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

Abstract

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 . ...

DPP4 inhibitors and respiratory infection, a systematic review and meta-analysis of the CardioVascular Outcomes Trials conducted before the pandemic and implications for the management of diabetes during COVID-19

“…Discrepancies were resolved by consensus. In line with our previous meta-analysis, 26 we used the Cochrane Collaboration’s tool for assessing risk of bias in RCTs. 28…”

“…The protocol of the present review has not been registered, but the hypothesis, the bibliographic search, the outcome definition and the statistical plan were defined a priori , notably using our previous meta-analysis (which was registered in PROSPERO), 26 and the previous meta-analysis of Yang et al, specifically designed for assessing the risk of infections with DPP4 inhibitors. 5…”

“…We updated a previous systematic review and meta-analysis. 25,26 The search strategy was previously published. 26 We updated the searche for CVOTs assessing a DPP4 inhibitor versus a placebo, in type 2 diabetes mellitus, in PubMed and CENTRAL, up to January 27, 2020.…”

Mesa 3: Efectos cardiovasculares de fármacos antidiabéticos

“…Los metaanálisis que evalúan drogas antidiabéticas contemporáneas en relación a mortalidad global, CV o MACE presentan datos contradictorios, sin evidencia suficiente para arribar a conclusiones [48][49][50][51][52][53][54] .…”

Sodium-glucose cotransporter-2 inhibitors: updated evidence on their efficacy and safety in patients with type-2 diabetes

“…The statistical representation is done by OR=0.82 [95% CrI: 0.69; 0.98]. 19 A network meta-analysis of 171,253 participants from 91 randomized controlled trials assessing the comparative effect of these anti-diabetic agents on heart failure outcomes reported that, SGLT-2 were significantly superior to insulin (OR: 0.75, 95% CI 0.62-0.91), dipeptidyl peptidase 4 inhibitors (OR: 0.68, 95% CI 0.59-0.78), GLP-1 RA (OR: 0.65, 95% CI 0.54-0.78), and thiazolidinediones (OR: 0.46, 95% CI 0.27-0.77) in terms of heart failure risk. Furthermore, in an exploratory analysis among subjects with underlying heart failure or at risk of heart failure, the superiority of SGLT-2 was still significant.…”