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Nauck M.A.,Diabeteszentrum Bad Lauterberg | Kemmeries G.,Conservative Emergency Room | Holst J.J.,Copenhagen University | Meier J.J.,Ruhr University Bochum
Diabetes | Year: 2011

OBJECTIVE - Glucagon-like peptide (GLP)-1 lowers postprandial glycemia primarily through inhibition of gastric emptying. We addressed whether the GLP-1-induced deceleration of gastric emptying is subject to rapid tachyphylaxis and if so, how this would alter postprandial glucose control. RESEARCH DESIGN AND METHODS - Nine healthy volunteers (25 ± 4 years old, BMI: 24.6 ± 4.7 kg/m 2) were examined with intravenous infusion of GLP-1 (0.8 pmol · kg -1 · min -1) or placebo over 8.5 h. Two liquid mixed meals were administered at a 4-h interval. Gastric emptying was determined, and blood samples were drawn frequently. RESULTS - GLP-1 decelerated gastric emptying significantly more after the first meal compared with the second meal (P = 0.01). This was associated with reductions in pancreatic polypeptide levels (marker of vagal activation) after the first but not the second meal (P < 0.05). With GLP-1, glucose concentrations declined after the first meal but increased after the second meal (P < 0.05). The GLP-1-induced reductions in postprandial insulin and C-peptide levels were stronger during the first meal course (P < 0.05). Likewise, glucagon levels were lowered by GLP-1 after the first meal but increased after the second test meal (P < 0.05). CONCLUSIONS - The GLP-1-induced delay in gastric emptying is subject to rapid tachyphylaxis at the level of vagal nervous activation. As a consequence, postprandial glucose control by GLP-1 is attenuated after its chronic administration. © 2011 by the American Diabetes Association. Source

Nauck M.A.,Diabeteszentrum Bad Lauterberg | Meier J.J.,Ruhr University Bochum
Nature Reviews Endocrinology | Year: 2011

Up to one-third of patients treated with levothyroxine for primary hypothyroidism have biochemical evidence of inadequate thyroid hormone replacement. Could treatment effects of levothyoxine be optimized by bedtime administration on an empty stomach? A new study reveals the answer and also sheds light on other possible benefits of this alternative timing. © 2011 Macmillan Publishers Limited. All rights reserved. Source

Nauck M.A.,Diabeteszentrum Bad Lauterberg
Drug Design, Development and Therapy | Year: 2014

The importance of the kidney's role in glucose homeostasis has gained wider understanding in recent years. Consequently, the development of a new pharmacological class of anti-diabetes agents targeting the kidney has provided new treatment options for the management of type 2 diabetes mellitus (T2DM). Sodium glucose co-transporter type 2 (SGLT2) inhibitors, such as dapagliflozin, canagliflozin, and empagliflozin, decrease renal glucose reabsorption, which results in enhanced urinary glucose excretion and subsequent reductions in plasma glucose and glycosylated hemoglobin concentrations. Modest reductions in body weight and blood pressure have also been observed following treatment with SGLT2 inhibitors. SGLT2 inhibitors appear to be generally well tolerated, and have been used safely when given as monotherapy or in combination with other oral anti-diabetes agents and insulin. The risk of hypoglycemia is low with SGLT2 inhibitors. Typical adverse events appear to be related to the presence of glucose in the urine, namely genital mycotic infection and lower urinary tract infection, and are more often observed in women than in men. Data from long-term safety studies with SGLT2 inhibitors and from head-to-head SGLT2 inhibitor comparator studies are needed to fully determine their benefit–risk profile, and to identify any differences between individual agents. However, given current safety and efficacy data, SGLT2 inhibitors may present an attractive option for T2DM patients who are failing with metformin monotherapy, especially if weight is part of the underlying treatment consideration. © 2014 Nauck. Source

Nauck M.A.,Diabeteszentrum Bad Lauterberg
Diabetes, Obesity and Metabolism | Year: 2012

Liraglutide is a once-daily human glucagon-like peptide-1 analogue used in the treatment of type 2 diabetes (T2D). It has been prospectively investigated in a series of multinational, randomised, controlled phase 3 trials (the Liraglutide Effect and Action in Diabetes programme), as well as in an additional direct head-to-head study with sitagliptin. These trials were designed to clarify the use and safety of liraglutide in clinical practice across the treatment continuum of T2D, and consequently involved a large number and diverse range of patients. These studies also included active comparisons against antidiabetic agents including metformin, rosiglitazone, glimepiride, insulin glargine, exenatide and sitagliptin, and therefore have helped to examine clinical differences and similarities between liraglutide and these commonly used agents. © 2012 Blackwell Publishing Ltd. Source

Meier J.J.,Ruhr University Bochum | Nauck M.A.,Diabeteszentrum Bad Lauterberg
Diabetologia | Year: 2014

Aims/hypothesis: Incretin-based therapies have been suggested to increase the risk of pancreatitis, but the results of the available studies are controversial. Because results from prospective trials are limited by low statistical power, and because retrospective studies are often subject to bias, a pooled analysis of phase III clinical trials and two endpoint trials was performed. Methods: Event numbers for acute pancreatitis and patient-years of exposure (PYOs) were obtained from representatives of the pharmaceutical companies, or by literature research. Data were pooled for glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl-peptidase 4 (DPP-4) inhibitors in comparison with their respective controls and expressed as exposure-adjusted incidence rates. Results: A total of 38 cases of pancreatitis were reported in clinical trials with GLP-1 receptor agonists, comprising 17,775 PYOs. With the comparator treatment, nine events occurred in 5,863 PYOs. The pooled event rates were 2.1 and 1.5 per 1,000 PYOs, respectively, resulting in an OR of 1.39 (95% CI 0.67, 2.88). With DPP-4 inhibitors, 57 events were reported in 45,132 PYOs compared with 46 events in 38,883 PYOs with the comparator treatment. Pooled event rates were 1.3 and 1.2 per 1,000 PYOs, respectively, resulting in an OR of 1.07 (CI 0.72, 1.58). Conclusions/interpretation: This analysis suggests a trend towards a slightly elevated risk of pancreatitis with GLP-1 receptor agonists. With DPP-4 inhibitors, no consistent trend was found. However, the incidence numbers of cases of pancreatitis were still very small, and the statistical power was limited. Future endpoint trials may help to provide a better estimate of the true risk of pancreatitis with incretin-based therapies. © 2014 Springer-Verlag. Source

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