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Thomas R. Pieber
Joanneum Research GmbH, HEALTH - Institute for Biomedicine and Health Sciences, Graz, Austria

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Journal article
Published: 18 June 2021 in Diabetes Care
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OBJECTIVE To evaluate the efficacy and safety of dasiglucagon, a ready-to-use, next-generation glucagon analog in aqueous formulation for subcutaneous dosing, for treatment of severe hypoglycemia in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS This randomized, double-blind trial included 170 adult participants with type 1 diabetes, each randomly assigned to receive a single subcutaneous dose of 0.6 mg dasiglucagon, placebo, or 1 mg reconstituted glucagon (2:1:1 randomization) during controlled insulin-induced hypoglycemia. The primary end point was time to plasma glucose recovery, defined as an increase of ≥20 mg/dL from baseline without rescue intravenous glucose. The primary comparison was dasiglucagon versus placebo; reconstituted lyophilized glucagon was included as reference. RESULTS Median (95% CI) time to recovery was 10 (10, 10) minutes for dasiglucagon compared with 40 (30, 40) minutes for placebo (P< 0.001); the corresponding result for reconstituted glucagon was 12 (10, 12) minutes. In the dasiglucagon group, plasma glucose recovery was achieved within 15 min in all but one participant (99%), superior to placebo (2%; P< 0.001) and similar to glucagon (95%). Similar outcomes were observed for the other investigated time points at 10, 20, and 30 min after dosing. The most frequent adverse effects were nausea and vomiting, as expected with glucagon treatment. CONCLUSIONS Dasiglucagon provided rapid and effective reversal of hypoglycemia in adults with type 1 diabetes, with safety and tolerability similar to those reported for reconstituted glucagon injection. The ready-to-use, aqueous formulation of dasiglucagon offers the potential to provide rapid and reliable treatment of severe hypoglycemia.

ACS Style

Thomas R. Pieber; Ronnie Aronson; Ulrike Hövelmann; Julie Willard; Leona Plum-Mörschel; Kim M. Knudsen; Benedikte Bandak; Ramin Tehranchi. Dasiglucagon—A Next-Generation Glucagon Analog for Rapid and Effective Treatment of Severe Hypoglycemia: Results of Phase 3 Randomized Double-Blind Clinical Trial. Diabetes Care 2021, 44, 1361 -1367.

AMA Style

Thomas R. Pieber, Ronnie Aronson, Ulrike Hövelmann, Julie Willard, Leona Plum-Mörschel, Kim M. Knudsen, Benedikte Bandak, Ramin Tehranchi. Dasiglucagon—A Next-Generation Glucagon Analog for Rapid and Effective Treatment of Severe Hypoglycemia: Results of Phase 3 Randomized Double-Blind Clinical Trial. Diabetes Care. 2021; 44 (6):1361-1367.

Chicago/Turabian Style

Thomas R. Pieber; Ronnie Aronson; Ulrike Hövelmann; Julie Willard; Leona Plum-Mörschel; Kim M. Knudsen; Benedikte Bandak; Ramin Tehranchi. 2021. "Dasiglucagon—A Next-Generation Glucagon Analog for Rapid and Effective Treatment of Severe Hypoglycemia: Results of Phase 3 Randomized Double-Blind Clinical Trial." Diabetes Care 44, no. 6: 1361-1367.

Original article
Published: 03 June 2021 in Diabetes, Obesity and Metabolism
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Aims Fasting periods represent a significant challenge for glycaemic control in hospitalised patients. The study aims to evaluate the efficacy and safety of basal-bolus insulin therapy in managing glycaemia during fasting periods in hospitalised patients with type 2 diabetes. Materials and Methods We performed a post-hoc analysis of two prospective, uncontrolled interventional trials that applied electronic decision support system guided basal-bolus (meal-related and correction) insulin therapy. We searched for fasting periods (invasive or diagnostic procedures, medical condition) during inpatient stays. In a mixed-model analysis, patients’ glucose levels and insulin doses on days with regular food intake were compared to days with fasting periods. Results Out of 249 patients, 115 patients (33.9% female, age 68.3±10.3 years, diabetes duration 15.1±10.9 years, BMI 30.1±5.4 kg/m2, HbA1c 69±20 mmol/mol) had 194 days with fasting periods. Mean daily blood glucose was lower (Modelled difference (ModDiff): -0.5±0.2 mmol/L, p=0.006), and the proportion of glucose values within the target range (3.9-10.0 mmol/L) increased on days with fasting periods compared to days with regular food intake (ModDiff: +0.06±0.02, p=0.005). Glycaemic control on fasting days was driven by a reduction in daily bolus insulin doses (ModDiff: -11.0±0.9 IU, p<0.001), while basal insulin was similar (ModDiff: -1.1±0.6 IU, p=0.082) as compared to non-fasting days. Regarding hypoglycaemic events (BG <3.9 mmol/L), there was no difference between fasting and non-fasting days (χ2 0.9% vs. 1.7%, p=0.174). Conclusions When using well titrated basal-bolus insulin therapy in hospitalised patients with type 2 diabetes, the basal insulin dose does not require adjustment during fasting periods to achieve safe glycaemic control, provided meal-related bolus insulin is omitted and correction bolus insulin is tailored to glucose levels.

ACS Style

Daniel A. Hochfellner; Raphael Rainer; Haris Ziko; Felix Aberer; Amra Simic; Katharina M. Lichtenegger; Peter Beck; Klaus Donsa; Thomas R. Pieber; Friedrich M. Fruhwald; Alexander R. Rosenkranz; Lars‐Peter Kamolz; Petra M. Baumann; Julia K. Mader; Johannes Plank. Efficient and safe glycaemic control with basal‐bolus insulin therapy during fasting periods in hospitalized patients with type 2 diabetes using decision support technology: A post hoc analysis. Diabetes, Obesity and Metabolism 2021, 23, 2161 -2169.

AMA Style

Daniel A. Hochfellner, Raphael Rainer, Haris Ziko, Felix Aberer, Amra Simic, Katharina M. Lichtenegger, Peter Beck, Klaus Donsa, Thomas R. Pieber, Friedrich M. Fruhwald, Alexander R. Rosenkranz, Lars‐Peter Kamolz, Petra M. Baumann, Julia K. Mader, Johannes Plank. Efficient and safe glycaemic control with basal‐bolus insulin therapy during fasting periods in hospitalized patients with type 2 diabetes using decision support technology: A post hoc analysis. Diabetes, Obesity and Metabolism. 2021; 23 (9):2161-2169.

Chicago/Turabian Style

Daniel A. Hochfellner; Raphael Rainer; Haris Ziko; Felix Aberer; Amra Simic; Katharina M. Lichtenegger; Peter Beck; Klaus Donsa; Thomas R. Pieber; Friedrich M. Fruhwald; Alexander R. Rosenkranz; Lars‐Peter Kamolz; Petra M. Baumann; Julia K. Mader; Johannes Plank. 2021. "Efficient and safe glycaemic control with basal‐bolus insulin therapy during fasting periods in hospitalized patients with type 2 diabetes using decision support technology: A post hoc analysis." Diabetes, Obesity and Metabolism 23, no. 9: 2161-2169.

Journal article
Published: 14 April 2021 in Biomolecules
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The EndoBarrier™ medical device is a duodenal-jejunal bypass liner designed to mimic the effects of gastric bypass surgery to induce weight loss and glycaemic improvement. In this study, 10 participants with type 2 diabetes mellitus (T2DM), a mean body mass index (BMI) of 43.3 ± 5.0 (kg/m2) and a mean glycated haemoglobin A1c (HbA1c) of 60.6 ± 8.6 mmol/mol were examined at baseline (before implantation of EndoBarrier™), 4 weeks after implantation, at 36 weeks (right before explantation) and 24 weeks after the removal of the device to explore the short and long-term effects on glucose metabolism. Besides a significant reduction in body weight and fat mass, EndoBarrier™ treatment significantly improved insulin sensitivity during Botnia clamp investigations after four weeks of implantation. The beneficial effects decreased over time but remained significant 24 weeks after removal of the device.

ACS Style

Anna Obermayer; Norbert Tripolt; Faisal Aziz; Christoph Högenauer; Felix Aberer; Florian Schreiber; Andreas Eherer; Caren Sourij; Vanessa Stadlbauer; Eva Svehlikova; Martina Brunner; Nandu Goswami; Harald Kojzar; Peter Pferschy; Thomas Pieber; Harald Sourij. EndoBarrier™ Implantation Rapidly Improves Insulin Sensitivity in Obese Individuals with Type 2 Diabetes Mellitus. Biomolecules 2021, 11, 574 .

AMA Style

Anna Obermayer, Norbert Tripolt, Faisal Aziz, Christoph Högenauer, Felix Aberer, Florian Schreiber, Andreas Eherer, Caren Sourij, Vanessa Stadlbauer, Eva Svehlikova, Martina Brunner, Nandu Goswami, Harald Kojzar, Peter Pferschy, Thomas Pieber, Harald Sourij. EndoBarrier™ Implantation Rapidly Improves Insulin Sensitivity in Obese Individuals with Type 2 Diabetes Mellitus. Biomolecules. 2021; 11 (4):574.

Chicago/Turabian Style

Anna Obermayer; Norbert Tripolt; Faisal Aziz; Christoph Högenauer; Felix Aberer; Florian Schreiber; Andreas Eherer; Caren Sourij; Vanessa Stadlbauer; Eva Svehlikova; Martina Brunner; Nandu Goswami; Harald Kojzar; Peter Pferschy; Thomas Pieber; Harald Sourij. 2021. "EndoBarrier™ Implantation Rapidly Improves Insulin Sensitivity in Obese Individuals with Type 2 Diabetes Mellitus." Biomolecules 11, no. 4: 574.

Review
Published: 10 February 2021 in Diabetologia
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Aims/hypothesis The hyperinsulinaemic–hypoglycaemic glucose clamp technique has been developed and applied to assess effects of and responses to hypoglycaemia under standardised conditions. However, the degree to which the methodology of clamp studies is standardised is unclear. This systematic review examines how hyperinsulinaemic–hypoglycaemic clamps have been performed and elucidates potential important differences. Methods A literature search in PubMed and EMBASE was conducted. Articles in English published between 1980 and 2018, involving adults with or without diabetes, were included. Results A total of 383 articles were included. There was considerable variation in essential methodology of the hypoglycaemic clamp procedures, including the insulin dose used (49-fold difference between the lowest and the highest rate), the number of hypoglycaemic steps (range 1−6), the hypoglycaemic nadirs (range 2.0–4.3 mmol/l) and the duration (ranging from 5 to 660 min). Twenty-seven per cent of the articles reported whole blood glucose levels, most venous levels. In 70.8% of the studies, a dorsal hand vein was used for blood sampling, with some form of hand warming to arterialise venous blood in 78.8% of these. Key information was missing in 61.9% of the articles. Conclusions/interpretation Although the hyperinsulinaemic–hypoglycaemic clamp procedure is considered the gold standard to study experimental hypoglycaemia, a uniform standard with key elements on how to perform these experiments is lacking. Methodological differences should be considered when comparing results between hypoglycaemic clamp studies. PROSPERO registration This systematic review is registered in PROSPERO (CRD42019120083). Graphical abstract

ACS Style

Therese W. Fabricius; on behalf of the Hypo-RESOLVE consortium; Clementine E. M. Verhulst; Peter L. Kristensen; Cees J. Tack; Rory J. McCrimmon; Simon Heller; Mark L. Evans; Stephanie A. Amiel; Thomas R. Pieber; Bastiaan E. de Galan; Ulrik Pedersen-Bjergaard. Hyperinsulinaemic–hypoglycaemic glucose clamps in human research: a systematic review of the literature. Diabetologia 2021, 64, 727 -736.

AMA Style

Therese W. Fabricius, on behalf of the Hypo-RESOLVE consortium, Clementine E. M. Verhulst, Peter L. Kristensen, Cees J. Tack, Rory J. McCrimmon, Simon Heller, Mark L. Evans, Stephanie A. Amiel, Thomas R. Pieber, Bastiaan E. de Galan, Ulrik Pedersen-Bjergaard. Hyperinsulinaemic–hypoglycaemic glucose clamps in human research: a systematic review of the literature. Diabetologia. 2021; 64 (4):727-736.

Chicago/Turabian Style

Therese W. Fabricius; on behalf of the Hypo-RESOLVE consortium; Clementine E. M. Verhulst; Peter L. Kristensen; Cees J. Tack; Rory J. McCrimmon; Simon Heller; Mark L. Evans; Stephanie A. Amiel; Thomas R. Pieber; Bastiaan E. de Galan; Ulrik Pedersen-Bjergaard. 2021. "Hyperinsulinaemic–hypoglycaemic glucose clamps in human research: a systematic review of the literature." Diabetologia 64, no. 4: 727-736.

Brief report
Published: 02 February 2021 in Diabetes, Obesity and Metabolism
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Maintaining good glycemic control with the same infusion set for longer than three days may improve quality of life of insulin pump users. The aim of the present study was to assess the efficacy and safety of the novel, extended‐wear infusion set over seven days of wear in adults with type 1 diabetes. Sixteen participants completed three identical 8‐hour euglycemic clamp experiments on days 1, 4, and 7 of infusion set wear. Between the experiments, the participants were discharged home for routine diabetes management while wearing the same extended‐wear infusion set throughout the study. Time to reach the maximum glucose infusion rate (TGIRmax) on day 7 was reduced by 67% compared to day 1 (p<0.001). The corresponding area under the glucose infusion rate curve (AUCGIR) was comparable for the first two hours of the clamp (p=0.891) but decreased by 28% over time (p<0.008). While the extent of insulin absorption decreased with prolonged wear, it was accompanied by an increase in insulin absorption rate. The infusion set survival rate was 100% without leakages, occlusion alarms, severe hypoglycemia or ketoacidosis. The extended‐wear infusion set proved safe and effective during prolonged wear in real‐life conditions.

ACS Style

Amra Simic; Pernelle K. Schøndorff; Tobias Stumpe; Matthias Heschel; Werner Regittnig; Tina Pöttler; Daniela Ninaus; Thomas Augustin; Andrea Groselj‐Strele; Thomas R. Pieber; Julia K. Mader. Survival assessment of the extended‐wear insulin infusion set featuring lantern technology in adults with type 1 diabetes by the glucose clamp technique. Diabetes, Obesity and Metabolism 2021, 23, 1402 -1408.

AMA Style

Amra Simic, Pernelle K. Schøndorff, Tobias Stumpe, Matthias Heschel, Werner Regittnig, Tina Pöttler, Daniela Ninaus, Thomas Augustin, Andrea Groselj‐Strele, Thomas R. Pieber, Julia K. Mader. Survival assessment of the extended‐wear insulin infusion set featuring lantern technology in adults with type 1 diabetes by the glucose clamp technique. Diabetes, Obesity and Metabolism. 2021; 23 (6):1402-1408.

Chicago/Turabian Style

Amra Simic; Pernelle K. Schøndorff; Tobias Stumpe; Matthias Heschel; Werner Regittnig; Tina Pöttler; Daniela Ninaus; Thomas Augustin; Andrea Groselj‐Strele; Thomas R. Pieber; Julia K. Mader. 2021. "Survival assessment of the extended‐wear insulin infusion set featuring lantern technology in adults with type 1 diabetes by the glucose clamp technique." Diabetes, Obesity and Metabolism 23, no. 6: 1402-1408.

Journal article
Published: 16 December 2020 in Diabetes Care
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OBJECTIVE To investigate the pharmacokinetic and pharmacodynamic properties and safety of a novel formulation of insulin aspart (AT247) versus two currently marketed insulin aspart formulations (NovoRapid [IAsp] and Fiasp [faster IAsp]). RESEARCH DESIGN AND METHODS This single-center, randomized, double-blind, three-period, crossover study was conducted in 19 men with type 1 diabetes, receiving single dosing of trial products (0.3 units/kg) in a random order on three visits. Pharmacokinetics and pharmacodynamics were assessed during a euglycemic clamp lasting up to 8 h. RESULTS Onset of insulin appearance was earlier for AT247 compared with IAsp (−12 min [95% CI −14; −8], P = 0.0004) and faster IAsp (−2 min [−5; −2], P = 0.0003). Onset of action was accelerated compared with IAsp (−23 min [−37; −15], P = 0.0004) and faster IAsp (−9 min [−11; −3], P = 0.0006). Within the first 60 min, a higher exposure was observed for AT247 compared with IAsp by the area under the curve (AUC) glucose infusion rate (GIR) from 0 to 60 min (AUCAsp0–60min: treatment ratio vs. IAsp 2.3 [1.9; 2.9] vs. faster IAsp 1.5 [1.3; 1.8]), which was underpinned by a greater early glucose-lowering effect (AUCGIR,0–60min: treatment ratio vs. IAsp 2.8 [2.0; 5.5] vs. faster IAsp 1.7 [1.3; 2.3]). Furthermore, an earlier offset of exposure was observed for AT247 compared with IAsp (−32 min [−58; −15], P = 0.0015) and faster IAsp (−27 min [−85; −15], P = 0.0017), while duration of the glucose-lowering effect, measured by time to late half-maximum effect, did not differ significantly. CONCLUSIONS AT247 exhibited an earlier insulin appearance, exposure, and offset, with corresponding enhanced early glucose-lowering effect compared with IAsp and faster IAsp. It therefore represents a promising candidate in the pursuit for second-generation prandial insulin analogs to improve postprandial glycemic control.

ACS Style

Eva Svehlikova; Ines Mursic; Thomas Augustin; Christoph Magnes; David Gerring; Jan Jezek; Daniela Schwarzenbacher; Maria Ratzer; Michael Wolf; Sarah Howell; Leon Zakrzewski; Martina Urschitz; Bernd Tschapeller; Christina Gatschelhofer; Franz Feichtner; Fiona Lawrence; Thomas R. Pieber. Pharmacokinetics and Pharmacodynamics of Three Different Formulations of Insulin Aspart: A Randomized, Double-Blind, Crossover Study in Men With Type 1 Diabetes. Diabetes Care 2020, 44, 448 -455.

AMA Style

Eva Svehlikova, Ines Mursic, Thomas Augustin, Christoph Magnes, David Gerring, Jan Jezek, Daniela Schwarzenbacher, Maria Ratzer, Michael Wolf, Sarah Howell, Leon Zakrzewski, Martina Urschitz, Bernd Tschapeller, Christina Gatschelhofer, Franz Feichtner, Fiona Lawrence, Thomas R. Pieber. Pharmacokinetics and Pharmacodynamics of Three Different Formulations of Insulin Aspart: A Randomized, Double-Blind, Crossover Study in Men With Type 1 Diabetes. Diabetes Care. 2020; 44 (2):448-455.

Chicago/Turabian Style

Eva Svehlikova; Ines Mursic; Thomas Augustin; Christoph Magnes; David Gerring; Jan Jezek; Daniela Schwarzenbacher; Maria Ratzer; Michael Wolf; Sarah Howell; Leon Zakrzewski; Martina Urschitz; Bernd Tschapeller; Christina Gatschelhofer; Franz Feichtner; Fiona Lawrence; Thomas R. Pieber. 2020. "Pharmacokinetics and Pharmacodynamics of Three Different Formulations of Insulin Aspart: A Randomized, Double-Blind, Crossover Study in Men With Type 1 Diabetes." Diabetes Care 44, no. 2: 448-455.

Original article
Published: 30 September 2020 in Diabetes, Obesity and Metabolism
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Aims The ability to differentiate patient populations with type 2 diabetes at high risk of severe hypoglycaemia could impact clinical decision making. The aim of this study was to develop a risk score, using patient characteristics, that could differentiate between populations with higher and lower 2‐year risk of severe hypoglycaemia among individuals at increased risk of cardiovascular disease. Materials and methods Two models were developed for the risk score based on data from the DEVOTE cardiovascular outcomes trials. The first, a data‐driven machine learning model, used stepwise regression with bidirectional elimination to identify risk factors for severe hypoglycaemia. The second, a risk score based on known clinical risk factors accessible in clinical practice identified from the data‐driven model, included: insulin treatment regimen, diabetes duration, sex, age and HbA1c, all at baseline. Both the data‐driven model and simple risk score were evaluated for discrimination, calibration and generalizability using data from DEVOTE and were validated against the external LEADER cardiovascular outcomes trial dataset. Results Both the data‐driven model and simple risk score discriminated between patients at higher and lower hypoglycaemia risk, and performed similarly well based on the time‐dependent area under the curve index (0.63 and 0.66, respectively) over a 2‐year time horizon. Conclusions Both the data‐driven model and simple hypoglycaemia risk score were able to discriminate between patients at higher and lower risk of severe hypoglycaemia, the latter doing so using easily accessible clinical data. The implementation of such a tool (http://www.hyporiskscore.com/) may facilitate improved recognition of, and education about, severe hypoglycaemia risk, potentially improving patient care. Trial registration Clinicaltrials.gov identifier NCT01959529. This article is protected by copyright. All rights reserved.

ACS Style

Simon Heller; Ildiko Lingvay; Steven P. Marso; Athena Philis‐Tsimikas; Thomas R. Pieber; Neil R. Poulter; Richard E. Pratley; Elise Hachmann‐Nielsen; Kajsa Kvist; Martin Lange; Alan C. Moses; Marie Trock Andresen; John B. Buse; DEVOTE Study Group. Development of a hypoglycaemia risk score to identify high‐risk individuals with advanced type 2 diabetes in DEVOTE. Diabetes, Obesity and Metabolism 2020, 22, 2248 -2256.

AMA Style

Simon Heller, Ildiko Lingvay, Steven P. Marso, Athena Philis‐Tsimikas, Thomas R. Pieber, Neil R. Poulter, Richard E. Pratley, Elise Hachmann‐Nielsen, Kajsa Kvist, Martin Lange, Alan C. Moses, Marie Trock Andresen, John B. Buse, DEVOTE Study Group. Development of a hypoglycaemia risk score to identify high‐risk individuals with advanced type 2 diabetes in DEVOTE. Diabetes, Obesity and Metabolism. 2020; 22 (12):2248-2256.

Chicago/Turabian Style

Simon Heller; Ildiko Lingvay; Steven P. Marso; Athena Philis‐Tsimikas; Thomas R. Pieber; Neil R. Poulter; Richard E. Pratley; Elise Hachmann‐Nielsen; Kajsa Kvist; Martin Lange; Alan C. Moses; Marie Trock Andresen; John B. Buse; DEVOTE Study Group. 2020. "Development of a hypoglycaemia risk score to identify high‐risk individuals with advanced type 2 diabetes in DEVOTE." Diabetes, Obesity and Metabolism 22, no. 12: 2248-2256.

Original article
Published: 18 September 2020 in Wiener klinische Wochenschrift
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Summary Background Sarcopenia, defined as loss of muscle mass, quality and function, is a part of the frailty syndrome. In critical illness, sarcopenia has rarely been evaluated regarding clinical outcomes. Therefore, we evaluated the association of sarcopenia with both hospital length of stay (HLOS) and 6‑month mortality in critically ill patients using abdominal computed tomography (CT) scans. Methods In a post hoc analysis from the high dose vitamin D3 vs. placebo in adult vitamin D deficient patients (VITdAL-ICU) trial, we retrospectively reviewed all available abdominal CT scans (18 women, 19 men). We measured and calculated total psoas area (TPA), psoas muscle density (PMD), skeletal muscle index (SMI) and bone mineral density (BMD) and analyzed the relation of these endpoints with HLOS and mortality. Defining sarcopenia we used cut-off values for TPA as 642.1 mm2/m2 in women and 784 mm2/m2 in men and PMD as 31.1 Hounsfield units (HU) in women and 33.3 HU in men, both measured at the level of L3, as well as for SMI (38.5 cm2/m2 in women and 52.4 cm2/m2 in men). Likely osteoporosis was defined by L1 trabecular attenuation of ≤110 HU. Values for TPA, PMD and SMI could not be obtained in 11 patients and BMD in 1 patient. Results Mean adjusted TPA was lower in women versus men (478 vs. 749 mm2/m2) as well as PMD (34.6 vs. 41.3 HU), SMI (62.36 vs. 76.81 cm2/m2) and BMD (141.1 vs. 157.2 HU). No significant influence on hospital length of stay and on 6‑month mortality was found, irrespective of the morphometric parameter used (TPA, PMD, SMI, BMD; p > 0.05). Survivors showed statistically nonsignificantly better values than nonsurvivors: TPA: 652 vs. 530 mm2/m2 (p = 0.27); PMD: 38.4 vs. 37.4 HU (p = 0.85); SMI: 70.32 vs. 69.54 cm2/m2 (p = 0.91); BMD: 156 vs. 145.8 HU (p = 0.81). Conclusion Although the study is limited by the small sample size, our data do not support a strong predictive value for TPA/PMD/SMI or BMD for HLOS or mortality in critically ill patients with vitamin D deficiency.

ACS Style

Oliver Malle; Dietmar Maurer; Doris Wagner; Christian Schnedl; Steven Amrein; Thomas Pieber; Astrid Fahrleitner-Pammer; Hans Peter Dimai; Karin Amrein. Morphometric parameters of muscle and bone in critically ill patients. Wiener klinische Wochenschrift 2020, 133, 529 -535.

AMA Style

Oliver Malle, Dietmar Maurer, Doris Wagner, Christian Schnedl, Steven Amrein, Thomas Pieber, Astrid Fahrleitner-Pammer, Hans Peter Dimai, Karin Amrein. Morphometric parameters of muscle and bone in critically ill patients. Wiener klinische Wochenschrift. 2020; 133 (11-12):529-535.

Chicago/Turabian Style

Oliver Malle; Dietmar Maurer; Doris Wagner; Christian Schnedl; Steven Amrein; Thomas Pieber; Astrid Fahrleitner-Pammer; Hans Peter Dimai; Karin Amrein. 2020. "Morphometric parameters of muscle and bone in critically ill patients." Wiener klinische Wochenschrift 133, no. 11-12: 529-535.

Original research
Published: 01 June 2020 in Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
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Purpose: Organic cation transporters (Octs) use cations like endogenous compounds, toxins, and drugs, such as metformin, as substrates. Therefore, these proteins determine the pharmacokinetics and -dynamics of metformin and thus its efficacy. Of note, metformin is today the most commonly used pharmaceutical in the treatment of type 2 diabetes (T2DM) with nevertheless a great variability in clinical response, which attributes to genetic variances. The aim of this study was to determine the influence of intronic OCT1 SNPs on prevalence of all-cause and cardiovascular death. Patients and Methods: Genotypes of 27 intronic SNPs in OCT1 were investigated in the LURIC study, a prospective cohort of 3316 participants scheduled for coronary angiography. We investigated whether these variants were associated with all-cause and cardiovascular death in 73 individuals with T2DM under metformin therapy, in individuals without diabetes, individuals with T2DM and individuals with T2DM without metformin therapy. Results: In a multivariate Cox regression analysis adjusted for classical cardiovascular risk factors, 4 intronic OCT1 SNPs were significantly associated with all-cause and cardiovascular mortality in individuals with T2DM on metformin therapy. Conclusion: According to their OCT1 genotype, some individuals with T2DM on metformin therapy might be prone to an increased risk of cardiovascular death.

ACS Style

Natascha Schweighofer; Bernd Genser; Winfried Maerz; Marcus E Kleber; Olivia Trummer; Thomas R Pieber; Barbara Obermayer-Pietsch. Intronic Variants in OCT1 are Associated with All-Cause and Cardiovascular Mortality in Metformin Users with Type 2 Diabetes. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2020, ume 13, 2069 -2080.

AMA Style

Natascha Schweighofer, Bernd Genser, Winfried Maerz, Marcus E Kleber, Olivia Trummer, Thomas R Pieber, Barbara Obermayer-Pietsch. Intronic Variants in OCT1 are Associated with All-Cause and Cardiovascular Mortality in Metformin Users with Type 2 Diabetes. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2020; ume 13 ():2069-2080.

Chicago/Turabian Style

Natascha Schweighofer; Bernd Genser; Winfried Maerz; Marcus E Kleber; Olivia Trummer; Thomas R Pieber; Barbara Obermayer-Pietsch. 2020. "Intronic Variants in OCT1 are Associated with All-Cause and Cardiovascular Mortality in Metformin Users with Type 2 Diabetes." Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy ume 13, no. : 2069-2080.

Journal article
Published: 05 May 2020 in Nutrients
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Background: Besides anemia, iron deficiency may cause more subtle symptoms, including the restless legs syndrome (RLS), the chronic fatigue syndrome (CFS) or sleeping disorders. Objective: The aim of this pre-planned secondary analysis of the IronWoMan randomized controlled trial (RCT) was to compare the frequency and severity of symptoms associated with iron deficiency before and after (intravenous or oral) iron supplementation in iron deficient blood donors. Methods/Design: Prospective, randomized, controlled, single-centre trial. (ClinicalTrials.gov: NCT01787526). Setting: Tertiary care center in Graz, Austria. Participants: 176 (138 female and 38 male) whole-blood and platelet apheresis donors aged ≥ 18 and ≤ 65 years with iron deficiency (ferritin ≤ 30ng/mL at the time of blood donation). Interventions: Intravenous iron (1 g ferric carboxymaltose, n = 86) or oral iron supplementation (10 g iron fumarate, 100 capsules, n = 90). Measurements: Clinical symptoms were evaluated by a survey before iron therapy (visit 0, V0) and after 8–12 weeks (visit 1, V1), including questions about symptoms of restless legs syndrome (RLS), chronic fatigue syndrome (CFS), sleeping disorders, quality of life and symptoms like headaches, dyspnoea, dizziness, palpitations, pica and trophic changes in fingernails or hair. Results: We found a significant improvement in the severity of symptoms for RLS, fatigue and sleep quality (p < 0.001). Furthermore, a significant decrease in headaches, dyspnoea, dizziness and palpitations was reported (p < 0.05). There was no difference between the type of iron supplementation (intravenous versus oral) and clinical outcome data. Conclusion: Iron supplementation in iron-deficient blood donors may be an effective strategy to improve symptoms related to iron deficiency and the wellbeing of blood donors.

ACS Style

Susanne Macher; Cornelia Herster; Magdalena Holter; Martina Moritz; Eva Maria Matzhold; Tatjana Stojakovic; Thomas R. Pieber; Peter Schlenke; Camilla Drexler; Karin Amrein. The Effect of Parenteral or Oral Iron Supplementation on Fatigue, Sleep, Quality of Life and Restless Legs Syndrome in Iron-Deficient Blood Donors: A Secondary Analysis of the IronWoMan RCT. Nutrients 2020, 12, 1313 .

AMA Style

Susanne Macher, Cornelia Herster, Magdalena Holter, Martina Moritz, Eva Maria Matzhold, Tatjana Stojakovic, Thomas R. Pieber, Peter Schlenke, Camilla Drexler, Karin Amrein. The Effect of Parenteral or Oral Iron Supplementation on Fatigue, Sleep, Quality of Life and Restless Legs Syndrome in Iron-Deficient Blood Donors: A Secondary Analysis of the IronWoMan RCT. Nutrients. 2020; 12 (5):1313.

Chicago/Turabian Style

Susanne Macher; Cornelia Herster; Magdalena Holter; Martina Moritz; Eva Maria Matzhold; Tatjana Stojakovic; Thomas R. Pieber; Peter Schlenke; Camilla Drexler; Karin Amrein. 2020. "The Effect of Parenteral or Oral Iron Supplementation on Fatigue, Sleep, Quality of Life and Restless Legs Syndrome in Iron-Deficient Blood Donors: A Secondary Analysis of the IronWoMan RCT." Nutrients 12, no. 5: 1313.

Original article
Published: 06 April 2020 in Diabetes, Obesity and Metabolism
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Aims To undertake a post hoc analysis, utilizing a hypoglycaemia risk score based on DEVOTE trial data, to investigate if a high risk of severe hypoglycaemia was associated with an increased risk of cardiovascular events, and whether reduced rates of severe hypoglycaemia in patients identified as having the highest risk impacted the risk of cardiovascular outcomes. Materials and methods The DEVOTE population was divided into quartiles according to patients’ individual hypoglycaemia risk scores. For each quartile, the observed incidence and rate of severe hypoglycaemia, major adverse cardiovascular event (MACE) and all‐cause mortality were determined to investigate whether those with the highest risk of hypoglycaemia were also at the greatest risk of MACE and all‐cause mortality. In addition, treatment differences within each risk quartile (insulin degludec [degludec] vs insulin glargine 100 units/mL [glargine U100]) in terms of severe hypoglycaemia, MACE and all‐cause mortality were also investigated. Results Patients with the highest risk scores had the highest rates of severe hypoglycaemia, MACE and all‐cause mortality. Treatment ratios between degludec and glargine U100 in the highest risk quartile were 0.56 [0.39;0.80]95%CI (severe hypoglycaemia), 0.76 [0.58;0.99]95%CI (MACE) and 0.77 [0.55;1.07]95%CI (all‐cause mortality). Conclusions The risk score demonstrated that a high risk of severe hypoglycaemia was associated with a high incidence of MACE and all‐cause mortality and that, in this high‐risk group, those treated with degludec had a lower incidence of MACE. These observations support the hypothesis that hypoglycaemia is a risk factor for cardiovascular events.

ACS Style

Simon Heller; Ildiko Lingvay; Steven P. Marso; Athena Philis‐Tsimikas; Thomas R. Pieber; Neil R. Poulter; Richard E. Pratley; Elise Hachmann‐Nielsen; Kajsa Kvist; Martin Lange; Alan C. Moses; Marie Trock Andresen; John B. Buse; DEVOTE Study Group. Risk of severe hypoglycaemia and its impact in type 2 diabetes in DEVOTE. Diabetes, Obesity and Metabolism 2020, 22, 2241 -2247.

AMA Style

Simon Heller, Ildiko Lingvay, Steven P. Marso, Athena Philis‐Tsimikas, Thomas R. Pieber, Neil R. Poulter, Richard E. Pratley, Elise Hachmann‐Nielsen, Kajsa Kvist, Martin Lange, Alan C. Moses, Marie Trock Andresen, John B. Buse, DEVOTE Study Group. Risk of severe hypoglycaemia and its impact in type 2 diabetes in DEVOTE. Diabetes, Obesity and Metabolism. 2020; 22 (12):2241-2247.

Chicago/Turabian Style

Simon Heller; Ildiko Lingvay; Steven P. Marso; Athena Philis‐Tsimikas; Thomas R. Pieber; Neil R. Poulter; Richard E. Pratley; Elise Hachmann‐Nielsen; Kajsa Kvist; Martin Lange; Alan C. Moses; Marie Trock Andresen; John B. Buse; DEVOTE Study Group. 2020. "Risk of severe hypoglycaemia and its impact in type 2 diabetes in DEVOTE." Diabetes, Obesity and Metabolism 22, no. 12: 2241-2247.

Preprint
Published: 31 March 2020
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Background: Besides anemia, iron deficiency may cause more subtle symptoms including those of the restless legs syndrome (RLS), the chronic fatigue syndrome (CFS) or sleeping disorders. Objective: The aim of this pre-planned secondary analysis was to compare the frequency and severity of symptoms associated with iron deficiency before and after (intravenous or oral) iron supplementation in iron deficient blood donors. Methods/Design: Prospective, randomized, controlled, single centre trial. (ClinicalTrials.gov: NCT01787526). Setting: Tertiary care center in Graz, Austria Participants: 138 female and 38 male whole blood and platelet apheresis donors aged ≥18 and ≤65 years with iron deficiency (ferritin ≤30ng/ml at the time of blood donation). Interventions: Intravenous iron (1 g ferric carboxymaltose, n=86) or oral iron supplementation (10 g iron fumarate, 100 capsules, n=90). Measurements: Clinical symptoms were evaluated by a survey before iron therapy (visit 0, V0) and after 8-12 weeks (visit 1, V1) including questions about symptoms of RLS, CFS, sleeping disorders, quality of life and symptoms like headaches, dyspnoea, dizziness, palpitations, pica and trophic changes of fingernails or hair. Results: We found a significant improvement in the severity of symptoms for RLS, fatigue and sleep quality (p<0.001). Furthermore, a significant decrease of headaches, dyspnoea, dizziness and palpitations was reported (p<0.05). There was no difference between the type of iron supplementation (intravenous versus oral) and clinical outcome data. Conclusion: Iron supplementation in iron deficient blood donors may be an effective strategy to improve symptoms related to iron deficiency and the wellbeing of blood donors.

ACS Style

Susanne Macher; Cornelia Herster; Magdalena Holter; Martina Moritz; Eva Maria Matzhold; Tatjana Stojakovic; Thomas R. Pieber; Peter Schlenke; Camilla Drexler; Karin Amrein. The Effect of Parenteral or Oral Iron Supplementation on Fatigue, Sleep, Quality of Life and Restless Legs Syndrome in Iron Deficient Blood Donors: A Secondary Analysis of the Ironwoman Rct. 2020, 1 .

AMA Style

Susanne Macher, Cornelia Herster, Magdalena Holter, Martina Moritz, Eva Maria Matzhold, Tatjana Stojakovic, Thomas R. Pieber, Peter Schlenke, Camilla Drexler, Karin Amrein. The Effect of Parenteral or Oral Iron Supplementation on Fatigue, Sleep, Quality of Life and Restless Legs Syndrome in Iron Deficient Blood Donors: A Secondary Analysis of the Ironwoman Rct. . 2020; ():1.

Chicago/Turabian Style

Susanne Macher; Cornelia Herster; Magdalena Holter; Martina Moritz; Eva Maria Matzhold; Tatjana Stojakovic; Thomas R. Pieber; Peter Schlenke; Camilla Drexler; Karin Amrein. 2020. "The Effect of Parenteral or Oral Iron Supplementation on Fatigue, Sleep, Quality of Life and Restless Legs Syndrome in Iron Deficient Blood Donors: A Secondary Analysis of the Ironwoman Rct." , no. : 1.

Journal article
Published: 19 February 2020 in Journal of Clinical Medicine
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The 25-Hydroxyvitamin D (25[OH)D) serum concentration depends on vitamin D intake, endogenous vitamin D production and genetic factors. The latter have been demonstrated in large genome-wide association studies indicating that single nucleotide polymorphisms (SNPs) in genes related to the vitamin D metabolism are as important for serum 25(OH)D levels as the influence of season. The mechanism on how these SNPs influence serum 25(OH)D levels are still unclear. The aim of the present study was to investigate the genetic effects of ten selected SNPs related to vitamin D metabolism on 25-hydroxyvitamin D increase (∆25(OH)D) after vitamin D supplementation in three randomized controlled trials. Genotypes of SNPs related to vitamin D metabolism were determined in 411 participants with 25(OH)D concentrations < 75 nmol/l receiving 20,000 IU cholecalciferol per week for 8 or 12 weeks after study inclusion. For the vitamin D receptor (VDR) rs10783219 polymorphism, the minor A-allele was associated with lower ∆25(OH)D values in the entire study population (p = 0.022), which was not consistent in all three cohorts when analysed separately. VDR rs10783219 might therefore be a genetic modulator of increasing 25-hydroxyvitamin D concentrations. Considering the wide-spread use of vitamin D supplementation, future large and well-designed randomized controlled trials (RCTs) should investigate the clinical impact of this polymorphism.

ACS Style

Olivia Trummer; Natascha Schweighofer; Christoph W. Haudum; Christian Trummer; Stefan Pilz; Verena Theiler-Schwetz; Martin H. Keppel; Martin Grübler; Thomas R. Pieber; Wilfried Renner; Barbara Obermayer-Pietsch; Elisabeth Lerchbaum. Genetic Components of 25-Hydroxyvitamin D Increase in Three Randomized Controlled Trials. Journal of Clinical Medicine 2020, 9, 570 .

AMA Style

Olivia Trummer, Natascha Schweighofer, Christoph W. Haudum, Christian Trummer, Stefan Pilz, Verena Theiler-Schwetz, Martin H. Keppel, Martin Grübler, Thomas R. Pieber, Wilfried Renner, Barbara Obermayer-Pietsch, Elisabeth Lerchbaum. Genetic Components of 25-Hydroxyvitamin D Increase in Three Randomized Controlled Trials. Journal of Clinical Medicine. 2020; 9 (2):570.

Chicago/Turabian Style

Olivia Trummer; Natascha Schweighofer; Christoph W. Haudum; Christian Trummer; Stefan Pilz; Verena Theiler-Schwetz; Martin H. Keppel; Martin Grübler; Thomas R. Pieber; Wilfried Renner; Barbara Obermayer-Pietsch; Elisabeth Lerchbaum. 2020. "Genetic Components of 25-Hydroxyvitamin D Increase in Three Randomized Controlled Trials." Journal of Clinical Medicine 9, no. 2: 570.

Commentary
Published: 10 January 2020 in Diabetes Therapy
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Thomas R. Pieber; Lars Bardtrum; Joakim Isendahl; Lily Wagner; Rimei Nishimura. Commentary to “Differential Effect of Hypoalbuminemia on Hypoglycemia on Type 2 Diabetes Patients Treated with Insulin Glargine 300 U/ml and Insulin Degludec” by Kawaguchi et al. Diabetes Therapy 2019. Diabetes Therapy 2020, 11, 561 -567.

AMA Style

Thomas R. Pieber, Lars Bardtrum, Joakim Isendahl, Lily Wagner, Rimei Nishimura. Commentary to “Differential Effect of Hypoalbuminemia on Hypoglycemia on Type 2 Diabetes Patients Treated with Insulin Glargine 300 U/ml and Insulin Degludec” by Kawaguchi et al. Diabetes Therapy 2019. Diabetes Therapy. 2020; 11 (2):561-567.

Chicago/Turabian Style

Thomas R. Pieber; Lars Bardtrum; Joakim Isendahl; Lily Wagner; Rimei Nishimura. 2020. "Commentary to “Differential Effect of Hypoalbuminemia on Hypoglycemia on Type 2 Diabetes Patients Treated with Insulin Glargine 300 U/ml and Insulin Degludec” by Kawaguchi et al. Diabetes Therapy 2019." Diabetes Therapy 11, no. 2: 561-567.

Journal article
Published: 09 June 2019 in The Lancet Diabetes & Endocrinology
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Summary Background Oral semaglutide is the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes. We aimed to compare the efficacy and safety of flexible dose adjustments of oral semaglutide with sitagliptin 100 mg. Methods In this 52-week, multicentre, randomised, open-label, phase 3a trial, we recruited patients with type 2 diabetes from 81 sites in ten countries. Patients were eligible if they were aged 18 years or older (19 years or older in South Korea), had type 2 diabetes (diagnosed ≥90 days before screening), HbA1c of 7·5–9·5% (58–80 mmol/mol), and were inadequately controlled on stable daily doses of one or two oral glucose-lowering drugs (for 90 days or more before screening). Participants were randomly assigned (1:1) by use of an interactive web-response system, stratified by background glucose-lowering medication at screening, to oral semaglutide with flexible dose adjustments to 3, 7, or 14 mg once daily or sitagliptin 100 mg once daily. To approximate treatment individualisation in clinical practice, oral semaglutide dose could be adjusted on the basis of prespecified HbA1c and tolerability criteria. Two efficacy-related estimands were prespecified: treatment policy (regardless of treatment discontinuation or use of rescue medication) and trial product (on treatment and without use of rescue medication) for participants randomly assigned to treatment. The primary endpoint was achievement of HbA1c of less than 7% (53 mmol/mol) at week 52 and the confirmatory secondary efficacy endpoint was change in bodyweight from baseline to week 52. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02849080, and European Clinical Trials Database, EudraCT number 2015-005593-38, and an open-label extension is ongoing. Findings Between Sept 20, 2016, and Feb 7, 2017, of 804 patients assessed for eligibility, 504 were eligible and randomly assigned to oral semaglutide (n=253) or sitagliptin (n=251). Most participants were male (285 [57%] of 504) with a mean age of 57·4 years (SD 9·9). All participants were given at least one dose of their allocated study drug except for one participant in the sitagliptin group. From a mean baseline HbA1c of 8·3% (SD 0·6%; 67 mmol/mol [SD 6·4]), a greater proportion of participants achieved an HbA1c of less than 7% with oral semaglutide than did with sitagliptin (treatment policy estimand: 58% [134 of 230] vs 25% [60 of 238]; and trial product estimand: 63% [123 of 196] vs 28% [52 of 184]). The odds of achieving an HbA1c of less than 7% was significantly better with oral semaglutide than sitagliptin (treatment policy estimand: odds ratio [OR] 4·40, 95% CI 2·89–6·70, p<0·0001; and trial product estimand: 5·54, 3·54–8·68, p<0·0001). The odds of decreasing mean bodyweight from baseline to week 52 were higher with oral semaglutide than with sitagliptin (estimated mean change in bodyweight, treatment policy estimand: −2·6 kg [SE 0·3] vs −0·7 kg [SE 0·2], estimated treatment difference [ETD] −1·9 kg, 95% CI −2·6 to −1·2; p<0·0001; and trial product estimand: −2·9 kg [SE 0·3] vs −0·8 kg [SE 0·3], ETD −2·2 kg, −2·9 to −1·5; p<0·0001). Adverse events occurred in 197 (78%) of 253 participants in the oral semaglutide group versus 172 (69%) of 250 in the sitagliptin group, and nausea was the most common adverse event with oral semaglutide (53 [21%]). Two deaths occurred in the sitagliptin group during the trial. Interpretation Oral semaglutide, with flexible dose adjustment, based on efficacy and tolerability, provided superior glycaemic control and weight loss compared with sitagliptin, and with a safety profile consistent with subcutaneous GLP-1 receptor agonists. Funding Novo Nordisk A/S.

ACS Style

Thomas R Pieber; Bruce Bode; Ann Mertens; Young Min Cho; Erik Christiansen; Christin L Hertz; Signe O R Wallenstein; John B Buse; S Akın; N Aladağ; A A Arif; L J Aronne; S Aronoff; Hayriye Esra Ataoglu; S H Baik; H Bays; P L Beckett; D Berker; S Bilz; E W Braun; L H S Canani; C H Chung; I Colin; J Condit; J Cooper; B Delgado; D C Eagerton; I N El Ebrashy; M H M F El Hefnawy; F G Eliaschewitz; M P Finneran; S Fischli; E Fließer-Görzer; J Geohas; N A Godbole; A Golay; S Gorban de Lapertosa; J L Gross; H L Gulseth; F Helland; H O Høivik; C Issa; E S Kang; C Keller; S H A Khalil; N H Kim; I J Kim; L J Klaff; M Laimer; J C LaRocque; S N Lederman; K-W Lee; W R Litchfield; M B Manning; E J Morawski; A V Murray; P R Nicol; T M O'Connor; A Oğuz; S Ong; A Özdemir; E M Palace; B A Palchick; J Pereles-Ortiz; R Prager; V Preumont; E Riffer; L Rista; G Rudofsky; R Sarı; A Scheen; B Schultes; J A Seo; S A Shelbaya; K Sivalingam; C H Sorli; S Stäuble; D A Streja; G T'Sjoen; T Tetiker; L Van Gaal; C Vercammen; M L Warren; D L Weinstein; D Weiss; A White; M Winnie; C Wium; Dilek Gogas Yavuz. Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial. The Lancet Diabetes & Endocrinology 2019, 7, 528 -539.

AMA Style

Thomas R Pieber, Bruce Bode, Ann Mertens, Young Min Cho, Erik Christiansen, Christin L Hertz, Signe O R Wallenstein, John B Buse, S Akın, N Aladağ, A A Arif, L J Aronne, S Aronoff, Hayriye Esra Ataoglu, S H Baik, H Bays, P L Beckett, D Berker, S Bilz, E W Braun, L H S Canani, C H Chung, I Colin, J Condit, J Cooper, B Delgado, D C Eagerton, I N El Ebrashy, M H M F El Hefnawy, F G Eliaschewitz, M P Finneran, S Fischli, E Fließer-Görzer, J Geohas, N A Godbole, A Golay, S Gorban de Lapertosa, J L Gross, H L Gulseth, F Helland, H O Høivik, C Issa, E S Kang, C Keller, S H A Khalil, N H Kim, I J Kim, L J Klaff, M Laimer, J C LaRocque, S N Lederman, K-W Lee, W R Litchfield, M B Manning, E J Morawski, A V Murray, P R Nicol, T M O'Connor, A Oğuz, S Ong, A Özdemir, E M Palace, B A Palchick, J Pereles-Ortiz, R Prager, V Preumont, E Riffer, L Rista, G Rudofsky, R Sarı, A Scheen, B Schultes, J A Seo, S A Shelbaya, K Sivalingam, C H Sorli, S Stäuble, D A Streja, G T'Sjoen, T Tetiker, L Van Gaal, C Vercammen, M L Warren, D L Weinstein, D Weiss, A White, M Winnie, C Wium, Dilek Gogas Yavuz. Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial. The Lancet Diabetes & Endocrinology. 2019; 7 (7):528-539.

Chicago/Turabian Style

Thomas R Pieber; Bruce Bode; Ann Mertens; Young Min Cho; Erik Christiansen; Christin L Hertz; Signe O R Wallenstein; John B Buse; S Akın; N Aladağ; A A Arif; L J Aronne; S Aronoff; Hayriye Esra Ataoglu; S H Baik; H Bays; P L Beckett; D Berker; S Bilz; E W Braun; L H S Canani; C H Chung; I Colin; J Condit; J Cooper; B Delgado; D C Eagerton; I N El Ebrashy; M H M F El Hefnawy; F G Eliaschewitz; M P Finneran; S Fischli; E Fließer-Görzer; J Geohas; N A Godbole; A Golay; S Gorban de Lapertosa; J L Gross; H L Gulseth; F Helland; H O Høivik; C Issa; E S Kang; C Keller; S H A Khalil; N H Kim; I J Kim; L J Klaff; M Laimer; J C LaRocque; S N Lederman; K-W Lee; W R Litchfield; M B Manning; E J Morawski; A V Murray; P R Nicol; T M O'Connor; A Oğuz; S Ong; A Özdemir; E M Palace; B A Palchick; J Pereles-Ortiz; R Prager; V Preumont; E Riffer; L Rista; G Rudofsky; R Sarı; A Scheen; B Schultes; J A Seo; S A Shelbaya; K Sivalingam; C H Sorli; S Stäuble; D A Streja; G T'Sjoen; T Tetiker; L Van Gaal; C Vercammen; M L Warren; D L Weinstein; D Weiss; A White; M Winnie; C Wium; Dilek Gogas Yavuz. 2019. "Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial." The Lancet Diabetes & Endocrinology 7, no. 7: 528-539.

Original article
Published: 08 May 2019 in Diabetes, Obesity and Metabolism
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Aims To investigate the pharmacokinetic/pharmacodynamic properties of fast‐acting insulin aspart (faster aspart) versus insulin aspart (IAsp) in subjects with type 2 diabetes (T2D). Materials and methods In a randomized, double‐blind, cross‐over design, 61 subjects with T2D usually treated with insulin±oral antidiabetic drug(s) received single‐dose faster aspart and IAsp (0.3 U/kg) at separate visits. Blood samples for pharmacokinetic assessment were collected frequently until 12 h post‐dose. Glucose‐lowering effect was determined in a euglycaemic clamp lasting up to 12 h post‐dose (target 5.0 mmol/L). Results The serum IAsp pharmacokinetic profile and glucose‐lowering effect profile were shifted to the left for faster aspart versus IAsp. Least square mean (±standard error) onset of appearance was 3.3±0.3 minutes for faster aspart, which was 1.2 minutes earlier than for IAsp (95% confidence interval faster aspart‐IAsp: [‐1.8;‐0.5], p=0.001). Onset of action for faster aspart was 8.9 minutes earlier [‐12.1;‐5.7] (p<0.001) than for IAsp. During the first 30 minutes after dosing, 89% larger IAsp exposure (ratio faster aspart/IAsp 1.89 [1.56;2.28], p<0.001) and 147% greater glucose‐lowering effect (2.47 [1.58;6.22], p<0.001) were observed for faster aspart compared with IAsp. Offset of exposure (tLate 50% Cmax) occurred earlier for faster aspart (difference faster aspart‐IAsp ‐36.4 minutes [‐55.3;‐17.6], p<0.001). The treatment difference of faster aspart‐IAsp in offset of glucose‐lowering effect (tLate 50% GIRmax) was ‐14.4 minutes [‐34.4;5.5], p=0.152. Conclusions In subjects with T2D, faster aspart was associated with earlier onset and greater initial exposure and glucose‐lowering effect compared with IAsp, as previously shown in subjects with type 1 diabetes. ClinicalTrials.gov identifier: NCT02933853 This article is protected by copyright. All rights reserved.

ACS Style

Thomas R. Pieber; Eva Svehlikova; Martina Brunner; Inge B. Halberg; Karen Margrete Due Thomsen; Hanne Haahr. Fast‐acting insulin aspart in people with type 2 diabetes: Earlier onset and greater initial exposure and glucose‐lowering effect compared with insulin aspart. Diabetes, Obesity and Metabolism 2019, 21, 2068 -2075.

AMA Style

Thomas R. Pieber, Eva Svehlikova, Martina Brunner, Inge B. Halberg, Karen Margrete Due Thomsen, Hanne Haahr. Fast‐acting insulin aspart in people with type 2 diabetes: Earlier onset and greater initial exposure and glucose‐lowering effect compared with insulin aspart. Diabetes, Obesity and Metabolism. 2019; 21 (9):2068-2075.

Chicago/Turabian Style

Thomas R. Pieber; Eva Svehlikova; Martina Brunner; Inge B. Halberg; Karen Margrete Due Thomsen; Hanne Haahr. 2019. "Fast‐acting insulin aspart in people with type 2 diabetes: Earlier onset and greater initial exposure and glucose‐lowering effect compared with insulin aspart." Diabetes, Obesity and Metabolism 21, no. 9: 2068-2075.

Original article
Published: 29 March 2019 in Diabetes, Obesity and Metabolism
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Aims To evaluate the short‐term cost‐effectiveness of insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) from a Canadian public healthcare payer perspective in patients with type 2 diabetes (T2D) at high risk of cardiovascular events and hypoglycaemia. Materials and methods A decision analytic model was developed to estimate costs (2017 Canadian dollars [CAD]) and clinical outcomes (quality‐adjusted life years [QALYs]) with degludec versus glargine U100 over a 2‐year time horizon. The model captured first major adverse cardiovascular events, death, severe hypoglycaemia and insulin dosing. Clinical outcomes were informed by a post hoc subgroup analysis of DEVOTE (NCT01959529), a trial comparing the cardiovascular safety of degludec and glargine U100 in patients with T2D at high cardiovascular risk. High hypoglycaemia risk was defined as the top quartile of patients (n = 1887) based on an index of baseline hypoglycaemia risk factors. Results In patients at high hypoglycaemia risk, degludec was associated with mean cost savings (CAD 129 per patient) relative to glargine U100, driven by a lower incidence of non‐fatal myocardial infarction, non‐fatal stroke and severe hypoglycaemia, which offset the slightly higher treatment costs with degludec. A reduced risk of cardiovascular death and severe hypoglycaemia resulted in improved effectiveness (+0.0132 QALYs) with degludec relative to glargine U100. In sensitivity analyses, changes to the vast majority of model parameters did not materially affect model outcomes. Conclusion Over 2 years, degludec improved clinical outcomes at a lower cost versus glargine U100 in patients with T2D at high risk of cardiovascular events and hypoglycaemia.

ACS Style

Richard F. Pollock; Simon Heller; Thomas R. Pieber; Vincent Woo; Jens Gundgaard; Nino Hallén; Maria Luckevich; Deniz Tutkunkardas; Bernard Zinman; On Behalf of the DEVOTE Study Group. Short‐term cost‐utility of degludec versus glargine U100 for patients with type 2 diabetes at high risk of hypoglycaemia and cardiovascular events: A Canadian setting (DEVOTE 9). Diabetes, Obesity and Metabolism 2019, 21, 1706 -1714.

AMA Style

Richard F. Pollock, Simon Heller, Thomas R. Pieber, Vincent Woo, Jens Gundgaard, Nino Hallén, Maria Luckevich, Deniz Tutkunkardas, Bernard Zinman, On Behalf of the DEVOTE Study Group. Short‐term cost‐utility of degludec versus glargine U100 for patients with type 2 diabetes at high risk of hypoglycaemia and cardiovascular events: A Canadian setting (DEVOTE 9). Diabetes, Obesity and Metabolism. 2019; 21 (7):1706-1714.

Chicago/Turabian Style

Richard F. Pollock; Simon Heller; Thomas R. Pieber; Vincent Woo; Jens Gundgaard; Nino Hallén; Maria Luckevich; Deniz Tutkunkardas; Bernard Zinman; On Behalf of the DEVOTE Study Group. 2019. "Short‐term cost‐utility of degludec versus glargine U100 for patients with type 2 diabetes at high risk of hypoglycaemia and cardiovascular events: A Canadian setting (DEVOTE 9)." Diabetes, Obesity and Metabolism 21, no. 7: 1706-1714.

Journal article
Published: 20 March 2019 in Clinical Nutrition
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Vitamin D supplementation may affect glycemic as well as hormonal regulation. Thus, the aim of the current study was to investigate whether vitamin D supplementation has any significant effects on metabolic and endocrine parameters in healthy premenopausal women. Primary outcome measure was the plasma glucose area under the curve (AUCgluc). The current study was a single-center, double-blind, randomized placebo-controlled trial that was conducted at the Medical University of Graz, Austria, between March 2013 and October 2017. One-hundred and fifty healthy premenopausal women with 25-hydroxyvitamin D [25(OH)D] concentrations <75 nmol/L once weekly received either 20,000 IU of cholecalciferol or placebo (2:1 ratio) over a total of 24 weeks. In total, 127 women [age 36.2 ± 8.7 years; BMI 25.3 ± 5.6 kg/m2; baseline 25(OH)D 55.8 ± 19.7 nmol/L] completed the study. Vitamin D supplementation had no significant effect on AUCgluc (mean treatment effect 11.70; p = 0.069), while it had a significant treatment effect on homeostatic model assessment-insulin resistance (HOMA-IR; mean treatment effect 0.31; p = 0.019) and quantitative insulin-sensitivity check index (QUICKI; mean treatment effect −0.019; p = 0.013). There was no significant effect on the remaining secondary outcome parameters. In this randomized-controlled trial in healthy premenopausal women, there was a significant treatment effect of vitamin D supplementation on HOMA-IR and QUICKI, while there was no significant treatment effect on AUCgluc.

ACS Style

Christian Trummer; Verena Theiler-Schwetz; Martina Kollmann; Monika Wölfler; Julia Münzker; Stefan Pilz; Thomas R. Pieber; Annemieke C. Heijboer; Barbara Obermayer-Pietsch; Elisabeth Lerchbaum. Effects of vitamin D supplementation on metabolic and endocrine parameters in healthy premenopausal women: A randomized controlled trial. Clinical Nutrition 2019, 39, 718 -726.

AMA Style

Christian Trummer, Verena Theiler-Schwetz, Martina Kollmann, Monika Wölfler, Julia Münzker, Stefan Pilz, Thomas R. Pieber, Annemieke C. Heijboer, Barbara Obermayer-Pietsch, Elisabeth Lerchbaum. Effects of vitamin D supplementation on metabolic and endocrine parameters in healthy premenopausal women: A randomized controlled trial. Clinical Nutrition. 2019; 39 (3):718-726.

Chicago/Turabian Style

Christian Trummer; Verena Theiler-Schwetz; Martina Kollmann; Monika Wölfler; Julia Münzker; Stefan Pilz; Thomas R. Pieber; Annemieke C. Heijboer; Barbara Obermayer-Pietsch; Elisabeth Lerchbaum. 2019. "Effects of vitamin D supplementation on metabolic and endocrine parameters in healthy premenopausal women: A randomized controlled trial." Clinical Nutrition 39, no. 3: 718-726.

Original article
Published: 08 March 2019 in Diabetes, Obesity and Metabolism
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Aims To describe the risks of cardiovascular (CV) events and severe hypoglycaemia with insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) in patients with type 2 diabetes (T2D) aged 65 years or older. Materials and Methods A total of 7637 patients in DEVOTE − a treat‐to‐target, randomized, double‐blind trial evaluating the CV safety of degludec versus glargine U100, were divided into three age groups (50−64 years: n = 3682, 65−74 years: n = 3136 and ≥75 years: n = 819). Outcomes by overall age group and randomized treatment differences were analysed for major adverse cardiovascular events (MACE), all‐cause mortality, severe hypoglycaemia and serious adverse events (SAEs). Results Patients with increasing age had higher risks of CV death, all‐cause mortality and SAEs, and non‐significant trends towards higher risks of MACE and severe hypoglycaemia. Treatment effects on the risks of MACE, all‐cause mortality, severe hypoglycaemia and SAEs were consistent across the age groups, based on the non‐significant interactions between treatment and age with regard to these outcomes. Conclusions There were higher risks of CV death, all‐cause mortality and SAEs, and trends towards higher risks of MACE and severe hypoglycaemia, with increasing age after adjusting for baseline differences. The effects across age groups of degludec versus glargine U100 on MACE, all‐cause mortality and severe hypoglycaemia were comparable, suggesting that the risk for MACE as well as all‐cause mortality are similar and risk for severe hypoglycaemia is lower with degludec regardless of age (conclusive evidence only up until 74 years of age).

ACS Style

Richard E. Pratley; Scott S. Emerson; Edward Franek; Matthew P. Gilbert; Steven P. Marso; Darren K. McGuire; Thomas R. Pieber; Bernard Zinman; Charlotte T. Hansen; Melissa V. Hansen; Thomas Mark; Alan C. Moses; John B. Buse; on behalf of the DEVOTE Study Group. Cardiovascular safety and lower severe hypoglycaemia of insulin degludec versus insulin glargine U100 in patients with type 2 diabetes aged 65 years or older: Results from DEVOTE (DEVOTE 7). Diabetes, Obesity and Metabolism 2019, 21, 1625 -1633.

AMA Style

Richard E. Pratley, Scott S. Emerson, Edward Franek, Matthew P. Gilbert, Steven P. Marso, Darren K. McGuire, Thomas R. Pieber, Bernard Zinman, Charlotte T. Hansen, Melissa V. Hansen, Thomas Mark, Alan C. Moses, John B. Buse, on behalf of the DEVOTE Study Group. Cardiovascular safety and lower severe hypoglycaemia of insulin degludec versus insulin glargine U100 in patients with type 2 diabetes aged 65 years or older: Results from DEVOTE (DEVOTE 7). Diabetes, Obesity and Metabolism. 2019; 21 (7):1625-1633.

Chicago/Turabian Style

Richard E. Pratley; Scott S. Emerson; Edward Franek; Matthew P. Gilbert; Steven P. Marso; Darren K. McGuire; Thomas R. Pieber; Bernard Zinman; Charlotte T. Hansen; Melissa V. Hansen; Thomas Mark; Alan C. Moses; John B. Buse; on behalf of the DEVOTE Study Group. 2019. "Cardiovascular safety and lower severe hypoglycaemia of insulin degludec versus insulin glargine U100 in patients with type 2 diabetes aged 65 years or older: Results from DEVOTE (DEVOTE 7)." Diabetes, Obesity and Metabolism 21, no. 7: 1625-1633.

Original article
Published: 22 February 2019 in Diabetes, Obesity and Metabolism
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Aims: In patients with type 2 diabetes (T2D) and high cardiovascular risk, the cardiovascular safety of insulin degludec (degludec) and insulin glargine 100 units/mL (glargine U100) has been established, as has the superior efficacy of liraglutide versus placebo on major adverse cardiovascular events (MACE) and mortality. Here, the associations with risk of MACE and mortality are compared between liraglutide versus no liraglutide use in the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE; NCT01959529). Materials and methods: Patients with T2D and high cardiovascular risk were randomized 1:1 to degludec or glargine U100. Hazard ratios for MACE/mortality were calculated using a Cox regression model adjusted for treatment and time‐varying liraglutide use at any time during the trial, without interaction. Sensitivity analyses adjusted for baseline covariates including, but not limited to, age, sex, smoking and prior cardiovascular disease. Results: At baseline, 436/7637 (5.7%) patients were treated with liraglutide; after baseline, 187/7637 (2.4%) started and 210/7637 (2.7%) stopped liraglutide. Mean liraglutide exposure from randomization was 530.2 days. Liraglutide use versus no liraglutide use was associated with significantly lower hazard rates for MACE (0.62 [0.41; 0.92]95%CI) and all‐cause mortality (0.50 [0.29; 0.88]95%CI). There was no significant difference in the rate of severe hypoglycaemia with versus without liraglutide use. Multiple sensitivity analyses yielded similar results. Conclusions: Use of liraglutide was associated with significantly lower risk of MACE and death in patients with T2D and high cardiovascular risk using basal insulin.

ACS Style

Kirstine Brown‐Frandsen; Scott S. Emerson; Darren K. McGuire; Thomas R. Pieber; Neil R. Poulter; Richard E. Pratley; Bernard Zinman; Mattis Flyvholm Ranthe; Randi Grøn; Martin Lange; Alan C. Moses; Petra Örsy; John B. Buse; on behalf of the DEVOTE Study Group. Lower rates of cardiovascular events and mortality associated with liraglutide use in patients treated with basal insulin: A DEVOTE subanalysis (DEVOTE 10). Diabetes, Obesity and Metabolism 2019, 21, 1437 -1444.

AMA Style

Kirstine Brown‐Frandsen, Scott S. Emerson, Darren K. McGuire, Thomas R. Pieber, Neil R. Poulter, Richard E. Pratley, Bernard Zinman, Mattis Flyvholm Ranthe, Randi Grøn, Martin Lange, Alan C. Moses, Petra Örsy, John B. Buse, on behalf of the DEVOTE Study Group. Lower rates of cardiovascular events and mortality associated with liraglutide use in patients treated with basal insulin: A DEVOTE subanalysis (DEVOTE 10). Diabetes, Obesity and Metabolism. 2019; 21 (6):1437-1444.

Chicago/Turabian Style

Kirstine Brown‐Frandsen; Scott S. Emerson; Darren K. McGuire; Thomas R. Pieber; Neil R. Poulter; Richard E. Pratley; Bernard Zinman; Mattis Flyvholm Ranthe; Randi Grøn; Martin Lange; Alan C. Moses; Petra Örsy; John B. Buse; on behalf of the DEVOTE Study Group. 2019. "Lower rates of cardiovascular events and mortality associated with liraglutide use in patients treated with basal insulin: A DEVOTE subanalysis (DEVOTE 10)." Diabetes, Obesity and Metabolism 21, no. 6: 1437-1444.