The study explored the utility of four-point preprandial glucose self-monitoring to calculate several indices of glycemic control and variability in a study adding the DPP-4 inhibitor vildagliptin to ...ongoing insulin therapy. This analysis utilized data from a double-blind, randomized, placebo-controlled crossover study in 29 patients with type 2 diabetes treated with vildagliptin or placebo on top of stable insulin dose. During two 4-week treatment periods, self-monitoring of plasma glucose was undertaken at 4 occasions every day. Glucose values were used to assess several indices of glycemic control quality, such as glucose mean, GRADE, M-VALUE, hypoglycemia and hyperglycemia index, and indices of glycemic variability, such as standard deviation, CONGA, J-INDEX, and MAGE. We found that vildagliptin improved the glycemic condition compared to placebo: mean glycemic levels, and both GRADE and M-VALUE, were reduced by vildagliptin ( P < 0.01 ) . Indices also showed that vildagliptin reduced glycemia without increasing the risk for hypoglycemia. Almost all indices of glycemic variability showed an improvement of the glycemic condition with vildagliptin ( P < 0.02 ) , though more marked differences were shown by the more complex indices. In conclusion, the study shows that four-sample preprandial glucose self-monitoring is sufficient to yield information on the vildagliptin effects on glycemic control and variability.
To establish recycling routes in the early secretory pathway we have studied the recycling of the ER-Golgi intermediate compartment (ERGIC) marker ERGIC-53 in HepG2 cells. Immunofluorescence ...microscopy showed progressive concentration of ERGIC-53 in the Golgi area at 15 degreesC. Upon rewarming to 37 degreesC ERGIC-53 redistributed into the cell periphery often via tubular processes that largely excluded anterograde transported albumin. Immunogold labeling of cells cultured at 37 degreesC revealed ERGIC-53 predominantly in characteristic beta-COP-positive tubulo-vesicular clusters both near the Golgi apparatus and in the cell periphery. Concentration of ERGIC-53 at 15 degreesC resulted from both accumulation of ERGIC-53 in the ERGIC and movement of ERGIC membranes closer to the Golgi apparatus. Upon rewarming to 37 degreesC the labeling of ERGIC-53 in the ERGIC rapidly returned to normal levels whereas ERGIC-53's labeling in the cis-Golgi was unchanged. Temperature manipulations had no effect on the average number of ERGIC-53 clusters. Density gradient centrifugation indicated that the surplus ERGIC-53 accumulating in the ERGIC at 15 degreesC was rapidly transported to the ER upon rewarming. These results suggest that the ERGIC is a dynamic membrane system composed of a constant average number of clusters and that the major recycling pathway of ERGIC-53 bypasses the Golgi apparatus.
Introduction
Patients with type 2 diabetes (T2DM) are at increased risk for renal impairment (RI) and, in addition, there is an age-related decline in renal function. At the same time, T2DM treatment ...is more complex and treatment options are more limited in elderly patients as well as patients with RI, with the patient population ≥75 years with moderate or severe RI posing unique challenges, in particular, the high risk and more severe consequences of hypoglycemia. It was, therefore, of interest to assess the efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor vildagliptin in patients with T2DM ≥75 years who also have moderate or severe RI.
Methods
In this sub-analysis of data derived from a previously described randomized, double-blind, parallel-group, 24-week study, 105 patients (50 randomized to vildagliptin 50 mg qd and 55 to placebo) ≥75 years (mean age ~78 years) with T2DM and moderate or severe RI (mean baseline estimated glomerular filtration rate ~35 ml/min/1.73 m
2
) were included.
Results
The adjusted mean change in glycated hemoglobin (HbA
1c
) with vildagliptin was −1.0% from a baseline of 7.8% (between-group difference −0.8%;
p
< 0.001). This improvement in glycemic control was not associated with an increased risk of hypoglycemia; the rate of confirmed hypoglycemia was 0.49 events per patient-year with vildagliptin and 0.96 events per patient-year with placebo (not significant). Weight remained stable with vildagliptin treatment. Adverse events (AEs) (58.0% vs. 72.7%), serious AEs (14.0% vs. 16.4%), discontinuations due to AEs (4.0% vs. 9.1%) and deaths (0% vs. 5.5%) were reported at a comparable or lower frequency in patients receiving vildagliptin versus patients receiving placebo.
Conclusion
In this uniquely fragile elderly population ≥75 years with T2DM and moderate or severe RI, vildagliptin was well tolerated and efficacious, with no increase in the rate of hypoglycemia compared to placebo despite the marked improvement in glycemic control.
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 monotherapy trials on previously drug-naive 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. Keywords: TG, HDL, LDL, body weight DPP-4 inhibitor, GLP-1
SAP7 of Candida albicans is induced after vaginal infection of mice. Conversely, virulence during vaginal infection was not affected in a Deltasap7/Deltasap7 mutant strain. Only a partial virulence ...phenotype was detectable after intravenous injection. In conclusion, SAP7 expression does not correlate with C. albicans virulence in mice.
OBJECTIVE:--To compare the efficacy and tolerability of vildagliptin and rosiglitazone during a 24-week treatment in drug-naïve patients with type 2 diabetes. RESEARCH DESIGN AND METHODS--This was a ...double-blind, randomized, active-controlled, parallel-group, multicenter study of 24-week treatment with vildagliptin (100 mg daily, given as equally divided doses; n = 519) or rosiglitazone (8 mg daily, given as a once-daily dose; n = 267). RESULTS:--Monotherapy with vildagliptin and rosiglitazone decreased A1C (baseline = 8.7%) to a similar extent during the 24-week treatment, with most of the A1C reduction achieved by weeks 12 and 16, respectively. At end point, vildagliptin was as effective as rosiglitazone, improving A1C by -1.1 ± 0.1% (P < 0.001) and -1.3 ± 0.1% (P < 0.001), respectively, meeting the statistical criterion for noninferiority (upper-limit 95% CI for between-treatment difference <=0.4%). Fasting plasma glucose decreased more with rosiglitazone (-2.3 mmol/l) than with vildagliptin (-1.3 mmol/l). Body weight did not change in vildagliptin-treated patients (-0.3 ± 0.2 kg) but increased in rosiglitazone-treated patients (+1.6 ± 0.3 kg, P < 0.001 vs. vildagliptin). Relative to rosiglitazone, vildagliptin significantly decreased triglycerides, total cholesterol, and LDL, non-HDL, and total-to-HDL cholesterol (-9 to -16%, all P <= 0.01) but produced a smaller increase in HDL cholesterol (+4 vs. +9%, P = 0.003). The proportion of patients experiencing an adverse event was 61.4 vs. 64.0% in patients receiving vildagliptin and rosiglitazone, respectively. Only one mild hypoglycemic episode was experienced by one patient in each treatment group, while the incidence of edema was greater with rosiglitazone (4.1%) than vildagliptin (2.1%). CONCLUSIONS:--Vildagliptin is an effective and well-tolerated treatment option in patients with type 2 diabetes, demonstrating similar glycemic reductions as rosiglitazone but without weight gain.
The study evaluated the efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor, vildagliptin, and metformin in drug-naïve elderly patients with type 2 diabetes. The primary objective was ...to demonstrate non-inferiority of vildagliptin vs. metformin in glycated haemoglobin (HbA₁c) reduction. This was a double-blind, randomized, multicentre, active-controlled, parallel-group study of 24-week treatment with vildagliptin (100 mg daily, n = 169) or metformin (titrated to 1500 mg daily, n = 166) in drug-naïve patients with type 2 diabetes aged greater-than-or-equal65 years (baseline HbA₁c 7-9%). Participants had a mean age of 71 years, known duration of diabetes of 3 years and mean baseline HbA₁c of 7.7%. At end-point, vildagliptin was as effective as metformin, improving HbA₁c by -0.64 ± 0.07% and -0.75 ± 0.07%, respectively, meeting the predefined statistical criterion for non-inferiority (upper limit of 95% confidence interval for between-treatment difference less-than or equal to0.3%). Body weight changes were -0.45 ± 0.20 kg in vildagliptin-treated patients (p = 0.02) and -1.25 ± 0.19 kg in metformin-treated patients (p < 0.001; p = 0.004 vs. vildagliptin). The proportion of patients experiencing an adverse event (AE) was 44.3 vs. 50.3% in patients receiving vildagliptin and metformin respectively. Gastrointestinal (GI) AEs were significantly more frequent with metformin (24.8%) than with vildagliptin (15.0%, p = 0.028), mainly driven by a 4.4-fold higher incidence of diarrhoea. A low incidence of hypoglycaemia was observed in both treatment groups (0% with vildagliptin and 1.2% with metformin). Vildagliptin is an effective and well-tolerated treatment option in elderly patients with type 2 diabetes, demonstrating similar improvement in glycaemic control as metformin, with superior GI tolerability.
Abstract This 24-week, double-blind, randomized, multicenter, placebo-controlled, parallel-group study performed in 354 drug-naïve patients with type 2 diabetes (T2DM) assessed efficacy and ...tolerability of vildagliptin (50 mg qd, 50 mg bid, or 100 mg qd). The primary assessment was change from baseline to endpoint in hemoglobin A1c (A1C), comparing vildagliptin to placebo by ANCOVA. Baseline A1C averaged 8.4% and the between-treatment difference (vildagliptin-placebo) in adjusted mean change (AMΔ) in A1C was −0.5 ± 0.2% ( P = 0.011), −0.7 ± 0.2% ( P < 0.001), and −0.9 ± 0.2% ( P < 0.001) in patients receiving vildagliptin 50 mg qd, 50 mg bid, or 100 mg qd, respectively. Baseline FPG averaged 10.5 mmol/L; the between-treatment difference in AMΔ FPG was −0.6 ± 0.4 mmol/L in patients receiving vildagliptin 50 mg qd and −1.3 ± 0.4 mmol/L ( P = 0.001) in both groups receiving 100 mg daily. Relative to baseline, body weight did not change significantly in any of the three vildagliptin groups and decreased by 1.4 ± 0.4 kg in the placebo group. Adverse events (AEs) occurred with similar frequency in each group: 55.8%, 59.3%, 59.3%, and 57.6% of patients receiving vildagliptin 50 mg qd, 50 mg bid, 100 mg qd, or placebo, respectively, experienced an AE. No confirmed hypoglycemia was reported. Conclusion : Vildagliptin is effective and well-tolerated in drug-naïve patients with T2DM and 100 mg vildagliptin provides similar clinical benefit whether given as single or in divided doses.
Several observational studies were conducted with vildagliptin in patients with type 2 diabetes mellitus (T2DM) fasting during Ramadan, showing significantly lower incidences of hypoglycemia with ...vildagliptin versus sulfonylureas, including gliclazide. It was of interest to complement the existing real-life evidence with data from a randomized, double-blind, clinical trial.
NCT01758380.
This multiregional, double-blind study randomized 557 patients with T2DM (mean glycated hemoglobin HbA1c, 6.9%), previously treated with metformin and any sulfonylurea to receive either vildagliptin (50 mg twice daily) or gliclazide plus metformin. The study included four office visits (three pre-Ramadan) and multiple telephone contacts, as well as Ramadan-focused advice. Hypoglycemic events were assessed during Ramadan; HbA(1c) and weight were analyzed before and after Ramadan.
The proportion of patients reporting confirmed (<3.9 mmol/L and/or severe) hypoglycemic events during Ramadan was 3.0% with vildagliptin and 7.0% with gliclazide (P=0.039; one-sided test), and this was 6.0% and 8.7%, respectively, for any hypoglycemic events (P=0.173). The adjusted mean change pre- to post-Ramadan in HbA(1c) was 0.05%±0.04% with vildagliptin and -0.03%±0.04% with gliclazide, from baselines of 6.84% and 6.79%, respectively (P=0.165). In both groups, the adjusted mean decrease in weight was -1.1±0.2 kg (P=0.987). Overall safety was similar between the treatments.
In line with the results from previous observational studies, vildagliptin was shown in this interventional study to be an effective, safe, and well-tolerated treatment in patients with T2DM fasting during Ramadan, with a consistently low incidence of hypoglycemia across studies, accompanied by good glycemic and weight control. In contrast, gliclazide showed a lower incidence of hypoglycemia in the present interventional than the previous observational studies. This is suggested to be linked to the specific circumstances of this study, including frequent patient-physician contacts, Ramadan-focused advice, a recent switch in treatment, and very well-controlled patients, which is different from what is often seen in real life.
The mannose receptor (MR), the prototype of a new family of multilectin receptor proteins important in innate immunity, undergoes rapid internalization and recycling from the endosomal system back to ...the cell surface. Sorting of the MR in endosomes prevents the receptor from entering lysosomes where it would be degraded. Here, we focused on a diaromatic sequence (Tyr18-Phe19) in the MR cytoplasmic tail as an endosomal sorting signal. The subcellular distribution of chimeric constructs between the MR and the cation-dependent mannose 6-phosphate receptor was assessed by Percoll density gradients and cell surface assays. Unlike the wild type constructs, mutant receptors with alanine substitutions of Tyr18-Phe19 were highly missorted to lysosomes, indicating that the di-aromatic motif of the MR cytoplasmic tail mediates sorting in endosomes. Within this sequence Tyr18is the key residue with Phe19 contributing to this function. Moreover, Tyr18 was also found to be essential for internalization, consistent with the presence of overlapping signals for internalization and endosomal sorting in the cytosolic tail of the MR.
A di-aromatic amino acid sequence in the cytosolic tail has now been shown to function in two receptors known to be internalized from the plasma membrane, the MR and the cation-dependent mannose 6-phosphate receptor. This feature therefore appears to be a general determinant for endosomal sorting.
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