GLUcose COntrol Safety & Efficacy in type 2 DIabetes, a systematic review and NETwork meta-analysis.

BACKGROUND: The last international consensus on the management of type 2 diabetes (T2D) recommends SGLT-2 inhibitors or GLP-1 agonists for patients with clinical cardiovascular (CV) disease; metformin remains the first-line glucose lowering medication. Last studies suggested beneficial effects of SGLT-2 inhibitors or GLP-1 agonists compared to DPP-4 inhibitors, in secondary CV prevention. Recently, a potential benefit of SGLT-2 inhibitors in primary CV prevention also has been suggested. However, no comparison of all the new and the old hypoglycemic drugs is available on CV outcomes. We aimed to compare the effects of old and new hypoglycemic drugs in T2D, on major adverse cardiovascular events (MACE) and mortality. METHODS AND FINDINGS: We conducted a systematic review and network meta-analysis of clinical trials. Randomized trials, blinded or not, assessing contemporary hypoglycemic drugs on mortality or MACE in patients with T2D, were searched for in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. References screening and data extraction were done by multiple observers. Each drug was analyzed according to its therapeutic class. A random Bayesian network meta-analysis model was used. The primary outcomes were overall mortality, cardiovascular mortality, and MACE. Severe adverse events and severe hypoglycemia were also recorded. 175,966 patients in 34 trials from 1970 to 2018 were included. No trials evaluating glinides or alpha glucosidase inhibitors were found. 17 trials included a majority of patients with previous cardiovascular history, 16 trials a majority of patients without. Compared to control, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.84 [95% CrI: 0.74; 0.95]), SGLT-2 inhibitors and GLP-1 agonists with a decreased risk of MACE (OR = 0.89 [95% CrI: 0.81; 0.98] and OR = 0.88 [95% CrI: 0.81; 0.95], respectively). Compared to DPP-4 inhibitors, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.82 [95% CrI: 0.69; 0.98]), GLP-1 agonists with a decreased risk of MACE (OR = 0.88 [95% CrI: 0.79; 0.99]). Insulin was also associated with an increased risk of MACE compared to GLP-1 agonists (OR = 1.19 [95% CrI: 1.01; 1.42]). Insulin and sulfonylureas were associated with an increased risk of severe hypoglycemia. In the trials including a majority of patients without previous CV history, the comparisons of SGLT-2 inhibitors, metformin and control did not showed significant differences on primary outcomes. We limited our analysis at the therapeutic class level. CONCLUSIONS: SGLT-2 inhibitors and GLP-1 agonists have the most beneficial effects, especially in T2D patients with previous CV diseases. Direct comparisons of SGLT-2 inhibitors, GLP-1 agonists and metformin are needed, notably in primary CV prevention. TRIAL REGISTRATION: PROSPERO CRD42016043823.

Use of available clinical evidence to extrapolate drug effects from adults to children.

The extrapolation of the benefit risk ratio from adults to children is performed during drug development and often implicitly used by many paediatricians when prescribing off-label drugs in children. This is due to the specific constraints of paediatric clinical research leading to a lack of safety and efficacy data in children. Extrapolation frameworks for drug development have been proposed by several regulatory agencies. Using a meta-epidemiological approach, we explored the similarities and differences of the benefit, the benefit risk ratio and the perceived placebo effect between adults and children from meta-analyses including randomized double-blinded placebo-controlled trials evaluating a drug intervention in an indication in adults and children with separate data for both populations. We also explored the use of the effect model using adult data to predict the treatment effect in children and to calibrate future paediatric clinical trials. Our research highlights the importance of using all available evidence and quantitative methods before extrapolating the benefit risk ratio from adults to children and carrying out new studies in the context of the existing evidence. More generally, this should be applied to any research to avoid a waste of time and resources invested.

Reducing waste in pediatric clinical research.

The importance of reducing waste and increasing value when conducting research has been emphasized by a series of articles published in the Lancet in 2014. A survey indicates that, one year later, these articles have not influenced how research is conducted. In this review, we explore four stages described by Moher et al. in research production that lead to waste. We show that all four stages including, questions relevant to users, appropriate design conduct and analysis, accessible full research, unbiased and usable reports, efficient research regulation and management of biomedical research are also producing an important waste in pediatric research. We conclude that methods to improve research quality and limit waste need to be implemented in pediatric research and recognized by authorities as a priority.