Pattern of Onset and Risk Factors for Peripheral Oedema During Vildagliptin Use: Analysis from the Vildagliptin Prescription–Event Monitoring Study in England
Clinical trials have identified peripheral oedema (PO) as an adverse event of vildagliptin (an oral anti-diabetic drug [OAD]). A post-marketing study (PMS) was conducted to advance the understanding of vildagliptin use and particular safety concerns identified within the risk-management plan. PMS objectives included comparing the hazards between vildagliptin monotherapy and combination therapy for selected a priori identified risks, including PO.
This study was a per-protocol supplementary analysis to investigate the pattern of onset and effect of vildagliptin combination therapy on PO risk.
The PMS used an observational cohort design. OAD exposure, selected risk factors and outcome data were collected from general practitioners in England regarding vildagliptin users for the 6-month period after starting treatment. Data analysis comprised univariate case/non-case analysis, time-to-onset analysis and Cox proportional hazard models to estimate hazard ratios (HR) of PO adjusting for selected patients’ baseline characteristics.
The study cohort included 4828 patients (median age 63 years; interquartile range [IQR] 54–71), 2692 of whom were male (55.8 %). The crude cumulative hazard of PO was 19.09 cases (95 % confidence interval [CI] 13.54–26.10) per 1000 person-years; 50 % of cases occurred during the first 34 days of treatment. A significantly faster time to PO onset was observed in patients prescribed concomitant sulfonylureas versus other treatment combinations (log rank test [LRT] p = 0.0365); in patients with a prior history of PO (LRT p < 0.001), arrhythmia (LRT p = 0.0003) or hypertension (LRT p = 0.0125); and in patients aged ≥60 years (LRT p = 0.0047). Similarly, the case/non-case univariate analysis indicated that patients with PO were older; had a higher prevalence of a history of either arrhythmia, hypertension or PO; and frequently used a sulfonylurea in combination. In the hazard function analysis, only sex and prior PO history had a profound effect on risk of PO after starting vildagliptin. Furthermore, effect modification was observed between sex and prior PO history; in male patients of average age (62 years), the HR was 12.84 (95 % CI 4.96–33.23); in females, it was 1.44 (95 % CI 0.32–6.40).
In this planned supplementary analysis, the findings suggest that PO occurred most frequently within 1 month after starting treatment with vildagliptin, and previous PO history and male sex in elderly patients were important predictors of this risk. The observation that concomitant use of a sulfonylurea may also increase PO risk early after starting treatment should be taken into consideration if prescribing OADs in combination with vildagliptin.
KeywordsNational Health Service Pioglitazone Peripheral Oedema Vildagliptin General Surveillance
The authors thank all the staff at the DSRU who contributed to this study. We would like to thank Mr Shayne Freemantle for his assistance with data management and IT support. We thank the GPs who participated in this study and without whose general support PEM and M-PEM studies would not be possible. We also thank the NHSBSA for their important participation.
Compliance with Ethical Standards
The DSRU is an independent charity (No. 327206) that works in association with the University of Portsmouth. It receives unconditional donations from pharmaceutical companies. The companies have no control over the conduct or the publication of the studies conducted by the DSRU. The DSRU has received funding for the PEM study from the manufacturer of Galvus® (Novartis Pharmaceuticals UK Ltd., Surrey, UK).
Conflicts of interest
Saad Shakir reports receiving personal fees for providing consultancy training in pharmacovigilance to pharmaceutical companies, outside the submitted work. Deborah Layton has received money for development of an educational module on ADR reporting for the Royal Pharmaceutical Society and as a guest lecturer to undergraduate pharmacy students, outside the submitted work. Abigail Coughtrie and Naseer Qayum have no conflicts of interest directly relevant to the content of this study.
This study was conducted in accordance with national and international guidelines [39, 40]. In addition, the DSRU has approval under Section 251 of the NHS Act 2006 to use patient information without consent for the purpose of conducting these drug safety studies. Application for this approval involves thorough examination of the DSRU’s information security procedures, and approval is subject to annual review and rigorous annual information governance requirements .
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