BackgroundDespite the improvements in drug eluting stents (DES) technology, suboptimal results have been observed in certain higher‐risk subsets of patients, as in diabetes mellitus (DM). Drug‐coated balloons (DCB) could represent an alternative to DES in complex populations and anatomies, as in DM.AimsThe present meta‐analysis aimed at assessing the role of DCBs in patients with diabetes mellitus.MethodsStudies comparing DCB versus percutaneous coronary revascularization (PCI) with/without DES for PCI in high‐risk populations (>30% DM) were included. The primary efficacy endpoint was overall mortality, secondary endpoints were myocardial infarction, target lesion revascularization (TLR), and major adverse cardiovascular events (MACE).ResultsWe included 10 studies, comprising 2026 patients. Among them, 1002 patients (49.5%) were treated with DCB and 1024 with DES implantation. Among the included studies, 6 only enrolled diabetic patients and 2 had a prevalence of diabetes of 50%. At a mean follow‐up of 15.3 months, mortality rate was 3.8% (82 patients), significantly lower with DCB (3.2% vs. 4.9% with DES; odds ratio [OR] [95% confidence interval {CI}] = 0.61 [0.38, 0.97], p = 0.04 phet = 0.34. A similar reduction in favor of DCB was observed for MACE (13.6% vs. 17.6%; OR [95% CI] = 0.79 [0.61, 1.04], p = 0.09, phet = 0.25), while TLR was significantly reduced only in the diabetic‐restricted sub‐analysis.ConclusionIn the present meta‐analysis, we showed a significant survival benefit and an absolute reduction in MACE and TLR with a DCB‐based strategy as compared to DES in high‐risk patients, mostly with DM. Future large‐scale randomized trials, dedicated to this population, are deserved to confirm our findings.What is KnownComplex coronary anatomies and diabetes mellitus (DM) represent the pitfall of drug eluting stents (DES), mainly due to inflammatory and thrombotic complications, which should be reduced with drug‐coated balloons (DCB).What is NewWe confirmed a significant advantage of DCB versus DES in the treatment of de novo lesions in high‐risk patients and mainly in DM, reducing overall mortality, MACE and target lesion revascularization.