The efficacy and safety of novel classes of glucose-lowering drugs for cardiovascular outcomes: a network meta-analysis of randomised clinical trials.

Several cardiovascular outcome trials on sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been released recently, including trials enrolling patients with congestive heart failure (CHF) and chronic kidney disease (CKD). Comparisons of the efficacy and safety of SGLT2i, glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) thus require an update. Assessments in patient subgroups, i.e., as stratified by age or the presence of CHF, CKD or atherosclerotic cardiovascular disease (ASCVD), are also currently lacking. We searched the PubMed, Embase and Cochrane databases for relevant studies published up until 5 December 2020. RCTs comparing SGLT2i, GLP-1RA and DPP-4i with placebo (or other controls) or with each other with cardiovascular (CV) or renal outcomes were eligible for inclusion. The primary efficacy endpoint was 3-point major adverse cardiovascular events (3P-MACE), which are defined as CV death, non-fatal myocardial infarction and non-fatal ischaemic stroke. All-cause mortality, hospitalisation for heart failure (HHF) and composite renal outcomes were also analysed. Pre-specified subgroup analyses of 3P-MACE were also performed. A total of 21 trials with 170,930 participants were included in this network meta-analysis. Both GLP-1RA and SGLT2i were associated with lower risks of 3P-MACE than placebo (RR 0.89, 95% CI 0.84, 0.94 and RR 0.88, 95% CI 0.83, 0.94, respectively). GLP-1RA and SGLT2i were also associated with lower risks of 3P-MACE than DPP-4i (RR 0.89, 95% CI 0.82, 0.98 and RR 0.89, 95% CI 0.81, 0.97, respectively). A comparison between SGLT2i and GLP-1RA demonstrated no difference in their risks of 3P-MACE (RR 0.99, 95% CI 0.91, 1.08). Only GLP-1RA was associated with a lower risk of stroke compared with placebo (RR 0.85, 95% CI 0.76, 0.94). SGLT2i is superior to GLP-1RA in reducing HHF (RR 0.76, 95% CI 0.68, 0.84) and renal outcomes (RR 0.78, 95% CI 0.65, 0.93). Subgroup analyses indicated that the benefits of SGLT2i and GLP-1RA were more pronounced in elderly patients, white and Asian patients, those with established ASCVD and those with longer durations of diabetes mellitus and worse glycaemic control. SGLT2i and GLP-1RA are superior to DPP-4i in terms of CV and renal outcomes. GLP-1RA is the only drug class that reduces the risk of stroke. SGLT2i is superior in reducing HHF and renal outcomes. Therefore, the choice between SGLT2i and GLP-1RA should be individualised according to patient profiles. CRD42020206600.

Lin DS ，Lee JK ，Hung CS ，Chen WJ ... -  《-》

The effect of DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors on cardiorenal outcomes: a network meta-analysis of 23 CVOTs.

Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose co-transporter-2 (SGLT-2) inhibitors reduce cardiorenal outcomes. We performed a network meta-analysis to compare the effect on cardiorenal outcomes among GLP-1 RAs, SGLT-2 inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. We searched the PUBMED, Embase and Cochrane databases for relevant studies published up until 10 December 2021. Cardiovascular and renal outcome trials reporting outcomes on GLP-1RA, SGLT-2 inhibitors and DPP-4 inhibitors in patients with or without type 2 diabetes mellitus were included. The primary outcome was major adverse cardiovascular events (MACE); other outcomes were cardiovascular and total death, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure (HHF), and renal outcome. Twenty-three trials enrolling a total number of 181,143 participants were included. DPP-4 inhibitors did not lower the risk of any cardiorenal outcome when compared with placebo and were associated with higher risks of MACE, HHF, and renal outcome when compared with the other two drug classes. SGLT-2 inhibitors significantly reduced cardiovascular (RR = 0.88) and total (RR = 0.87) death, as compared with DPP-4 inhibitors, while GLP-1 RA reduced total death only (RR = 0.87). The comparison between GLP-1RA and SGLT-2 inhibitors showed no difference in their risks of MACE, nonfatal MI, nonfatal stroke, CV and total death; SGLT-2 inhibitors were superior to GLP-1RA in reducing the risk of HHF and the renal outcome (24% and 22% lower risk, respectively). Only GLP-1RA reduced the risk of nonfatal stroke (RR = 0.84), as compared with placebo. There was no head-to-head trial directly comparing these antidiabetic drug classes. SGLT-2 inhibitors and GLP-1RA are superior to DPP-4 inhibitors in reducing the risk of most cardiorenal outcomes; SGLT-2 inhibitors are superior to GLP-1RA in reducing the risk of HHF and renal events; GLP-1RA only reduced the risk of nonfatal stroke. Both SGLT-2 inhibitors and GLP-1RA should be the preferred treatment for type 2 diabetes and cardiorenal diseases.

Giugliano D ，Longo M ，Signoriello S ，Maiorino MI ，Solerte B ，Chiodini P ，Esposito K ... -  《Cardiovascular Diabetology》

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.

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. 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. 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. 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. 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. 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. 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.

Kanie T ，Mizuno A ，Takaoka Y ，Suzuki T ，Yoneoka D ，Nishikawa Y ，Tam WWS ，Morze J ，Rynkiewicz A ，Xin Y ，Wu O ，Providencia R ，Kwong JS ... -  《Cochrane Database of Systematic Reviews》

Network meta-analysis on the effects of finerenone versus SGLT2 inhibitors and GLP-1 receptor agonists on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus and chronic kidney disease.

To evaluate the cardiovascular and renal benefits of finerenone, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagonlike peptide-1 receptor agonists (GLP-1 RA) in patients with Type 2 Diabetes Mellitus (T2DM) and chronic kidney disease (CKD) with network meta-analysis. Systematic literature searches were conducted of PubMed, Cochrane Library, Web of Science, Medline and Embase covering January 1, 2000 to December 30, 2021. Randomized control trials (RCTs) comparing finerenone, SGLT-2i and GLP-1 RA in diabetics with CKD were selected. We performed a network meta-analysis to compare the two drugs and finerenone indirectly. Results were reported as risk ratio (RR) with corresponding 95% confidence interval (CI). 18 RCTs involving 51,496 patients were included. Finerenone reduced the risk of major adverse cardiovascular events (MACE), renal outcome and hospitalization for heart failure (HHF) (RR [95% CI]; 0.88 [0.80-0.97], 0.86 [0.79-0.93], 0.79 [0.67,0.92], respectively). SGLT-2i were associated with reduced risks of MACE (RR [95% CI]; 0.84 [0.78-0.90]), renal outcome (RR [95% CI]; 0.67 [0.60-0.74], HHF (RR [95% CI]; 0.60 [0.53-0.68]), all-cause death (ACD) (RR [95% CI]; 0.89 [0.81-0.91]) and cardiovascular death (CVD) (RR [95% CI]; 0.86 [0.77-0.96]) compared to placebo. GLP-1 RA were associated with a lower risk of MACE (RR [95% CI]; 0.86 [0.78-0.94]). SGLT2i had significant effect in comparison to finerenone (finerenone vs SGLT2i: RR [95% CI]; 1.29 [1.13-1.47], 1.31 [1.07-1.61], respectively) and GLP-1 RA (GLP-1 RA vs SGLT2i: RR [95% CI]; 1.36 [1.16-1.59], 1.49 [1.18-1.89], respectively) in renal outcome and HHF. In patients with T2DM and CKD, SGLT2i, GLP-1 RA and finerenone were comparable in MACE, ACD and CVD. SGLT2i significantly decreased the risk of renal events and HHF compared with finerenone and GLP-1 RA. Among GLP-1 RA, GLP-1 analogues showed significant effect in reducing cardiovascular events compared with exendin-4 analogues.

Zhang Y ，Jiang L ，Wang J ，Wang T ，Chien C ，Huang W ，Fu X ，Xiao Y ，Fu Q ，Wang S ，Zhao J ... -  《Cardiovascular Diabetology》

Cardiovascular outcomes associated with SGLT-2 inhibitors versus other glucose-lowering drugs in patients with type 2 diabetes: A real-world systematic review and meta-analysis.

Li CX ，Liang S ，Gao L ，Liu H ... -  《PLoS One》