Date Published: June 25, 2019
Publisher: Public Library of Science
Author(s): Guillaume Grenet, Shams Ribault, Giao Bao Nguyen, Faustine Glais, Augustin Metge, Thomas Linet, Behrouz Kassai-Koupai, Catherine Cornu, Théodora Bejan-Angoulvant, Sylvie Erpeldinger, Rémy Boussageon, Aurore Gouraud, Fabrice Bonnet, Michel Cucherat, Philippe Moulin, François Gueyffier, Jennifer A. Hirst.
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.
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.
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.
Type 2 diabetes (T2D) is a public health issue, with a dramatically increasing incidence in the world. Cardiovascular diseases (CVD) are the main cause of mortality in T2D patients. Many hypoglycemic drugs are currently available; their benefits have been evaluated with conflicting results. Network meta-analysis allows several treatments to be compared through direct and indirect comparisons. Previous network meta analyses on hypoglycemic drugs were focused on intermediate outcomes, such as glycated hemoglobin (HbA1c), or did not compare the effect of the drugs on mortality or major adverse cardiovascular events (MACE) in the absence of data . Since then, new clinical trials assessing SGLT-2 inhibitors or GLP-1 receptor agonists showed promising results on mortality or on cardiovascular outcomes (EMPAREG-OUTCOME , CANVAS-Program , LEADER , SUSTAIN-6 ), allowing Zheng et al to show a lower mortality rate with SGLT-2 inhibitors or GLP-1 receptor agonists compared to control or DPP-4 inhibitors, mainly in secondary cardiovascular prevention . The last international consensus recommends SGLT-2 inhibitors or GLP-1 receptor agonists for patients with clinical cardiovascular disease; metformin remains the first-line therapy for glucose lowering medication . However, the last cardiovascular outcome trial assessing a GLP-1 receptor agonists did not showed a decreased risk of overall mortality . Following the recently published DECLARE TIMI 58 trial , a meta-analysis suggested a potential benefit of SGLT-2 inhibitors in primary cardiovascular prevention, but did not include GLP-1 receptor agonists or metformin . Most of hypoglycemic drugs have not been directly compared in head to head clinical trials. Up to now, no comparison of all the new and the old hypoglycemic drugs is available on major cardiovascular outcomes. The purpose of this study was to compare all the currently available hypoglycemic drug classes on major adverse cardiovascular events (MACE) and on mortality in patients with T2D, through a network meta-analysis approach of randomized clinical trials.
Methods have been previously described . This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and its extension for reviews incorporating network meta-analyses (S1 Fig) .
Hypoglycemic drugs are used to control glycaemia and reduce diabetic complications in tens of millions of people worldwide. This study helps to summarize factual knowledge of those therapeutic classes on major clinical outcomes. SGLT-2 inhibitors and GLP-1 receptor agonists appear to have the most beneficial effects on MACE, especially in type 2 diabetic patients with previous cardiovascular diseases.