Effects of DPP‐4 inhibitors, GLP‐1 receptor agonists, SGLT‐2 inhibitors and sulphonylureas on mortality, cardiovascular and renal outcomes in type 2 diabetes: A network meta‐analyses‐driven approach

Abstract

Aims The aim of our meta‐analyses was to compare the effects of glucose‐lowering drugs on mortality, cardiovascular and renal endpoints for a range of type 2 diabetes (T2D) subgroups defined by their specific cardiovascular risk profile. Methods Meta‐analyses comparing drugs within the classes of GLP‐1RAs and SGLT‐2 inhibitors were performed and compared to sulphonylureas and DPP‐4 inhibitors with available cardiovascular outcome trials. The comparison between the different classes of glucose‐lowering drugs included analyses of T2D populations with low risk and high risk for cardiovascular disease including populations with established cardiovascular disease and/or kidney disease. Outcomes included mortality, major cardiovascular adverse events (MACE), hospitalisation for heart failure (HHF) and a composite renal endpoint as applied in the underlying clinical trials. Results SGLT‐2 inhibitors and GLP‐1RAs showed beneficial effects on mortality and MACE compared to the classes of DPP‐4 inhibitors and sulphonylureas. SGLT‐2 inhibitors were shown to be the most effective treatment in terms of HHF and kidney disease. Metformin was used as background therapy for the vast majority of participants in all included studies. Overall, the absolute effects of SGLT‐2 inhibitors and GLP‐1RAs on these important outcomes were evident for patients with established or at high risk for cardiovascular disease but limited for the low‐risk subgroup. Conclusions The findings from our analyses substantiate the relevance of treatment with SGLT‐2 inhibitors or GLP‐1RAs as an add‐on to metformin in patients with T2D and a high risk for cardiovascular disease, and furthermore, support the recommendation for SGLT‐2 inhibitor treatment in patients with T2D and heart failure or established kidney disease.

Hypoglycemic Drugs in Patients with Diabetes Mellitus and Heart Failure: A Narrative Review

“…Of note, this beneficial effect was independent of baseline metformin treatment, and the exact mechanism by which some of these agents reduce CV outcome remains unclear [ 75 ]. GLP1-RA superiority in the reduction in 3P-MACE was also noticed in a network meta-analysis comparing GLP-1RAs to DPP-4 or SUs [ 76 , 77 , 78 ].…”

“…Of note, this beneficial effect was independent of baseline metformin treatment, and the exact mechanism by which some of these agents reduce CV outcome remains unclear [75]. GLP1-RA superiority in the reduction in 3P-MACE was also noticed in a network meta-analysis comparing GLP-1RAs to DPP-4 or SUs [76][77][78]. The LEADER (Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes) trial was the first CVOT comparing liraglutide versus placebo in patients with T2DM irrespectively of their HF status, which showed an important reduction in 3P-MACE [HR 0.87 (95% CI 0.78-0.97)].…”

Bioactive Compounds Formulated in Phytosomes Administered as Complementary Therapy for Metabolic Disorders

“…Metabolic disorders (MDs) are the main cause of life-threatening diseases such as diabetes mellitus (DM), cardiovascular diseases (CVDs) and liver pathologies, affecting people worldwide, despite the various therapies developed for their treatment [1][2][3][4][5][6]. Connections between these pathologies were established, and the underlying mechanisms interconnecting them are intricated and involve the activation of different molecular pathways [7][8][9].…”

Relative efficacy of five SGLT2 inhibitors: a network meta-analysis of 20 cardiovascular and respiratory outcomes

“…Since there have not been head-to-head cardiovascular outcome randomized controlled trials (RCTs) comparing a gliflozin with one other gliflozin, the relative efficacy of various gliflozins on cardiovascular outcomes has not been established. Several published network meta-analyses ( Kanie et al, 2021 ; Lin et al, 2021 ; Giugliano et al, 2022 ; Zhang et al, 2022 ; Brønden et al, 2023 ) assessing the cardiovascular outcomes of SGLT2 inhibitors have compared SGLT2 inhibitors with non-gliflozin drugs, such as glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and finerenone; but have not performed the comparisons among various gliflozins. Moreover, these studies ( Kanie et al, 2021 ; Lin et al, 2021 ; Giugliano et al, 2022 ; Zhang et al, 2022 ; Brønden et al, 2023 ) of network meta-analysis have focused on evaluating those composite cardiovascular outcomes, such as major adverse cardiovascular events (defined as a composite of cardiovascular death, myocardial infarction, and stroke), but have evaluated a limited number of individual cardiovascular outcomes.…”

“…Several published network meta-analyses ( Kanie et al, 2021 ; Lin et al, 2021 ; Giugliano et al, 2022 ; Zhang et al, 2022 ; Brønden et al, 2023 ) assessing the cardiovascular outcomes of SGLT2 inhibitors have compared SGLT2 inhibitors with non-gliflozin drugs, such as glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and finerenone; but have not performed the comparisons among various gliflozins. Moreover, these studies ( Kanie et al, 2021 ; Lin et al, 2021 ; Giugliano et al, 2022 ; Zhang et al, 2022 ; Brønden et al, 2023 ) of network meta-analysis have focused on evaluating those composite cardiovascular outcomes, such as major adverse cardiovascular events (defined as a composite of cardiovascular death, myocardial infarction, and stroke), but have evaluated a limited number of individual cardiovascular outcomes. Some important individual outcomes, such as complete atrioventricular block and hypertensive crisis, have not been evaluated in any of these studies ( Kanie et al, 2021 ; Lin et al, 2021 ; Giugliano et al, 2022 ; Zhang et al, 2022 ; Brønden et al, 2023 ).…”