Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis (Protocol)

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To systematically review the available evidence on the effects (benefits and harms) of DPP‐4 inhibitors, GLP‐1 receptor agonists, and SGLT‐2 inhibitors in people with established CVD, using network meta‐analysis

The relationship between coronary stent strut thickness and the incidences of clinical outcomes after drug-eluting stent implantation: A systematic review and meta-regression analysis

Background: Drug-eluting stents (DESs) have been developed with thinner stent struts, and more biocompatible polymers and anti-proliferative drugs to improve the clinical performance. However, it remains unclear whether thinner struts are associated with favorable short- and long-term clinical outcomes such as target lesion revascularization (TLR), periprocedural myocardial infarction (PMI), and stent thrombosis (ST). Methods: We searched MEDLINE, Embase and other online sources for randomized controlled trials (RCTs) comparing clinical outcomes between a DES and other stent(s), with independent clinical event adjudication. We investigated stent-related events (TLR, PMI, and ST) in 5 years. Each outcome was analyzed with random-effects meta-regression model against strut thickness, then adjusted for DES generation and patient and lesion characteristics. Results: We identified 49 RCTs enrolling 97,465 patients, of which strut thickness ranged from 60 to 140 μm. Incidences of 1-year TLR, PMI, and early ST were reduced with thinner stent struts, when adjusted for stent generation (adjusted relative risk [RR] per 10 μm increase 1.12 [95% CI 1.04–1.21], 1.15 [95% CI 1.05–1.26], and 1.15 [95% CI 1.06–1.25], respectively). Strut thickness was not independently associated with incidences of 5-year TLR, late and very late ST. In addition, early DESs contributed to a higher incidence of very late ST (adjusted RR 2.97 [95% CI 1.36–6.50]). Conclusions: In this meta-regression analysis, a thinner strut thickness was associated with reduced incidences of early stent-related adverse events (1-year TLR, PMI, and early ST), but not with later events (5-year TLR, late ST, and very late ST)

A ubiquitin ligase complex assembles linear polyubiquitin chains

The ubiquitin system plays important roles in the regulation of numerous cellular processes by conjugating ubiquitin to target proteins. In most cases, conjugation of polyubiquitin to target proteins regulates their function. In the polyubiquitin chains reported to date, ubiquitin monomers are linked via isopeptide bonds between an internal Lys and a C-terminal Gly. Here, we report that a protein complex consisting of two RING finger proteins, HOIL-1L and HOIP, exhibits ubiquitin polymerization activity by recognizing ubiquitin moieties of proteins. The polyubiquitin chain generated by the complex is not formed by Lys linkages, but by linkages between the C- and N-termini of ubiquitin, indicating that the ligase complex possesses a unique feature to assemble a novel head-to-tail linear polyubiquitin chain. Moreover, the complex regulates the stability of Ub-GFP (a GFP fusion protein with an N-terminal ubiquitin). The linear polyubiquitin chain generated post-translationally may function as a new modulator of proteins

Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis (Review)

Background: Cardiovascular disease (CVD) is a leading cause of death globally. Recently, dipeptidyl peptidase‐4 inhibitors (DPP4i), glucagon‐like peptide‐1 receptor agonists (GLP‐1RA) and sodium‐glucose co‐transporter‐2 inhibitors (SGLT2i) were approved for treating people with type 2 diabetes mellitus. Although metformin remains the first‐line pharmacotherapy for people with type 2 diabetes mellitus, a body of evidence has recently emerged indicating that DPP4i, GLP‐1RA and SGLT2i may exert positive effects on patients with known CVD. Objectives: To systematically review the available evidence on the benefits and harms of DPP4i, GLP‐1RA, and SGLT2i in people with established CVD, using network meta‐analysis. Search methods: We searched CENTRAL, MEDLINE, Embase, and the Conference Proceedings Citation Index on 16 July 2020. We also searched clinical trials registers on 22 August 2020. We did not restrict by language or publication status. Selection criteria: We searched for randomised controlled trials (RCTs) investigating DPP4i, GLP‐1RA, or SGLT2i that included participants with established CVD. Outcome measures of interest were CVD mortality, fatal and non‐fatal myocardial infarction, fatal and non‐fatal stroke, all‐cause mortality, hospitalisation for heart failure (HF), and safety outcomes. Data collection and analysis: Three review authors independently screened the results of searches to identify eligible studies and extracted study data. We used the GRADE approach to assess the certainty of the evidence. We conducted standard pairwise meta‐analyses and network meta‐analyses by pooling studies that we assessed to be of substantial homogeneity; subgroup and sensitivity analyses were also pursued to explore how study characteristics and potential effect modifiers could affect the robustness of our review findings. We analysed study data using the odds ratios (ORs) and log odds ratios (LORs) with their respective 95% confidence intervals (CIs) and credible intervals (Crls), where appropriate. We also performed narrative synthesis for included studies that were of substantial heterogeneity and that did not report quantitative data in a usable format, in order to discuss their individual findings and relevance to our review scope. Main results: We included 31 studies (287 records), of which we pooled data from 20 studies (129,465 participants) for our meta‐analysis. The majority of the included studies were at low risk of bias, using Cochrane's tool for assessing risk of bias. Among the 20 pooled studies, six investigated DPP4i, seven studied GLP‐1RA, and the remaining seven trials evaluated SGLT2i. All outcome data described below were reported at the longest follow‐up duration. 1. DPP4i versus placebo: Our review suggests that DPP4i do not reduce any risk of efficacy outcomes: CVD mortality (OR 1.00, 95% CI 0.91 to 1.09; high‐certainty evidence), myocardial infarction (OR 0.97, 95% CI 0.88 to 1.08; high‐certainty evidence), stroke (OR 1.00, 95% CI 0.87 to 1.14; high‐certainty evidence), and all‐cause mortality (OR 1.03, 95% CI 0.96 to 1.11; high‐certainty evidence). DPP4i probably do not reduce hospitalisation for HF (OR 0.99, 95% CI 0.80 to 1.23; moderate‐certainty evidence). DPP4i may not increase the likelihood of worsening renal function (OR 1.08, 95% CI 0.88 to 1.33; low‐certainty evidence) and probably do not increase the risk of bone fracture (OR 1.00, 95% CI 0.83 to 1.19; moderate‐certainty evidence) or hypoglycaemia (OR 1.11, 95% CI 0.95 to 1.29; moderate‐certainty evidence). They are likely to increase the risk of pancreatitis (OR 1.63, 95% CI 1.12 to 2.37; moderate‐certainty evidence). 2. GLP‐1RA versus placebo: Our findings indicate that GLP‐1RA reduce the risk of CV mortality (OR 0.87, 95% CI 0.79 to 0.95; high‐certainty evidence), all‐cause mortality (OR 0.88, 95% CI 0.82 to 0.95; high‐certainty evidence), and stroke (OR 0.87, 95% CI 0.77 to 0.98; high‐certainty evidence). GLP‐1RA probably do not reduce the risk of myocardial infarction (OR 0.89, 95% CI 0.78 to 1.01; moderate‐certainty evidence), and hospitalisation for HF (OR 0.95, 95% CI 0.85 to 1.06; high‐certainty evidence). GLP‐1RA may reduce the risk of worsening renal function (OR 0.61, 95% CI 0.44 to 0.84; low‐certainty evidence), but may have no impact on pancreatitis (OR 0.96, 95% CI 0.68 to 1.35; low‐certainty evidence). We are uncertain about the effect of GLP‐1RA on hypoglycaemia and bone fractures. 3. SGLT2i versus placebo: This review shows that SGLT2i probably reduce the risk of CV mortality (OR 0.82, 95% CI 0.70 to 0.95; moderate‐certainty evidence), all‐cause mortality (OR 0.84, 95% CI 0.74 to 0.96; moderate‐certainty evidence), and reduce the risk of HF hospitalisation (OR 0.65, 95% CI 0.59 to 0.71; high‐certainty evidence); they do not reduce the risk of myocardial infarction (OR 0.97, 95% CI 0.84 to 1.12; high‐certainty evidence) and probably do not reduce the risk of stroke (OR 1.12, 95% CI 0.92 to 1.36; moderate‐certainty evidence). In terms of treatment safety, SGLT2i probably reduce the incidence of worsening renal function (OR 0.59, 95% CI 0.43 to 0.82; moderate‐certainty evidence), and probably have no effect on hypoglycaemia (OR 0.90, 95% CI 0.75 to 1.07; moderate‐certainty evidence) or bone fracture (OR 1.02, 95% CI 0.88 to 1.18; high‐certainty evidence), and may have no impact on pancreatitis (OR 0.85, 95% CI 0.39 to 1.86; low‐certainty evidence). 4. Network meta‐analysis: Because we failed to identify direct comparisons between each class of the agents, findings from our network meta‐analysis provided limited novel insights. Almost all findings from our network meta‐analysis agree with those from the standard meta‐analysis. GLP‐1RA may not reduce the risk of stroke compared with placebo (OR 0.87, 95% CrI 0.75 to 1.0; moderate‐certainty evidence), which showed similar odds estimates and wider 95% Crl compared with standard pairwise meta‐analysis. Indirect estimates also supported comparison across all three classes. SGLT2i was ranked the best for CVD and all‐cause mortality. Authors' conclusions: Findings from both standard and network meta‐analyses of moderate‐ to high‐certainty evidence suggest that GLP‐1RA and SGLT2i are likely to reduce the risk of CVD mortality and all‐cause mortality in people with established CVD; high‐certainty evidence demonstrates that treatment with SGLT2i reduce the risk of hospitalisation for HF, while moderate‐certainty evidence likely supports the use of GLP‐1RA to reduce fatal and non‐fatal stroke. Future studies conducted in the non‐diabetic CVD population will reveal the mechanisms behind how these agents improve clinical outcomes irrespective of their glucose‐lowering effects