Mickael Arnaud

Addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas and risk of hypoglycaemia: systematic review and meta-analysis

Objective To quantify the risk of hypoglycaemia associated with the concomitant use of dipeptidyl peptidase-4 (DPP-4) inhibitors and sulphonylureas compared with placebo and sulphonylureas. Design Systematic review and meta-analysis. Data sources Medline, ISI Web of Science, SCOPUS, Cochrane Central Register of Controlled Trials, and clinicaltrial.gov were searched without any language restriction. Study selection Placebo controlled randomised trials comprising at least 50 participants with type 2 diabetes treated with DPP-4 inhibitors and sulphonylureas. Review methods Risk of bias in each trial was assessed using the Cochrane Collaboration tool. The risk ratio of hypoglycaemia with 95% confidence intervals was computed for each study and then pooled using fixed effect models (Mantel Haenszel method) or random effect models, when appropriate. Subgroup analyses were also performed (eg, dose of DPP-4 inhibitors). The number needed to harm (NNH) was estimated according to treatment duration. Results 10 studies were included, representing a total of 6546 participants (4020 received DPP-4 inhibitors plus sulphonylureas, 2526 placebo plus sulphonylureas). The risk ratio of hypoglycaemia was 1.52 (95% confidence interval 1.29 to 1.80). The NNH was 17 (95% confidence interval 11 to 30) for a treatment duration of six months or less, 15 (9 to 26) for 6.1 to 12 months, and 8 (5 to 15) for more than one year. In subgroup analysis, no difference was found between full and low doses of DPP-4 inhibitors: the risk ratio related to full dose DPP-4 inhibitors was 1.66 (1.34 to 2.06), whereas the increased risk ratio related to low dose DPP-4 inhibitors did not reach statistical significance (1.33, 0.92 to 1.94). Conclusions Addition of DPP-4 inhibitors to sulphonylurea to treat people with type 2 diabetes is associated with a 50% increased risk of hypoglycaemia and to one excess case of hypoglycaemia for every 17 patients in the first six months of treatment. This highlights the need to respect recommendations for a decrease in sulphonylureas dose when initiating DPP-4 inhibitors and to assess the effectiveness of this risk minimisation strategy.

Risk of motor vehicle accidents related to sleepiness at the wheel: a systematic review and meta-analysis

Study objectives Sleepiness at the wheel is widely believed to be a cause of motor vehicle accidents. Nevertheless, a systematic review of studies investigating this relationship has not yet been published. The objective of this study was to quantify the relationship between sleepiness at the wheel and motor vehicle accidents. Methods A systematic review was performed using Medline, Scopus, and ISI Web of Science. The outcome measure of interest was motor vehicle accident defined as involving four- or two-wheeled vehicles in road traffic, professional and nonprofessional drivers, with or without objective consequences. The exposure was sleepiness at the wheel defined as self-reported sleepiness at the wheel. Studies were included if they provided adjusted risk estimates of motor vehicle accidents related to sleepiness at the wheel. Risk estimates and 95% confidence intervals (95% CIs) were extracted and pooled as odds ratios (ORs) using a random-effect model. Heterogeneity was quantified using Q statistics and the I2 index. The potential causes of heterogeneity were investigated using meta-regressions. Results Ten cross-sectional studies (51,520 participants), six case-control studies (4904 participants), and one cohort study (13,674 participants) were included. Sleepiness at the wheel was associated with an increased risk of motor vehicle accidents (pooled OR 2.51 [95% CI 1.87; 3.39]). A significant heterogeneity was found between the individual risk estimates (Q = 93.21; I2 = 83%). Conclusions Sleepiness at the wheel increases the risk of motor vehicle accidents and should be considered when investigating fitness to drive. Further studies are required to explore the nature of this relationship. Systematic review registration number PROSPERO 2015 CRD42015024805.

Methods for safety signal detection in healthcare databases: a literature review

ABSTRACT Introduction: With increasing availability, the use of healthcare databases as complementary data source for drug safety signal detection has been explored to circumvent the limitations inherent in spontaneous reporting. Areas covered: To review the methods proposed for safety signal detection in healthcare databases and their performance. Expert opinion: Fifteen different data mining methods were identified. They are based on disproportionality analysis, traditional pharmacoepidemiological designs (e.g. self-controlled designs), sequence symmetry analysis (SSA), sequential statistical testing, temporal association rules, supervised machine learning (SML), and the tree-based scan statistic. When considering the performance of these methods, the self-controlled designs, the SSA, and the SML seemed the most interesting approaches. In the perspective of routine signal detection from healthcare databases, pragmatic aspects such as the need for stakeholders to understand the method in order to be confident in the results must be considered. From this point of view, the SSA could appear as the most suitable method for signal detection in healthcare databases owing to its simple principle and its ability to provide a risk estimate. However, further developments, such as automated prioritization, are needed to help stakeholders handle the multiplicity of signals.

Risk of Myopathy Associated With DPP-4 Inhibitors in Combination With Statins: A Disproportionality Analysis Using Data From the WHO and French Spontaneous Reporting Databases.

Recently, a pharmacovigilance safety warning was released by the European Medicines Agency concerning the risk of myopathy and rhabdomyolysis associated with the use of dipeptidyl peptidase 4 (DPP-4) inhibitors (1,2). The warning was based on several cases in which DPP-4 inhibitors were used in association with statins; a drug-drug interaction was suggested (3). As statin use is likely to be common in patients with diabetes, it is important to investigate this potential serious risk and the underlying drug-drug interaction hypothesis. This need is enforced by the recent marketing in several countries of fixed combinations containing both statins and DPP-4 inhibitors (4). The aim of the study, therefore, was to assess the association between myopathy and the use of DPP-4 inhibitors, alone and in combination with statins, by analyzing data from two pharmacovigilance spontaneous reporting databases. Data from the French Base Nationale de Pharmacovigilance (BNPV) and the World Health Organization (WHO) global individual case safety reports database, VigiBase, were analyzed for the 2009–2015 time period. Cases consisted of all reported adverse drug reactions (ADRs) of muscular injury, which were identified in both databases by using the dedicated Standardized MedDRA Queries (“myopathy/rhabdomyolysis”). All reports of other ADRs were considered noncases. The exposures of interest were the use of DPP-4 inhibitors along with statins at the time the ADR occurred, as we were investigating a potential drug-drug interaction between DPP-4 inhibitors and statins. We conducted complementary analyses considering exposures to all noninsulin antidiabetes agents other than DPP-4 inhibitors and to fibrates. As other noninsulin antidiabetes agents share indications with DPP-4 inhibitors, the …

Risk of Serious Trauma with Glucose-Lowering Drugs in Older Persons: A Nested Case-Control Study: Risk of trauma with glucose-lowering drugs

To assess the risk of hospitalization for trauma associated with use of hypoglycemic glucose‐lowering drugs (GLDs) in individuals aged 65 and older.

Authors’ reply to Tufan and colleagues and Boucaud-Maitre

In response to Tufan and colleagues, it is true that older frail patients are under-represented in our meta-analysis, but such patients are under-represented in clinical trials in general, not just those investigating type 2 diabetes.1 2 Even when there is no formal age limit, the common exclusion of patients with organ dysfunction and comorbidities means that most older people are excluded.3 We can but hope that further trials will provide more information on benefits and risks of drugs in older people and will update …