, Eric Ho Man Tang, Thaison Tong, Praveen Thokala, Cindy Lo Kuen Lam
      Abstract: AimsStudies have shown that health service utilization often increases in few years immediately before death. Estimates of direct medical cost of diabetes mellitus (DM) in mortality year and the previous year is not well understood. This study aimed to report the health resource use and estimate the direct medical costs among DM patients in the year of mortality and the year before mortality.Materials and MethodsWe analysed a population-based, retrospective cohort study including all adults with DM diagnosis in Hong Kong between 2009 and 2013, and death between January 1, 2010 and December 31, 2013. Annual direct medical costs in year of mortality and year before mortality were determined by summing costs of health services utilized within the respective year. The costs were analysed by gender, the presence of co-morbidities, diabetic complications and primary cause of death.ResultsA total of 10,649 patients met the eligibility criteria for analysis. On average, the direct medical costs in the year of death were 1.947 times higher than those in the year before death. Male and female patients had similar costs in the year before mortality and mortality year. Patients with any diabetic complications had greater costs in the year of mortality and before mortality than those without.ConclusionsThis analysis provides new evidence on incorporating additional direct medical costs in the mortality year, and refining the structure of total cost estimates for use in costing and cost-effectiveness analyses of interventions for DM.
      PubDate: 2018-02-12T04:00:24.240154-05:
      DOI: 10.1111/dom.13253
  • Dulaglutide 1.5 mg as an Add-on Option for Patients Uncontrolled on
           Insulin: Subgroup Analysis by Age, Duration of Diabetes and Baseline HbA1c
    • Authors: Kevin M. Pantalone; Hiren Patel, Maria Yu, Laura Fernández Landó
      Abstract: AimsTo assess efficacy and safety of dulaglutide 1.5 mg combined with insulin, categorised by subgroups of baseline HbA1c (≤9% and>9%), age (
      PubDate: 2018-02-12T03:31:12.257591-05:
      DOI: 10.1111/dom.13252
  • HNF1A variant, energy-reduced diets and insulin resistance improvement
           during weight loss: the POUNDS Lost and DIRECT trials
    • Authors: Tao Huang; Tiange Wang, Yoriko Heianza, Dianjianyi Sun, Kerry Ivey, Ronen Durst, Dan Schwarzfuchs, Meir J. Stampfer, George A. Bray, Frank M. Sacks, Iris Shai, Lu Qi
      Abstract: BackgroundThe majority of patients with maturity-onset diabetes of the young (MODY) has mutations in the hepatocyte nuclear factor 1α (HNF1A) gene. A common variant rs7957197 at HNF1A locus for type 2 diabetes was identified. Dietary macronutrients regulate the HNF1A gene expression.ObjectiveWe aimed to determine whether weight loss diets varying in macronutrients modulate the genetic effect of HNF1A rs7957197 on weight loss and improvement of insulin resistance.MethodsWe analyzed interaction between the HNF1A rs7957197 and weight-loss diets on weight loss and insulin resistance improvement among 722 overweight/obese adults from a 2-year randomized weight-loss trial (POUNDS Lost). The findings were replicated in another independent 2-year weight-loss trial (Dietary Intervention Randomized Controlled Trial, DIRECT) in 280 overweight/obese adults.ResultsIn the POUNDS Lost, we found high-fat diet significantly modified the genetic effect of HNF1A on weight loss and waist loss (P for interaction=0.006, and 0.005, respectively). Borderline significant interactions for fasting insulin and insulin resistance (P for interaction=0.07 and 0.06, respectively) were observed. We replicated the results in the DRIECT. Pooled results showed similar significant interactions on weight loss, waist loss, and improvement of fasting insulin and insulin resistance (P for interaction=0.001, 0.005, 0.02 and 0.03, respectively). Greater decreases in weight, waist, fasting insulin, and insulin resistance were observed in participants with T allele compared to those without T allele among high-fat diet group (P=0.04, 0.03 and 0.01, respectively).ConclusionsOur replicable findings provide strong evidence that individuals with HNF1A rs7957197 T allele might obtain more benefits in weight loss and improvement of insulin resistance by choosing hypocaloric and high-fat diet.
      PubDate: 2018-02-09T08:40:37.666032-05:
      DOI: 10.1111/dom.13250
  • Results of ACCORDIAN in Accord with Lower Blood Pressure Begetting Lower
           Mortality in Patients with Diabetes
    • Authors: Luke J. Laffin; George L. Bakris
      Abstract: The ACCORD trial used 2x2 factorial design and enrolled 10,251 participants. The trial recruited patients with Type 2 diabetes and randomized them to two different glucose levels and office systolic blood pressure (SBP) goal of < 140mmHg versus an intensive goal of < 120mmHg
      PubDate: 2018-02-09T08:15:19.26116-05:0
      DOI: 10.1111/dom.13249
  • Effect of Intensive Blood Pressure Control in Patients with Type 2
           Diabetes Mellitus Over 9 Years of Follow-Up: A Subgroup Analysis of
           High-Risk ACCORDION Trial Participants
    • Authors: Leo F. Buckley; Dave L. Dixon, George F. Wohlford, Dayanjan S. Wijesinghe, William L. Baker, Benjamin W. Van Tassell
      Abstract: Although guidelines recommend strict blood pressure (BP) control in patients with type 2 diabetes mellitus (T2DM) and elevated cardiovascular risk, the long-term effects of this approach are unknown. We investigated the effect of intensive BP control on clinical outcomes in patients with T2DM over 9 years of follow-up. We included ACCORD BP participants in the standard glucose control arm who had established cardiovascular disease, chronic kidney disease, age ≥75 years or 10-year coronary heart risk ≥15%. Participants were randomized to either intensive (systolic BP
      PubDate: 2018-02-09T08:05:23.95959-05:0
      DOI: 10.1111/dom.13248
  • Long-term efficacy and safety of ertugliflozin monotherapy in patients
           with inadequately controlled T2DM despite diet and exercise: VERTIS MONO
           extension study
    • Authors: Ronnie Aronson; Juan Frias, Allison Goldman, Amanda Darekar, Brett Lauring, Steven G. Terra
      Abstract: AimThis phase III, multicenter, randomised study evaluated the efficacy and safety of ertugliflozin monotherapy in adults with inadequately controlled type 2 diabetes (glycated haemoglobin [HbA1c] 7.0% to 10.5% [53-91 mmol/mol]) despite diet and exercise.Materials and methodsThe 52-week study comprised a 26-week, double-blind, placebo-controlled period (phase A) where 461 participants received placebo, ertugliflozin 5-mg/day, or ertugliflozin 15-mg/day. This was followed by a 26-week active-controlled period (phase B) where participants in the placebo group who had not received glycaemic rescue therapy had blinded metformin added. Results through to week 52 are reported. Due to the use of metformin in phase B, no statistical comparisons of efficacy were made between the ertugliflozin and placebo/metformin groups at week 52.ResultsThe mean (standard error) change from baseline to week 52 in HbA1c was –0.9% (0.1) and –1.0% (0.1) in the ertugliflozin 5-mg and 15-mg groups, respectively. The proportions of participants with HbA1c
      PubDate: 2018-02-08T08:45:23.040721-05:
      DOI: 10.1111/dom.13251
  • Cardiovascular biomarkers in clinical studies of type 2 diabetes
    • Authors: M. P. A. Baldassarre; A. Andersen, A. Consoli, F. K. Knop, T. Vilsbøll
      Abstract: When planning cardiovascular studies in type 2 diabetes, selection of cardiovascular biomarkers is a complex issue. Since the pathophysiology of cardiovascular disease in type 2 diabetes is multifactorial, ideally, the selected cardiovascular biomarkers should cover all aspects of the known pathophysiology of the disease. This will allow the researcher to distinguish between effects on different aspects of the pathophysiology. To this end, we will discuss a host of biomarkers grouped according to their role in the pathogenesis of CV disease, namely: 1) cardiac damage biomarkers 2) inflammatory biomarkers and 3) novel biomarkers (oxidative stress and endothelial dysfunction biomarkers). Within each category we present the currently best validated biomarkers with special focus on the population of interest (type 2 diabetes). For each individual biomarker, the physiological role, the validation in the general population and in type 2 diabetes, analytical methodology, the modifying factors, the effects of glucose-lowering drugs, and the interpretation are discussed. This approach will provide clinical researchers with all information necessary for planning, conducting and interpreting results from clinical trials. Furthermore, a systematic approach to selection of cardiovascular biomarkers in type 2 diabetes research will improve the quality of future research.
      PubDate: 2018-02-08T08:30:43.780629-05:
      DOI: 10.1111/dom.13247
  • Effect of race on the glycaemic response to sitagliptin: Insights from the
           Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS)
    • Authors: Timothy M. E. Davis; Hillary Mulder, Yuliya Lokhnygina, Pablo Aschner, Lee-Ming Chuang, Carlos A. Raffo Grado, Eberhard Standl, Eric D. Peterson, Rury R. Holman,
      Abstract: AimPooled efficacy studies suggest that glycaemic responses to dipeptidyl-peptidase 4 inhibitors in type 2 diabetes are greatest in Asians, who may also respond better to alpha-glucosidase inhibitors. We assessed the glycaemic impact of sitagliptin by race in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), and whether this was enhanced in Asians with concomitant acarbose therapy.Materials and MethodsTECOS enrolled 14,671 patients with type 2 diabetes, cardiovascular disease and HbA1c of 48–64 mmol/mol (6.5–8.0%), and randomised them double-blind to sitagliptin or placebo. There were 3,265 patients (22.3%) from Asian countries. Background glucose-lowering therapies were unaltered for the first 4 months post-randomisation unless clinically essential, facilitating comparison of sitagliptin-associated effects in self-identified Oriental (East) Asian, Other (South) Asian, White Caucasian, Hispanic, Black and Indigenous groups.ResultsMedian baseline HbA1c by race was 54–57 mmol/mol (7.1–7.4%). Mean 4-month placebo-adjusted HbA1c reduction was greatest in Oriental Asians (-6.6 mmol/mol [-0.60%] vs ≤6.0 mmol/mol [≤0.55%] in other groups), with significantly greater reduction vs the two largest groups (White Caucasians, Other Asians; P
      PubDate: 2018-02-06T07:41:03.29779-05:0
      DOI: 10.1111/dom.13242
  • Legacy benefits of blood glucose, blood pressure and lipid control in
           people with diabetes and cardiovascular disease: Time to overcome
           multifactorial therapeutic inertia'
    • Authors: Kamlesh Khunti; Mikhail Kosiborod, Kausik K Ray
      Abstract: Cardiovascular disease is a major cause of morbidity and mortality, in particular in people with diabetes and is also the largest contributor to healthcare costs in this population (1). However, good quality randomised controlled trials and systematic reviews have shown that management of risk factors such as blood pressure, dyslipidaemia and glucose can lead to improved microvascular and macrovascular complications in people with type 2 diabetes mellitus (T2DM). Legacy effect or metabolic memory has been a phenomenon used to describe the prolonged benefits of glucose, blood pressure or lipid control in people with cardiovascular disease, diabetes or in primary prevention of cardiovascular disease by early risk factor control. This paper reviews the evidence in relation to longer term benefits of early risk factor control in people with diabetes.
      PubDate: 2018-02-06T06:50:31.849336-05:
      DOI: 10.1111/dom.13243
  • Rationale and protocol of the Study of Diabetic Nephropathy with
           Atrasentan (SONAR) trial: A clinical trial design novel to diabetic
    • Authors: Hiddo J.L. Heerspink; Dennis L. Andress, George Bakris, John J. Brennan, Ricardo Correa-Rotter, Jyotirmoy Dey, Fan-Fan Hou, Dalane W. Kitzman, Donald Kohan, Hirofumi Makino, John McMurray, Vlado Perkovic, Sheldon Tobe, Melissa Wigderson, Hans-Henrik Parving, Dick de Zeeuw
      Abstract: AimsPeople with diabetes and chronic kidney disease (CKD) are at high risk for renal events. Recent trials of novel treatments have been negative, possibly because of variability in response to treatment of the target risk factor. Atrasentan is a selective endothelin A receptor antagonist that reduces urinary albumin-to-creatinine ratio (UACR) with a large variability between patients. We are assessing its effect on renal outcomes in the Study of Diabetic Nephropathy with atrasentan (SONAR; NCT01858532) with an enrichment design (>30% lowering of albuminuria) to select patients most likely to benefit.Materials and MethodsSONAR is a randomized, double-blind, placebo-controlled trial in approximately 3,500 participants, with CKD stage 2–4 and macroalbuminuria receiving a maximum tolerated dose of a renin angiotensin system inhibitor.ResultsAfter 6 weeks’ exposure to 0.75 mg once daily atrasentan (enrichment period), participants with ≥30% UACR decrease and no tolerability issues (responders) were randomly assigned to placebo or atrasentan 0.75 mg/day. The responder group will be used for the primary efficacy and safety analyses. Approximately 1,000 participants with
      PubDate: 2018-02-06T06:40:56.488177-05:
      DOI: 10.1111/dom.13245
  • Metformin does not Affect Postabsorptive Hepatic Free Fatty Acid Uptake,
           Oxidation or Resecretion in Humans: A 3-months Placebo Controlled Clinical
           Trial in Patients with Type 2 Diabetes and Healthy Controls
    • Authors: Lars C. Gormsen; Esben Søndergaard, Nana L. Christensen, Steen Jakobsen, Erik H. T. Nielsen, Ole L. Munk, Lars P. Tolbod, Niels Jessen, Søren Nielsen
      Abstract: AimsMetformin is due to its well-documented glucose lowering effect the most commonly used drug in patients with T2D. However, metformin have also in pre-clinical studies been shown to improve lipid metabolism, possibly through modulation of intrahepatic partitioning of fatty acids towards oxidation and away from reesterification and resecretion as triglycerides.Materials and methodsTo explore whether these pre-clinical findings can be translated to a human setting, we performed a 3-month randomized, placebo controlled, parallel-group clinical trial in patients with T2D (24 patients) and healthy controls (12 subjects). T2D subjects received either placebo (PLA) or 1000 mg metformin bid. (MET) whereas healthy subjects were all treated with metformin (CONT). Hepatic fatty acid metabolism was measured by [11C]palmitate PET, hepatic triglyceride secretion and peripheral oxidation by ex-vivo labelled [1-14C]VLDL-TG and VLDL-particle size by TG/ApoB ratio. Body composition was assessed by DXA and whole body lipid oxidation by indirect calorimetry.ResultsMetformin treatment for three months produced the anticipated decrease in FPG in the MET group [FPG (mM): 7.9±1.8 (study day 1) vs. 6.4±1.1 (study day 2)] whereas patients in the PLA group and healthy controls had similar FPG levels before and after the trial (mixed model group vs. time interaction, p=0.003). However, contrary to our hypothesis, metformin treatment did not affect hepatic lipid metabolism or peripheral oxidation.ConclusionThe observed beneficial effects on lipid metabolism during metformin treatment in humans appear to be secondary to long-term alterations in body composition or glucose homeostasis.
      PubDate: 2018-02-06T06:15:35.633634-05:
      DOI: 10.1111/dom.13244
  • Elevations of metabolic risk factors 20 years or more before diagnosis of
           type 2 diabetes – experience from the AMORIS study
    • Authors: Håkan Malmström; Göran Walldius, Sofia Carlsson, Valdemar Grill, Ingmar Jungner, Soffia Gudbjörnsdottir, Mikhail Kosiborod, Niklas Hammar
      Abstract: OBJECTIVERisk factors for type 2 diabetes (T2D) may be present long before diagnosis but few studies have documented the impact of such factors during a pre-diabetic period exceeding 10 years. Here we describe trajectories for metabolic risk factors up to 25 years prior to diagnosis and estimate the absolute 20-year risk for T2D based on a simple set of commonly measured key risk factors.RESEARCH DESIGN AND METHODSFrom the Swedish AMORIS cohort we included 296,428 individuals with a fasting glucose from a health examination during 1985-96 (baseline period). All subjects were followed through 2012 for development of incident T2D. The 20-year T2D risk based on age, sex, body mass index (BMI), fasting glucose (fGlu) and triglycerides (TG) was estimated Trajectories for biomedical risk factors of T2D going back more than 20 years before diagnosis and including fGlu, TG, and BMI were evaluated by yearly means for cases and controls.RESULTSWe identified 28,244 new T2D cases during the study period with an average 20- year risk of 8.1%. This risk was substantially increased in overweight and obese subjects and those with elevated fGlu and TG among both men and women. T2D cases had higher mean BMI, fGlu and TG compared to controls more than 20 years before diagnosis and the difference in fGlu increased over time.CONCLUSIONSDevelopment of T2D is associated with subtle elevations of glucose and lipids more than 20 years before diagnosis. This suggests that diabetogenic processes tied to chronic insulin resistance operate for decades prior to the development of T2D. A simple risk classification can help in early identification of individuals at increased risk
      PubDate: 2018-02-05T09:01:34.685155-05:
      DOI: 10.1111/dom.13241
  • Perspectives on diabetes mortality due to residual confounding and reverse
           causality by common disease
    • Authors: Anne Cathrine Baun Thuesen; Allan Vaag
      Abstract: Type 2 diabetes (T2D) is associated with major global health burdens, including a 2-4 times increased morbidity and mortality from cardiovascular disease. However, T2D remains an exclusion diagnosis in people with arbitrarily elevated blood-glucose levels. While it is well-established that diabetes is associated with an elevated risk of cardiovascular disease and cancer, it has recently been shown that heart failure and cancer may precede and even contribute to the development of T2D. In the present article, we have summarized these findings and discuss their potential implications for our understanding of the T2D disease entity, including its treatment, and associated increased mortality. We suggest that the existence of a hitherto unrecognized distinct T2D subtype secondary to heart failure and/or cancer may substantially contribute to the excess mortality reported in T2D patients with mild disease. Treatment and clinical care of this subtype needs to be defined separately from the general T2D phenotype.
      PubDate: 2018-01-30T10:24:18.282645-05:
      DOI: 10.1111/dom.13238
  • Accuracy and Precision of Flash Glucose Monitoring Sensors Inserted Into
           the Abdomen and Upper Thigh Compared to the Upper Arm (out of sight)
    • Authors: Sara Charleer; Chantal Mathieu, Frank Nobels, Pieter Gillard
      Abstract: Nowadays, most Belgian patients with type 1 diabetes use flash glucose monitoring (FreeStyle® Libre™ [FSL]) to check their glucose values, but some patients find the sensor on the upper arm too visible. The aim of this study was to compare accuracy and precision of FSL sensors when placed on different sites. Twenty-three adults with type 1 diabetes used three FSL sensors simultaneously for 14 days on upper arm, abdomen, and upper thigh. FSL measurements were compared to capillary blood glucose (BG) measurements obtained with built-in FSL BG meter. Aggregated mean absolute relative difference was 11.8±12.0%, 18.5±18.4% and 12.3±13.8% for arm, abdomen (p=0.002 vs. arm) and thigh (p=0.5 vs. arm) respectively. Clarke error grid analysis for arm and thigh were comparable (zone A: 84.9% vs. 84.5%, p=0.6), while less accuracy was seen for abdomen (69.4%, p=0.01). Apart from the first day, accuracy of FSL sensors on arm and thigh was more stable across the 14-day wear duration than accuracy of sensors on abdomen, which deteriorated mainly during week two (p
      PubDate: 2018-01-30T08:48:44.467624-05:
      DOI: 10.1111/dom.13239
  • Brown adipose tissue lipid metabolism in morbid obesity: the effect of
           bariatric surgery-induced weight loss
    • Authors: Prince Dadson; Jarna C. Hannukainen, Mueez U Din, Minna Lahesmaa, Kari K. Kalliokoski, Patricia Iozzo, Jussi Pihlajamäki, Henry K. Karlsson, Riitta Parkkola, Paulina Salminen, Kirsi A. Virtanen, Pirjo Nuutila
      Abstract: AIMWe aimed to investigate the effect of bariatric surgery on lipid metabolism in supraclavicular brown adipose tissue in morbidly obese women. We hypothesized that lipid metabolism improves after surgery-induced weight loss.MATERIALS AND METHODSTwenty-three morbidly obese women (BMI 42.1 ± 4.2 kg/m2; age 43.8 ± 9.8 years) were studied before and 6 months after bariatric surgery and 15 age- and sex-matched controls (22.6 ± 2.8 kg/m2) were studied once. In the supraclavicular fat depot, fractional (FUR) and NEFA uptake rates were measured with 18F-FTHA-PET. We assessed tissue morphology (triglyceride content) using computed tomography (CT)-radiodensity [in Hounsfield Units (HU)] and the proportion of fat with high density [sBAT (%)] in the entire supraclavicular fat depot.RESULTSSupraclavicular fractional uptake rate was lower in obese women compared to controls: (0.0055 ± 0.0035 vs 0.0161 ± 0.0177 1/min, P = 0.001). Both FUR (to 0.0074 ± 0.0035 1/min, P = 0.01) and NEFA uptake rates (to 0.50 ± 0.50 µmol/100 g/min, P = 0.001) increased after surgery. Compared to controls, obese women had lower CT-radiodensity (−101.2 ± 10.1 vs −82.5 ± 5.8 HU, P 
      PubDate: 2018-01-29T06:26:00.2487-05:00
      DOI: 10.1111/dom.13233
  • Counterpoint to the hypothesis that SGLT2 inhibitors protects the heart by
           antagonizing leptin
    • Authors: Angelo Avogaro; Gian Paolo Fadini
      Abstract: Galileo Galilei, who was Professor at the University of Padova, taught us one of the foundations of modern science: experimental evidence always supersedes theoretical evidence. As fascinating as a hypothesis can be, it should be backed by solid experimental data and should be verifiable or rebuttable experimentally.
      PubDate: 2018-01-27T15:52:21.632369-05:
      DOI: 10.1111/dom.13234
  • A 2-year Trial of Intermittent Insulin Therapy versus Metformin for the
           Preservation of Beta-cell Function after Initial Short-term Intensive
           Insulin Induction in early Type 2 Diabetes
    • Authors: Ravi Retnakaran; Haysook Choi, Chang Ye, Caroline K. Kramer, Bernard Zinman
      Abstract: AimsWhen administered in early type 2 diabetes (T2DM), short-term intensive insulin therapy (IIT) can improve reversible beta-cell dysfunction and induce subsequent remission of diabetes. However, this remission is ultimately temporary, as beta-cell function deteriorates over time after stopping IIT. Thus, to preserve beta-cell function, we hypothesized that “induction” IIT needs to be followed by a “maintenance therapy.” In this context, we sought to evaluate the impact on beta-cell function over 2-years of two approaches to maintenance therapy: intermittent short-term IIT every 3-months versus daily metformin.MethodsIn this trial, 24 adults with T2DM of 2.0±1.7 years duration and A1c 6.4±0.1% were randomized to 3-weeks of induction IIT (glargine, lispro) followed by either (i) repeat IIT for up to 2-weeks every 3-months or (ii) daily metformin. Participants underwent serial assessment of beta-cell function by Insulin Secretion-Sensitivity Index-2 (ISSI-2) on oral glucose tolerance test every 3-months.ResultsThe primary outcome of baseline-adjusted ISSI-2 at 2-years was higher in the metformin arm compared to intermittent IIT (245.0±31.7 vs 142.2±18.4, p=0.008). Baseline-adjusted A1c at 2-years (secondary outcome) was lower in the metformin arm (6.0±0.2% vs 7.3±0.2%, p=0.0006). At study completion, 66.7% of participants randomized to metformin had A1c≤6.0% compared to 8.3% of those on intermittent IIT (p=0.009). There were no differences in insulin sensitivity.ConclusionFollowing induction IIT, metformin was superior to intermittent IIT for maintaining beta-cell function and glycemic control over 2-years. The strategy of induction and maintenance therapy to preserve beta-cell function warrants exploration in early T2DM.
      PubDate: 2018-01-27T02:50:19.603931-05:
      DOI: 10.1111/dom.13236
  • Effect of the PCSK9-monoclonal antibodies on new-onset diabetes mellitus
           and glucose metabolism: a systematic review and meta-analysis
    • Authors: Ye-Xuan Cao; Hui-Hui Liu, Qiu-Ting Dong, Sha Li, Jian-Jun Li
      Abstract: AimsTo investigate the effect of two clinically applied proprotein convertase subtilisin/kexin type 9 monoclonal antibody (PCSK9-mAb) on glycaemia and new-onset diabetes mellitus (NODM).Materials and methodsPubMed, MEDLINE, Embase, Cochrane databases and websites were systematically searched for randomized controlled trials that reported the fasting plasma glucose (FPG), Hemoglobin A1c (HbA1c) or NODM incidence. Risk ratios (RR) for NODM and Mean Difference (MD) for FPG and HbA1c with 95% confidence intervals (CI) were calculated using a fixed-effect model. Heterogeneity was examined using the I2 statistic and potential publication bias was assessed with funnel plots and Egger's test.ResultsA total of 18 studies with 26,123 non-diabetic participants were identified. No significant difference was observed in terms of NODM (RR:1.05, 95%CI:0.95 to 1.16), FPG (MD:0.00 mmol/L,95%CI:-0.02 to 0.02) and HbA1c (MD:0.00%, 95%CI:-0.01 to 0.01) compared with control group. Subgroup (PCSK9-mAb types, participant characteristics, treatment duration, treatment method and differences of control treatment) and sensitivity analyses did not significantly alter the results. Meta-regression analyses showed that risk of NODM was not associated with baseline age, baseline body mass index (BMI), proportion of male, treatment duration or percent LDL-C reduction.ConclusionsAlirocumab and Evolocumab, two kinds of PCSK9-mAb approved by FDA and EMA, had no significant impact on NODM and glucose homeostasis, despite of PCSK9-mAb types, participant characteristics, treatment duration, treatment method and differences of control treatment. Baseline age, BMI, male rate, treatment duration, and percent change of LDL-C did not influence diabetes risks.
      PubDate: 2018-01-27T02:45:28.164945-05:
      DOI: 10.1111/dom.13235
  • Dulaglutide Treatment Results in Effective Glycemic Control in Latent
           Autoimmune Diabetes in Adults (LADA): A Post-Hoc Analysis of the AWARD-2,
           -4, and -5 Trials
    • Authors: Paolo Pozzilli; Richard D Leslie, Anne L Peters, Raffaella Buzzetti, Sudha S Shankar, Zvonko Milicevic, Imre Pavo, Jeremie Lebrec, Sherry Martin, Nanette C Schloot
      Abstract: AimsPatients with a type-2-diabetes (T2D) phenotype positive for glutamic acid decarboxylase antibodies (GADA) represent the majority of latent autoimmune diabetes of the adult (LADA). The GLP-1 receptor agonist dulaglutide, recently introduced for treatment of T2D, has yet to be evaluated in LADA patients. Our primary objective was to evaluate the effect of dulaglutide on glycemic control (HbA1c) in GADA-positive LADA vs. GADA-negative T2D patients.MethodsA post-hoc analysis was performed using data from three randomized phase 3 trials (AWARD-2,-4,-5; patients with GADA assessment) which were part of the dulaglutide clinical development program in T2D. LADA patients were identified by GADA ≥5 IU/mL (ELISA). Changes in HbA1c during 12-months treatment with dulaglutide or comparator were analyzed using Mixed-Effect Model Repeated Measures.ResultsOf 2466 adults tested for GADA (dulaglutide 1710, glargine 298, sitagliptin 294, placebo 164), 2278 (92.4%) were GADA-negative and 188 (7.6%) GADA-positive, including 58 GADA-high patients (>200 IU/mL) and 130 GADA-low patients (≤200 and ≥5 IU/mL). Overall, baseline parameters were comparable between the groups.Dulaglutide resulted in comparable HbA1c reductions in GADA-negative (LSmean change [95%CI], -1.09% [-1.15,-1.03]) and GADA-positive patients (-0.94% [-1.15,-0.72]) at 12 months. HbA1c reductions were numerically but not statistically significantly larger in GADA-low (-1.02% [-1.26,-0.78]) vs. GADA-high patients (-0.72% [-1.21,-0.24]) at 12 months. Similar outcomes were observed at 3 and 6 months.ConclusionsThese data are the first to indicate that dulaglutide was effective at reducing HbA1c in LADA patients.
      PubDate: 2018-01-27T02:35:23.365849-05:
      DOI: 10.1111/dom.13237
  • Comparisons of diabetic retinopathy events associated with
           glucose-lowering drugs in patients with type 2 diabetes mellitus: a
           network meta-analysis
    • Authors: Huilin Tang; Guangyao Li, Ying Zhao, Fei Wang, Emily W Gower, Luwen Shi, Tiansheng Wang
      Abstract: AimTo assess the comparative effects of glucose-lowering drugs (GLDs) on diabetic retinopathy (DR) risk in patients with type 2 diabetes mellitus (T2DM).MethodsWe systematically searched Cochrane Central Register of Controlled Trials, PUBMED, and EMBASE from each database's inception to January 17, 2017 to identify randomized controlled trials (RCTs) that reported DR events among the T2DM patients receiving any GLD. Random-effects pairwise and network meta-analyses were performed to calculate the odds ratios (ORs) with 95% confidence intervals (CIs).ResultsA total of 37 independent RCTs with 1,806 DR events among 100,928 patients with T2DM were included. The mean duration of diabetes was 8.7 years and mean baseline HbA1c was 8.2% (SD, 0.5%). Our network meta-analysis found that DPP-4i (OR, 1.20; 95% CI, 0.87 to1.65), GLP-1RA (OR, 1.19; 95% CI, 0.94 to1.52), and SGLT2 inhibitors (OR, 0.79; 95% CI, 0.49 to 1.28) were not associated with a higher risk of DR than placebo; however, a significantly increased risk of DR was associated with DPP-4i in the pairwise meta-analysis (OR, 1.27; 95% CI, 1.05 to 1.53). Sulfonylureas, on the other hand, were associated with a significantly increased risk of DR compared to placebo (OR, 1.67; 95% CI, 1.01 to 2.76).ConclusionsCurrent evidence indicates that the association between DPP-4i, GLP-1RA, or SGLT2 inhibitors and risk of DR remains uncertain in patients with T2DM. Some evidence suggests that sulfonylureas may be associated with increased risk of DR. However, given that DR events were not systematically assessed, these effects should be explored further in large-scale, well-designed studies.
      PubDate: 2018-01-25T08:30:22.06311-05:0
      DOI: 10.1111/dom.13232
  • One-year weight losses in the Tianjin Gestational Diabetes Mellitus
           Prevention Program: A Randomized Clinical Trial
    • Authors: Huikun Liu; Leishen Wang, Shuang Zhang, Junhong Leng, Nan Li, Weiqin Li, Jing Wang, Huiguang Tian, Lu Qi, Xilin Yang, Zhijie Yu, Jaakko Tuomilehto, Gang Hu
      Abstract: AimsTo report the findings on weight loss after the first year of the lifestyle intervention trial among women with gestational diabetes mellitus (GDM).MethodsA total of 1180 GDM women were randomly assigned (1:1) to receive a 4-year lifestyle intervention (intervention group, n=586) or standard care (control group, n=594) between August 2009 and July, 2011. Major elements of the intervention included six face-to-face sessions with study dietitians and two telephone calls in the first year, and two individual sessions and two telephone calls in each subsequent year.ResultsAmong 79% of participants who completed the Year 1 trial, mean weight loss was 0.82 kg (1.12% of initial weight) in the intervention group and 0.09 kg (0.03% of initial weight) in the control group (p=0.001). In a prespecified subgroup analysis of subjects who completed the trial, weight loss was more pronounced in women who were overweight (body mass index ≥24 kg/m2) at baseline: mean weight loss was 2.01 kg (2.87% of initial weight) in the intervention group and 0.44 kg (0.52% of initial weight) in the control group (p
      PubDate: 2018-01-23T11:00:48.573796-05:
      DOI: 10.1111/dom.13225
  • Do Sodium-Glucose Cotransporter-2 Inhibitors Prevent Heart Failure With a
           Preserved Ejection Fraction by Counterbalancing the Effects of Leptin'
           A Novel Hypothesis
    • Authors: Milton Packer
      Abstract: Sodium-glucose transporter-2 (SGLT2) inhibitors reduce the risk of serious heart failure events in patients with type 2 diabetes, but little is known about mechanisms that might mediate this benefit. The most common heart failure phenotype in type 2 diabetes is obesity-related heart failure with a preserved ejection fraction (HFpEF). It has been hypothesized that the synthesis of leptin in this disorder leads to sodium retention and plasma volume expansion as well as to cardiac and renal inflammation and fibrosis. Interestingly, leptin-mediated neurohormonal activation appears to enhance the expression of SGLT2 in the renal tubules, and SGLT2 inhibitors exert natriuretic actions at multiple renal tubular sites in a manner that can oppose the sodium retention produced by leptin. In addition, SGLT2 inhibitors reduce the accumulation and inflammation of perivisceral adipose tissue, thus minimizing the secretion of leptin and its paracrine actions on the heart and kidneys to promote fibrosis. Such fibrosis likely contributes to the impairment of cardiac distensibility and glomerular function that characterizes obesity-related HFpEF. Ongoing clinical trials with SGLT2 inhibitors in heart failure are positioned to confirm or refute the hypothesis that these drugs may favorably influence the course of obesity-related HFpEF by their ability to attenuate the secretion and actions of leptin.
      PubDate: 2018-01-23T08:10:50.85733-05:0
      DOI: 10.1111/dom.13229
  • Optimising the management of hypoglycaemia in people with Type 2 Diabetes.
           A randomised crossover comparison of a weight-based protocol compared with
           two fixed-dose glucose regimens
    • Authors: J.D Krebs; M Weatherall, B Corley, E Wiltshire, L McTavish
      Abstract: AimsTo determine whether an individualised body-weight based glucose treatment in adults with Type-2 diabetes (T2DM) is more likely to resolve hypoglycaemia with a single treatment without excessive rebound hyperglycaemia compared to fixed doses of 12g or 30g glucose.MethodsAdults with T2DM were enrolled into a cross-over study. Each episode of hypoglycaemia (capillary glucose
      PubDate: 2018-01-23T07:45:21.018961-05:
      DOI: 10.1111/dom.13231
  • Antibiotic exposure in early life and childhood overweight and obesity: A
           systematic review and meta-analysis
    • Authors: Sara H Rasmussen; Sarita Shrestha, Lise G Bjerregaard, Lars H Ängquist, Jennifer L Baker, Tine Jess, Kristine H Allin
      Abstract: We conducted a systematic review and meta-analysis of observational studies investigating the association between antibiotic exposure in infancy and risk of childhood overweight and obesity. Thirteen studies counting a total of 527,504 children were included in the systematic review and eight were included in meta-analyses. Exposure to antibiotics in infancy was associated with an increased odds ratio (OR) of childhood overweight and obesity (OR = 1.11 [95% CI 1.02-1.20]). Whereas exposure to one treatment only and exposure between 6 and 24 months were not associated with increased risk of childhood overweight and obesity, exposure to more than one treatment was associated with an OR of 1.24 (95% CI 1.09-1.43) and exposure within the first six months of life was associated with an OR of 1.20 (95% CI 1.04-1.37). In conclusion, antibiotic exposure in infancy is associated with a slightly increased risk of childhood overweight and obesity, mainly if children are exposed to repeated treatments or treatment within the first six months of life. It remains elusive whether this association is mediated via direct effects of antibiotics on the gut microbiota.
      PubDate: 2018-01-23T07:35:20.963463-05:
      DOI: 10.1111/dom.13230
  • Morbid obesity and type 2 diabetes alter intestinal fatty acid uptake and
           blood flow
    • Authors: Jukka Koffert; Mia Ståhle, Henry Karlsson, Patricia Iozzo, Paulina Salminen, Anne Roivainen, Pirjo Nuutila
      Abstract: Background and aimsBariatric surgery is the most effective treatment to tackle morbid obesity and type 2 diabetes, but the mechanisms of action are still unclear. The objective of this study was to investigate the effects of bariatric surgery on intestinal fatty acid (FA) uptake and blood flow.Materials and methodsWe recruited 27 morbidly obese subjects of which 10 had type 2 diabetes and 15 healthy age-matched controls. Intestinal blood flow and fatty acid uptake from circulation were measured during fasting state using positron emission tomography (PET). Obese subjects were restudied six months after bariatric surgery. The mucosal location of intestinal FA retention was verified in insulin resistant mice with autoradiography.ResultsCompared to lean subjects, morbidly obese subjects had higher duodenal and jejunal FA uptake ( P < 0.001) but similar intestinal blood flow (NS). Within six months after bariatric surgery, obese subjects had lost 24% of their weight and 7 out of 10 diabetic subjects were in remission. Jejunal FA uptake was further increased (P
      PubDate: 2018-01-20T04:57:19.947389-05:
      DOI: 10.1111/dom.13228
  • Individual variability in response to renin-angiotensin-aldosterone system
           inhibition predicts cardiovascular outcome in patients with type 2
           diabetes: a primary care cohort study
    • Authors: Ellen M Apperloo; Michelle J Pena, Dick de Zeeuw, Petra Denig, Hiddo JL Heerspink
      Abstract: AimsVariability in response to Renin-Angiotensin-Aldosterone System (RAAS) inhibition has been shown in clinical trials but its occurrence and impact in clinical practice are unknown. We assessed variability in systolic blood pressure (SBP) and albuminuria (UACR) responses in patients with type 2 diabetes mellitus initiating RAAS inhibition, and assessed the association of response variability with cardiovascular outcomes.MethodsWe performed an observational cohort study in patients with type 2 diabetes who started RAAS inhibition between 2007 and 2013 (n=1600) were identified from general practices in the Netherlands. Individual response in SBP and UACR was assessed within 15 months follow-up. Patients were categorized as: good responders (∆SBP 0%). Multivariable Cox regression was performed to test the association between initial RAAS inhibition response and subsequent cardiovascular outcomes.ResultsAfter starting RAAS inhibition , mean SBP change was -13.2 mmHg and median UACR was -36.6%, with a large between individual variability, both in SBP [5th to 95th percentile: -48.5 to 20] and UACR [5th to 95th percentile: -87.6 to 171.4]. 812 patients (51%) were good responders, 353 (22%) had a good SBP but poor UACR response, 268 (17%) had a good UACR but poor SBP response, and 167 patients (10%) were poor responders. Good responders had a lower risk of cardiovascular events than poor responders (HR 0.51, 95% CI: 0.30 –0.86; p=0.012).ConclusionsSBP and UACR response after RAAS inhibition initiation varies between and within individual patients with type 2 diabetes treated in primary care. Poor responders have the highest risk of cardiovascular events, so more efforts are needed to develop personalized treatment plans for these patients.
      PubDate: 2018-01-18T06:10:23.095206-05:
      DOI: 10.1111/dom.13226
  • Intra- and Inter-Subject Variability for Increases in Serum Ketone Bodies
           in Patients With Type 2 Diabetes Treated With the Sodium Glucose
           Co-transporter 2 Inhibitor Canagliflozin
    • Authors: David Polidori; Hiroaki Iijima, Maki Goda, Nobuko Maruyama, Nobuya Inagaki, Peter A. Crawford
      Abstract: SGLT2 inhibitors have been associated with increased serum ketone bodies in patients with type 2 diabetes mellitus (T2DM). This analysis evaluated serum ketone body levels and variability in 1,278 Japanese patients with T2DM treated with canagliflozin 100 or 200 mg. Similar mean increases in ketone body concentrations of ~2-fold were seen with both canagliflozin doses. Median (interquartile range) percent change from baseline was 62% (0;180) for acetoacetate and 78% (2;236) for β-hydroxybutyrate. Approximately 2/3 of the variability in each ketone measure was attributed to intra-subject variability. Intra-subject variability was higher for serum ketones than other metabolites. Subjects in the lowest-response tertile exhibited no increase in ketones. Those in the highest-response tertile tended to be male and have higher fasting glucose, lower insulin, and longer T2DM duration at baseline. Moreover, changes in serum ketones were not fully explained by changes in plasma fatty acids, suggesting downstream effects of SGLT2 inhibition on hepatic metabolism that favour ketogenesis. In summary, increases in serum ketone bodies with canagliflozin were greater and more variable than changes in other metabolic measures in Japanese subjects with T2DM.
      PubDate: 2018-01-17T04:50:23.862334-05:
      DOI: 10.1111/dom.13224
  • Effect of immediate and prolonged GLP-1 receptor agonist administration on
           uric acid and its kidney clearance: post-hoc analyses of four clinical
    • Authors: Lennart Tonneijck; Marcel H.A. Muskiet, Mark M. Smits, Petter Bjornstad, Mark H.H. Kramer, Michaela Diamant, Ewout J. Hoorn, Jaap A. Joles, Daniël H. van Raalte
      Abstract: AimsTo determine effects of glucagon-like peptide (GLP)-1 receptor agonists (RA) on uric acid (UA)-levels and kidney UA-clearance.Material and methodsPost-hoc analyses of four controlled clinical trials, which assessed actions of GLP-1RA-administration on kidney physiology. Immediate effects of GLP-1RA exenatide-infusion versus placebo was determined in 9 healthy overweight males (Study-A) and in 52 overweight T2DM-patients (Study-B). Effects were also examined of 12-week long-acting GLP-1RA liraglutide versus placebo in 36 overweight T2DM-patients (Study-C) and of 8-week short-acting GLP-1RA lixisenatide versus once-daily titrated insulin-glulisine in 35 overweight T2DM-patients (Study-D). Plasma-UA, fractional (inulin-corrected) and absolute urinary-excretion of UA (UEUA) and sodium (UENa), and urine-pH was determined.ResultsMedian baseline plasma-UA levels was 5.39 to 6.33 mg/dL across all studies (17-22% of subjects were hyperuricemic). In study-A, exenatide-infusion slightly increased plasma-UA (+0.07±0.02mg/dL, P=0.04), and raised absolute-UEUA (+1.58±0.65mg/min/1.73m2, P=0.02), but did not affect fractional-UEUA compared to placebo. Fractional-UEUA and absolute-UEUA correlated with increases in urine-pH (r:0.86, P=0.003 and r:0.92, P
      PubDate: 2018-01-17T04:40:21.65258-05:0
      DOI: 10.1111/dom.13223
  • A Vitamin B12 Conjugate of Exendin-4 Improves Glucose Tolerance Without
           Associated Nausea or Hypophagia in Rodents
    • Authors: Elizabeth G. Mietlicki-Baase; Claudia G. Liberini, Jayme L. Workinger, Ron L. Bonaccorso, Tito Borner, David J. Reiner, Kieran Koch-Laskowski, Lauren E. McGrath, Rinzin Lhamo, Lauren M. Stein, Bart C. De Jonghe, George G. Holz, Christian L. Roth, Robert P. Doyle, Matthew R. Hayes
      Abstract: AimsWhile pharmacological glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved for treating type 2 diabetes mellitus (T2DM) and obesity, a major side effect is nausea/malaise. We recently developed a conjugate of vitamin B12 bound to the GLP-1R agonist exendin-4 (Ex4), which displays enhanced proteolytic stability and retention of GLP-1R agonism. Here, we evaluate whether the conjugate (B12-Ex4) can improve glucose tolerance without producing anorexia and malaise.Materials and MethodsWe evaluated the effects of systemic B12-Ex4 and unconjugated Ex4 on food intake and body weight change, oral glucose tolerance, and nausea/malaise in male rats, and on intraperitoneal glucose tolerance in mice. To evaluate whether differences in the profile of effects of B12-Ex4 versus unconjugated Ex4 are due to altered CNS penetrance, rats received systemic injections of fluorescein-Ex4 (Flex), Cy5-B12 or Cy5-B12-Ex4 and brain penetrance was evaluated using confocal microscopy. Uptake of systemically administered Cy5-B12-Ex4 in insulin-containing pancreatic beta cells was also examined.ResultsB12-Ex4 conjugate improves glucose tolerance, but does not elicit the malaise and anorexia produced by unconjugated Ex4. While Flex robustly penetrates into the brain (dorsal vagal complex, paraventricular hypothalamus), Cy5-B12 and Cy5-B12-Ex4 fluorescence were not observed centrally, supporting a lack of CNS penetrance in line with observed reduction in CNS-associated Ex4 side effects. Cy5-B12-Ex4 colocalizes with insulin in the pancreas, suggesting direct pancreatic action as a potential mechanism underlying the hypoglycemic effects of B12-Ex4.ConclusionsThese novel findings highlight the potential clinical utility of B12-Ex4 conjugates as possible future T2DM therapeutics with reduced incidence of adverse effects.
      PubDate: 2018-01-12T01:40:56.644048-05:
      DOI: 10.1111/dom.13222
  • Short and medium-term efficacy of sodium glucose co-transporter-2 (SGLT-2)
           inhibitors: a meta-analysis of randomized clinical trials
    • Authors: Matteo Monami; Francesco Liistro, Alessia Scatena, Besmir Nreu, Edoardo Mannucci
      Abstract: AimsSodium glucose co-transport-2 (SGLT-2) inhibitors reduce tubular glucose reabsorption, producing a reduction of blood glucose without stimulating insulin release. Aim of this meta-analysis is the systematic collection of available data from randomized trials, in order to establish the durability of the efficacy of SGLT-2 inhibitors on glycemic control and body mass index.MethodsA meta-analysis was performed including all trials with a duration of at least 12 weeks, comparing SGLT-2 inhibitors with a non-SGLT-2 inhibitor agents in type 2 diabetes. The principal outcome was the effect of SGLT-2 inhibitors on HbA1c at 12, 24, 52, and 104 weeks. Data on body mass index at the same time points were also collected.ResultsAmong 66 randomized trials, hemoglobin A1c (HbA1c) reduction at 12, 24, 52, and 104 weeks was 0.63[0.57;0.68], 0.63[0.57;0.70], 0.66[0.57;0.74], and 0.60[0.40;0.81]%, respectively. SGLT-2 inhibitors showed a greater efficacy than Dipeptidyl-Peptidase-4 inhibitors (DPP-4i). Sulfonylureas appeared to be superior to SGLT-2 inhibitors at 12 weeks, but not at 24 and 52 weeks; SGLT-2 inhibitors produced a greater reduction of HbA1c than sulfonylureas at 104 weeks. SGLT-2 inhibitor-induced weight loss in placebo-controlled trials appeared to increase progressively with the duration of treatment.ConclusionsSGLT-2 inhibitors showed a good persistence of efficacy, at least up to two years, with a small but significant superiority over DPP-4i. Sulfonylureas are more effective in the very short term, but less effective in the longer term.
      PubDate: 2018-01-12T00:55:22.112201-05:
      DOI: 10.1111/dom.13221
  • Safety and efficacy of once-weekly semaglutide versus additional oral
           antidiabetic drugs, in Japanese subjects with inadequately controlled T2D:
           a randomised trial
    • Authors: Kohei Kaku; Yuichiro Yamada, Hirotaka Watada, Atsuko Abiko, Tomoyuki Nishida, Jeppe Zacho, Arihiro Kiyosue
      Abstract: AimsSemaglutide is a glucagon-like peptide 1 analogue in development for type 2 diabetes (T2D). Safety and efficacy of once-weekly subcutaneous semaglutide as monotherapy or combined with an oral antidiabetic drug (OAD) vs an additional OAD was evaluated in Japanese subjects with T2D inadequately controlled on diet/exercise or OAD monotherapy.MethodsIn this phase 3, open-label trial, adults with T2D were randomised 2:2:1 to semaglutide 0.5 mg or 1.0 mg, or one additional OAD (dipeptidyl peptidase-4 inhibitor, biguanide, sulphonylurea, glinide, α-glucosidase inhibitor or thiazolidinedione) with different modes of action. Primary endpoint was number of adverse events (AEs) after 56 weeks.ResultsBaseline characteristics were balanced between treatment arms (601 randomised). More AEs were reported with semaglutide 0.5 mg (86.2%) and 1.0 mg (88.0%) vs additional OAD (71.7%). These were typically mild/moderate. Gastrointestinal AEs were most frequent with semaglutide, which diminished over time. Mean HbA1c (baseline 8.1%) was significantly reduced with semaglutide 0.5 mg and 1.0 mg vs additional OAD (1.7% and 2.0% vs 0.7%, respectively; estimated treatment difference [ETD] vs additional OAD –1.08% and –1.37%, both p
      PubDate: 2018-01-11T01:36:21.304385-05:
      DOI: 10.1111/dom.13218
  • Declare-Timi 58: Participants’ Baseline Characteristics
    • Authors: Itamar Raz; Ofri Mosenzon, Marc P Bonaca, Avivit Cahn, Eri T Kato, Michael G Silverman, Deepak L Bhatt, Lawrence A. Leiter, Darren K. McGuire, John Wilding, Ingrid AM Gause-Nilsson, Anna Maria Langkilde, Peter A. Johansson, Marc S. Sabatine, Stephen D. Wiviott
      Abstract: BackgroundCardiovascular (CV) outcome trials with new glucose lowering agents (GLA) are designed to prove CV safety in high CV risk populations. However, the level of CV risk differs greatly among trials, which may influence comparability and generalizability of results.AimWe describe baseline characteristics of participants randomized in the Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58) trial, the pivotal study to assess CV outcomes with dapagliflozin.ResultsThe DECLARE-TIMI 58 trial randomized and will analyze 17,160 patients with type 2 diabetes (T2D) to treatment with dapagliflozin (10 mg/day) or matching placebo. The participants' mean age (SD): 63.8±6.8, 62.6%: male, mean diabetes duration: 11.8±7.8 years, HbA1c: 8.3%±1.2% and BMI: 32.1±6.0 kg/m2. Randomization included 6,971 (40.6%) patients with atherosclerotic cardiovascular disease (CVD), and 10,189 (59.4%) patients with multiple risk factors (MRF) for CV disease (defined as men: age ≥55 or women: ≥60; with at least one of: dyslipidemia, hypertension, or smoking). Patients with CVD compared with patients with MRF were younger (62.5±8.1 vs. 64.7±5.6 years), more frequently male (72.1% vs. 56.1%), less often used metformin (74.6% vs. 81.2%), more often used insulin (44.2% vs. 36.4%), and more frequently used statins, aspirin, clopidogrel and beta blockers (82.2% 71.1%, 24.7% and 66.6% vs. 63.7%, 39.1%, 1.5% and 32.3%), respectively.ConclusionThe DECLARE-TIMI 58 trial is expected to provide conclusive data on the effect of treatment with dapagliflozin versus placebo, each in addition to standard of care, on CV outcomes in a broad patient population with T2D and CVD or MRF for CVD.
      PubDate: 2018-01-11T01:15:29.271293-05:
      DOI: 10.1111/dom.13217
  • PREVIEW: Prevention of diabetes through lifestyle intervention in a
           multicentre study in Europe in children (10-17y). Design, methods, and
           baseline results
    • Authors: Elke Dorenbos; Mathijs Drummen, Jesse Rijks, Tanja Adam, Pauline Stouthart, J. Alfredo Martínez, Santiago Navas-Carretero, Gareth Stratton, Nils Swindell, Mikael Fogelholm, Anne Raben, Margriet Westerterp-Plantenga, Anita Vreugdenhil
      Abstract: Insulin resistance (IR) in adolescence is associated with T2DM. The PREVIEW study assesses the effectiveness of a high-protein, low-glycaemic index diet and moderate-protein, moderate-glycaemic index diet to decrease IR in insulin resistant children with overweight/obesity. Inclusion criteria were age 10-17y, HOMA-IR≥2.0 and overweight/obesity. In 126 children (13.6±2.2y, BMI z-score 3.04±0.66, HOMA-IR 3.48±2.28) anthropometrics, fat mass percentage (FM%), metabolic parameters, physical activity, food intake and sleep were measured. Baseline characteristics did not differ between the groups. IR was higher in pubertal children with morbid obesity than in prepubertal children with morbid obesity (5.41±1.86 vs. 3.23±1.86, p=0.007) and prepubertal and pubertal children with overweight/obesity (vs. 3.61±1.60, p=0.004 and vs. 3.40±1.50, p
      PubDate: 2018-01-11T01:00:36.297596-05:
      DOI: 10.1111/dom.13216
    • PubDate: 2018-01-10T02:10:22.947805-05:
      DOI: 10.1111/dom.13201
  • Basal Insulin Peglispro Increases Lipid Oxidation, Metabolic Flexibility,
           Thermogenesis And Ketone Bodies Compared To Insulin Glargine In Subjects
           With Type 1 Diabetes Mellitus
    • Authors: Niels K. Porksen; Helle Linnebjerg, Eric Chen Quin Lam, Parag Garhyan, Alok Pachori, Richard E. Pratley, Steven R. Smith
      Abstract: AIMSWhen treated with basal insulin peglispro (BIL), patients with type 1 diabetes mellitus (T1DM) exhibit weight loss and lower prandial insulin requirements versus insulin glargine (GL), while total insulin requirements remain similar. One possible explanation is enhanced lipid oxidation and improved ability to switch between glucose and lipid metabolism with BIL. This study compared the effects of BIL and GL on glucose and lipid metabolism in subjects with T1DM.MATERIALS AND METHODSFifteen subjects with T1DM were enrolled into this open-label, randomised, crossover study, and received once-daily stable, individualised, subcutaneous doses of BIL and GL for 4 weeks each. Respiratory quotient (RQ) was measured using whole-room calorimetry, and energy expenditure (EE) and concentrations of ketone bodies (3-hydroxybutyrate) and acylcarnitines were assessed.RESULTSMean sleep RQ was lower during the BIL (0.822) than the GL (0.846) treatment period, indicating greater lipid metabolism during the post-absorptive period with BIL. Increases in carbohydrate oxidation following breakfast were greater during BIL than GL treatment (mean change in RQ following breakfast = 0.111 for BIL, 0.063 for GL). Furthermore, BIL treatment increased total daily EE versus GL (2215.9 kcal/day for BIL, 2135.5 kcal/day for GL). Concentrations of ketone bodies and acylcarnitines appeared to be higher following BIL than GL treatment.CONCLUSIONSBIL increased sleeping fat oxidation, EE, ketone bodies, acylcarnitines and post-prandial glucose metabolism when switching from conventional insulin, thus, restoring metabolic flexibility and increasing thermogenesis. These changes may explain the previously observed weight loss with BIL versus GL.
      PubDate: 2018-01-08T04:55:24.478131-05:
      DOI: 10.1111/dom.13215
  • Effect of prandial treatment timing adjustment, based on continuous
           glucose monitoring, in patients with type 2 diabetes uncontrolled on once
           daily basal insulin: a randomized, phase IV study
    • Authors: Jacob Ilany; Hamad Bhandari, Dan Nabriski, Yoel Toledano, Noa Konvalina, Ohad Cohen,
      Abstract: OBJECTIVETo evaluate the glycemic control achieved by prandial once daily insulin glulisine injection timing adjustment based on continuous glucose monitoring sensor in comparison to once daily insulin glulisine injection before breakfast in type 2 diabetes patients uncontrolled on once daily basal insulin glargine.RESEARCH DESIGN AND METHODSThis was a 24-week open-label, randomized-controlled, multicenter trial. At the end of 8 weeks of basal insulin optimization period, patients with HbA1c ≥ 7.5% and FPG < 130 mg/dL were randomized (1:1) to either arm A (no sensor) or arm B (sensor) to receive 16-week intensified prandial glulisine treatment. Patients in arm A received pre-breakfast glulisine, and patients in arm B received glulisine before the meal with the highest glucose elevation based on the sensor data. The primary outcome was mean HbA1c at week 24 and secondary outcomes included rates of hypoglycemia events and insulin dosage.RESULTSA total of 121 patients were randomized to arm A (n = 61) or arm B (n = 60). There was no difference in the mean HbA1c at week 24 in arm A and arm B (8.5 ± 1.2% vs 8.4 ± 1.0%; P = 0.66). The prandial insulin glulisine dosage for arm A and arm B was 9.3 and 10.1 units, respectively (P = 0.39). The frequency of hypoglycemic events did not differ between study arms (36.1% vs. 51.7%; P = 0.08).CONCLUSIONUsing CGM sensor for identifying the meal with highest glucose excursion and adjusting the prandial insulin treatment timing does not show any advantage in terms of glycemic control or safety in our patients.
      PubDate: 2018-01-08T04:45:44.709032-05:
      DOI: 10.1111/dom.13214
  • Efficacy and safety of fast-acting insulin aspart in comparison with
           insulin aspart in type 1 diabetes (onset 1): a 52-week, randomized,
           treat-to-target, phase 3 trial
    • Authors: Chantal Mathieu; Bruce W. Bode, Edward Franek, Athena Philis-Tsimikas, Ludger Rose, Tina Graungaard, Anne Birk Østerskov, David Russell-Jones
      Abstract: AimsCompare safety and efficacy of fast-acting insulin aspart (faster aspart) with conventional insulin aspart (IAsp) in adults with type 1 diabetes (T1D).Materials and methodsonset 1 was a randomized, multicentre, treat-to-target, phase 3, 52-week (initial 26 weeks + additional 26 weeks) trial conducted at 165 sites across nine countries. Adults with T1D were randomly allocated to double-blind mealtime faster aspart or IAsp, each with once- or twice-daily insulin detemir. The primary endpoint, change in HbA1c from baseline after the initial 26 weeks, has been reported previously; here, we report data from the full 52-week study period.ResultsBetween August 2013 and June 2015, 381 subjects were assigned to double-blind faster aspart and 380 subjects to IAsp. After 52 weeks, estimated mean changes from baseline in HbA1c levels were −0.08% (faster aspart) and +0.01% (IAsp); estimated treatment difference (ETD) significantly favoured faster aspart (−0.10% [95% CI: [−0.19;−0.00]; P = 0.0424). Changes from baseline in 1-h postprandial plasma glucose (PPG) increment (meal test) (faster aspart, −1.05 mmol/l; IAsp, −0.14 mmol/l) also significantly favoured faster aspart (ETD: −0.91 mmol/l [−1.40;−0.43]; −16.48 mg/dl [−25.17;−7.80]; P = 0.0002). There was no difference in overall severe or blood glucose-confirmed hypoglycaemic episodes or treatment-emergent adverse events between treatments.ConclusionsAt 52 weeks, overall glycaemic control had significantly improved with faster aspart versus IAsp, consistent with the 26-week study findings. Achieving an insulin profile closer to physiological insulin secretion with faster aspart translates into lower PPG and HbA1c levels in subjects with T1D compared with IAsp.
      PubDate: 2018-01-08T04:30:51.473678-05:
      DOI: 10.1111/dom.13205
  • Long-term safety and efficacy of tofogliflozin add-on to insulin in
           patients with type 2 diabetes: results from a 52-week, multicenter,
           randomized, double-blind, open-label extension, Phase 4 study in Japan
    • Authors: Yasuo Terauchi; Masahiro Tamura, Masayuki Senda, Ryoji Gunji, Kohei Kaku
      Abstract: AimsTo evaluate the long-term safety and efficacy of tofogliflozin as an add-on treatment to insulin over 52 weeks.Materials and methodsThis 52-week, multicenter, Phase 4 study consisted of a 16-week, randomized, double-blind, placebo-controlled phase and a 36-week open label extension phase (NCT02201004). Japanese patients with type 2 diabetes mellitus aged 20–75 years with suboptimal glycemic control (7.5%–10.5%) on insulin monotherapy (basal-bolus, bolus, premix [low and high], and basal) or on combination therapy of basal insulin and dipeptidyl peptidase-4 inhibitor were eligible for participation. Patients who received tofogliflozin throughout the study (52 weeks) were referred to as “tofo-tofo group” and patients who received placebo and tofogliflozin (36 weeks) were referred to as “pla-tofo group”.ResultsA total of 210 patients received treatment as per randomization. Hypoglycemia was the most common treatment-emergent adverse event (AE) (42.9% in tofo-tofo group and 29.4% in pla-tofo group). Patients reported genital infection, urinary tract infection, excessive urination, and AEs related to volume depletion (2.1%, 2.1%, 7.1%, and 10.0% of patients in tofo-tofo group; and 0%, 1.5%, 2.9%, and 7.4% of patients in pla-tofo group, respectively). Mean HbA1c and body weight at baseline (mean changes ± standard error from baseline to Week 52) in the tofo-tofo and pla-tofo groups were 8.53% (−0.76% ± 0.077) and 8.40% (−0.73% ± 0.102); 68.84 kg (−1.52 kg ± 0.207) and 72.24 kg (−2.13 kg ± 0.313), respectively.ConclusionsThis study demonstrates the safety and efficacy of tofogliflozin as add-on to insulin therapy in type 2 diabetes mellitus patients, offering a new therapeutic solution to diabetes management.
      PubDate: 2018-01-05T11:00:27.277903-05:
      DOI: 10.1111/dom.13213
  • Tofogliflozin decreases body fat mass and improves peripheral insulin
    • Authors: Ren Matsuba; Ikuro Matsuba, Mototsugu Shimokawa, Yoshio Nagai, Yasushi Tanaka
      Abstract: The impact of tofogliflozin, a sodium glucose transporter 2 inhibitor, on peripheral glucose uptake in patients with type 2 diabetes mellitus (T2DM) was investigated by the hyperinsulinemic-euglycemic clamp method in a single-arm, open-label study. The following parameters were compared between before and after tofogliflozin administration for 12 weeks in 16 T2DM patients using dipeptidyl peptidase 4 inhibitors: body weight, blood pressure, glucose metabolism, liver function, lipid profile, and body composition. Peripheral glucose uptake (M value and M/I ratio) was examined by the hyperinsulinemic-euglycemic clamp method. After 12 weeks, there was a significant decrease (P < .001) of hemoglobin A1c, body weight, body fat mass, and lean body mass. Peripheral glucose uptake, which indicates insulin sensitivity, increased significantly (M value by 0.90 and M/I ratio by 0.49; both P < .05). The change in the M value after 12 weeks of tofogliflozin therapy was correlated with the change in body fat mass (P < .05). Tofogliflozin significantly improved insulin sensitivity and peripheral glucose uptake in T2DM patients. These improvements were significantly correlated with reduction of body fat mass.
      PubDate: 2018-01-05T10:45:20.947074-05:
      DOI: 10.1111/dom.13211
  • Sustained high fat diet modulates inflammation, insulin signalling and
           cognition in mice and a modified xenin peptide ameliorates neuropathology
           in a chronic high fat model
    • Authors: Paul Denver; Victor A Gault, Paula L McClean
      Abstract: AimsMetabolic disease increases risk of Alzheimer's disease and cognitive dysfunction. Chronic high fat diet (HFD) feeding leads to cognitive impairment and neuroinflammation. This study demarcated pathological events in brain as a result of short-term to chronic HFD feeding. Efficacy of Xenin-25[Lys(13)PAL] was assessed in chronic HFD-fed mice.MethodsC57BL/6 mice were fed HFD or normal diet for 18 days, 34 days, 10 and 21 weeks. Cognition was assessed using novel object recognition and Morris water maze. Markers of insulin signaling and inflammation were measured in brain and plasma using immunohistochemistry, qPCR and multi-array technology. Xenin-25[Lys(13)PAL] was also administered for 5 weeks in chronic HFD-fed mice to assess therapeutic potential at a pathological stage.ResultsRecognition memory was consistently impaired in HFD-fed mice and spatial learning was impaired in 18-day and 21-week HFD-fed mice. Gliosis, oxidative stress and IRS-1 pSer616 were increased in the brain at day 18 in HFD-fed mice and were reduced by Xenin-25[Lys(13)PAL] in 21-week HFD-fed mice. In plasma, HFD feeding elevated IL-6 and CXCL1 at day 34 and IL-5 at week 10. In brain, HFD feeding reduced ERK2, mTOR, NF-κB1, PKCθ and TLR4 mRNA at week 10 and increased expression of GLP-1R, IKKβ, ERK2, mTOR, NF-κB1, PKCθ and TLR4 at week 21, elevations that were abrogated by Xenin-25[Lys(13)PAL].ConclusionsHFD feeding modulates cognitive function, synapse density, inflammation and insulin resistance in brain. Xenin-25[Lys(13)PAL] ameliorated markers of inflammation and insulin signalling dysregulation and may have therapeutic potential in the treatment of diseases associated with neuroinflammation or perturbed insulin signalling in the brain.
      PubDate: 2018-01-05T10:40:22.440716-05:
      DOI: 10.1111/dom.13210
  • The association of hypoglycaemia severity and clinical, patient-reported
           and economic outcomes in US patients with type 2 diabetes using basal
    • Authors: Luigi F. Meneghini; Lulu Lee, Shaloo Gupta, Ron Preblick
      Abstract: AimsTo evaluate the clinical and patient-reported outcomes and healthcare utilization and costs associated with patient-reported hypoglycaemia in US adults with type 2 diabetes (T2D) treated with basal insulin.Materials and methodsThis was an observational, cross-sectional, survey-based study of adults with T2D on basal insulin ± oral antidiabetes drugs (OADs) or rapid-acting/premix insulin who had in the past ever experienced hypoglycaemia, using US data from the National Health and Wellness Survey. Eligible patients were categorized as having no hypoglycaemia (38.7%), non-severe hypoglycaemia (55.1%), or severe hypoglycaemia (6.2%) in the preceding 3 months. Outcomes included health-related quality of life (HRQoL), work productivity and activity impairment, healthcare-resource utilization, and estimated direct and indirect costs. Multivariable regression models were performed to control for patient characteristics.ResultsPatients who experienced severe hypoglycaemia had significantly (P < 0.05) lower HRQoL scores, greater overall impairment of work productivity and activity, greater healthcare-resource utilization, and higher costs compared with those who experienced non-severe or no hypoglycaemia. Patients with non-severe hypoglycaemia also reported an impact on the number of provider visits, indirect costs, and HRQoL.ConclusionsPatients with T2D using basal insulin ± rapid-acting/premix insulin in the US who experienced severe hypoglycaemia had greater impairment of activity and work productivity, utilized more healthcare resources, and incurred higher associated costs than those with non-severe or no hypoglycaemia. The study also demonstrated the impact that non-severe hypoglycaemia events have on economic and HRQoL outcomes. Reducing the incidence and severity of hypoglycaemia could lead to clinically meaningful improvements in HRQoL and may result in lower healthcare utilization and associated costs.
      PubDate: 2018-01-05T10:25:21.865934-05:
      DOI: 10.1111/dom.13208
  • Dapagliflozin for prednisone-induced hyperglycemia in acute exacerbation
           of chronic obstructive pulmonary disease
    • Authors: Maaike C. Gerards; Gerdien E. Venema, Kornelis W. Patberg, Martijn Kross, Bert Jan Potter van Loon, Ilse M. G. Hageman, Dominic Snijders, Dees P.M. Brandjes, Joost B. L. Hoekstra, Titia M. Vriesendorp, Victor E. A. Gerdes
      Abstract: This study aimed to compare the effectiveness and safety of add-on treatment with dapagliflozin to placebo in subjects with prednisone-induced hyperglycemia during treatment for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). We enrolled 46 patients hospitalized for an AECOPD in a multicenter double-blind randomized controlled study in which add-on treatment with dapagliflozin 10 mg was compared to placebo. Glycemic control and incidence of hypoglycemia were measured through a blinded subcutaneous continuous glucose measurement device. Subjects in the dapagliflozin group, spent 54 ± 27.7% of the time in target range (3.9-10 mmol/L) and this was 53.6 ± 23.4% in the placebo group (p = 0.96). Mean glucose concentration was 10.1 mmol/L in the dapagliflozin group and 10.4 mmol/L in the placebo group (p = 0.66). One patient using dapagliflozin and 2 patients using placebo experienced a symptomatic hypoglycemia. Treatment with dapagliflozin was safe and there was no difference in risk of hypoglycemia compared to placebo. Dapagliflozin did not result in better glycemic control compared to placebo in patients with prednisone-induced hyperglycemia during AECOPD.
      PubDate: 2018-01-05T10:15:20.050523-05:
      DOI: 10.1111/dom.13209
  • Have We Really Demonstrated the Cardiovascular Safety of Antihyperglycemic
           Drugs' Rethinking the Concepts of Macrovascular and Microvascular
           Disease in Type 2 Diabetes
    • Authors: Milton Packer
      Abstract: A primary goal of the treatment of type 2 mellitus is the prevention of morbidity and mortality due to cardiovascular disease. However, antihyperglycemic drugs have the capacity to cause deleterious effects on the circulation, a risk that is not adequately reflected by the endpoints selected for emphasis in large-scale clinical trials that are designed to evaluate cardiovascular safety. The primary endpoint of the large-scale studies mandated by regulatory authorities focuses only on 3-4 events that depict only a limited view of the circulatory system.One of the most serious adverse effects of many glucose-lowering drugs is new-onset or worsening heart failure. Most antidiabetic drugs can aggravate heart failure because they exert antinatriuretic actions, and possibly, adverse effects on the myocardium. In addition, certain antihyperglycemic agents may worsen peripheral vascular disease and trigger cardiac arrhythmias that may lead to sudden death. Initiation of treatment with antidiabetic medications may also cause deterioration of the function of the kidneys, retina and peripheral nerves, which are typically regarded as reflecting microvascular disease.The current confusion about the cardiovascular effects of glucose-lowering drugs may be exacerbated by conceptual uncertainties about the classification of large and small vessel disease in determining the clinical course of diabetes. Physicians should not be falsely reassured by claims that a new treatment appears to have passed a narrowly-defined regulatory test. The management of diabetic patients often carries with it the risk of important cardiovascular consequences, even for drugs that do not overtly increase the risk of myocardial infarction or stroke.
      PubDate: 2018-01-05T09:25:24.614908-05:
      DOI: 10.1111/dom.13207
  • Effects of exenatide once weekly plus dapagliflozin, exenatide once
           weekly, or dapagliflozin added to metformin monotherapy on body weight,
           systolic blood pressure, and triglycerides in patients with type 2
           diabetes in the DURATION-8 study
    • Authors: Serge A. Jabbour; Juan P. Frías, Cristian Guja, Elise Hardy, Azazuddin Ahmed, Peter Öhman
      Abstract: This post hoc analysis assessed the effects on cardiovascular risk factors of body weight, systolic blood pressure (SBP), and triglycerides after 28 weeks’ treatment with exenatide once weekly (QW) plus dapagliflozin, as compared with exenatide QW or dapagliflozin, in patient subpopulations from the DURATION-8 trial of patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin alone. Subgroups of patients were stratified according to their baseline body weight, SBP, and triglycerides. Body weight, SBP, and triglycerides were reduced across most respective subgroups, with no significant subgroup-by-treatment interactions. For each treatment, weight loss was numerically greater as baseline body mass index increased. SBP reductions were greater among patients with SBP ≥140 versus
      PubDate: 2018-01-05T08:40:55.19915-05:0
      DOI: 10.1111/dom.13206
  • Erratum to: Effect of GLP-1 receptor agonist treatment on body weight in
           obese antipsychotic-treated patients with schizophrenia: a randomized,
           placebo-controlled trial
    • Authors: Bjørn H. Ebdrup; Brian V. Broberg, Pelle L. Ishøy, Nikolaj Bak, Ulrik B. Andersen, Niklas R. Jørgensen, Jens J. Holst, Filip K. Knop, Birte Y. Glenthøj
      Abstract: “Treatment of antipsychotic-associated obesity with a GLP-1 receptor agonist (GLP-1RA): The TAO trial” is the first clinical investigation of GLP-1RA treatment (exenatide 2 mg once-weekly or placebo) in antipsychotic-treated schizophrenia patients with obesity.1 Recently, we published the main results from the TAO trial as an original article in Diabetes, Obesity and Metabolism.2We regret to report, that further analyses of the TAO dataset have revealed an error in our secondary analyses presented in the original publication.
      PubDate: 2018-01-05T08:25:20.088971-05:
      DOI: 10.1111/dom.13204
  • Diabetes, Obesity and Metabolism
    • Pages: 477 - 478
      PubDate: 2018-02-13T23:36:33.674185-05:
      DOI: 10.1111/dom.13091
  • News and Views
    • Authors: Iskandar Idris
      Pages: 756 - 758
      PubDate: 2018-02-13T23:36:38.65133-05:0
      DOI: 10.1111/dom.13227
    • PubDate: 2017-12-28T21:25:42.37377-05:0
      DOI: 10.1111/dom.13187
  • Effect of a Glucagon Receptor Antibody (REMD-477) in Type 1 Diabetes: A
           Randomized Controlled Trial
    • Authors: Jeremy Pettus; Dominic Reeds, Tricia Santos Cavaiola, Schafer Boeder, Michelle Levin, Gary Tobin, Edda Cava, Dung Thai, Jim Shi, Hai Yan, Edgar Bautista, John McMillan, Roger Unger, Robert R. Henry, Samuel Klein
      Abstract: The aim of the current study was to study the efficacy and safety of REMD-477, a glucagon receptor antagonist, in type 1 diabetes. This was a randomized controlled trial in which 21 patients with type 1 diabetes were enrolled. Glycemic control and insulin use were evaluated during outpatient and inpatient settings, before and after, a single 70-mg dose of REMD-477 (half-life 7-10 days) or placebo. Inpatient insulin use was 26% (95% CI:47%,4%) lower 1 day after dosing with REMD-477 than placebo (p=0.02). Continuous glucose monitoring during post-treatment days 6-12 showed average daily glucose was 27 mg/dl lower (p180 mg/dl) was ~40% lower (~4 hours/day) (p=0.001) in the REMD-477 than the placebo group, without a difference in percent time-in-hypoglycemic-range (
      PubDate: 2017-12-28T09:21:32.854089-05:
      DOI: 10.1111/dom.13202
  • Injecting without pressing a button: an exploratory study of a
           shield-triggered injection mechanism
    • Authors: Eric Zijlstra; Hans-Veit Coester, Tim Heise, Leona Plum-Mörschel, Ole Rasmussen, Tord Rikte, Line Kynemund Pedersen, Marianne Qvist, Thomas Sparre
      Abstract: AimsTo evaluate injection success and user perception of a shield-triggered pen-injector mechanism.MethodsThe trial ( NCT02627287) was an exploratory, two-centre, one-visit, open-label, randomized controlled trial conducted in Germany in 150 injection-experienced subjects with type 1 or type 2 diabetes. Subjects self-administered subcutaneous injections of a placebo solution using a prototype shield-triggered pen-injector, DV3316 (Novo Nordisk, Bagsvaerd, Denmark), and FlexPen® (Novo Nordisk, Bagsvaerd, Denmark). Injection success was evaluated on a yes/no basis by the investigator. Subject confidence, leakage of fluid and pain were evaluated after each injection. Pain and device experience were assessed after completion of all injections with each pen-injector. Overall preference was assessed after completion of all injections with both pen-injectors.ResultsInjection success was high with both pen-injectors (97.0%, DV3316 vs. 99.7%, FlexPen). Subject confidence in dose delivery was similar between devices (88% of injections with DV3316 vs. 81% with FlexPen were scored as 'extremely confident'). Median injection pain score on a visual analogue scale (0–100), was 3 with DV3316 vs. 4 with FlexPen after each injection, and 4 with DV3316 vs. 5 with FlexPen after all injections with each device. After all injections were completed, 55% of subjects reported an overall preference for DV3316 vs. 21% for FlexPen.ConclusionThis study demonstrates that injection-experienced subjects can achieve a high injection success rate with a shield-triggered pen-injector, with similar subject confidence and injection pain compared with FlexPen.
      PubDate: 2017-12-27T07:19:15.120803-05:
      DOI: 10.1111/dom.13203
  • Relationship between treatment persistence and A1C trends among patients
           with type 2 diabetes newly initiated on basal insulin
    • Authors: Fang Liz Zhou; Lin Xie, Chunshen Pan, Yuexi Wang, Neel Vaidya, Fen Ye, Ronald Preblick, Luigi Meneghini
      Abstract: This study examines the relationship between glycated hemoglobin (A1C) levels and treatment persistence with, or time to discontinuation of, basal insulin in patients with type 2 diabetes (T2D) newly initiating insulin. Claims data were extracted from the Optum™ Clinformatics database from January 2010 to June 2015. Adult patients with T2D initiating insulin glargine 100 U/mL (Gla-100) or insulin detemir (DET) with ≥1 A1C measurement during 12-month baseline and 18-month follow-up periods were included. Patients with a refill gap of>90 days were considered non-persistent; otherwise patients were considered persistent with insulin. The main outcome was A1C, measured closest to the end of each quarter during the follow-up period. 3,993 of 109,934 patients met the inclusion criteria (43.0% persistent: 57.0% non-persistent). Persistent patients were older (54.7 vs 52.7 years; P < .001), male (59.4% vs 54.4%, P = .002), had significantly lower mean unadjusted A1C values at 18 months (8.26% vs 8.60%; P < .001) and quarterly. Only 43.0% of adults initiating basal insulin persisted with treatment for 18 months, with earlier discontinuation associated with higher A1C.
      PubDate: 2017-12-26T09:35:20.961401-05:
      DOI: 10.1111/dom.13200
  • The effect of low-volume high-intensity interval training versus endurance
           training on glycemic control in individuals with type 2 diabetes
    • Authors: Kamilla Munch Winding; Gregers Winding Munch, Ulrik Winning Iepsen, Gerrit Van Hall, Bente Klarlund Pedersen, Stefan Peter Mortensen
      Abstract: AIMTo evaluate if high-intensity interval training (HIIT) with a lower time commitment can be equally effective as endurance training (END) on glycemic control, physical fitness and body composition in individuals with type 2 diabetes.MATERIALS AND METHODSTwenty-nine individuals with type 2 diabetes were allocated to control (CON; no training), END, or HIIT. Training groups were prescribed three training sessions per week consisting of either 40 min cycling at 50% of peak workload (END) or ten 1 min intervals at 95% of peak workload interspersed by 1 min active recovery (HIIT). Glycemic control (HbA1c, oral glucose tolerance test, 3-hours mixed meal tolerance test with double tracer technique, and continuous glucose monitoring (CGM)), lipolysis, VO2peak and body composition were evaluated before and after 11 weeks of intervention.RESULTSExercise training increased VO2peak more in HIIT (20±20%) compared with END (8±9%) despite lower total energy expenditure and time usage during the training sessions. HIIT decreased whole body and android fat mass compared with CON. In addition, visceral fat mass, HbA1c, fasting glucose, postprandial glucose, glycemic variability and HOMA-IR decreased after HIIT. The reduced postprandial glucose in HIIT was primarily driven by a lower rate of exogenous glucose appearance. In CON, postprandial lipolysis was augmented over the 11 week control period.CONCLUSIONSDespite a ~45% lower training volume, HIIT resulted in similar or even better improvements in physical fitness, body composition and glycemic control compared to END. HIIT therefore appears to be an important time-efficient treatment for individuals with type 2 diabetes.
      PubDate: 2017-12-22T09:25:24.090598-05:
      DOI: 10.1111/dom.13198
  • Real-world evidence on clinical and economic outcomes of switching to
           insulin glargine 300 Units/mL vs other basal insulins in patients with
           type 2 diabetes on basal insulin
    • Authors: Fang Liz Zhou; Fen Ye, Paulos Berhanu, Vineet E. Gupta, Rishab A. Gupta, Jennifer Sung, Jukka Westerbacka, Timothy S. Bailey, Lawrence Blonde
      Abstract: This retrospective cohort study compared real-world clinical and healthcare-resource utilization (HCRU) data in patients with type 2 diabetes using basal insulin (BI) who switched to insulin glargine 300 units/mL (Gla-300) or another BI. Data from the Predictive Health Intelligence Environment database 12 months before (baseline) and 6 months after (follow-up) the switch date (index date, 1 March 2015 to 31 May 2016) included glycated haemoglobin A1c (HbA1c), hypoglycaemia, HCRU and associated costs. Baseline characteristics were balanced using propensity score matching. Change in HbA1c from baseline was similar in both matched cohorts (n = 1,819 in each); hypoglycaemia incidence and adjusted event rate were significantly lower with Gla-300. Patients switching to Gla-300 had a significantly lower incidence of HCRU related to hypoglycaemia. All-cause and diabetes-related hospitalization and emergency-department HCRU were also favourable for Gla-300. Lower HCRU translated to lower costs in patients using Gla-300. In this real-world study, switching to Gla-300 reduced risk of hypoglycaemia in patients with type 2 diabetes when compared with those switching to another BI, resulting in less HCRU and potential savings of the associated costs.
      PubDate: 2017-12-22T09:25:19.571598-05:
      DOI: 10.1111/dom.13199
  • Non-severe hypoglycemia is associated with weight gain in patients with
    • Authors: Anisoara Bumbu; Abdul Moutairou, Odette Matar, Frédéric Fumeron, Gilberto Velho, Jean-Pierre Riveline, Jean-François Gautier, Michel Marre, Ronan Roussel, Louis Potier
      Abstract: It is unclear whether the frequent non-severe episodes of hypoglycemia observed during intensive glucose control in people with type 1 diabetes (T1D) are associated with later weight gain. We analyzed the association between non-severe hypoglycemia and weight gain in 1441 DCCT participants. Non-severe hypoglycemia was assessed by a hypo-score (number of blood glucose values
      PubDate: 2017-12-22T09:20:19.466116-05:
      DOI: 10.1111/dom.13197
  • Long-term outcome on glycaemic control and β-cell preservation of early
           intensive treatment in patients with newly diagnosed Type 2 Diabetes: A
           Multicentre Randomised Trial
    • Authors: Suk Chon; Sang Youl Rhee, Kyu Jeung Ahn, Sei Hyun Baik, Yongsoo Park, Moon Suk Nam, Kwan Woo Lee, Soon Jib Yoo, Gwanpyo Koh, Dae Ho Lee, Young Seol Kim, Jeong-Taek Woo
      Abstract: AimTo determine the effects of early intensive glycaemic control with intensive insulin treatment (IIT) or initial combined oral anti-diabetic therapy (COAD) on long-term glycaemic control and the preservation of β-cell function in subjects with type 2 diabetes mellitus (T2DM).MethodsNewly diagnosed drug-naïve T2DM patients from eight outpatient diabetes centres were randomised to receive either IIT (n = 50; glargine/glulisine) or COAD (n = 47; glimepiride/metformin) as intensive treatment (IT) until the termination criteria to ensure euglycaemia were met. Following IT, the patients completed a follow-up (FU) period with either lifestyle modification (LSM) alone or rescue therapy to maintain target A1c levels < 7% up to Week 104. The primary outcomes were analysed after excluding anti-GAD Ab-positive patients.ResultsBoth IT methods were effective for short-term glycaemic control but improvements in the disposition index (DI) were significantly greater in the IIT group than the COAD group (p = 0.021). During the FU period after IT, the two groups significantly differed in rescue method regarding the maintenance of comparable levels of glycaemic control (p = 0.010) and more subjects that received IIT exhibited well-controlled T2DM with LSM alone. Additionally, the IIT group maintained a higher DI than the COAD group during the FU period. A Cox regression analysis revealed that the IIT method was associated with a 52.5% lower risk of failing to maintain drug-free glycaemic remission compared to the COAD method (p = 0.015).ConclusionsThe present findings indicate that outpatient clinic-based IIT to ensure euglycaemia in newly diagnosed T2DM patients might be an effective initial therapeutic option for improvements in β-cell function and glycaemic control over the long-term without serious adverse events.
      PubDate: 2017-12-22T09:15:26.56473-05:0
      DOI: 10.1111/dom.13196
  • Ertugliflozin Plus Sitagliptin Versus Either Individual Agent Over 52
           Weeks in Patients with Type 2 Diabetes Mellitus Inadequately Controlled
           With Metformin: The VERTIS FACTORIAL Randomized Trial
    • Authors: Richard E. Pratley; Roy Eldor, Annaswamy Raji, Gregory Golm, Susan B. Huyck, Yanping Qiu, Sheila Sunga, Jeremy Johnson, Steven G. Terra, James P. Mancuso, Samuel S. Engel, Brett Lauring
      Abstract: AIMSTo evaluate the efficacy and safety of ertugliflozin and sitagliptin co-administration vs the individual agents in patients with type 2 diabetes inadequately controlled on metformin.METHODSPatients with glycated haemoglobin (HbA1c) ≥7.5% and ≤11.0% (≥58 and ≤97 mmol/mol) on metformin ≥1500 mg/day (n = 1233) were randomized to ertugliflozin 5 (E5) or 15 (E15) mg/day, sitagliptin 100 mg/day (S100), or co-administration of E5/S100 or E15/S100. The primary endpoint was change from baseline in HbA1c at Week 26.RESULTSAt Week 26, least squares mean HbA1c reductions from baseline were greater with E5/S100 (–1.5%) and E15/S100 (–1.5%) than with individual agents (–1.0%, –1.1%, and –1.1% for E5, E15, and S100, respectively; P < 0.001 for all comparisons). HbA1c
      PubDate: 2017-12-21T09:25:36.922272-05:
      DOI: 10.1111/dom.13194
  • Visit-to-visit HbA1c variability and systolic blood pressure (SBP)
           variability are significantly and additively associated with mortality in
           people with type 1 diabetes: an observational study
    • Authors: Stuart S. Wightman; Christopher A.R. Sainsbury, Gregory C. Jones
      Abstract: TitleVisit-to-visit HbA1c variability and systolic blood pressure (SBP) variability are significantly and additively associated with mortality in people with type 1 diabetes: an observational study.AimTo investigate relationship between variability in both visit-to-visit HbA1c and SBP, and mortality in people with Type 1 diabetes.MethodsThe Scottish Care Information (SCI) Diabetes dataset was used to identify 5,952 people with type 1 diabetes for inclusion in this observational study. The SCI-Diabetes dataset allowed access to blood pressure values, HbA1c readings, demographic information and mortality rates for all study participants. Participants were dichotomised to above and below median values for both HbA1c coefficient of variation (CV) and SBP CV, thus dividing participants into four cohorts for survival analysis. Survival analysis was carried out over 1,430 days. A Cox proportional hazard model was used to allow comparison of mortality between the four cohorts.ResultsOf the 5,952 patients, death occurred in 416. CV for both HbA1c and SBP were significantly associated with mortality. The median value for HbA1c CV and SBP CV was 8.0 and 8.1 respectively. Hazard ratio for high HbA1c CV only (p=0.0015) was 1.78±0.36. Hazard ratio for high SBP CV only (p=0.0018) was 1.69±0.33. Hazard ratio for both high HbA1c CV and high SBP CV (p
      PubDate: 2017-12-21T08:55:21.571506-05:
      DOI: 10.1111/dom.13193
    • PubDate: 2017-12-19T04:30:37.372665-05:
      DOI: 10.1111/dom.13188
  • Effect of a single dose of the DPP-4 inhibitor sitagliptin on β-cell
           function and incretin hormone secretion after meal ingestion in healthy
           volunteers and drug-naïve, well-controlled type 2 diabetes subjects
    • Authors: Wathik Alsalim; Olga Göransson, Richard D. Carr, Roberto Bizzotto, Andrea Tura, Giovanni Pacini, Andrea Mari, Bo Ahrén
      Abstract: To explore the effects of a single dose of the DPP-4 inhibitor sitagliptin on glucose-standardized insulin secretion and β-cell glucose sensitivity after meal ingestion, twelve healthy- and twelve drug naïve well-controlled type 2 diabetes subjects (T2D; mean HbA1c 43 mmol/mol, 6.2%) received sitagliptin (100mg) or placebo before a meal (525 kcal). β-cell function was measured as the insulin secretory rate at a standardized glucose concentration and the β-cell glucose sensitivity (the slope between glucose and insulin secretory rate). Incretin levels were also monitored. Sitagliptin increased standardized insulin secretion both in healthy and T2D subjects compared to placebo but without increasing β-cell glucose sensitivity. Sitagliptin also increased active glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) and reduced total (reflecting the secretion) GIP but not total GLP-1 levels. We conclude that a single dose of DPP-4 inhibition induces dissociated effects on different aspects of β-cell function and incretin hormones after meal ingestion in healthy subjects and in well-controlled T2D.
      PubDate: 2017-12-11T11:05:47.020767-05:
      DOI: 10.1111/dom.13192
  • Comparative effectiveness of metformin monotherapy in extended release and
           immediate release formulations for the treatment of type 2 diabetes in
           treatment-naïve Chinese patients: analysis of results from the CONSENT
    • Authors: Linong Ji; Jing Liu, Jing Yang, Yufeng Li, Li Liang, Dalong Zhu, Quanmin Li, Tianrong Ma, Haiyan Xu, Yanlan Yang, Jiaoe Zeng, Bo Feng, Shen Qu, Yiming Li, Lizhen Ma, Shanshan Lin, Jianping Wang, Wei Li, Weihong Song, Xiaoxing Li, Yong Luo, Shugang Xi, Mei Lin, Yu Liu, Zerong Liang
      Abstract: AimsMetformin treatment for type 2 diabetes (T2DM) can be limited by gastrointestinal (GI) adverse events (AEs), resulting in treatment discontinuation. We investigated whether once-daily metformin extended release (XR) is superior in terms of GI tolerability, with non-inferior efficacy, compared with thrice-daily metformin immediate release (IR) in treatment-naïve Chinese patients with T2DM.Materials and MethodsThis prospective, open-label, randomized, multicenter, phase IV interventional study enrolled Chinese T2DM patients to receive either metformin XR or metformin IR with a 2-week screening period, 16-week treatment period, and 2-week follow-up period without treatment. Co-primary endpoints were a non-inferiority assessment of XR metformin versus IR metformin in glycated hemoglobin (HBA1c) least squares mean (LSM) change from baseline to week 16 and the superiority of GI tolerability for metformin XR versus metformin IR.ResultsOverall, 532 patients were randomized to metformin IR (n=267) or metformin XR (n=265). The HbA1c LSM change was −1.61% and −1.58% in each group, respectively (LSM difference, 0.03; 95% confidence interval [CI], −0.10, 0.17). Incidences of drug-related AEs were 26.5% (n=66) in the metformin IR-only group and 32.2% (n=85) in the metformin XR-only group, and GI AEs were 23.8% and 22.3% in each group, respectively (difference, −1.52; 95% CI, −8.60, 5.56). The treatment difference met the predefined non-inferiority upper CI margin of 0.4% in HbA1c.ConclusionsMetformin XR was non-inferior to metformin IR for the LSM change in HbA1c from baseline to week 16 and not superior to metformin IR for overall GI AE incidence during treatment of Chinese T2DM patients.
      PubDate: 2017-12-11T10:55:20.218568-05:
      DOI: 10.1111/dom.13190
  • Role of the Sodium-Hydrogen Exchanger in Mediating the Renal Effects of
           Drugs Commonly Used in the Treatment of Type 2 Diabetes
    • Authors: Milton Packer
      Abstract: Diabetes is characterized by an increased activity of the sodium-hydrogen exchanger (NHE) in the glomerulus and renal tubules, which contributes importantly to the development of nephropathy. Despite the established role played by the exchanger in experimental studies, it has not been specifically targeted by those seeking to develop novel pharmacological treatments for diabetes. This review demonstrates that many existing drugs that are commonly prescribed to patients with diabetes act on the NHE1 and NHE3 isoforms in the kidney. This action may explain their effects on sodium excretion, albuminuria and the progressive decline of glomerular function in clinical trials; these responses cannot be readily explained by the influence of these drugs on blood glucose. Agents that may affect the kidney in diabetes by virtue of an action on NHE include: (1) insulin and insulin sensitizers; (2) incretin-based agents; (3) sodium-glucose cotransporter 2 inhibitors; (4) antagonists of the renin-angiotensin system (angiotensin converting-enzyme inhibitors, angiotensin receptor blockers, and angiotensin receptor neprilysin inhibitors); and (5) inhibitors of aldosterone action and cholesterol synthesis (spironolactone, amiloride and statins). The renal effects of each of these drug classes in patients with type 2 diabetes may be related to a single shared biological mechanism.
      PubDate: 2017-12-11T10:35:29.910248-05:
      DOI: 10.1111/dom.13191
  • Insulin Secretion Predicts the Response to Therapy with Exenatide Plus
           Pioglitazone but not to Basal/Bolus Insulin in Poorly Controlled T2DM
           Patients: Results from the Qatar Study
    • Authors: Muhammad Abdul-Ghani; Osama Migahid, Ayman Megahed, Rajvir Singh, Dalia Kamal, Ralph A. DeFronzo, Amin Jayyousi
      Abstract: The present study aims to identify predictors for response to combination therapy with pioglitazone plus exenatide versus basal/bolus insulin therapy in T2DM patients who are poorly controlled on maximum/near-maximum doses metformin plus a sulfonylurea. Participants in the Qatar study received a 75-gram OGTT with measurement of plasma glucose, insulin, and C-peptide concentration at baseline and then were randomized to receive treatment with pioglitazone plus exenatide or basal/bolus insulin therapy for one year. Insulin secretion measured with plasma C-peptide concentration during the OGTT was the strongest predictor of response to combination therapy (HbA1c ≤7.0%) with pioglitazone plus exenatide. A 54% increase in 2-h plasma C-peptide concentration above the fasting level identified subjects who achieved the glycemic goal (HbA1c
      PubDate: 2017-12-11T10:30:56.09849-05:0
      DOI: 10.1111/dom.13189
  • Claims-based studies of oral glucose-lowering medications can achieve
           balance in critical clinical parameters only observed in electronic health
    • Authors: E Patorno; C Gopalakrishnan, JM Franklin, KG Brodovicz, E Masso-Gonzalez, DB Bartels, J Liu, S Schneeweiss
      Abstract: BackgroundHealthcare claims databases can provide information on the effects of type 2 diabetes (T2DM) medications as used in routine care, but often do not contain data on important clinical characteristics, which may be captured in electronic health records (EHR).ObjectivesTo evaluate the extent to which balance in unmeasured patient characteristics was achieved in claims data, by comparing against more detailed information from linked EHR data.MethodsWithin a large US commercial insurance database and using a cohort design, we identified T2DM patients initiating linagliptin or a comparator agent within class (i.e., other DPP-4 inhibitors) or outside class (i.e., (pioglitazone or sulfonylureas) between 05/2011-12/2012. We focused on comparators used at a similar stage of diabetes as linagliptin. For each comparison, 1:1 propensity score (PS) matching was used to balance over 100 baseline claims-based characteristics, including proxies of diabetes severity and duration. Additional clinical data from EHRs was available for a subset of patients. We assessed representativeness of the claims-EHR linked subset, evaluated the balance of claims- and EHR-based covariates before and after PS-matching via standardized differences (SD), and quantified the potential bias associated with observed imbalances.ResultsFrom a claims-based study population of 166,613 T2DM patients, 7,219 (4.3%) patients were linked to their EHR data. Claims-based characteristics between the EHR-linked and EHR-unlinked patients were comparable (SD
      PubDate: 2017-12-05T08:55:26.033525-05:
      DOI: 10.1111/dom.13184
  • Reversibility of Myocardial Metabolism and Remodeling in Morbidly Obese
           Patients Six Months after Bariatric Surgery
    • Authors: Jarna C. Hannukainen; Riikka Lautamäki, Jussi Pärkkä, Marjatta Strandberg, Virva Saunavaara, Saija Hurme, Minna Soinio, Prince Dadson, Kirsi A. Virtanen, Tove Grönroos, Sarita Forsback, Paulina Salminen, Patricia Iozzo, Pirjo Nuutila
      Abstract: Aims/hypothesisTo study myocardial substrate uptake, structure and function before and after bariatric surgery to clarify the interaction between myocardial metabolism and cardiac remodeling in morbid obesity.MethodsWe studied 46 subjects (age 44±10 yrs, BMI 42±4 kg/m2), including 18 with type 2 diabetes before and six months after bariatric surgery and 25 healthy age-matched controls. Myocardial fasting free fatty acid uptake (MFAU) and insulin-stimulated glucose uptake (MGU) were measured using PET. Myocardial structure, function, triglyceride content (MTGC) and intrathoracic fat were measured with MRI and MRS.ResultsMorbidly obese subjects, with or without type 2 diabetes, had cardiac hypertrophy, impaired myocardial function and substrate metabolism compared to controls. Surgery led to marked weight reduction and remission of type 2 diabetes in most of the subjects. Post-operatively, myocardial function and structure improved and myocardial substrate metabolism normalized. Intrathoracic fat, but not MTGC, was reduced. Before surgery, BMI and MFAU correlated with LV hypertrophy and BMI, age and intrathoracic fat mass were the main parameters associated with cardiac function. The improvement in whole-body insulin sensitivity correlated positively with the increase in MGU and the decrease in MFAU.Conclusions/interpretationIn the present study, obesity and age, rather than myocardial substrate uptake, were the causes of cardiac remodeling in morbidly obese subjects with or without type 2 diabetes. Cardiac remodeling and impaired myocardial substrate metabolism are reversible after surgically induced weight loss and amelioration of type 2 diabetes.
      PubDate: 2017-12-05T08:41:11.823177-05:
      DOI: 10.1111/dom.13183
  • Plasma PCSK9 and Cardiovascular Events in Type 2 Diabetes
    • Authors: Petra El Khoury; Ronan Roussel, Frederic Fumeron, Yara Abou-Khalil, Gilberto Velho, Kamel Mohammedi, Marie-Paule Jacob, P. Gabriel Steg, Louis Potier, Youmna Ghaleb, S El Bitar, S Ragot, Francesco Andreata, Giusepinna Caligiuri, Samy Hadjadj, Catherine Boileau, Michel Marre, Marianne Abifadel, Mathilde Varret, Boris Hansel
      Abstract: AimsThe prognostic value of proprotein-convertase-subtilisin/kexin type 9 (PCSK9) specifically in type 2 diabetes mellitus (T2DM) is unknown. Our aim was to investigate whether plasma concentrations of PCSK9 was associated with cardiovascular (CV) events in two cohorts of patients with T2DM.MethodsWe considered patients from the DIABHYCAR (n=3,137) and the SURDIAGENE (n=1,468) studies. Baseline plasma PCSK9 was measured by an immunofluorescence assay. In a post-hoc but preplanned analyses, we assessed the relationship between PCSK9 and the following endpoints: (1) a combined endpoint of major CV events: CV death, non-fatal myocardial infarction (MI), stroke and heart failure-related hospital admission; (2) a composite of all CV events: MI, stroke, heart failure-related hospital admission, coronary/peripheral angioplasty or bypass, CV death; (3) MI, (4) stroke/transient ischemic attack (TIA), and (5) CV death.ResultsIn DIABHYCAR, plasma PCSK9 tertiles were associated with the incidence of MI, all CV events and stroke/TIA (p for trend
      PubDate: 2017-12-05T08:21:27.245643-05:
      DOI: 10.1111/dom.13181
  • LH-21 and Abn-CBD improve β-cell function in isolated human and mouse
           islets through GPR55-dependent and -independent signalling
    • Authors: Inmaculada Ruz-Maldonado; Attilio Pingitore, Bo Liu, Patricio Atanes, Guo Cai Huang, David Baker, Francisco José Alonso, Francisco Javier Bermúdez-Silva, Shanta J. Persaud
      Abstract: AimsCB1 and GPR55 are GPCRs expressed by islet β-cells. Pharmacological compounds have been used to investigate their function, but off-target effects of ligands have been reported. This study examined the effects of Abn-CBD (GPR55 agonist) and LH-21 (CB1 antagonist) on human and mouse islet function, and islets from GPR55-/- mice were used to determine signalling via GPR55.Materials and methodsIslets isolated from human organ donors and mice were incubated in the absence or presence of Abn-CBD or LH-21 and insulin secretion, [Ca2+]i, cAMP, apoptosis, β-cell proliferation and CREB and AKT phosphorylation were examined by standard techniques.ResultsAbn-CBD potentiated glucose-stimulated insulin secretion and elevated [Ca2+]i in human islets and islets from both GPR55+/+ and GPR55-/- mice. LH-21 also increased insulin secretion and [Ca2+]i in human islets and GPR55+/+ mouse islets, but concentrations of LH-21 up to 0.1 μM were ineffective in islets from GPR55-/- mice. Neither ligand affected basal insulin secretion or islet cAMP levels. Abn-CBD and LH-21 reduced cytokine-induced apoptosis in human islets and GPR55+/+ mouse islets, and these effects were suppressed following GPR55 deletion. They also increased β-cell proliferation: the effects of Abn-CBD were preserved in islets from GPR55-/- mice, while those of LH-21 were abolished. Abn-CBD and LH-21 increased AKT phosphorylation in mouse and human islets.ConclusionsThis study demonstrated that Abn-CBD and LH-21 improve human and mouse islet β-cell function and viability. Use of islets from GPR55-/- mice suggests that designation of Abn-CBD and LH-21 as GPR55 agonist and CB1 antagonist, should be revised.
      PubDate: 2017-12-05T07:40:30.595225-05:
      DOI: 10.1111/dom.13180
  • Clinical correlates of hypoglycaemia over 4 years in people with type 2
           diabetes starting insulin: An analysis from the CREDIT study
    • Authors: Philip Home; Francoise Calvi-Gries, Lawrence Blonde, Valerie Pilorget, Joseph Berlingieri, Nick Freemantle
      Abstract: AimTo identify factors associated with documented symptomatic and severe hypoglycaemia over 4 years in people with type 2 diabetes starting insulin therapy.Materials and methodsCREDIT, a prospective international observational study, collected data over 4 years on people starting any insulin in 314 centers; 2729 and 2271 people had hypoglycaemia data during the last 6 months of years 1 and 4. Multivariable logistic regression was used to select characteristics associated with documented symptomatic hypoglycaemia, and the model tested against severe hypoglycaemia.ResultsParticipants reporting ≥1 non-severe event were 18.5% and 16.6% in years 1 and 4, 24.6% and 18.3% in those achieving an HbA1c
      PubDate: 2017-12-05T07:25:20.684045-05:
      DOI: 10.1111/dom.13179
  • Pharmacokinetics and tolerability of semaglutide in subjects with hepatic
    • Authors: Lene Jensen; Viera Kupcova, Gerhard Arold, Jonas Pettersson, Julie B. Hjerpsted
      Abstract: AimsTo investigate whether the pharmacokinetic characteristics of semaglutide were altered in subjects with hepatic impairment, assessed using Child-Pugh criteria, versus those with normal hepatic function.MethodsIn this multicentre, open-label, parallel-group trial (sponsor Novo Nordisk, ID NCT02210871), four groups of subjects with normal hepatic function (n = 19) or mild (n = 8), moderate (n = 10) or severe (n =7) hepatic impairment received a single, subcutaneous dose of 0.5 mg semaglutide. Semaglutide plasma concentrations were assessed frequently for 35 days after dosing. The primary endpoint was area under the semaglutide plasma concentration-time curve from time zero to infinity (AUC0-∞). No effect of hepatic impairment was declared if the 90% confidence interval (CI) for the between-groups ratio (hepatic impairment/normal) was within the interval 0.70–1.43.ResultsSemaglutide exposure was similar across all groups, with AUC0-∞ treatment ratios for mild impairment/normal of 0.95 (90% CI 0.77, 1.16), moderate impairment/normal 1.02 (0.93, 1.12), and severe impairment/normal 0.97 (0.84, 1.12). The maximum plasma semaglutide concentration (Cmax) did not appear to be influenced by hepatic function, with mild impairment/normal treatment ratios of 0.99 (0.80, 1.23), moderate impairment/normal 1.02 (0.88, 1.18) and severe impairment/normal 1.15 (0.89, 1.48) (sensitivity analysis excluding one extreme semaglutide concentration: 1.05 (0.88, 1.25)). Ten subjects reported twelve mild or moderate non-serious adverse events. No unexpected safety or tolerability issues were observed.ConclusionsSemaglutide exposure did not appear to be affected by hepatic impairment, suggesting that no dose adjustment may be necessary in patients with hepatic impairment. Semaglutide was well tolerated and there were no unexpected safety issues.
      PubDate: 2017-12-05T02:00:47.645429-05:
      DOI: 10.1111/dom.13186
  • Comparison of glucose-lowering agents following dual therapy failure in
           type 2 diabetes Systematic review and network meta–analysis of
           randomised controlled trials
    • Authors: Francesco Zaccardi; Nafeesa N. Dhalwani, Jolyon Dales, Hamid Mani, Kamlesh Khunti, Melanie J. Davies, David R. Webb
      Abstract: AimsTo assess the evidence supporting the choice of third–line agents in adults with inadequately controlled type 2 diabetes.Materials and MethodsWe searched RCTs published between Jan 2000 and July 2017 reporting data on cardiometabolic outcomes and hypoglycaemia for glucose–lowering agents added to metformin–based dual treatments. Data were stratified by background therapy and RCT duration and synthesised, when possible, with network meta–analyses.Results43 RCTs (16590 participants) were included, with metformin combined to sulphonylurea (SU) in 20 RCTs; thiazolidinedione (TZD) in 10; basal or rapid acting insulin in 6; DPP–4i in 3; GLP–1RA in 2; and SGLT–2i in 2. When added to metformin and SU, after 24–36 weeks rapid acting insulin resulted in the largest reduction of HbA1c (1.6% vs placebo) followed by GLP–1RA (1.0%), basal insulin (0.8%), and SGLT–2i (0.7%), with no difference between GLP–1RA and SGLT–2i; body weight increased with insulin treatment (about 3 kg vs placebo) while the greatest reduction was observed for SGLT–2i compared to all other therapies. Limited data for hypoglycaemia indicated a similar risk for SGLT–2i and GLP–1RA. Results for third–line agents added to metformin and TZD were comparable, showing similar HbA1c reduction and risk of hypoglycaemia between SGLT–2i and GLP–1RA and a slightly greater reduction of body weight with SGLT–2i vs GLP–1RA. Data for 52–54 weeks were more limited: added to metformin and SU, a TZD, GLP–1RA, or SGLT–2i reduced HbA1c to a similar extent but had different effects on body weight (7 kg and 5 kg more with TZD vs SGLT–2i and GLP–1RA, respectively; 2 kg less comparing SGLT–2i vs GLP–1RA). Formal analyses could not be performed for any other dual failure combinations due to the small number of available RCTs.ConclusionsModerate–quality evidence supports the choice of a third–line agent only in patients on metformin combined with SU or TZD, with SGLT–2i performing generally better than other drugs. In suggesting third–line agents, future guidelines should recognise the widely different evidence across possible dual failures.
      PubDate: 2017-12-05T01:50:26.929454-05:
      DOI: 10.1111/dom.13185
  • Use and effectiveness of a fixed-ratio combination of insulin
           degludec/liraglutide (IDegLira) in a real-world population with type 2
           diabetes: Results from a European, multicentre, retrospective chart review
    • Authors: Hermione Price; Matthias Blüher, Rudolf Prager, Tra-Mi Phan, Brian Larsen Thorsted, Bernd Schultes,
      Abstract: AimsEXTRA aimed to describe real-world use and effectiveness of IDegLira, a fixed-ratio combination of the basal insulin degludec, and the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide.Materials and methodsThis European, multicentre, retrospective chart review comprised adults (n=611) with type 2 diabetes, who started IDegLira ≥6 months before data collection. Clinical characteristics were assessed at baseline (defined as the most recent recording during the 6 months before the first IDegLira prescription) and 3, 6, 9 and 12 months (± 45 days for each time point) after commencing IDegLira, where data available.ResultsBaseline regimens included non-injectables (19%), basal insulin (19%), GLP-1RA (10%), free combination (insulin/GLP-1RA, 24%) and multiple daily-dose insulin injections (MDI, 28%), all ± oral antidiabetic drugs. After 6 months, significant HbA1c reductions were observed in patients overall and in all subgroups (–0.9% [–10 mmol/mol] overall, p
      PubDate: 2017-12-05T01:20:31.389683-05:
      DOI: 10.1111/dom.13182
  • Incretin-based therapies and risk of pancreatic cancer in patients with
           type 2 diabetes: a meta-analysis of randomised controlled trials
    • Authors: Haining Wang; Ye Liu, Qing Tian, Jin Yang, Ran Lu, Siyan Zhan, Jari Haukka, Tianpei Hong
      Abstract: AimsConflicting evidence exists regarding the potential risk of pancreatic cancer with use of incretin drugs in patients with type 2 diabetes (T2DM). We performed a meta-analysis of randomised controlled trials (RCTs), including six recently published large-scale cardiovascular outcome trials (CVOTs), to evaluate the risk of pancreatic cancer with incretin-based therapies in patients with T2DM.Materials and methodsThe PubMed, Embase, Cochrane Central Register and databases were searched for RCTs in T2DM that compared incretin drugs with placebo or other antidiabetic drugs, with treatment and follow-up durations of no less than 52 weeks, from January 1, 2007 to May 1, 2017. Two reviewers screened the studies, extracted the data and assessed the risk of bias independently and in duplicate.ResultsThirty-three studies (n=79,971), including the six CVOTs, with 87 pancreatic cancer events were identified. Overall, the pancreatic cancer risk was not increased in patients administered with incretin drugs compared to controls (Peto OR 0.67 [95%CI 0.44 to 1.02]). In the six CVOTs, 79 pancreatic cancer events were identified in 55,248 subjects. Pooled estimates of the six CVOTs displayed the identical tendency (Peto OR 0.65 [95%CI 0.42 to 1.01]). Notably, in the subgroup of patients who received treatment and follow-up for 104 weeks or more, 84 pancreatic cancer events were identified in 59,919 subjects, and a lower risk of pancreatic cancer was associated with incretin-based therapies (Peto OR 0.62 [95%CI 0.41 to 0.95]).ConclusionsTreatment with incretin drugs is not associated with an increased risk of pancreatic cancer in patients with T2DM. Instead, it might protect against the pancreatic malignancy in patients treated for 104 weeks or more. The major limitations of this study are that pancreatic safety was not the primary outcome of these enrolled trials, and the event number and follow-up time are limited.
      PubDate: 2017-11-30T02:15:21.556222-05:
      DOI: 10.1111/dom.13177
  • Initiation of dapagliflozin and treatment-emergent fractures
    • Authors: Konstantinos A. Toulis; John P. Bilezikian, G. Neil Thomas, Wasim Hanif, Kalliopi Kotsa, Rasiah Thayakaran, Deepiksana Keerthy, Abd Tahrani, Krishnarajah Nirantharakumar
      Abstract: An increase in the fracture risk was reported in patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin, possibly mediated by effects induced by all members of the sodium-glucose co-transporter 2 inhibitors (SGLT2i) class. It is unclear whether initiation of dapagliflozin is followed by an increase in the risk of fracture. Therefore, we performed a population-based, open cohort study was performed (January 2013-January 2016) using The Health Improvement Network (THIN). 22,618 patients with T2DM (4,548 exposed to dapagliflozin and 18,070 under standard antidiabetic treatment, matched for age and sex) with no history of fractures at baseline. The primary outcome was the occurrence of any fragility fracture during the observation period. Risk of any fracture served as a secondary outcome. Adjusted Hazard Rate Ratios (aHR) with 95% confidence intervals (CI) were calculated using Cox regression. A total of 289 fractures (132 fragility fractures) were recorded during the observation period. No difference in the risk of fragility fracture was detected between patients prescribed dapagliflozin and matched controls (Crude HR: 0.90, 95% CI: 0.59-1.39, p-value = 0.645 and adjusted HR: 0.87, 95% CI: 0.56-1.35, p-value = 0.531). Similarly, no difference in the risk of any fracture was detected (aHR: 0.89, 95% CI: 0.66-1.20, p-value =0.427). Sensitivity analyses limited to the subset of the population at high risk of fracture produced similar results. Thus, there was no evidence to suggest an increase in the risk of treatment-emergent fractures in patients with T2DM being initiated treatment with dapagliflozin.
      PubDate: 2017-11-30T02:05:25.821658-05:
      DOI: 10.1111/dom.13176
  • Effectiveness and tolerability of therapy with exenatide once-weekly
           versus basal insulin among injectable-naïve elderly or renal impaired
           patients with type 2 diabetes in the United States
    • Authors: Anita M Loughlin; Qing Qiao, Anthony Philip Nunes, Peter Öhman, Stephen Ezzy, Laura Yochum, C. Robin Clifford, Robert Gately, David D Dore, John Seeger
      Abstract: AimTo evaluate the effectiveness and tolerability of exenatide once-weekly (EQW) compared to basal insulin (BI) among injectable-naïve T2DM patients who are elderly or have renal impairment (RI).Methods and MaterialsInitiators of EQW and BI with T2DM were identified from 2012-2015 within a United States electronic health record database and matched by propensity score. Matched EQW and BI initiators aged 65+ years or who have RI were compared. Weight, HbA1c, eGFR, blood pressure, and lipids were obtained at baseline and quarterly (Q1-Q4) or semi-annually for one year following drug initiation. Hypoglycemia and gastrointestinal symptoms were identified using diagnosis codes and data abstracted from clinical notes.ResultsAmong patients aged 65+ years, HbA1c changed by -0.50 and -0.31 percentage points from baseline to Q4 for EQW and BI initiators, respectively. Weight changed by -1.6 kg among EQW initiators compared to 0.2 kg among BI initiators. Compared to BI initiators, EQW initiators had a 1.45-fold increased risk of nausea and vomiting. Among RI patients, HbA1c changed by -0.58 and -0.33 percentage points from baseline to Q4 for EQW and BI initiators, respectively. Weight changed by -1.9 kg for EQW initiators while BI initiators had no change in weight. EQW initiators had a 1.28-fold increased risk of constipation and diarrhea compared to BI initiators.ConclusionRegardless of age or renal function, the benefits of EQW relative to BI treatment are improved glycemic control and increased weight loss, which should be weighed against the increased risk of gastrointestinal symptoms.
      PubDate: 2017-11-30T01:35:22.804786-05:
      DOI: 10.1111/dom.13175
  • Overtreatment of older patients with type 2 diabetes mellitus in primary
    • Authors: E Hart Huberta; E Rutten Guy, N Bontje Kyra, C Vos Rimke
      Abstract: There are indications of overtreatment in older type 2 diabetes patients in both the US and Europe. We assessed the level of personalized diabetes treatment for older patients in primary care, focusing on overtreatment.Based on Dutch guidelines individuals ≥ 70 years were classified into three HbA1c treatment target groups: 7% (53 mmol/mol), 7.5% (58 mmol/mol) and 8% (64 mmol/mol).In our cohort of 1.002 patients (n=319 ≥ 70 yrs), the 165 patients with target above 7% had more micro- and macrovascular complications, used more often ≥ 5 medicines and were more often frail compared to those with an HbA1c target ≤ 7%. Of these 165 patients 64 (38.8%) were overtreated, i.e. 20% of all people ≥ 70 years. The majority of overtreated people were frail and used ≥ 5 medicines. Hypoglycemia occurred in 20.3% of these patients and almost 30% reported fall accidents.Personalized treatment in older people with type 2 diabetes is no common practice. A substantial number of older people are overtreated, with likely harmful consequences. To prevent overtreatment, definition of lower HbA1C limits might be helpful.
      PubDate: 2017-11-30T01:25:29.469813-05:
      DOI: 10.1111/dom.13174
  • Semaglutide, reduction in HbA1c and the risk of diabetic retinopathy
    • Authors: Tina Vilsbøll; Stephen C. Bain, Lawrence A. Leiter, Ildiko Lingvay, David Matthews, Rafael Simó, Ida Carøe Helmark, Nelun Wijayasinghe, Michael Larsen
      Abstract: AimsTo evaluate diabetic retinopathy data from across the SUSTAIN clinical trial programme.Materials and methodsThe SUSTAIN clinical trial programme evaluated the efficacy and safety of semaglutide, a glucagon-like peptide-1 analogue, for the treatment of type 2 diabetes (T2D). In SUSTAIN 6 − a 2-year, preapproval cardiovascular outcomes trial − semaglutide was associated with a significant increase in the risk of diabetic retinopathy complications (DRC) versus placebo. Diabetic retinopathy (DR) data from across the SUSTAIN trials were evaluated and post hoc analyses of the SUSTAIN 6 data were conducted. These included subgroup analyses to identify at-risk patients and a mediation analysis with initial change in HbA1c (percentage-points at Week 16) as a covariate, to examine the role of the magnitude of reduction in HbA1c as an intermediate factor on risk of DRC.ResultsThere was no imbalance in DR adverse events across the SUSTAIN 1−5 and Japanese trials. The majority of the effect with semaglutide versus placebo in SUSTAIN 6 may be attributed to the magnitude and rapidity of HbA1c reduction during the first 16 weeks of treatment in patients with pre-existing DR, poor glycaemic control at baseline, and treated with insulin.ConclusionsEarly worsening of DR is a known phenomenon associated with the rapidity and magnitude of improvement in glycaemic control with insulin; the DRC findings in SUSTAIN 6 are consistent with this. Guidance regarding the early worsening of DR is recommended with insulin; similar recommendations may be appropriate for semaglutide.
      PubDate: 2017-11-27T05:16:15.135424-05:
      DOI: 10.1111/dom.13172
  • The effect of non-surgical weight management on weight and glycaemic
           control in people with type 2 diabetes: a comparison of interventional and
           non-interventional outcomes at three years
    • Authors: Shani Botha; Lorna Forde, Sheila MacNaughton, Ross Shearer, Robert Lindsay, Naveed Sattar, David Morrison, Paul Welsh, Jennifer Logue
      Abstract: BackgroundLifestyle weight management interventions are recommended in clinical guidelines for patients with type 2 diabetes and obesity, but lack evidence regarding their long term effectiveness.Materials and MethodsElectronic health records were used to follow 23,208 patients with type 2 diabetes and obesity in Glasgow, Scotland, for up to 3 years between 2005 and 2014. Patients were stratified by referral to and attendance at a lifestyle weight management intervention, and by attainment of a target weight loss of ≥5kg over 7-9 sessions (“successful completers”). Outcomes were change in weight, HbA1c, and diabetes medications.Results3471 potentially eligible patients were referred to the service, and less than half of those attended (n=1537). Of those who attended 7-9 sessions,>40% successfully completed with a 5kg weight loss (334/808). Successful completers maintained greater weight loss (change at 3 years -8.03kg; 95%CI -9.44;-6.62) than the non-completers (-3.26kg; 95%CI; -4.01;-2.51; p
      PubDate: 2017-11-27T05:16:11.251826-05:
      DOI: 10.1111/dom.13171
  • “Risk of a first ever acute myocardial infarction and all-cause
           mortality with sulphonylurea treatment: a population-based cohort study”
    • Authors: Judith van Dalem; Martijn CGJ Brouwers, Coen DA Stehouwer, André Krings, Olaf H Klungel, Johanna HM Driessen, Frank de Vries, Andrea M Burden
      Abstract: We investigated the association between the current use of individual sulphonylureas and the risk of a first ever acute myocardial infarction (AMI) and all-cause mortality, in a population-based cohort study using primary care data from the Clinical Practice Research Datalink (CPRD) database (2004–2012). New users (N=121,869) with at least one prescription for a non-insulin antidiabetic agent, and aged ≥18 years were included. The first prescription defined start of follow-up. Time-dependent Cox proportional hazards models were used to estimate the risk of a first ever AMI and all-cause mortality associated with the use of individual sulphonylureas, and other non-insulin glucose-lowering drugs. No differences in risk of a first ever AMI (adjusted hazard ratio [HRadj]: 1.02, 95% Confidence Interval [CI]: 0.70-1.50) or all-cause mortality (HRadj: 0.97, 95% CI: 0.80-1.17) were observed comparing gliclazide use with non-gliclazide sulphonylurea use. Similar results were found for each individual sulphonylurea. As evidence is accumulating that gliclazide is no safer than other sulphonylureas, current guidelines suggesting superiority should be carefully evaluated.
      PubDate: 2017-11-24T08:45:24.689142-05:
      DOI: 10.1111/dom.13168
  • Uric Acid lowering in relation to HbA1c reductions with the SGLT2
           inhibitor Tofogliflozin
    • Authors: Motoshi Ouchi; Kenzo Oba, Kohei Kaku, Hideki Suganami, Akihiro Yoshida, Yasunori Fukunaka, Promsuk Jutabha, Asuka Morita, Naoyuki Otani, Keitaro Hayashi, Tomoe Fujita, Tatsuya Suzuki, Masahiro Yasutake, Naohiko Anzai
      Abstract: An integrated analysis was performed with data from four phase 2 and phase 3 studies of tofogliflozin in which patients with type 2 diabetes mellitus received the sodium-glucose cotransporter 2 inhibitor tofogliflozin for up to 24 weeks. Sex differences, baseline haemoglobin A1c (HbA1c) and serum uric acid (UA) levels, and log10-transformed urinary N-acetyl-β-D-glucosaminidase ratio were significantly correlated with the reduction in serum UA levels at both 4 weeks and 24 weeks in multivariate analysis (respectively, P < 0.0001). The decrease in HbA1c levels was greatest in the group with the highest baseline HbA1c level (quartile 4; HbA1c> 8.6%) and lowest in the group with the lowest baseline HbA1c level (quartile 1; HbA1c ≤ 7.4%). The decrease in serum UA levels was greatest in the quartile 1 group and lowest in the quartile 4 group. In most groups, the maximum decrease in serum UA levels was seen in the first 4 weeks, while the maximum decrease in HbA1c was seen at week 24. Thus, serum UA levels were significantly decrease in those with moderate HbA1c levels.
      PubDate: 2017-11-24T08:35:19.926357-05:
      DOI: 10.1111/dom.13170
  • Practical Strategies for Improving Outcomes in T2DM: the potential role of
           pioglitazone and DPP4 inhibitors
    • Authors: Stefano Del Prato; Robert Chilton
      Abstract: T2DM is a complex disease recognizing multiple pathogenic defects responsible for the development and progression of hyperglycemia. Each of these factors can now be tackled in a more targeted manner thanks to glucose-lowering drugs made available in the past two to three decades. Recognition of the multiplicity of the mechanisms underlying hyperglycemia calls for treatments addressing more than one these mechanisms with more emphasis placed on the earlier use of combination therapies. Although chronic hyperglycemia contributes to and amplifies cardiovascular risk, several trials have failed to show a marked effect from intensive glycemic control. During the past ten years, the effect of specific glucose-lowering agents on cardiovascular risk has been explored with dedicated trials. Overall, the cardiovascular safety of the new glucose-lowering agents has been proven with some of the trials summarized in this review, showing significant reduction of cardiovascular risk. Against this background, pioglitazone, in addition to exerting a sustained glucose-lowering effect, also has ancillary metabolic actions of potential interest in addressing the cardiovascular risk of T2DM, such as preservation of beta-cell mass and function. As such it seems a logical agent to combine with other oral anti-hyperglycemic agents, including dipeptidyl peptidase-4 inhibitors (DPP4i). DPP4i, which may also have a potential to preserve beta-cell function, is available as a fixed-dose combination with pioglitazone, and could, potentially, attenuate some of the side effects of pioglitazone, particularly if a lower dose of the thiazolidinedione is used. This review critically discusses the potential for early combination of pioglitazone and DPP4i.
      PubDate: 2017-11-24T08:15:21.835799-05:
      DOI: 10.1111/dom.13169
  • In response to: Metformin for the Management of Peri-operative
    • Authors: A.H. Hulst; J. Hermanides, J.H. DeVries, B. Preckel
      Abstract: We thank Dr Brown and Dr Paul for their insightful commentary on our study1 and the subject of perioperative continuation of metformin, stressing again the importance of perioperative hyperglycaemia and treatment of diabetes mellitus (DM).
      PubDate: 2017-11-20T03:10:38.863614-05:
      DOI: 10.1111/dom.13166
  • Systemic Use of Antibiotics and Risk of Diabetes in Adults: A Nested
           Case-control Study of Alberta's Tomorrow Project
    • Authors: Ming Ye; Paula J. Robson, Dean T. Eurich, Jennifer E. Vena, Jian-Yi Xu, Jeffrey A. Johnson
      Abstract: AimsPrevious observational studies using administrative health records have suggested an increased risk of diabetes with use of antibiotics. However, unmeasured confounding factors may explain these results. This study characterized the association between systemic use of antibiotics and risk of diabetes in a cohort of adults in Canada, accounting for both clinical and self-reported disease risk factors.Materials and methodsIn this nested case-control study, we used data from Alberta's Tomorrow Project (ATP), a longitudinal cohort study in Canada, and the linked administrative health records (2000-2015). Incident cases of diabetes were matched with up to eight age-, sex- controls per case. Conditional logistic regression was used to examine the association between antibiotic exposures and incident diabetes after sequentially adjusting for important clinical and lifestyle factors.ResultsThis study included 1,676 diabetes cases and 13,401 controls. Although 17.9% of cases received more than 5 courses of antibiotics compared to 13.8% of controls (p=5 courses].ConclusionsAfter adjustment for clinical and difficult-to-capture lifestyle data, we found no association between systemic use of antibiotics and risk of diabetes. Our results suggest that those positive associations observed by previous studies using only administrative records might have been confounded.
      PubDate: 2017-11-20T02:50:23.280628-05:
      DOI: 10.1111/dom.13163
  • NHE3 Blockade Ameliorates Type 2 Diabetes Mellitus via Inhibition of
           SGLT1-Mediated Glucose Absorption in the Small Intestine
    • Authors: Leo K.Y. Chan; Yi Wang, Enders K.W. Ng, Po Sing Leung
      Abstract: AimNa+/H+ exchanger 3 (NHE3) is an exchanger localized to the small intestinal brush border membrane (BBM). Here, we unraveled the role of NHE3 in SGLT1-mediated small intestinal BBM glucose absorption and functional implication in type 2 diabetes mellitus (T2DM).Materials and methodsHuman jejunal samples were obtained from patients undergoing gastrectomy. 14C-glucose absorption was measured by liquid scintillation counting. NHE3 expression was suppressed by siRNA-mediated knockdown or augmented in Caco2 cells. Glucose and insulin tolerance in db/db and m+/db mice were assessed with oral and intraperitoneal glucose tolerance tests, and intraperitoneal insulin tolerance test. Insulin resistance and β-cell function were assessed with the homeostatic model assessment of insulin resistance (HOMA-IR) and β-cell function (HOMA-β).ResultsNHE3 expression was upregulated in db/db mouse jejunal BBM and high-glucose-treated Caco2 cells. NHE3 blockade impaired SGLT1-mediated glucose absorption in human jejunum, m+/db and db/db mouse jejunums, and Caco2 cells, via serum/glucocorticoid-regulated kinase 1 (SGK1). NHE3 knockdown suppressed SGLT1-mediated glucose uptake and reduced mRNA and protein levels of SGK1 and SGLT1, which were conversely enhanced by NHE3 overexpression. Chronic S3226 treatment diminished postprandial glucose levels and ameliorated glucose intolerance in db/db mice.ConclusionNHE3 is essential in the modulation of small intestinal BBM glucose absorption. Our findings provide a rationale for future possible clinical application of NHE3 for treatment of T2DM through reducing intestinal glucose uptake and counteracting post-prandial hyperglycemia.
      PubDate: 2017-11-07T04:25:39.598771-05:
      DOI: 10.1111/dom.13151
  • A Semi-Physiologic Model of Postprandial Triglyceride Response in Lean,
           Obese and Very Obese Subjects Following a High Fat Meal
    • Authors: Jennifer Leohr; Michael Heathman, Maria C. Kjellsson
      Abstract: AIMSTo quantify the postprandial triglyceride response of chylomicrons and very low-density lipoprotein-V6 (VLDL-V6) following a high fat meal in lean, obese and very obese healthy subjects, using a mechanistic population lipokinetic modeling approach.METHODSHealthy subjects from three BMI population categories: lean (18.5-24.9), obese (30-33), and very obese (34-40) were enrolled in a clinical study to assess the triglyceride response after a high-fat meal, containing 60% fat. Nonlinear mixed-effect modeling was used to analyze the triglyceride concentrations of chylomicrons and large VLDL-V6 particles.RESULTSThe triglycerides in chylomicrons and VLDL-V6 particles had a prominent postprandial peak and represented the majority of the postprandial response. A turn-over model successfully described the triglyceride concentration versus time profiles of both chylomicron and large VLDL-V6 particles post the high fat meal. This model consisted of four compartments: two transit compartments for the lag between meal consumption and appearance of triglycerides in the blood and one compartment for the chylomicron and large VLDL-V6, respectively. The rate constants for the production of chylomicron and elimination of large VLDL-V6 along with the conversion rate of chylomicron to large VLDL-V6 were well defined.CONCLUSIONSThis is the first lipokinetic model that describes the absorption of triglycerides from dietary fats into the blood stream and compares the dynamics of triglycerides in chylomicron and large VLDL-V6 among lean, obese and very obese subjects. Such a model can be used to identify where pharmacological therapies act, thereby improving the determination of efficacy, and identifying complementary mechanisms for combinational drug therapies.
      PubDate: 2017-10-26T08:45:40.447587-05:
      DOI: 10.1111/dom.13138
  • Why do SGLT2 inhibitors reduce heart failure hospitalization' A
           differential volume regulation hypothesis
    • Authors: Karen M. Hallow; Gabriel Helmlinger, Peter J. Greasley, John J. V. McMurray, David W. Boulton
      Pages: 479 - 487
      Abstract: The effect of a sodium glucose cotransporter 2 inhibitor (SGLT2i) in reducing heart failure hospitalization in the EMPA-REG OUTCOMES trial has raised the possibility of using these agents to treat established heart failure. We hypothesize that osmotic diuresis induced by SGLT2 inhibition, a distinctly different diuretic mechanism than that of other diuretic classes, results in greater electrolyte-free water clearance and, ultimately, in greater fluid clearance from the interstitial fluid (IF) space than from the circulation, potentially resulting in congestion relief with minimal impact on blood volume, arterial filling and organ perfusion. We utilize a mathematical model to illustrate that electrolyte-free water clearance results in a greater reduction in IF volume compared to blood volume, and that this difference may be mediated by peripheral sequestration of osmotically inactive sodium. By coupling the model with data on plasma and urinary sodium and water in healthy subjects who received either the SGLT2i dapagliflozin or loop diuretic bumetanide, we predict that dapagliflozin produces a 2-fold greater reduction in IF volume compared to blood volume, while the reduction in IF volume with bumetanide is only 78% of the reduction in blood volume. Heart failure is characterized by excess fluid accumulation, in both the vascular compartment and interstitial space, yet many heart failure patients have arterial underfilling because of low cardiac output, which may be aggravated by conventional diuretic treatment. Thus, we hypothesize that, by reducing IF volume to a greater extent than blood volume, SGLT2 inhibitors might provide better control of congestion without reducing arterial filling and perfusion.
      PubDate: 2017-11-15T23:00:44.296357-05:
      DOI: 10.1111/dom.13126
  • Identification of barriers to insulin therapy and approaches to overcoming
    • Authors: David Russell-Jones; Frans Pouwer, Kamlesh Khunti
      Pages: 488 - 496
      Abstract: Poor glycaemic control in type 2 diabetes (T2D) is a global problem despite the availability of numerous glucose-lowering therapies and clear guidelines for T2D management. Tackling clinical or therapeutic inertia, where the person with diabetes and/or their healthcare providers do not intensify treatment regimens despite this being appropriate, is key to improving patients’ long-term outcomes. This gap between best practice and current level of care is most pronounced when considering insulin regimens, with studies showing that insulin initiation/intensification is frequently and inappropriately delayed for several years. Patient- and physician-related factors both contribute to this resistance at the stages of insulin initiation, titration and intensification, impeding achievement of optimal glycaemic control. The present review evaluates the evidence and reasons for this delay, together with available methods for facilitation of insulin initiation or intensification.
      PubDate: 2017-11-22T22:55:29.690013-05:
      DOI: 10.1111/dom.13132
  • Initiating therapy in patients newly diagnosed with type 2 diabetes:
           Combination therapy vs a stepwise approach
    • Authors: Eugenio Cersosimo; Eric L. Johnson, Christina Chovanes, Neil Skolnik
      Pages: 497 - 507
      Abstract: There is clear evidence that achieving glycaemic targets reduces the risk of developing complications as a result of type 2 diabetes (T2D). Many patients, however, continue to have suboptimal glycaemic control because of issues that include unclear advice on how to achieve these targets as well as clinical inertia. The two management approaches recommended for patients newly diagnosed with T2D are stepwise and combination therapy, each of which has advantages and disadvantages.Stepwise therapy may result in good patient adherence and allow greater individualization of therapy, and minimization of side effects and cost, and so may be appropriate for patients who are closer to goal. Stepwise therapy, however, may also lead to frequent delays in achieving glycaemic goals and longer exposure to hyperglycaemia. Combination therapy, which is now emerging as an important therapy option, has a number of potential advantages over stepwise therapy, including reduction in clinical inertia and earlier and more frequent achievement of glycated haemoglobin goals by targeting multiple pathogenic mechanisms simultaneously, which may more effectively delay disease progression. Compared with stepwise therapy, the disadvantages of combination therapy include reduced patient adherence resulting from complex, multi-drug regimens, difficulty determining the cause of poor efficacy and/or side effects, patient refusal to accept disease, and higher cost. Fixed-dose and fixed-ratio combinations are novel therapeutic approaches which may help address several issues of treatment complexity and patient burden associated with combination therapy comprising individual drugs. The choice of which drugs to administer and the decision to use stepwise vs combination therapy, however, should always be made on an individualized basis.
      PubDate: 2017-10-02T03:10:07.273019-05:
      DOI: 10.1111/dom.13108
  • Effects of glucagon-like peptide-1 receptor agonists on cardiovascular
           risk factors: A narrative review of head-to-head comparisons
    • Authors: Niels B. Dalsgaard; Tina Vilsbøll, Filip K. Knop
      Pages: 508 - 519
      Abstract: Cardiovascular (CV) disease is the leading cause of death and morbidity in patients with type 2 diabetes. Five CV risk factors (blood pressure, resting heart rate, body weight, cholesterol levels and blood glucose) are monitored routinely as safety and efficacy endpoints in randomized clinical trials for diabetes therapies. To determine if different glucagon-like peptide-1 receptor agonists (GLP-1RAs) had varying effects on these CV risk factors, we reviewed 16 head-to-head trials directly comparing GLP-1RAs that included at least one of the five factors. Few trials reported statistical differences between GLP-1RAs in terms of systolic blood pressure (SBP), body weight and total cholesterol. Liraglutide increased heart rate vs its comparators in three separate trials. All GLP-1RAs reduced glycated haemoglobin (HbA1c), but exenatide twice daily and lixisenatide had statistically smaller effects compared with other GLP-1RAs. These descriptive data indicate that individual GLP-1RAs affect CV risk factors differently, potentially because of their individual pharmacokinetics and/or size. Short-acting GLP-1RAs appeared to result in smaller changes in SBP and total cholesterol compared with continuous-acting treatments, while large GLP-1RAs had a reduced effect on body weight compared with small GLP-1RAs. For glycaemic control, short-acting GLP-1RAs had a greater impact on postprandial glucose levels vs continuous-acting GLP-1RAs, but for fasting plasma glucose levels and HbA1c, continuous-acting treatments had the greater effect. No differentiating trends were obvious in heart rate data. These diverse actions of GLP-1RAs on CV risk factors should aid individualized patient treatment.
      PubDate: 2017-11-08T04:15:37.834175-05:
      DOI: 10.1111/dom.13128
  • Effect of ertugliflozin on glucose control, body weight, blood pressure
           and bone density in type 2 diabetes mellitus inadequately controlled on
           metformin monotherapy (VERTIS MET)
    • Authors: Julio Rosenstock; Juan Frias, Dénes Páll, Bernard Charbonnel, Raluca Pascu, Didier Saur, Amanda Darekar, Susan Huyck, Harry Shi, Brett Lauring, Steven G. Terra
      Pages: 520 - 529
      Abstract: AimWe evaluated the efficacy and safety of ertugliflozin, an SGLT2 inhibitor, in type 2 diabetes mellitus (T2DM) inadequately controlled (HbA1c, 7.0%-10.5%) with metformin monotherapy (≥1500 mg/d for ≥8 weeks).MethodsThis was a double-blind, 26-week, multicentre study with ongoing 78-week extension ( identifier: NCT02033889). A total of 621 participants were randomized 1:1:1 to placebo, or ertugliflozin 5 or 15 mg/d. The primary endpoint was change from baseline at week 26 in HbA1c. Secondary efficacy endpoints were change from baseline at week 26 in fasting plasma glucose (FPG), body weight, systolic/diastolic blood pressure (SBP/DBP) and number of participants with HbA1c
      PubDate: 2017-10-02T02:05:24.109947-05:
      DOI: 10.1111/dom.13103
  • Better glycaemic control and less hypoglycaemia with insulin glargine 300
           U/mL vs glargine 100 U/mL: 1-year patient-level meta-analysis of the
           EDITION clinical studies in people with type 2 diabetes
    • Authors: Robert Ritzel; Ronan Roussel, Andrea Giaccari, Jiten Vora, Claire Brulle-Wohlhueter, Hannele Yki-Järvinen
      Pages: 541 - 548
      Abstract: AimsTo investigate the efficacy and safety of insulin glargine 300 U/mL (Gla-300) vs insulin glargine 100 U/mL (Gla-100) over 12 months in a patient-level meta-analysis, using data from the EDITION studies in people with type 2 diabetes (T2DM).MethodsEDITION 1, 2 and 3 were multicentre, randomized, open-label, 2-arm, parallel-group, treat-to-target phase IIIa studies. Similar study designs and endpoints enabled a meta-analysis to be conducted.ResultsReductions in glycated haemoglobin (HbA1c) were better sustained over 12 months with Gla-300 than with Gla-100 (least squares [LS] mean difference in change from baseline: −0.10 % [95% confidence interval {CI} −0.18 to −0.02] or −1.09 mmol/mol [95% CI −2.01 to −0.20]; P = .0174). Risk of confirmed (≤3.9 mmol/L) or severe hypoglycaemia was 15% lower with Gla-300 vs Gla-100 at night (relative risk 0.85 [95% CI 0.77–0.92]) and 6% lower at any time of day (relative risk 0.94 [95% CI 0.90–0.98]). Rates of hypoglycaemia were 18% lower with Gla-300 vs Gla-100 at night (rate ratio 0.82 [95% CI 0.67–0.99]), but comparable at any time of day. HbA1c
      PubDate: 2017-10-05T02:00:40.177889-05:
      DOI: 10.1111/dom.13105
  • Performance of individually measured vs population-based C-peptide
           kinetics to assess β-cell function in the presence and absence of acute
           insulin resistance
    • Authors: Ron T. Varghese; Chiara Dalla Man, Marcello C. Laurenti, Francesca Piccinini, Anu Sharma, Meera Shah, Kent R. Bailey, Robert A. Rizza, Claudio Cobelli, Adrian Vella
      Pages: 549 - 555
      Abstract: AimsTo compare the performance of population-based kinetics with that of directly measured C-peptide kinetics when used to calculate β-cell responsivity indices, and to study people with and without acute insulin resistance to ensure that population-based kinetics apply to all conditions where β-cell function is measured.MethodsSomatostatin was used to inhibit endogenous insulin secretion in 56 people without diabetes. Subsequently, a C-peptide bolus was administered and the changing concentrations were used to calculate individual kinetic measures of C-peptide clearance. In addition, the participants were studied on 2 occasions in random order using an oral glucose tolerance test (OGTT). On one occasion, free fatty acid elevation, to cause insulin resistance, was achieved by infusion of Intralipid + heparin. The Disposition Index (DI) was then estimated by the oral minimal model using either population-based or individual C-peptide kinetics.ResultsThere were marked differences in the exchange variables (k12 and k21) of the model describing C-peptide kinetics, but smaller differences in the fractional clearance; that is, the irreversible loss from the accessible compartment (k01), obtained from population-based estimates compared with experimental measurement. Because it is predominantly influenced by k01, DI estimated using individual kinetics correlated well with DI estimated using population-based kinetics.ConclusionsThese data support the use of population-based measures of C-peptide kinetics to estimate β-cell function during an OGTT.
      PubDate: 2017-09-27T01:45:22.641891-05:
      DOI: 10.1111/dom.13106
  • Estimated glucose disposal rate predicts mortality in adults with type 1
    • Authors: Thomas Nyström; Martin J. Holzmann, Björn Eliasson, Ann-Marie Svensson, Ulrik Sartipy
      Pages: 556 - 563
      Abstract: AimsThis study aimed to investigate the association between insulin resistance as determined by the estimated glucose disposal rate (eGDR), and survival in adults with type 1 diabetes (T1D) in Sweden.Material and MethodsUsing the Swedish National Diabetes Register, indviduals with T1D were included from January 1, 2005 to December 31, 2012. Outcomes were retrieved from National healthcare registers. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for the associations between eGDR (mg/kg/min) categorized into
      PubDate: 2017-10-10T04:26:52.574297-05:
      DOI: 10.1111/dom.13110
  • Insulin resistance and cardiovascular outcomes in the ORIGIN trial
    • Authors: Hertzel C. Gerstein; Ele Ferrannini, Matthew C. Riddle, Salim Yusuf,
      Pages: 564 - 570
      Abstract: AimsIn the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial ( NCT000069784), titrated doses of basal insulin glargine targeting fasting normoglycaemia had a neutral effect on cardiovascular outcomes. The dose of insulin required to achieve normoglycaemia provides a unique measurement of each individual's resistance to insulin's action, and was therefore used to examine the link between insulin resistance and cardiovascular outcomes.Materials and MethodsSelf-titration of insulin doses targeting a fasting plasma glucose ≤5.3 mmoL/L (95 mg/dL) was promoted at every visit and cardiovascular and other serious health outcomes were ascertained. All analyses were restricted to participants allocated to insulin glargine, who added it to lifestyle or 1 glucose-lowering oral agent at randomization. Normoglycaemia was defined as a fasting plasma glucose
      PubDate: 2017-10-08T23:01:21.475748-05:
      DOI: 10.1111/dom.13112
  • Sitagliptin and Roux-en-Y gastric bypass modulate insulin secretion via
           regulation of intra-islet PYY
    • Authors: Claudia Guida; Laura J. McCulloch, Mahdieh Godazgar, Sam D. Stephen, Charlotte Baker, Davide Basco, Jiawen Dong, Duan Chen, Anne Clark, Reshma D Ramracheya
      Pages: 571 - 581
      Abstract: AimsThe gut hormone peptide tyrosine tyrosine (PYY) is critical for maintaining islet integrity and restoring islet function following Roux-en-Y gastric bypass (RYGB). The expression of PYY and its receptors (NPYRs) in islets has been documented but not fully characterized. Modulation of islet PYY by the proteolytic enzyme dipeptidyl peptidase IV (DPP-IV) has not been investigated and the impact of DPP-IV inhibition on islet PYY function remains unexplored. Here we have addressed these gaps and their effects on glucose-stimulated insulin secretion (GSIS). We have also investigated changes in pancreatic PYY in diabetes and following RYGB.MethodsImmunohistochemistry and gene expression analysis were used to assess PYY, NPYRs and DPP-IV expression in rodent and human islets. DPP-IV activity inhibition was achieved by sitagliptin. Secretion studies were used to test PYY and the effects of sitagliptin on insulin release, and the involvement of GLP-1. Radioimmunoassays were used to measure hormone content in islets.ResultsPYY and DPP-IV localized in different cell types in islets while NPYR expression was confined to the beta-cells. Chronic PYY application enhanced GSIS in rodent and diabetic human islets. DPP-IV inhibition by sitagliptin potentiated GSIS; this was mediated by locally-produced PYY, and not GLP-1. Pancreatic PYY was markedly reduced in diabetes. RYGB strongly increased islet PYY content, but did not lead to full restoration of pancreatic GLP-1 levels.ConclusionLocal regulation of pancreatic PYY, rather than GLP-1, by DPP-IV inhibition or RYGB can directly modulate the insulin secretory response to glucose, indicating a novel role of pancreatic PYY in diabetes and weight-loss surgery.
      PubDate: 2017-10-10T04:26:35.467929-05:
      DOI: 10.1111/dom.13113
  • Risk of lower extremity amputations in people with type 2 diabetes
           mellitus treated with sodium-glucose co-transporter-2 inhibitors in the
           USA: A retrospective cohort study
    • Authors: Zhong Yuan; Frank J. DeFalco, Patrick B. Ryan, Martijn J. Schuemie, Paul E. Stang, Jesse A. Berlin, Mehul Desai, Norm Rosenthal
      Pages: 582 - 589
      Abstract: AimsTo examine the incidence of amputation in patients with type 2 diabetes mellitus (T2DM) treated with sodium glucose co-transporter 2 (SGLT2) inhibitors overall, and canagliflozin specifically, compared with non-SGLT2 inhibitor antihyperglycaemic agents (AHAs).Materials and MethodsPatients with T2DM newly exposed to SGLT2 inhibitors or non-SGLT2 inhibitor AHAs were identified using the Truven MarketScan database. The incidence of below-knee lower extremity (BKLE) amputation was calculated for patients treated with SGLT2 inhibitors, canagliflozin, or non-SGLT2 inhibitor AHAs. Patients newly exposed to canagliflozin and non-SGLT2 inhibitor AHAs were matched 1:1 on propensity scores, and a Cox proportional hazards model was used for comparative analysis. Negative controls (outcomes not believed to be associated with any AHA) were used to calibrate P values.ResultsBetween April 1, 2013 and October 31, 2016, 118 018 new users of SGLT2 inhibitors, including 73 024 of canagliflozin, and 226 623 new users of non-SGLT2 inhibitor AHAs were identified. The crude incidence rates of BKLE amputation were 1.22, 1.26 and 1.87 events per 1000 person-years with SGLT2 inhibitors, canagliflozin and non-SGLT2 inhibitor AHAs, respectively. For the comparative analysis, 63 845 new users of canagliflozin were matched with 63 845 new users of non-SGLT2 inhibitor AHAs, resulting in well-balanced baseline covariates. The incidence rates of BKLE amputation were 1.18 and 1.12 events per 1000 person-years with canagliflozin and non-SGLT2 inhibitor AHAs, respectively; the hazard ratio was 0.98 (95% confidence interval 0.68–1.41; P = .92, calibrated P = .95).ConclusionsThis real-world study observed no evidence of increased risk of BKLE amputation for new users of canagliflozin compared with non-SGLT2 inhibitor AHAs in a broad population of patients with T2DM.
      PubDate: 2017-10-11T20:45:38.623818-05:
      DOI: 10.1111/dom.13115
  • Efficacy and safety of saxagliptin in combination with metformin as
           initial therapy in Chinese patients with type 2 diabetes: Results from the
           START study, a multicentre, randomized, double-blind, active-controlled,
           phase 3 trial
    • Authors: Jingtao Dou; Jianhua Ma, Jun Liu, Changjiang Wang, Eva Johnsson, Hui Yao, June Zhao, Changyu Pan
      Pages: 590 - 598
      Abstract: AimTo assess the efficacy and safety of saxagliptin plus metformin over 24 weeks in pharmacotherapy-naïve Chinese patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA1c, 8.0%-12.0%).Research Design and MethodsIn this multicentre, double-blind, active-controlled study (The START study: NCT02273050,, patients were randomized (1:1:1) to saxagliptin 5 mg plus metformin, saxagliptin 5 mg plus placebo or metformin plus placebo. Saxagliptin was taken once daily; metformin was taken once/twice daily and was titrated from 500 mg to a maximum of 2000 mg/d over 8 weeks. The primary end point was change in HbA1c from baseline to Week 24.ResultsData from 630 patients (66.5% men; mean age, 50.1 years; mean body mass index, 26.6 kg/m2; mean HbA1c, 9.4%; mean diabetes duration, 0.81 years) were analysed. Mean reduction in HbA1c was greater with saxagliptin plus metformin (−3.0%) than with saxagliptin plus placebo (−2.1%; P 
      PubDate: 2017-10-26T02:20:42.646208-05:
      DOI: 10.1111/dom.13117
  • Islet neuropeptide Y receptors are functionally conserved and novel
           targets for the preservation of beta-cell mass
    • Authors: Zara J. Franklin; Anastasia Tsakmaki, Patricia Fonseca Pedro, Aileen J. King, Guo Cai Huang, Sakeena Amjad, Shanta J. Persaud, Gavin A. Bewick
      Pages: 599 - 609
      Abstract: AimsTwo unmet therapeutic strategies for diabetes treatment are prevention of beta-cell death and stimulation of beta-cell replication. Our aim was to characterize the role of neuropeptide Y receptors in the control of beta-cell mass.Materials and MethodsWe used endogenous and selective agonists of the NPY receptor system to explore its role in the prevention of beta-cell apoptosis and proliferation in islets isolated from both mouse and human donors. We further explored the intra-cellular signalling cascades involved, using chemical inhibitors of key signalling pathways. As proof of principle we designed a long-acting analogue of [Leu31Pro34]-NPY, an agonist of the islet-expressed Y receptors, to determine if targeting this system could preserve beta-cell mass in vivo.ResultsOur data reveal that NPY Y1, 4 and 5 receptor activation engages a generalized and powerful anti-apoptotic pathway that protects mouse and human islets from damage. These anti-apoptotic effects were dependent on stimulating a Gαi-PLC-PKC signalling cascade, which prevented cytokine-induced NFkB signalling. NPY receptor activation functionally protected islets by restoring glucose responsiveness following chemically induced injury in both species. NPY receptor activation attenuated beta-cell apoptosis, preserved functional beta-cell mass and attenuated the hyperglycaemic phenotype in a low-dose streptozotocin model of diabetes.ConclusionTaken together, our observations identify the islet Y receptors as promising targets for the preservation of beta-cell mass. As such, targeting these receptors could help to maintain beta-cell mass in both type 1 and type 2 diabetes, and may also be useful for improving islet transplantation outcomes.
      PubDate: 2017-11-06T03:12:24.228755-05:
      DOI: 10.1111/dom.13119
  • Semaglutide improves postprandial glucose and lipid metabolism, and delays
           first-hour gastric emptying in subjects with obesity
    • Authors: Julie B. Hjerpsted; Anne Flint, Ashley Brooks, Mads B. Axelsen, Trine Kvist, John Blundell
      Pages: 610 - 619
      Abstract: AimTo investigate the effects of semaglutide on fasting and postprandial glucose and lipid responses, and on gastric emptying.Materials and methodsThis was a randomized, double-blind, placebo-controlled, 2-period, crossover trial. Subjects with obesity (N = 30) received once-weekly subcutaneous semaglutide, dose-escalated to 1.0 mg, or placebo. After each 12-week treatment period, glucose and lipid metabolism were assessed before and after standardized meals. Gastric emptying (paracetamol absorption test) and peptide YY (PYY) response were also assessed.ResultsSemaglutide treatment significantly lowered fasting concentrations of glucose and glucagon, and increased insulin vs placebo (estimated treatment ratio: 0.95 [95% confidence interval: 0.91, 0.98]; 0.86 [0.75, 0.98]; 1.45 [1.20, 1.75], respectively). Postprandial glucose metabolism significantly improved with semaglutide vs placebo (incremental area under the curve 0 to 5 hours [iAUC0-5h]; estimated treatment difference: glucose −1.34 mmol h/L [−2.42, −0.27]; insulin −921 pmol h/L [−1461, −381]; C-peptide −1.42 nmol h/L [−2.33, −0.51]). Fasting and postprandial lipid metabolism improved with semaglutide vs placebo. First-hour gastric emptying after the meal was delayed with semaglutide vs placebo (AUC0-1h; estimated treatment ratio: 0.73 [0.61, 0.87]); this may have contributed to the lower postprandial glucose increase in semaglutide-treated subjects. Overall gastric emptying (AUC0-5h) was not statistically different between treatments. Fasting and postprandial PYY responses were significantly lower with semaglutide vs placebo (P = .0397 and P = .0097, respectively).ConclusionSemaglutide improved fasting and postprandial glucose and lipid metabolism. Overall gastric emptying was similar to that with placebo; however, the observed first-hour delay with semaglutide may contribute to a slower entry of glucose into the circulation.
      PubDate: 2017-10-27T04:56:10.909921-05:
      DOI: 10.1111/dom.13120
  • Dapagliflozin in patients with type 2 diabetes mellitus: A pooled analysis
           of safety data from phase IIb/III clinical trials
    • Authors: Serge Jabbour; Jochen Seufert, Andre Scheen, Clifford J. Bailey, Cathrina Karup, Anna M. Langkilde
      Pages: 620 - 628
      Abstract: AimTo evaluate the safety and tolerability of dapagliflozin, a highly selective sodium-glucose co-transporter-2 inhibitor, in patients with type 2 diabetes mellitus (T2DM).MethodsData were pooled from 13 placebo-controlled trials of up to 24 weeks’ duration (dapagliflozin, n = 2360; placebo, n = 2295). Larger placebo-/comparator-controlled pools of 21 (≤208 weeks; dapagliflozin, n = 5936; control, n = 3403) and 30 trials (≥12 weeks; dapagliflozin, n = 9195; control, n = 4629) assessed the rare adverse events (AEs) of diabetic ketoacidosis (DKA) and lower limb amputation, respectively.ResultsOver 24 weeks, the overall incidence of AEs and serious AEs (SAEs) was similar for dapagliflozin and placebo: 60.0% vs 55.7% and 5.1% vs 5.4%, respectively. Rates of hypoglycaemia, volume depletion AEs, urinary tract infections (UTIs) and fractures were balanced between the groups. Genital infections were more frequent with dapagliflozin (5.5%) vs placebo (0.6%) and renal function AEs occurred in 3.2% vs 1.8% of patients (the most common renal AE was decreased creatinine clearance: 1.1% vs 0.7%). In the 21-study pool, 1 SAE of DKA and 3 AEs of ketonuria/metabolic acidosis occurred with dapagliflozin vs none with control; estimated combined incidence for these events was 0.03% (95% confidence interval 0.010-0.089). In the 30-study pool, lower limb amputation occurred in 8 (0.1%) and 7 (0.2%) patients receiving dapagliflozin and control, respectively.ConclusionThe overall incidence rates of AEs and SAEs were similar in the dapagliflozin and placebo/control groups, including the incidence of hypoglycaemia, volume depletion, fractures, UTIs, amputations and DKA. Genital infections were more frequent with dapagliflozin than placebo.
      PubDate: 2017-10-26T05:10:22.779296-05:
      DOI: 10.1111/dom.13124
  • Influence of metabolic syndrome and race on the relationship between
           intensive blood pressure control and cardiovascular outcomes in the SPRINT
    • Authors: Kathleen Dungan; Timothy E. Craven, Kyaw Soe, Jackson T. Wright, Jan Basile, William E. Haley, Nancy R. Kressin, Uzma Rani, Leonardo Tamariz, Jeff Whittle, Alan Wiggers, Kwame Osei
      Pages: 629 - 637
      Abstract: AimsTo determine whether baseline metabolic syndrome (MetS) modifies the effect of intensive blood pressure control on cardiovascular (CV) outcomes, and whether the effects varied by race/ethnicity.MethodsWe performed post hoc analyses among non-Hispanic black, non-hispanic white and Hispanic participants, with and without MetS, in the Systolic Blood Pressure Intervention Trial (SPRINT), who were randomized to a systolic blood pressure (SBP) target of
      PubDate: 2017-11-09T04:10:32.802801-05:
      DOI: 10.1111/dom.13127
  • Treatment satisfaction with ITCA 650, a novel drug-device delivering
           continuous exenatide, versus twice-daily injections of exenatide in type 2
           diabetics using metformin
    • Authors: Robert Henry; Julio Rosenstock, John F. McCarthy, Ginger Carls, Tom Alessi, John Yee, Michelle Baron
      Pages: 638 - 645
      Abstract: AimsTo evaluate treatment satisfaction in patients with type 2 diabetes (T2D) not adequately controlled by metformin, randomized to ITCA 650 (continuous exenatide in osmotic mini-pump) vs twice-daily exenatide injections (Ex-BID).Materials and methodsThe Diabetes Medication Satisfaction Tool (DM-SAT) was administered and assessments were made at baseline, Week 8 and Week 20 during a 24-week open-label phase 2 trial. In Stage I (Weeks 1-12), 155 patients, comprising the ITT population, were randomized to 3 groups: ITCA 650 20 μg/day, ITCA 650 40 μg/day and Ex-BID 10 μg BID. In Stage II (Weeks 13-24), ITCA 650 groups were re-randomized to either remain on the Stage I dose or receive a higher dose. Patients treated with Ex-BID were randomized to 40 or 60 μg/day ITCA 650.ResultsPatients using ITCA 650 reported significant increases in overall treatment satisfaction by Week 8 vs those using Ex-BID (P 
      PubDate: 2017-11-20T21:07:15.676164-05:
      DOI: 10.1111/dom.13133
  • Effects of common cold and concomitant administration of nasal
           decongestant on the pharmacokinetics and pharmacodynamics of nasal
           glucagon in otherwise healthy participants: A randomized clinical trial
    • Authors: Cristina B. Guzman; Helene Dulude, Claude Piché, Marianne Rufiange, Aziz A. Sadoune, Emmanouil Rampakakis, Dolores Carballo, Myriam Triest, Michelle Xiaotian Zhang, Shuyu Zhang, Maryam Tafreshi, Eric Sicard
      Pages: 646 - 653
      Abstract: AimsNasal glucagon (NG) is a nasally-administered glucagon powder, absorbed through the nasal mucosa, designed for treatment of severe hypoglycaemia. This study evaluated the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of NG in otherwise healthy participants with common colds and after recovery from cold symptoms, with and without concomitant nasal decongestant.Materials and MethodsThis was a single-centre, open-label study. Cohort 1 participants (N = 18) received 2 doses of NG: one while experiencing nasal congestion and another after recovery from cold symptoms. Cohort 2 participants (N = 18), who also had colds with nasal congestion, received a single dose of NG 2 hours after treatment with the decongestant oxymetazoline. Total symptoms score and other safety measures were assessed before and after NG administration.ResultsNG was well tolerated, without serious adverse events. Common adverse events (transient lacrimation, nasal discomfort, rhinorrhea and nausea) were more frequent in both Cohorts 1 and 2 during nasal congestion. Glucagon levels peaked 18 minutes post-dose and glucose levels peaked 30 to 42 minutes post-dose in all groups. Nasal congestion, with or without concomitant nasal decongestant, did not significantly affect PK of NG. Although glucose AUECs0-t was different between Cohort 1 with nasal congestion and Cohort 2, glucose concentrations at 30 minutes appeared similar in all groups.ConclusionsThere were no clinically relevant differences in safety or PK/PD of NG associated with nasal congestion or concomitant administration of nasal decongestant, suggesting that NG can be used to treat severe hypoglycaemia in individuals experiencing nasal congestion.
      PubDate: 2017-11-19T23:25:46.190753-05:
      DOI: 10.1111/dom.13134
  • High-sensitivity C-reactive protein, low-density lipoprotein cholesterol
           and cardiovascular outcomes in patients with type 2 diabetes in the
           EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus
           Standard of Care) trial
    • Authors: You-Cheol Hwang; David A. Morrow, Christopher P. Cannon, Yuyin Liu, Richard Bergenstal, Simon Heller, Cyrus Mehta, William Cushman, George L. Bakris, Faiez Zannad, William B. White
      Pages: 654 - 659
      Abstract: AimsWe sought to assess the risk of major adverse cardiovascular events (MACE) by utilizing high-sensitivity C-reactive protein (hsCRP) level and low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes and recent acute coronary syndrome.Materials and methodsStudy participants enrolled in the EXAMINE trial (Clinical trials registration number: NCT00968708) and were stratified by baseline hsCRP levels (3 mg/L). They were also sub-divided into 4 groups according to baseline hsCRP (≤3 or>3 mg/L) and achieved LDL-C (
      PubDate: 2017-11-21T00:30:35.754234-05:
      DOI: 10.1111/dom.13136
  • Recent trends in the prevalence of type 2 diabetes and the association
           with abdominal obesity lead to growing health disparities in the USA: An
           analysis of the NHANES surveys from 1999 to 2014
    • Authors: Herve Caspard; Serge Jabbour, Niklas Hammar, Peter Fenici, John J. Sheehan, Mikhail Kosiborod
      Pages: 667 - 671
      Abstract: AimTo assess whether the secular trends in type 2 diabetes prevalence differ between abdominally obese and non-obese individuals.MethodsData from the National Health and Nutrition Examination Surveys (NHANES) were used to estimate the prevalence of type 2 diabetes and abdominal obesity among individuals aged ≥20 years in the USA from 1999/2000 to 2013/2014, after standardization to the age, sex and ethnicity population distribution estimates on January 1, 2014, as published by the US Census Bureau.ResultsThe prevalence of abdominal obesity in the US population increased from 47.4% (95% confidence interval [CI] 42.6-52.2) in 1999/2000 to 57.2% (95% CI 55.9-58.5) in 2013/2014. A significant increase was observed in all age groups: 20 to 44, 45 to 64, and ≥65 years. The prevalence of type 2 diabetes has also increased from 8.8% (95% CI 7.2-10.4) in 1999/2000 to 11.7% (95% CI 10.9-12.6) in 2013/2014, with no substantial change in trend over the recent years. However, the increase in the prevalence of type 2 diabetes was limited to individuals with abdominal obesity, and more specifically to individuals aged ≥45 years with abdominal obesity, with no significant change in prevalence in the non-obese group and in individuals aged
      PubDate: 2017-12-01T03:45:23.49104-05:0
      DOI: 10.1111/dom.13143
  • All-cause and diabetes-related healthcare costs among US adults with type
           2 diabetes initiating exenatide once weekly or insulin glargine
    • Authors: Eric Wittbrodt; Amanda M. Kong, Laura Moore-Schiltz, Paul Juneau
      Pages: 672 - 680
      Abstract: AimsTo compare healthcare utilization and costs between patients with type 2 diabetes (T2D) treated with exenatide (Bydureon) once weekly (EQW) and patients treated with insulin glargine (IG).Materials and methodsUsing the MarketScan Commercial and Medicare Supplemental databases, we conducted a retrospective cohort study of adult US patients with claim with a diagnosis of T2D, initiating EQW or IG from February 1, 2012 to June 30, 2014 (first claim = index date). All-cause and diabetes-related utilization and costs were measured during the 12 months after the index date. EQW patients were matched 1:1 to IG patients, using propensity scores. Logistic and ordinary least-squares regression models were fit to model differences between the matched cohorts.ResultsThere were 7749 EQW patients matched to 7749 IG patients. EQW patients had significantly (P 
      PubDate: 2017-11-26T23:00:35.968855-05:
      DOI: 10.1111/dom.13145
  • A risk score including body mass index, glycated haemoglobin and
           triglycerides predicts future glycaemic control in people with type 2
    • Authors: Dorijn F. L. Hertroijs; Arianne M. J. Elissen, Martijn C. G. J. Brouwers, Nicolaas C. Schaper, Sebastian Köhler, Mirela C. Popa, Stylianos Asteriadis, Steven H. Hendriks, Henk J. Bilo, Dirk Ruwaard
      Pages: 681 - 688
      Abstract: AimTo identify, predict and validate distinct glycaemic trajectories among patients with newly diagnosed type 2 diabetes treated in primary care, as a first step towards more effective patient-centred care.MethodsWe conducted a retrospective study in two cohorts, using routinely collected individual patient data from primary care practices obtained from two large Dutch diabetes patient registries. Participants included adult patients newly diagnosed with type 2 diabetes between January 2006 and December 2014 (development cohort, n = 10 528; validation cohort, n = 3777). Latent growth mixture modelling identified distinct glycaemic 5-year trajectories. Machine learning models were built to predict the trajectories using easily obtainable patient characteristics in daily clinical practice.ResultsThree different glycaemic trajectories were identified: (1) stable, adequate glycaemic control (76.5% of patients); (2) improved glycaemic control (21.3% of patients); and (3) deteriorated glycaemic control (2.2% of patients). Similar trajectories could be discerned in the validation cohort. Body mass index and glycated haemoglobin and triglyceride levels were the most important predictors of trajectory membership. The predictive model, trained on the development cohort, had a receiver-operating characteristic area under the curve of 0.96 in the validation cohort, indicating excellent accuracy.ConclusionsThe developed model can effectively explain heterogeneity in future glycaemic response of patients with type 2 diabetes. It can therefore be used in clinical practice as a quick and easy tool to provide tailored diabetes care.
      PubDate: 2017-11-24T03:35:27.4502-05:00
      DOI: 10.1111/dom.13148
  • A European, multicentre, retrospective, non-interventional study
           (EU-TREAT) of the effectiveness of insulin degludec after switching basal
           insulin in a population with type 1 or type 2 diabetes
    • Authors: Thorsten Siegmund; Nikolaos Tentolouris, Søren T. Knudsen, Annunziata Lapolla, Rudolf Prager, Tra-Mi Phan, Michael L. Wolden, Bernd Schultes,
      Pages: 689 - 697
      Abstract: AimsTo evaluate the clinical effectiveness of switching to insulin degludec (IDeg) in insulin-treated patients with either type 1 diabetes (T1DM) or type 2 diabetes (T2DM) under conditions of routine clinical care.Materials and MethodsThis was a multicentre, retrospective, chart review study. In all patients, basal insulin was switched to IDeg at least 6 months before the start of data collection. Baseline was defined as the most recent recording during the 3-month period before first prescription of IDeg. Values are presented as mean [95%CI].ResultsT1DM (n = 1717): HbA1c decreased by −2.2 [−2.6; −2.0] mmol/mol (−0.20 [−0.24; −0.17]%) at 6 months vs baseline (P 
      PubDate: 2017-11-21T22:00:51.128331-05:
      DOI: 10.1111/dom.13149
  • Cannabinoid-1 receptor deletion in podocytes mitigates both glomerular and
           tubular dysfunction in a mouse model of diabetic nephropathy
    • Authors: Tony Jourdan; Joshua K. Park, Zoltán V. Varga, János Pálóczi, Nathan J. Coffey, Avi Z. Rosenberg, Grzegorz Godlewski, Resat Cinar, Ken Mackie, Pal Pacher, George Kunos
      Pages: 698 - 708
      Abstract: AimsTo determine the specific role of podocyte-expressed cannabinoid-1 receptor (CB1R) in the development of diabetic nephropathy (DN), relative to CB1R in other renal cell types.Material and methodsWe developed a mouse model with a podocyte-specific deletion of CB1R (pCB1Rko) and challenged this model with streptozotocin (STZ)-induced type-1 DN. We also assessed the podocyte response to high glucose in vitro and its effects on CB1R activation.ResultsHigh glucose exposure for 48 hours led to an increase in CB1R gene expression (CNR1) and endocannabinoid production in cultured human podocytes. This was associated with podocyte injury, reflected by decreased podocin and nephrin expression. These changes could be prevented by Cnr1-silencing, thus identifying CB1R as a key player in podocyte injury. After 12 weeks of chronic hyperglycaemia, STZ-treated pCB1Rko mice showed elevated blood glucose similar to that of their wild-type littermates. However, they displayed less albuminuria and less podocyte loss than STZ-treated wild-type mice. Unexpectedly, pCB1Rko mice also have milder tubular dysfunction, fibrosis and reduction of cortical microcirculation compared to wild-type controls, which is mediated, in part, by podocyte-derived endocannabinoids acting via CB1R on proximal tubular cells.ConclusionsActivation of CB1R in podocytes contributes to both glomerular and tubular dysfunction in type-1 DN, which highlights the therapeutic potential of peripheral CB1R blockade.
      PubDate: 2017-12-03T22:46:18.907099-05:
      DOI: 10.1111/dom.13150
  • Different intervention strategies for preventing type 2 diabetes mellitus
           in China: A systematic review and network meta-analysis of randomized
           controlled trials
    • Authors: Bing Pang; Lin-hua Zhao, Xin-long Li, Jun Song, Qing-wei Li, Xing Liao, Shuo Feng, Xi-yan Zhao, Yu-jiao Zheng, Xiao-wen Gou, Qing Ni, Xiao-lin Tong
      Pages: 718 - 722
      Abstract: Different strategies are increasingly used for early intervention in prediabetes in China, but the effects of these strategies on incident diabetes have not yet been confirmed. The aim of the present study was to assess systematically the effects of different strategies for preventing diabetes, aimed at Chinese people with prediabetes. Seven electronic databases were searched to identify eligible trials published from inception to September 20, 2016. Randomized controlled trials with a minimum follow-up duration of 6 months were included. Standard pairwise meta-analysis with a random-effects model and network meta-analysis with a frequentist framework were performed. A total of 63 studies, including 11 intervention strategies, were included. Compared with placebo, all strategies, except for lipid-affecting drugs and sitagliptin, reduced the rate of incident diabetes with different levels of effectiveness, ranging from 0.18 (95% confidence interval [CI] 0.12, 0.27) to 0.39 (95% CI 0.20, 0.75). Ranking probability analysis indicated that metformin and β-cell-stimulating drugs reduced the risk of diabetes most, with probabilities of 87.4% and 81%, respectively. Ethnicity and cultural factors should be considered for diabetes prevention. Most of the included trials were of poor methodological quality, however, and the results should be interpreted with caution.
      PubDate: 2017-11-08T02:45:40.438972-05:
      DOI: 10.1111/dom.13121
  • Non-ST-elevation myocardial infarction outcomes in patients with type 2
           diabetes with non-obstructive coronary artery stenosis: Effects of
           incretin treatment
    • Authors: Raffaele Marfella; Celestino Sardu, Paolo Calabrò, Mario Siniscalchi, Fabio Minicucci, Giuseppe Signoriello, Maria L. Balestrieri, Ciro Mauro, Maria R. Rizzo, Giuseppe Paolisso, Michelangela Barbieri
      Pages: 723 - 729
      Abstract: There are insufficient data on the prognosis and management of people with type 2 diabetes who experience a non-obstructive coronary artery stenosis (NOCS)–non-ST-elevation myocardial infarction (NSTEMI) event. We evaluated the 12-month prognosis of patients with diabetes and NOCS (20%-49% luminal stenosis) who experience a first NSTEMI as compared with patients without diabetes. In addition, we investigated the 12-month prognosis in patients with diabetes and NSTEMI-NOCS previously treated with incretin-based therapy compared with a matched cohort of patients with NSTEMI-NOCS never treated with such therapy. We categorized the patients with diabetes as current incretin users (6 months’ treatment with glucagon-like peptide-1 agonists or dipeptidyl peptidase-4 inhibitors) and non-users of incretins. The endpoint was all-cause mortality, cardiac death, recurrent acute coronary syndrome (ACS), and heart failure. The unadjusted Kaplan–Meier analysis, and a risk-adjusted hazard analysis showed that, all-cause mortality, cardiac death, readmission for ACS and heart failure rates during the 12-month follow-up were higher in patients with diabetes and NOCS-NSTEMI than in those with NOCS-NSTEMI without diabetes. Among the patients with diabetes, the current incretin users had a significantly lower rate of all-cause mortality, cardiac death and readmission for ACS at 12 months. In patients with type 2 diabetes and NOCS-NSTEMI, we observed a higher incidence of 1-year mortality and adverse cardiovascular outcomes, as compared with patients without diabetes with NOCS-NSTEMI. In people with diabetes, non-users of incretins had a worse prognosis than current incretin users.
      PubDate: 2017-11-03T00:20:40.513906-05:
      DOI: 10.1111/dom.13122
  • Metformin and β-cell function in insulin-treated patients with type 2
           diabetes: A randomized placebo-controlled 4.3-year trial
    • Authors: Wiebe Top; Coen Stehouwer, Philippe Lehert, Adriaan Kooy
      Pages: 730 - 733
      Abstract: In this trial, 390 insulin-treated patients with type 2 diabetes were randomized to either placebo or metformin. Fasting levels of glucose, insulin and C peptide were determined at baseline, after 4 months and yearly thereafter for 4 years to assess fasting estimates of beta cell function. The primary endpoint was the fasting C peptide-to-glucose ratio (FCPGR) and secondary measures were the disposition index (DI) and the fasting C peptide (FCP). We analysed the results with a general linear mixed model. Baseline FCPGR was 5.27 (95% CI, 4.83 – 5.71). Compared to placebo, FCPGR increased in the metformin group with 1.48 (95% CI, 1.09 – 1.87, P 
      PubDate: 2017-10-27T04:55:41.533724-05:
      DOI: 10.1111/dom.13123
  • Liraglutide and cardiovascular outcomes in adults with overweight or
           obesity: A post hoc analysis from SCALE randomized controlled trials
    • Authors: M. J. Davies; L. J. Aronne, I. D. Caterson, A. B. Thomsen, P. B. Jacobsen, S. P. Marso,
      Pages: 734 - 739
      Abstract: The cardiovascular safety of liraglutide, a glucagon-like peptide-1 receptor agonist approved for weight management at a dose of 3.0 mg, was evaluated post hoc using data from 5908 participants in 5 randomized, double-blind, placebo-controlled clinical trials. Participants were randomized to liraglutide or a comparator group (placebo or orlistat). The objective was to evaluate whether cardiovascular risk was increased with liraglutide treatment. The primary composite outcome of this time-to-event analysis was the first occurrence of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. These cardiovascular events were adjudicated prospectively for three of the trials and retrospectively for two trials by an event adjudication committee. The primary outcome was analyzed using a Cox proportional hazards model, stratified by trial. With liraglutide 3.0 mg, 8 participants had positively adjudicated cardiovascular events (1.54 events/1000 person-years) compared to 10 participants in the comparators group (3.65 events/1000 person-years). The hazard ratio for liraglutide 3.0 mg compared to comparators was 0.42 (95% confidence interval, 0.17-1.08). In this analysis, liraglutide 3.0 mg treatment was not associated with excess cardiovascular risk. However, the wide confidence intervals and retrospective adjudication of events in two of the trials are limitations of the analysis.
      PubDate: 2017-11-01T23:44:37.122969-05:
      DOI: 10.1111/dom.13125
  • Dipeptidyl peptidase-4 inhibitors moderate the risk of genitourinary tract
           infections associated with sodium-glucose co-transporter-2 inhibitors
    • Authors: Gian Paolo Fadini; Benedetta Maria Bonora, Sarangdhar Mayur, Mauro Rigato, Angelo Avogaro
      Pages: 740 - 744
      Abstract: Genitourinary tract infections (GUTIs) are the most common adverse event (AE) occurring during therapy with sodium-glucose co-transporter-2 (SGLT2) inhibitors. We evaluated whether dipeptidyl peptidase-4 inhibitors moderate the risk of GUTI during SGLT2 inhibitor therapy, using two approaches. First, we screened the literature for randomized controlled trials (RCTs) directly comparing the frequency of GUTIs in patients receiving DPP-4 inhibitor/SGLT2 inhibitor combination therapy vs those receiving an SGLT2 inhibitor only. In the five trials we retrieved, the pooled risk ratio for genital tract infections (GTIs) in patients on DPP-4 inhibitor/SGLT2 inhibitor combination therapy vs those on SGLT2 inhibitors alone was 0.51 (95% confidence interval [CI] 0.28-0.92). Second, we found that within the Food and Drug Administration AE Reporting System, the frequency of GUTIs among reports listing both SGLT2 and DPP-4 inhibitors as suspect or concomitant drugs was significantly lower than among reports listing SGLT2 inhibitors without DPP-4 inhibitors, with a proportional reporting ratio of 0.74 (95% CI 0.61-0.90). In conclusion, in RCTs and in a large pharmacovigilance database, combination therapy with a DPP-4 inhibitor appears to reduce the frequency of G(U)TIs associated with SGLT2 inhibitors.
      PubDate: 2017-11-15T22:55:45.768209-05:
      DOI: 10.1111/dom.13130
  • Preoperative weight loss with glucagon-like peptide-1 receptor agonist
           treatment predicts greater weight loss achieved by the combination of
           medical weight management and bariatric surgery in patients with type 2
           diabetes: A longitudinal analysis
    • Authors: Tien Tang; Sally Abbott, Carel W. le Roux, Violet Wilson, Rishi Singhal, Srikanth Bellary, Abd A. Tahrani
      Pages: 745 - 748
      Abstract: We examined the relationship between weight changes after preoperative glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment and weight changes from the start of medical weight management (MWM) until 12 months after bariatric surgery in patients with type 2 diabetes in a retrospective cohort study. A total of 45 patients (64.4% women, median [interquartile range] age 49 [45-60] years) were included. The median (interquartile range) weight loss from start of MWM until 12 months post-surgery was 17.9% (13.0%-29.3%). GLP-1RA treatment during MWM resulted in 5.0% (1.9%-7.7%) weight loss. Weight loss during GLP-1RA treatment predicted weight loss from the start of MWM until 12 months post-surgery, but not postoperative weight loss after adjustment. The proportion of weight loss from start of MWM to 12 months post-surgery attributed to GLP-1RA treatment was negatively associated with that attributed to surgery, after adjustment. In conclusion, weight change after GLP-1RA treatment predicted the weight loss achieved by a combination of MWM and bariatric surgery, but not weight loss induced by surgery only. Failure to lose weight after GLP-1RA treatment should not be considered a barrier to undergoing bariatric surgery.
      PubDate: 2017-11-22T22:55:25.773432-05:
      DOI: 10.1111/dom.13131
  • Peri-operative continuation of metformin does not improve glycaemic
           control in patients with type 2 diabetes: A randomized controlled trial
    • Authors: A. H. Hulst; J. A. W. Polderman, E. Ouweneel, A. J. Pijl, M. W. Hollmann, J. H. DeVries, B. Preckel, J. Hermanides
      Pages: 749 - 752
      Abstract: Historically, metformin was withheld before surgery for fear of metformin-associated lactic acidosis. Currently, however, this risk is deemed to be low and guidelines have moved towards the continuation of metformin. We hypothesized that continuing metformin peri-operatively would lower postoperative serum glucose level without an effect on plasma lactate levels. We performed a single-blind multicentre randomized controlled trial in people with type 2 diabetes mellitus scheduled for non-cardiac surgery and continued (MF+ group) or withheld (MF- group) metformin before surgery. The main outcome measures were the differences in peri-operative plasma glucose and lactate levels. We randomized 70 patients (37 MF+ group and 33 MF- group) with type 2 diabetes mellitus. Postoperative glucose levels were similar in the MF+ and the MF- groups (8.2 ± 1.8 vs 8.3 ± 2.3 mmol/L P = .95) Although preoperative lactate levels were slightly higher in the MF+ group compared with the MF- group (1.5 vs 1.2 mmol/L; P = .02), the postoperative lactate levels were not significantly different (1.2 vs 1.0 mmol/L; P = .18). In conclusion, continuation of metformin during elective non-cardiac surgery does not improve glucose control or raise lactate levels to a clinically relevant degree.
      PubDate: 2017-10-13T04:13:17.940177-05:
      DOI: 10.1111/dom.13118
  • Metformin for the management of peri-operative hyperglycaemia
    • Authors: Russell Brown; James Paul
      Pages: 753 - 754
      PubDate: 2017-12-01T03:50:50.274538-05:
      DOI: 10.1111/dom.13154
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