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Cardiovascular outcomes in trials of new antidiabetic drug classes: a network meta-analysis.

ABSTRACT: BACKGROUND:Recent trials suggested that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduced cardiovascular events. Comparative effectiveness of these new antidiabetic drug classes remains unclear. We therefore performed a network meta-analysis to compare the effect on cardiovascular outcomes among GLP-1 RAs, SGLT-2 and dipeptidyl peptidase-4 (DPP-4) inhibitors. METHODS:MEDLINE, EMBASE, Cochrane database, ClinicalTrials.gov, and congress proceedings from recent cardiology conferences were searched up to April 20, 2019. Cardiovascular outcome trials and renal outcome trials reporting cardiovascular outcomes on GLP-1 RAs, SGLT-2 and DPP-4 inhibitors in patients with type 2 diabetes mellitus were included. The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes were nonfatal myocardial infarction, nonfatal stroke, cardiovascular mortality, all-cause mortality, hospitalisation for heart failure (HF), and renal composite outcome. ORs and 95% CI were calculated using random-effects models. RESULTS:Fourteen trials enrolling 121,047 patients were included. SGLT-2 inhibitors reduced cardiovascular deaths and all-cause deaths compared to placebo (OR 0.82, 95% CI 0.73-0.93 and OR 0.84, 95% CI 0.77-0.92) and DPP-4 inhibitors (OR 0.83, 95% CI 0.70-0.99 and OR 0.83, 95% CI 0.73-0.94), respectively. SGLT-2 inhibitors and GLP-1 RAs significantly reduced MACE (OR 0.88, 95% CI 0.82-0.95 and OR 0.87, 95% CI 0.82-0.93), hospitalisation for HF (OR 0.68, 95% CI 0.61-0.77 and OR 0.87, 95% CI 0.82-0.93), and renal composite outcome (OR 0.59, 95% CI 0.52-0.67 and OR 0.86, 95% CI 0.78-0.94) compared to placebo, but SGLT-2 inhibitors reduced hospitalisation for HF (OR 0.79, 95% CI 0.69-0.90) and renal composite outcome (OR 0.69, 95% CI 0.59-0.80) more than GLP-1 RAs. Only GLP-1 RAs reduced nonfatal stroke (OR 0.88, 95% CI 0.77-0.99). DPP-4 inhibitors did not lower the risk of these outcomes when compared to placebo and were associated with higher risks of MACE, hospitalisation for HF, and renal composite outcome when compared to the other two drug classes. CONCLUSIONS:SGLT-2 inhibitors show clear superiority in reducing cardiovascular and all-cause deaths, hospitalisation for HF, and renal events among new antidiabetic drug classes. GLP-1 RAs also have cardiovascular and renal protective effects. DPP-4 inhibitors have no beneficial cardiovascular effects and are therefore inferior to the other two drug classes. SGLT-2 inhibitors should now be the preferred treatment for type 2 diabetes mellitus.

SUBMITTER: Fei Y

PROVIDER: S-EPMC6714383 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Cardiovascular outcomes in trials of new antidiabetic drug classes: a network meta-analysis.

Fei Yue Y Tsoi Man-Fung MF Cheung Bernard Man Yung BMY

Cardiovascular diabetology 20190828 1

<h4>Background</h4>Recent trials suggested that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduced cardiovascular events. Comparative effectiveness of these new antidiabetic drug classes remains unclear. We therefore performed a network meta-analysis to compare the effect on cardiovascular outcomes among GLP-1 RAs, SGLT-2 and dipeptidyl peptidase-4 (DPP-4) inhibitors.<h4>Methods</h4>MEDLINE, EMBASE, Cochrane database, ClinicalTri ...[more]

PMID: 31462224

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Project description:In the Guidance for Industry from the Food and Drug Administration in 2008, excess cardiovascular risk should be ruled out in trials of all new antidiabetic drugs; however, relatively few studies have focused on cardiovascular safety with antidiabetic drug use. We aimed to examine mortality and cardiovascular risk using a network meta-analysis. We searched the Medline, Embase, Cochrane, and ClinicalTrials.gov registry databases in March 2016 to identify randomized controlled trials reporting cardiovascular risk with the following oral antidiabetic drugs: metformin, sulfonylureas, thiazolidinedione (TZD), dipeptidyl peptidase-4 (DPP4) inhibitors, and sodium-glucose co-transporter-2 (SGLT2) inhibitors. We assessed the differences in the risks of all-cause mortality, cardiovascular-related mortality, acute coronary syndrome (ACS), and myocardial infarction (MI) among antidiabetic drugs with fixed effect models for direct pairwise comparisons and Bayesian network meta-analyses to integrate direct and indirect comparisons. Of the 101,183 patients in 73 randomized controlled trials, 3,434 (3.4%) died. The relative risks of all-cause mortality with SGLT2 inhibitor use were 0.68 (95% credible interval: 0.57-0.80), 0.74 (0.49-1.10), 0.63 (0.46-0.87), 0.71 (0.55-0.90), and 0.65 (0.54-0.78), compared with placebo, metformin, sulfonylurea, TZD, and DPP4 inhibitor, respectively. The relative risks of cardiovascular-related mortality with SGLT2 inhibitor use were 0.61 (0.50-0.76), 0.81(0.36-1.90), 0.52(0.31-0.88), 0.66(0.49-0.91), and 0.61(0.48-0.77), compared with placebo, metformin, sulfonylurea, TZD, and DPP4 inhibitor, respectively. The relative risks of ACS with SGLT2 inhibitor use was consistent with that of all-cause mortality. SGLT2 inhibitor use was associated with a lower risk of ACS than the other OADs and placebo. The relative risks of MI with SGLT2 inhibitor use were 0.77 (0.63-0.93) and 0.75 (0.60-0.94), compared with placebo and DPP4 inhibitor, respectively. The currently available data provide the evidence of cardiovascular benefit from use of SGLT2 inhibitors to patients with type 2 diabetes, although additional results from ongoing studies will be pivotal.

Project description:IntroductionCardiovascular benefits observed with new antidiabetic agents may not extend to chronic kidney disease (CKD) patients. This study performed a systematic review and meta-analysis of cardiovascular outcome trials (CVOTs) using new antidiabetic agents stratified by kidney function.MethodsMEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials were searched for eligible studies up to November 16, 2020. Data were stratified by the trial entry estimated glomerular filtration rate (eGFR) and albuminuria. Primary major cardiovascular event (MACE) outcomes were extracted, and a meta-analysis with a random effects model was performed to estimate overall risk ratios (RRs).ResultsOur search identified 16 studies for inclusion (glucagon-like peptide-1 [GLP-1] analogues, n = 6; dipeptidyl-peptidase 4 [DPP-4] inhibitors, n = 4; and sodium-glucose cotransporter-2 [SGLT-2] inhibitors, n = 6) with a combined total of 150,816 participants (28.2% with eGFR <60 ml/min per 1.73 m2, n = 42,534). The RR for MACE with GLP-1 analogues with an eGFR ≥60 ml/min per 1.73 m2 was 0.87 (95% confidence interval [CI], 0.77-0.98; P = 0.02) and 0.90 (95% CI, 0.78-1.04; P = 0.14) with an eGFR <60 ml/min per 1.73 m2. The RR for MACE with DPP-4 inhibitors with eGFR ≥60 ml/min per 1.73 m2 was 0.99 (95% CI, 0.92-1.07; P = 0.86) and 0.99 (95% CI, 0.91-1.08; P = 0.86) with an eGFR <60 ml/min per 1.73 m2. The RR for MACE with SGLT-2 inhibitors with an eGFR ≥60 ml/min per 1.73 m2 was 1.01 (95% CI, 0.92-1.10; P = 0.87) and 0.85 (95% CI, 0.75-0.95; P = 0.005) with an eGFR <60 ml/min per 1.73 m2. Most analyses had significant heterogeneity. Sufficient albuminuria data were unavailable to analyze empirically.ConclusionClear evidence for MACE prevention in diabetes patients with an eGFR <60 ml/min per 1.73 m2 currently exists for SGLT-2 inhibitors only. However, similar GLP-1 analogue effect sizes suggest a lack of sufficient power rather than a lack of effect.

Project description:Importance:Antihypertension medications have been associated with prevention of cardiovascular events, although less is known about the comparative effectiveness of different medication classes. Objective:To compare contemporary aggregated first-in-trial cardiovascular events among patients with hypertension and no substantial comorbidities. Data Sources:The PubMed, Embase, and Cochrane Library databases were systematically searched for articles published between January 1, 1990, and October 24, 2017. Study Selection:Randomized clinical trials that tested commonly used antihypertension medications (angiotensin-converting enzyme inhibitors, dihydropyridine calcium channel blockers, nondihydropyridine calcium channel blockers, β-blockers, angiotensin receptor blockers, and diuretics) and that reported selected cardiovascular outcomes for at least 6 months of follow-up. Data Extraction and Synthesis:The analysis was conducted from October 2017 to December 2019. Two reviewers extracted the number of cardiovascular events at the end of treatment for all study groups. For each outcome, a frequentist network meta-analysis was used to compare risk reductions between medication classes (random-effects models weighted by the inverse variance). The dose-response association between a 10-mm Hg reduction of systolic blood pressure and a 5-mm Hg reduction of diastolic blood pressure and the risk of first-in-trial cardiovascular events was estimated. Main Outcomes and Measures:First-in-trial cardiovascular events, including cardiovascular death, myocardial infarction, stroke, and revascularization. Results:In this systematic review and network meta-analysis, data were pooled from 46 eligible clinical trials (248 887 total participants with a mean [SD] age of 65.6 [5.8] years; 52.8% men). In the network meta-analysis, compared with placebo, angiotensin-converting enzyme inhibitors, dihydropyridine calcium channel blockers, and thiazide diuretics were reported to be similarly effective in reducing overall cardiovascular events (25%), cardiovascular death (20%), and stroke (35%); angiotensin-converting enzyme inhibitors were reported to be the most effective in reducing the risk of myocardial infarction (28%); and diuretics were reported to be the most effective in reducing revascularization (33%). In the metaregression analyses, each 10-mm Hg reduction in systolic blood pressure and 5-mm Hg reduction in diastolic blood pressure was significantly associated with a lower risk of cardiovascular death, stroke, and overall cardiovascular events. Conclusions and Relevance:In this network meta-analysis of clinical trials of patients with hypertension and no substantial comorbidities, different classes of antihypertension medications were associated with similar benefits in reducing cardiovascular events. Future studies should compare the effectiveness of combinations of antihypertension medications in reducing cardiovascular events.

Project description:BackgroundEffects of antihyperglycemic therapies on cardiovascular and heart failure (HF) risks have varied widely across cardiovascular outcome trials (CVOTs), and underlying factors remain incompletely understood. We aimed to determine the relationships of glycated hemoglobin (HbA1c) or bodyweight changes with these outcomes in all CVOTs of antihyperglycemic therapies.MethodsWe searched PubMed and EMBASE up to 25 January 2023 for all randomized controlled CVOTs of antihyperglycemic therapies reporting both major adverse cardiovascular events (MACE) and HF outcomes in patients with type 2 diabetes or prediabetes. We performed meta-regression analyses following random-effects meta-analyses to evaluate the effects of HbA1c or bodyweight reductions on each outcome.ResultsThirty-five trials comprising 256,524 patients were included. Overall, antihyperglycemic therapies reduced MACE by 9% [risk ratio (RR): 0.91; 95% confidence interval (CI) 0.88-0.94; P < 0.001; I2 = 36.5%]. In meta-regression, every 1% greater reduction in HbA1c was associated with a 14% reduction in the RR of MACE (95% CI 4-24; P = 0.010), whereas bodyweight change was not associated with the RR of MACE. The magnitude of the reduction in MACE risk associated with HbA1c reduction was greater in trials with a higher baseline prevalence of atherosclerotic cardiovascular disease. On the other hand, antihyperglycemic therapies showed no overall significant effect on HF (RR: 0.95; 95% CI 0.87-1.04; P = 0.28; I2 = 75.9%). In a subgroup analysis based on intervention type, sodium-glucose cotransporter-2 inhibitors (SGLT2i) conferred the greatest HF risk reduction (RR: 0.68; 95% CI 0.62-0.75; P < 0.001; I2 = 0.0%). In meta-regression, every 1 kg bodyweight reduction, but not HbA1c reduction, was found to reduce the RR of HF by 7% (95% CI 4-10; P < 0.001); however, significant residual heterogeneity (P < 0.001) was observed, and SGLT2i reduced HF more than could be explained by HbA1c or bodyweight reductions.ConclusionsAntihyperglycemic therapies reduce MACE in an HbA1c-dependent manner. These findings indicate that HbA1c can be a useful marker of MACE risk reduction across a wide range of antihyperglycemic therapies, including drugs with pleiotropic effects. In contrast, HF is reduced not in an HbA1c-dependent but in a bodyweight-dependent manner. Notably, SGLT2i have shown class-specific benefits for HF beyond HbA1c or bodyweight reductions.

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Cardiovascular outcomes in trials of new antidiabetic drug classes: a network meta-analysis.

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Cardiovascular outcomes in trials of new antidiabetic drug classes: a network meta-analysis.

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