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.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
National Institute for health and Care Excellence. Type 2 diabetes in adults: management. https://www.nice.org.uk/guidance/ng28. NICE 2015 December 2. [cited 2016 Jul 15]. http://nice.org.uk/guidance/ng28. Accessed 15 July 2016.
McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol. 2014;2(10):843–51.
Novartis Pharmaceuticals UK Ltd. Galvus® 50 mg tablets: summary of Product Characteristics. eMC 2007 September 26 [cited 2016 Jul 15]. https://www.medicines.org.uk/emc/medicine/20734. Accessed 15 July 2016.
Pi-Sunyer FX, Schweizer A, Mills D, Dejager S. Efficacy and tolerability of vildagliptin monotherapy in drug-naïve patients with type 2 diabetes. Diabetes Res Clin Pract. 2007;76(1):132–8.
Matthews DR, Dejager S, Ahren B, Fonseca V, Ferrannini E, Couturier A, et al. Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study. Diabetes Obes Metab. 2010;12(9):780–9.
Garber AJ, Foley JE, Banerji MA, Ebeling P, Gudbjornsdottir S, Camisasca RP, et al. Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes Obes Metab. 2008;10(11):1047–56.
Garber AJ, Schweizer A, Baron M, Rochotte E, Dejager S. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes Obes Metab. 2007;9(2):166–74.
Fonseca V, Baron M, Shao Q, Dejager S. Sustained efficacy and reduced hypoglycemia during one year of treatment with vildagliptin added to insulin in patients with type 2 diabetes mellitus. Horm Metab Res. 2008;40(6):427–30.
Garber AJ, Schweizer A, Baron MA, Rochotte E, Dejager S. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes Obes Metab. 2007;9(2):166–74.
Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Care. 2007;30(2):217–23.
European Medicines Agency. Galvus: European public assessment report (EPAR)—Scientific Discussion. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000771/WC500020330.pdf. EMEA. 2007. Accessed 4 Aug 2015.
European Medicines Agency. EMEA European Public Assessment Report (EPAR) Galvus (vildaglptin) Doc Ref: EMA/760416/2012 EMEA/H/C/000771. The European Medicines Agency (EMEA) 2016 February 2 [cited 2016 Jul 15]. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000771/WC500020328.pdf. Accessed 15 July 2016.
Layton D, Shakir SAW. Prescription-event Monitoring. In: Strom BL, Kimmel SE, Hennessy S, editors. Pharmacoepidemiology. 5th ed. Chichester: Wiley; 2011. p. 301–30.
Layton D, Shakir SAW. Prescription-event monitoring (PEM): the evolution to the new modified PEM and its support of risk management. In: Mann RD, Andrews EB, editors. Pharmacovigilance. 3rd ed. Chichester: Wiley Blackwell; 2014. p. 359–84.
Shakir SA. Prescription-event monitoring. In: Strom BL, editor. Pharmacoepidemiology. 4th ed. Chichester: Wiley; 2005. p. 203–16.
National Library of Medicine. Medical Subject Headings (MeSH) Descriptor Data: Edema, cardiac. www nlm nih gov 2016 [cited 2016 Jul 13]. https://www.nlm.nih.gov/cgi/mesh/2016/MB_cgi?mode=&term=Edema,+Cardiac&field=entry. Accessed 13 July 2016.
Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika. 1994;81(3):515–26.
Therneau TM, Grambsch PM. Modeling survival data: extending the cox model. New York: Springer; 2000. p. 127–30.
Schoenfeld D. Residuals for the proportional hazards regression model. Biometrika. 1982;69(1):239–41.
Therneau TM, Grambsch PM, Fleming TR. Martingale-based residuals for survival models. Biometrika. 1990;77(1):147–60.
Rosenstock J, Baron M, Dejager S, Mills D, Schweizer A. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Care. 2007;30(2):217–23.
Bolli G, Dotta F, Rochotte E, Cohen SE. Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind study. Diabetes Obes Metab. 2007;10(1):82–90.
Schweizer A, Dejager S, Foley JE, Kothny W. Assessing the general safety and tolerability of vildagliptin: value of pooled analyses from a large safety database versus evaluation of individual studies. Vasc Health Risk Manag. 2011;7:49–57.
Chang TJ, Liu PH, Liang YC, Chang YC, Jiang YD, Li HY, et al. Genetic predisposition and nongenetic risk factors of thiazolidinedione-related edema in patients with type 2 diabetes. Pharmacogenet Genom. 2011;21(12):829–36.
Scheen AJ. Cardiovascular effects of dipeptidyl peptidase-4 inhibitors: from risk factors to clinical outcomes. Postgrad Med. 2013;125(3):7–20.
van Poppel PC, Netea MG, Smits P, Tack CJ. Vildagliptin improves endothelium-dependent vasodilatation in type 2 diabetes. Diabetes Care. 2011;34(9):2072–7.
Cho S, Atwood JE. Peripheral edema. Am J Med. 2002;113(7):580–6.
Stromberg A, Martensson J. Gender differences in patients with heart failure. Eur J Cardiovasc Nurs. 2003;2(1):7–18.
Suissa S. Immortal time bias in observational studies of drug effects. Pharmacoepidemiol Drug Saf. 2007;16(3):241–9.
Vasileiou AM, Bull R, Kitou D, Alexiadou K, Garvie NJ, Coppack SW. Oedema in obesity; role of structural lymphatic abnormalities. Int J Obes (Lond). 2011;35(9):1247–50.
Blankfield RP. Blood pressure, fluid retention and the cardiovascular risk of drugs. Future Cardiol. 2012;8(4):489–93.
Heeley E, Riley J, Layton D, Wilton LV, Shakir SA. Prescription-event monitoring and reporting of adverse drug reactions. Lancet. 2001;358(9296):1872–3.
McAvoy BR, Kaner EF. General practice postal surveys: a questionnaire too far? BMJ. 1996;313(7059):732–3.
European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus.Ref CPMP/EWP/1080/00 Rev.1. 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf. Accessed 13 Mar 2016.
Schweizer A, Dejager S, Foley JE, Couturier A, Ligueros-Saylan M, Kothny W. Assessing the cardio-cerebrovascular safety of vildagliptin: meta-analysis of adjudicated events from a large Phase III type 2 diabetes population. Diabetes Obes Metab. 2010;12(6):485–94.
Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2014;24(7):689–97.
McInnes G, Evans M, Del PS, Stumvoll M, Schweizer A, Lukashevich V, et al. Cardiovascular and heart failure safety profile of vildagliptin: a meta-analysis of 17 000 patients. Diabetes Obes Metab. 2015;17(11):1085–92.
European Medicines Agency. Reflection paper on assessment of cardiovascular risk of medicinal products for the treatment of cardiovascular and metabolic diseases (Draft).Ref EMA/CHMP/50549/2015. 2015. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/06/WC500187801.pdf. Accessed 13 Mar 2016.
CIOMS/WHO. International Guidelines for Biomedical Research Involving Human Subjects.Geneva. CIOMS. 2002. http://www.cioms.ch/publications/layout_guide2002.pdf. Accessed 26 Feb 2008.
Royal College of Physicians of London. Guidelines on the practice of Ethical Committees in Medical Research with Human Subjects. London: Royal Colledge of Physicians of London; 2007. https://cdn.shopify.com/s/files/1/0924/4392/files/guidelines-practice-ethics-committees-medical-research.pdf?11143599859970562352.
Health Research Authority. Advisory Group advice and approval decisions. Prescription-event monitoring, CAG ref: ECC 5-07(b)/2009. Health Research Authority 2016 [cited 2015 Jan 31]. http://www.hra.nhs.uk/about-the-hra/our-committees/section-251/cag-advice-and-approval-decisions/.
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.
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 .
Rights and permissions
About this article
Cite this article
Layton, D., Coughtrie, A.L., Qayum, N. et al. Pattern of Onset and Risk Factors for Peripheral Oedema During Vildagliptin Use: Analysis from the Vildagliptin Prescription–Event Monitoring Study in England. Drug Saf 39, 1093–1104 (2016). https://doi.org/10.1007/s40264-016-0451-8
- National Health Service
- Peripheral Oedema
- General Surveillance