Use of Dipeptidyl Peptidase-4 Inhibitors and the Reporting of Infections: A Disproportionality Analysis in the World Health Organization VigiBase

OBJECTIVE - Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic drugs. They inactivate incretin hormones but also have many other effects throughout the body, among which are effects on the immune system. This might result in an increased infection risk. This study assessed the association between use of DPP-4 inhibitors and the reporting of infections. RESEARCH DESIGN AND METHODS - A nested case-control was conducted using VigiBase, the World Health Organization-Adverse Drug Reactions (WHO-ADR) database. The base cohort consisted of ADRs for antidiabetic drugs (Anatomical Therapeutic Chemical code A10). Cases were defined as ADRs of infection according to the Medical Dictionary for Regulatory Activities (MedDRA) classification system. All other ADRs were considered controls. Reporting odds ratios (RORs) were calculated to estimate the strength of the association between different classes of antidiabetic drugs and the reporting of infections. RESULTS - We identified 305,415 suspected ADRs involving antidiabetic drugs in 106,469 case reports, of which 8,083 involved DPP-4 inhibitors monotherapy. Overall, the reporting of infections was higher for patients using DPP-4 inhibitors compared with users of biguanides (ROR 2.3 [95% CI 1.9-2.7]). Reporting of upper respiratory tract infections (ROR 12.3 [95% CI 8.6-17.5]) was significantly associated with use of DPP-4 inhibitors. CONCLUSIONS - This study indicates an increased reporting of infections, in particular upper respiratory tract infections, for users of DPP-4 inhibitors compared with users of other antidiabetic drugs. However, the limitations of spontaneous reporting systems (e.g., underreporting, the Weber-effect, reporting bias) should be taken into account. Therefore, further research is needed to evaluate this suspicion and the underlying mechanism

Dipeptidyl Peptidase-4 Inhibition by Vildagliptin and the Effect on Insulin Secretion and Action in Response to Meal Ingestion in Type 2 Diabetes

OBJECTIVE—The purpose of this study was to determine the mechanism by which dipeptidyl peptidase-4 inhibitors lower postprandial glucose concentrations

Effects of Subcutaneous Pasireotide on Cardiac Repolarization in Healthy Volunteers: A Single-Center, Phase I, Randomized, Four-Way Crossover Study

The aim of this study was to evaluate the effects of subcutaneous pasireotide on cardiac repolarization in healthy volunteers. Healthy volunteers were randomized to one of four treatment sequences (n=112) involving four successive treatments in different order: pasireotide 600 mu g (therapeutic dose) or 1,950 mu g (maximum tolerated dose) bid by subcutaneous injection (sc), placebo injection and oral moxifloxacin. Maximum QTcI occurred 2 hours post-dose for both doses of pasireotide. Mean QTcI was 13.2milliseconds (90% CI: 11.4, 15.0) and 16.1milliseconds (90% CI: 14.3, 17.9) for the 600 and 1,950 mu g bid doses, respectively. Maximal placebo-subtracted change in QTcI from baseline for moxifloxacin was 11.1 (90% CI: 9.3, 12.9) milliseconds. Both pasireotide doses caused a reduction in heart rate: maximal heart rate change compared with placebo occurred at 1hour for pasireotide 600 mu g bid and at 0.5hours for pasireotide 1,950 mu g bid, with heart rate reductions of 10.4 and 14.9bpm, respectively. At the therapeutic dose of 600 mu g, pasireotide has a modest QT-prolonging effect. The relatively small increase of approximate to 3milliseconds in QTcI in the presence of a 3.25-fold increase in dose suggests a relatively flat dose-effect relationship of pasireotide on QTcI in healthy volunteers. No safety concerns for pasireotide were identified during the stud

Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushing's disease: results from an open-ended, open-label extension trial

Report the efficacy and safety of pasireotide sc in patients with Cushing's disease during an open-ended, open-label extension to a randomized, double-blind, 12-month, Phase III study. 162 patients entered the core study. 58 patients who had mean UFC ≤ ULN at month 12 or were benefiting clinically from pasireotide entered the extension. Patients received the same dose of pasireotide as at the end of the core study (300-1,200 μg bid). Dose titration was permitted according to efficacy or drug-related adverse events. 40 patients completed 24 months' treatment. Of the patients who entered the extension, 50.0% (29/58) and 34.5% (20/58) had controlled UFC (UFC ≤ ULN) at months 12 and 24, respectively. The mean percentage decrease in UFC was 57.3% (95% CI 40.7-73.9; n = 52) and 62.1% (50.8-73.5; n = 33) after 12 and 24 months' treatment, respectively. Improvements in clinical signs of Cushing's disease were sustained up to month 24. The most frequent drug-related adverse events in patients who received ≥1 dose of pasireotide (n = 162) from core baseline until the 24-month cut-off were diarrhea (55.6%), nausea (48.1%), hyperglycemia (38.9%), and cholelithiasis (31.5%). No new safety issues were identified during the extension. Reductions in mean UFC and improvements in clinical signs of Cushing's disease were maintained over 24 months of pasireotide treatment. The safety profile of pasireotide is typical for a somatostatin analogue, except for the frequency and degree of hyperglycemia; patients should be monitored for changes in glucose homeostasis. Pasireotide represents the first approved pituitary-targeted treatment for patients with Cushing's disease