Purpose To evaluate the prevalence and epidemiological characteristics of diabetic retinopathy (DR) in Slovakian patients with Type 1 and 2 diabetes mellitus (DM) in the DIARET SK study. Patients and methods An epidemiological multi-center survey that included 4,078 adult patients (aged ≥18 years) from 51 diabetologists and 47 ophthalmologists. Data were collected from February to December 2015. Results The final data set consisted of 4,014 patients; 3,700 were enrolled (Type 2 DM = 3,405, Type 1 DM = 295) using a quasi-random approach; 16 (Type 2 DM = 15, Type 1 DM = 1) patients in the pre-specified group had DM duration of <5 years with a history of DR while 298 patients (Type 2 DM = 204, Type 1 DM = 94) had DM duration of ≥ 20 years. The mean (standard deviation [SD]) age of patients at diagnosis for Types 2 and 1 DM was 53.4 (9.5) and 27.6 (12.9) years, respectively. The mean (SD) glycated hemoglobin (HbA1c) was 7.5 (1.4) and 8.5 (1.6) in Types 2 and 1 DM patients, respectively, whereas a slightly higher proportion of patients had >11.0 HbA1c in Type 1 DM (5.8%) than Type 2 (2.0%). The mean (SD) duration of Type 2 DM was shorter compared with Type 1 (7.5 [5.2] vs 10.3 [6.9] years). In Type 2 DM patients, there were 516 (15.5%) cases of DR, 19 (0.56%) of proliferative DR (PDR), and 106 (3.11%) of diabetic macular edema (DME). In Type 1 DM patients, there were 86 (29.15%) cases of DR, 10 (3.39%) PDR, and 12 (4.07%) DME. Conclusions In Slovakian patients with DM, the duration of disease and higher HbA1c were the most prevalent factors that contributed to the development of DR and DME.

Vildagliptin blocks glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) inactivation of the meal induced increases in GLP-1 and GIP so that elevated GLP-1 and GIP levels are maintained over 24 h. The primary insulin secretion effect of vildagliptin is to improve the impaired sensitivity of the β-cells to glucose in subjects with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) and in patients with type 2 diabetes mellitus (T2DM); this effect was seen acutely and maintained over at least 2 years in patients with T2DM. Vildagliptin was also associated with improved β-cell function that is likely secondary to the improved metabolic state. Although there was no evidence of restoration of β-cell mass, the preponderance of the vildagliptin data does indicate that for at least 2 years β-cell function was maintained in vildagliptin treated patients but not in the untreated patients. Vildagliptin suppressed an inappropriate glucagon response to an oral glucose challenge in patients with T2DM, to a mixed meal challenge in patients with T2DM and type 1 diabetes mellitus, and to a mixed meal challenge in subjects with IGT and IFG. The improved glucagon response was maintained for at least 2 years in patients with T2DM and there was no change in the glucagon response in normoglycemic individuals. Vildagliptin lowered glucose levels into the normal range without increasing hypoglycemia. These hypoglycemic benefits appear to be secondary in large part to the improved sensitivity of both the β and α-cell to glucose. In the case of the α-cell, if glucose levels are high, GLP-1 attenuates the glucagon levels and if glucose levels are low, GIP increases glucagon levels. Vildagliptin reduces fatty acid flux from the adipocyte leading to reduced liver fat which in turn leads to increased glucose utilization. The reduced glycosuria and reduced lipo-toxicity associated with vildagliptin therapy does not lead to weight gain presumably due to increased fat mobilization and oxidation during meals and to reduced fat extraction from the gut.

Aim To assess the long-term clinical benefits of early combination treatment with vildagliptin-metformin vs. standard-of-care, metformin monotherapy in the ongoing VERIFY study. Methods We randomized 2001 participants with multi-ethnic background, aged 18-70 years, having HbA(1c) levels 48-58 mmol/mol (6.5-7.5%) and BMI 22-40 kg/m(2). Baseline data included HbA(1c), fasting plasma glucose and homeostasis model beta-cell and insulin sensitivity. Standardized meal-tests, insulin secretion rate relative to glucose, and oral glucose insulin sensitivity were assessed in a subpopulation. Results Out of 4524 screened, data were collected from the 2001 eligible participants (53% women) across Europe (52.4%), Latin America (26.8%), Asia (17.2%), South Africa (3.1%) and Australia (0.5%). The median (interquartile range) disease duration was 3.4 (0.9, 10.2) months; mean (+/- SD) age 54.3 +/- 9.4 years; weight 85.5 +/- 17.5 kg and BMI 31.1 +/- 4.7 kg/m(2). Baseline HbA(1c) was 52 +/- 3 mmol/mol (6.9 +/- 0.3%), fasting plasma glucose 7.5 +/- 1.5 mmol/l and the median (interquartile range) of fasting insulin was 109 (75-160) mU/l. Homeostasis model beta-cell and insulin sensitivity values were 84% (60, 116) and 46% (31, 68), respectively. In those undertaking meal-tests, insulin secretion rate relative to glucose was 28 +/- 12 pmol/min/m(2)/mmol/l and oral glucose insulin sensitivity was 353 +/- 57 ml/min/m(2). Conclusions Our current, multi-ethnic, newly diagnosed VERIFY population reflects a characteristic presence of early insulin resistance in participants with increased demand for insulin associated with obesity. The VERIFY study will provide unique evidence in characterizing therapeutic intervention in a diverse population with hyperglycaemia, focusing on durability of early glycaemic control.

In a meta-analysis, we observed a significant 37% relative risk reduction in prospectively adjudicated major adverse cardiac events [MACEs, comprising of non-fatal myocardial infarction, non-fatal stroke, cardiovascular (CV) death] with vildagliptin vs. comparators in younger (< 65 years) patients with type 2 diabetes mellitus (T2DM), while the risk was similar in older patients (≥ 65 years). We carried out an exploratory analysis to identify the patient characteristics and on-treatment effects that may have contributed to the different outcomes in the two age groups.

Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors reduce hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by enhancing insulin and suppressing glucagon secretion. Since T2DM is associated with progressive loss of beta- cell function, we hypothesized that the DPP-4 inhibitor action to improve beta- cell function would be attenuated with longer duration of T2DM.Methods: Data from six randomized, placebo- controlled trials of 24 weeks duration, where a- cell response to vildagliptin 50 mg twice daily was assessed, were pooled. In each study, the insulin secretory rate relative to glucose (ISR/G 0-2h) during glucose load (standard meal or oral glucose tolerance test) was assessed at baseline and end of study. The mean placebo- subtracted difference (PSD) in the change in ISR/ G 0-2h from baseline for each study was evaluated as a function of age, duration of T2DM, baseline ISR/G 0-2h, glycated hemoglobin (HbA(1c)), fasting plasma glucose, body mass index, and mean PSD in the change in HbA(1c) from baseline, using univariate model.Results: There was a strong negative association between the PSD in the change from baseline in ISR/ G 0- 2h and duration of T2DM (r= -0.89, p< 0.02). However, there was no association between the PSD in the change from baseline in ISR/ G 0-2h and the PSD in the change from baseline in HbA 1c (r=0.33, p=0.52). None of the other characteristics were significantly associated with mean PSD change in ISR/G 0-2h.Conclusion: These findings indicate that the response of the beta- cell, but not the HbA(1c) reduction, with vildagliptin is dependent on duration of T2DM. Further, it can be speculated that glucagon suppression may become the predominant mechanism via which glycemic control is improved when treatment with a DPP- 4 inhibitor, such as vildagliptin, is initiated late in the natural course of T2DM.

Vildagliptin is one of the most extensively studied dipeptidyl peptidase-4 (DPP-4) inhibitors in terms of its clinical utility. Over the last decade, a vast panorama of evidence on the benefit–risk profile of vildagliptin has been generated in patients with type 2 diabetes mellitus (T2DM). In this article, we review the cumulative evidence on the safety of vildagliptin from the clinical development programme, as well as reports of rare adverse drug reactions detected during the post-marketing surveillance of the drug. Across clinical studies, the overall safety and tolerability profile of vildagliptin was similar to placebo, and it was supported by real-world data in a broad population of patients with T2DM, making DPP-4 inhibitors, like vildagliptin, a safe option for managing patients with T2DM.

CXC chemokine receptor 2 (CXCR2) is a key receptor in the chemotaxis of neutrophils to sites of inflammation. The studies reported here describe the pharmacological characterization of danirixin, a CXCR2 antagonist in the diaryl urea chemical class. Danirixin has high affinity for CXCR2, with a negative log of the 50% inhibitory concentration (pIC(50)) of 7.9 for binding to Chinese hamster ovary cell (CHO)-expressed human CXCR2, and 78-fold selectivity over binding to CHO-expressed CXCR1. Danirixin is a competitive antagonist against CXCL8 in Ca2+-mobilization assays, with a K-B (the concentration of antagonist that binds 50% of the receptor population) of 6.5 nM and antagonist potency (pA(2)) of 8.44, and is fully reversible in washout experiments over 180 minutes. In rat and human whole-blood studies assessing neutrophil activation by surface CD11b expression following CXCL2 (rat) or CXCL1 (human) challenge, danirixin blocks the CD11b upregulation with pIC(50)s of 6.05 and 6.3, respectively. Danirixin dosed orally also blocked the influx of neutrophils into the lung in vivo in rats following aerosol lipopolysaccharide or ozone challenge, with median effective doses (ED(50)s) of 1.4 and 16 mg/kg respectively. Thus, danirixin would be expected to block chemotaxis in disease states in which neutrophils are increased in response to inflammation, such as pulmonary diseases. In comparison with navarixin, a CXCR2 antagonist from a different chemical class, the binding characterization of danirixin is distinct. These observationsmay offer insight into the previously observed clinical differences in induction of neutropenia between these compounds.

Objective: To assess the association of adipocyte size with cellular lipolysis and between cellular lipolysis and whole-body lipid oxidation. This study also assessed the association between adipocyte size and cellular lipolysis with weight and fat mass gain.Methods: Subjects had assessment of percent body fat (% fat) and adipose tissue biopsy for in vitro lipolysis (n = 325), and a subset of subjects had measurement of whole-body lipid oxidation (n = 112). A subset of subjects (n = 243) returned for repeated measurements of body weight and composition (mean follow-up 8.2 +/- 5.5 years).Results: In vitro lipolysis (r = 0.47, P < 0.0001) and adipocyte size (r = 0.49, P < 0.0001) were strongly associated with % fat. In vitro lipolysis (P = 0.04) but not adipocyte size (P = 0.44) was associated with whole-body fat oxidation. Adipocyte size was not associated with rate of percent weight gain (P = 0.20) but was negatively associated with rate of percent fat mass gain (P = 0.01). In vitro lipolysis was negatively associated with rate of percent weight gain (P = 0.02) and had a marginal negative association with rate of percent fat mass gain (P = 0.08).Conclusions: These results indicate inherent characteristics of adipocytes, including size and lipolytic activity, may be important determinants of whole-body lipid oxidation and subsequent weight gain.

The discovery of the incretin hormone glucagon like peptide-1 (GLP-1), and its usefulness in the treatment of type 2 diabetes mellitus (T2DM) followed by the finding that dipeptidyl peptidase-4 (DPP-4) inhibition prevents GLP-1 inactivation, led to the discovery of DPP-728. In 1999, studies with DPP-728 established the first proof-of-concept that DPP-4 inhibition improves glycaemic control in patients with T2DM. Further efforts to improve the binding kinetics of DPP-728 resulted in the discovery of vildagliptin (LAF237). In the last 20 years, a plethora of studies conducted by Novartis in collaboration with external investigators has demonstrated the mechanism of action of vildagliptin and its efficacy as monotherapy and as an add-on therapy for patients with T2DM. The studies establish that vildagliptin is a selective DPP-4 inhibitor that blocks GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) inactivation, thereby prolonging their action, resulting in improved glycaemic control. This review aims to discuss the discovery and development of vildagliptin, with an emphasis on mechanism of action and clinical efficacy.

P001 - Sepsis impairs the capillary response within hypoxic capillaries and decreases erythrocyte oxygen-dependent ATP efflux

INTRODUCTION:We have previously shown modest weight loss with vildagliptin treatment. Since body weight balance is associated with changes in blood pressure (BP) and fasting lipids, we have assessed these parameters following vildagliptin treatment.METHODS:Data were pooled from all double-blind, randomized, controlled, vildagliptin mono-therapy trials on previously drug-naïve patients with type 2 diabetes mellitus who received vildagliptin 50 mg once daily (qd) or twice daily (bid; n=2,108) and wherein BP and fasting lipid data were obtained.RESULTS:Data from patients receiving vildagliptin 50 mg qd or bid showed reductions from baseline to week 24 in systolic BP (from 132.5±0.32 to 129.8±0.34 mmHg; P<0.0001), diastolic BP (from 81.2±0.18 to 79.6±0.19 mmHg; P<0.0001), fasting triglycerides (from 2.00±0.02 to 1.80±0.02 mmol/L; P<0.0001), very low density lipoprotein cholesterol (from 0.90±0.01 to 0.83±0.01 mmol/L; P<0.0001), and low density lipoprotein cholesterol (from 3.17±0.02 to 3.04±0.02 mmol/L; P<0.0001), whereas high density lipoprotein cholesterol increased (from 1.19±0.01 to 1.22±0.01 mmol/L; P<0.001). Weight decreased by 0.48±0.08 kg (P<0.001).CONCLUSION:This large pooled analysis demonstrated that vildagliptin shows a significant reduction in BP and a favorable fasting lipid profile that are associated with modest weight loss.

We hypothesized that the relative contribution of fasting plasma glucose (FPG) versus postprandial plasma glucose (PPG) to glycated haemoglobin (HbA1c) could be calculated using an algorithm developed by the A1c-Derived Average Glucose (ADAG) study group to make HbA1c values more clinically relevant to patients. The algorithm estimates average glucose (eAG) exposure, which can be used to calculate apparent PPG (aPPG) by subtracting FPG. The hypothesis was tested in a large dataset (comprising 17 studies) from the vildagliptin clinical trial programme. We found that 24 weeks of treatment with vildagliptin monotherapy (n = 2523) reduced the relative contribution of aPPG to eAG from 8.12% to 2.95% (by 64%, p < 0.001). In contrast, when vildagliptin was added to metformin (n = 2752), the relative contribution of aPPG to eAG insignificantly increased from 1.59% to 2.56%. In conclusion, glucose peaks, which are often prominent in patients with type 2 diabetes, provide a small contribution to the total glucose exposure assessed by HbA1c, and the ADAG algorithm is not robust enough to assess this small relative contribution in patients receiving combination therapy.