Frontiers in cardiovascular medicine · 2026
Cardiovascular outcomes of oral incretin-based drugs in type 2 diabetes: a GRADE-assessed meta-analysis of 67,679 patients.
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Ali Muhammad Faizan, Mohammed Omer Farooq, Suhail Amina, Naseer Faisal, Shafi Nimra, Arshad Muhammad Usman, Shazly Omar, Mohmand Muneeb Shad, Ahmad Husnain, Binashikhbubkr Noof K, Maaz Muhammad, Khan Muhammad, Neppala Sivaram, Al-Jarshawi Mustafa, Hemida Mohamed Fawzi
Аннотация
BACKGROUND: While injectable GLP-1 receptor agonists like semaglutide have demonstrated clear cardiovascular benefits in type 2 diabetes mellitus (T2DM), the role of oral incretin-based therapies, including oral semaglutide and DPP-4 inhibitors-remains less well defined. Comprehensive evaluation of their cardiovascular efficacy is warranted.
RESEARCH QUESTION: What are the cardiovascular outcomes associated with oral incretin-based therapies, specifically oral semaglutide and DPP-4 inhibitors, in patients with T2DM compared to placebo or standard care.
METHODS: We searched electronic databases for randomized controlled trials (RCTs). Meta-analysis was conducted in R version 4.4.3 using the "meta" and "metasens" packages. Statistical analysis was performed using R software and RStudio (version 4.4.2). We calculated pooled estimates using risk ratios (RR) with 95% confidence intervals (CIs).
RESULTS: A total of 9 studies comprising 67,679 patients were included, of which two evaluated oral semaglutide and the remaining seven assessed DPP-4 inhibitors. There was no significant reduction in all-cause mortality (RR 0.97, 95% CI 0.90-1.04, p = 0.35) or cardiovascular death (RR 0.98, 95% CI 0.91-1.05, p = 0.48). Major adverse cardiovascular events (MACE) showed a non-significant reduction overall (RR 0.95, 95% CI 0.91-1.00, p = 0.06), with oral semaglutide demonstrating a significant benefit (RR 0.86, 95% CI 0.78-0.95, p = 0.003). Non-fatal myocardial infarction (MI) (RR 0.98, 95% CI 0.88-1.09) and non-fatal stroke (RR 0.93, 95% CI 0.83-1.03) were not significantly affected. Hospitalizations due to heart failure (RR 0.98, 95% CI 0.84-1.13) and unstable angina (RR 1.00, 95% CI 0.87-1.15) remained unchanged. Coronary revascularization was slightly reduced with oral semaglutide (RR 0.76, 95% CI 0.64-0.91). Adverse events leading to discontinuation were higher with oral semaglutide (RR 1.51, 95% CI 1.15-1.98), while serious adverse events were significantly reduced (RR 0.96, 95% CI 0.94-0.99, p = 0.003). Sensitivity analyses were conducted due to significant heterogeneity in key outcomes. While omitting certain studies reduced heterogeneity, the overall results remained consistent.
CONCLUSION: Oral incretin-based therapies were not associated with significant reductions in all-cause mortality, cardiovascular death, or MACE overall, though oral semaglutide showed a significant MACE benefit and reduced coronary revascularization on subgroup analysis. Non-fatal MI, fatal or non-fatal MI, non-fatal stroke, fatal or non-fatal stroke and hospitalization due to heart failure or unstable angina were unaffected, and oral semaglutide carried a higher risk of treatment discontinuation. These findings suggest no clear class-wide cardiovascular benefit of oral incretins, with signals specific to oral semaglutide warranting confirmation in dedicated trials.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD420251113835.
RESEARCH QUESTION: What are the cardiovascular outcomes associated with oral incretin-based therapies, specifically oral semaglutide and DPP-4 inhibitors, in patients with T2DM compared to placebo or standard care.
METHODS: We searched electronic databases for randomized controlled trials (RCTs). Meta-analysis was conducted in R version 4.4.3 using the "meta" and "metasens" packages. Statistical analysis was performed using R software and RStudio (version 4.4.2). We calculated pooled estimates using risk ratios (RR) with 95% confidence intervals (CIs).
RESULTS: A total of 9 studies comprising 67,679 patients were included, of which two evaluated oral semaglutide and the remaining seven assessed DPP-4 inhibitors. There was no significant reduction in all-cause mortality (RR 0.97, 95% CI 0.90-1.04, p = 0.35) or cardiovascular death (RR 0.98, 95% CI 0.91-1.05, p = 0.48). Major adverse cardiovascular events (MACE) showed a non-significant reduction overall (RR 0.95, 95% CI 0.91-1.00, p = 0.06), with oral semaglutide demonstrating a significant benefit (RR 0.86, 95% CI 0.78-0.95, p = 0.003). Non-fatal myocardial infarction (MI) (RR 0.98, 95% CI 0.88-1.09) and non-fatal stroke (RR 0.93, 95% CI 0.83-1.03) were not significantly affected. Hospitalizations due to heart failure (RR 0.98, 95% CI 0.84-1.13) and unstable angina (RR 1.00, 95% CI 0.87-1.15) remained unchanged. Coronary revascularization was slightly reduced with oral semaglutide (RR 0.76, 95% CI 0.64-0.91). Adverse events leading to discontinuation were higher with oral semaglutide (RR 1.51, 95% CI 1.15-1.98), while serious adverse events were significantly reduced (RR 0.96, 95% CI 0.94-0.99, p = 0.003). Sensitivity analyses were conducted due to significant heterogeneity in key outcomes. While omitting certain studies reduced heterogeneity, the overall results remained consistent.
CONCLUSION: Oral incretin-based therapies were not associated with significant reductions in all-cause mortality, cardiovascular death, or MACE overall, though oral semaglutide showed a significant MACE benefit and reduced coronary revascularization on subgroup analysis. Non-fatal MI, fatal or non-fatal MI, non-fatal stroke, fatal or non-fatal stroke and hospitalization due to heart failure or unstable angina were unaffected, and oral semaglutide carried a higher risk of treatment discontinuation. These findings suggest no clear class-wide cardiovascular benefit of oral incretins, with signals specific to oral semaglutide warranting confirmation in dedicated trials.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD420251113835.