Abstract
Background
Diabetic patients undergoing percutaneous coronary intervention (PCI) frequently have complex coronary artery disease (CAD) and suboptimal outcomes with drug-eluting stents (DES). Sirolimus-coated balloons (SCB) have recently been introduced, but comparative data versus DES in diabetic patients with de novo CAD are lacking.
Methods
The SIMPLE-DM study is a pooled analysis of five observational registries including all-comer diabetic patients undergoing PCI for de novo CAD. Patients in the SCB cohort were treated with the phospholipid nanocarrier Magic Touch SCB, while those in the DES cohort received current-generation DES. Propensity score (PS) adjustment was used to balance clinical and angiographic characteristics. The primary endpoint was the 2-year cumulative incidence of target lesion failure (TLF), defined as the composite of cardiac death, target vessel MI (TV-MI), or target lesion revascularization (TLR).
Results
A total of 1838 patients were included, 599 treated with SCB-based PCI and 1239 with DES-only PCI. At 2 years, TLF occurred in 9.1% of SCB and 9.9% of DES patients (adj. hazard ratio HR 0.88, 95% confidence interval CI 0.43–1.81, p = 0.736). No significant differences were found in cardiac death, TV-MI or TLR. SCB-based PCI was associated with more favourable outcomes in patients with chronic kidney disease (p for interaction = 0.042) and long lesions (p for interaction = 0.003), whereas DES-only PCI performed better in those with short lesions.
Conclusions
In diabetic patients undergoing PCI for de novo CAD, an SCB-based strategy was associated with comparable 2-year outcomes to DES-only PCI, with signals of potential benefit in the highest clinical and anatomical risk subsets.
Graphical abstract
Abbreviations: ACS, acute coronary syndrome; ASTUTE, Amphilimus Italian multicentre registry; BP, biodegradable-polymer; CCS, chronic coronary syndrome; CKD, chronic kidney disease; DES, drug-eluting stent; EASTBOURNE, All-Comers Sirolimus-Coated Balloon European Registry; HR, hazard ratio; IDDM, insulin-dependent diabetes mellitus; PCI, percutaneous coronary intervention; PF, polymer-free; RUDI-FREE, Polymer-free biolimus-eluting stent implantation in all-comers population; SCB, sirolimus-coated balloon; TLF, target lesion failure; TLR, target lesion revascularization; TVF, target vessel failure; TV-MI, target vessel myocardial infarction; ULISSE, ULtimaster Italian multicenter all comerS Stent rEgistry.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12933-026-03110-6.
Keywords: Drug-coated balloon, Sirolimus, Diabetes, De novo coronary artery disease, Magic touch
Research insights
What is currently known about this topic?
Diabetic patients often have suboptimal long-term outcomes after percutaneous coronary intervention (PCI) with drug-eluting stent (DES).
Drug-coated balloons may improve outcomes by avoiding permanent metallic implants and reducing total stent length.
New-generation sirolimus-coated balloons (SCB) have limited evidence in diabetic patients.
What is the key research question?
How does an SCB-based PCI strategy compare with DES-only PCI in diabetic patients with de novo CAD?
What is new?
In this observational study of all-comer diabetic patients, SCB-based PCI was associated with comparable 2-year clinical outcomes to DES-only PCI, with signals of potential benefit among those with higher clinical and anatomical complexity.
How might this study influence clinical practice?
In patients with diabetes and de novo CAD, an SCB-based PCI strategy appears safe in routine clinical practice and may represent a potential alternative to DES-only PCI in selected cases where reducing metal implantation is desirable. Randomized clinical trials are warranted to confirm these findings and to define the role of DCB-based PCI in diabetic patients.
Background
Coronary artery disease (CAD) is a leading cause of morbidity and mortality in patients with diabetes mellitus (DM) [1, 2]. Compared with non-DM patients, those with DM typically present with more complex and rapidly progressive disease, characterized by smaller-caliber vessels, multivessel involvement, extensive calcification, and high-risk plaque features [3, 4]. DM—particularly insulin-dependent DM (IDDM)—remains a strong predictor of adverse outcomes following percutaneous coronary intervention (PCI) [5, 6].
Despite major improvements in PCI techniques and drug-eluting stent (DES) technology, clinical outcomes in diabetic patients remain inferior to non-diabetic patients, partly due to the persistent vascular injury and inflammation induced by permanent metallic scaffolds [7]. In this context, drug-coated balloons (DCB) offer a metal-free alternative, enabling delivery of antiproliferative drugs without stent implantation [8–10]. By reducing stent burden, a DCB-only or hybrid strategy, involving the use of DCB and DES in combination, may help mitigate long-term complications [11–15].
While DCB are a well-established treatment option for in-stent restenosis, data on their use for de novo lesions, particularly in patients with DM, are limited. Moreover, most evidence to date comes from studies on earlier-generation paclitaxel-coated balloons (PCB) [16, 17]. Sirolimus-coated balloons (SCB) represent a newer class of DCB with encouraging early results [18], but evidence on their clinical safety and efficacy in diabetic patients is scant.
The present study aimed to compare clinical outcomes of a SCB-based treatment strategy for de novo CAD in diabetic patients with those of conventional DES-only PCI.
Methods
Study design
The SIMPLE-DM (SIroliMus-coated balloon-based PCI versus DES-onLy PCI in patiEnts with DiabetES Mellitus) study is an individual patient data pooled analysis of five multicenter, observational, investigator-initiated cohort studies, whose designs have been previously published.
The SCB cohort included diabetic patients treated with the Magic Touch phospholipid nanocarrier SCB (Concept Medical, Surat, Gujarat, India) from the EASTBOURNE (All-Comers Sirolimus-Coated Balloon European Registry) and Milan-DCB registries. EASTBOURNE is a prospective, single-arm registry that enrolled all-comer CAD patients undergoing SCB angioplasty across 38 European and Asian centers [19], while Milan-DCB is a retrospective registry of patients undergoing DCB-based PCI at two Italian institutions (Humanitas Research Hospital IRCCS and Columbus Clinic - Milan, Italy) [11, 12, 18, 20]. The DES cohort pooled diabetic patients from the ULISSE (ULtimaster Italian multicenter all comerS Stent rEgistry), ASTUTE (Amphilimus Italian multicentre registry), and RUDI-FREE (Polymer-free biolimus-eluting stent implantation in all-comers population) registries [21–23]. These were single-arm, all-comers registries including patients undergoing PCI with the Ultimaster biodegradable-polymer sirolimus-eluting stent (BP-SES), the Cre8 polymer-free amphilimus-eluting stent (PF-AES), and the BioFreedom polymer-free biolimus-eluting stent (PF-BES), respectively.
A summary of study designs, enrolment periods and inclusion/exclusion criteria is provided in Supplementary Table 1. Patients undergoing PCI for in-stent restenosis were excluded from the pooled analysis. Inclusion criteria broadly reflected routine clinical practice, including both chronic and acute coronary syndromes (ACS), with or without ST-segment elevation. No restrictions were applied regarding the number of treated lesions, vessels, lesion length, comorbidities, or age. PCI was performed according to standard techniques, and device selection was at the operator’s discretion. All studies complied with the Declaration of Helsinki, were conducted in accordance with local Institutional Review Board requirements, and all patients provided informed consent for the procedure and subsequent data collection.
Study procedure
SCB-based PCI was performed according to the Third International DCB Consensus Document. A detailed description of the procedure has been previously reported [11–13]. In brief, all patients received lesion preparation with plain balloons, aiming to a balloon-to-vessel ratio of 1:1, specialty balloons, atherectomy, or intravascular lithotripsy. SCB angioplasty was performed only in cases of successful preparation, defined as residual stenosis < 30% and absence of flow-limiting or advanced dissections; otherwise, bailout DES implantation was performed. An upfront hybrid PCI approach, using DES for proximal lesions in combination with SCB could also be adopted, based on physicians’ preference.
The Magic Touch SCB delivers sirolimus at 1.3 µg/mm² via phospholipid bilayer nanoparticles. These nanoparticles serve as protective reservoirs, preventing drug degradation and enabling controlled transfer into the vessel wall upon balloon inflation, following Fick’s law of diffusion [19].
PCI with DES was performed according to standard practice. The choice about antithrombotic therapy composition and duration was left to operators’ discretion [21–24].
Study endpoints
Follow-up was conducted through clinical visits or telephone interviews. No systematic angiographic follow-up was planned.
The primary endpoint for the present analysis was target lesion failure (TLF) at 2-years follow-up, defined as the composite of target lesion revascularization (TLR), target vessel myocardial infarction (TV-MI) and cardiac death. Secondary endpoints were target vessel failure (TVF), defined as the composite of target vessel revascularization (TVR), TV-MI and cardiac death, the individual components of the composite endpoints and definite/probable stent or target lesion thrombosis. All study endpoints were defined according to Academic Research Consortium-2 criteria [25].
Statistical analysis
Continuous variables are presented as mean ± standard deviation or median (interquartile range) and compared using Student’s t-test or Wilcoxon test, as appropriate. Categorical variables are presented as number (%) and compared using the chi-square or Fisher’s exact test. Clinical follow-up was censored at the date of death or at 2 years. Data for patients lost to follow-up were censored at the time of last contact. The cumulative incidence of adverse events at the 2-year mark was assessed using the Kaplan–Meier method and compared between groups using the log-rank test for time to first event.
To minimize differences in terms of confounding variables among the two groups (SCB vs. DES), propensity score (PS) covariate adjustment was performed. PS were calculated using a multivariable logistic regression model with the dependent outcome being treatment with SCB vs. DES. The propensity model was generated iteratively using the method of Rosenbaum et al. [26] Cause-specific Cox proportional hazards regression models, which included PS stratified into quintiles as a covariate for adjustment, were then fitted to analyze time-to-event outcomes. Risk estimates are presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Variables included in the multivariable logistic regression model for PS calculation were: age, sex, hypertension, dyslipidemia, chronic kidney disease (CKD—defined as an estimated glomerular filtration rate < 60 mL/min), prior PCI, left ventricular ejection fraction (LVEF), clinical presentation (ACS vs. chronic coronary syndrome), lesion length, reference vessel diameter, use of intravascular imaging, angiographically defined moderate-to-severe calcification, ostial lesion, left main involvement, bifurcation involvement, chronic total occlusion and lesion type (B2/C).
To assess robustness, a sensitivity analysis was performed using 1:1 nearest-neighbor PS matching without replacement, based on a greedy algorithm with a caliper width of 0.3 standard deviations (SD) of the logit of the PS. The C-statistic for the PS model was 0.930, indicating excellent discrimination. A median bias of 2.1% among covariates demonstrated high standard matching. The pseudo-R2 value was 0.378 (p < 0.001) before matching and low (0.023; p = 0.512) after matching, thus confirming good quality of the match and adequate balance of covariate distribution between matched groups. Adequate balance was further verified by computing the absolute standardized mean difference (SMD) for each covariate, with SMD < 0.10 considered indicative of negligible imbalance. To further minimize the impact of residual confounding, a doubly-adjusted model including covariates with SMD > 0.10 was additionally applied when evaluating clinical outcomes in the PS-matched cohort.
The interaction between treatment strategy and key clinical and angiographic subgroups of interest, including sex, CKD, IDDM, clinical presentation, lesion length, moderate-severe calcification, type B2/C lesion and bifurcation involvement, was evaluated using formal interaction testing in a secondary exploratory analysis. A pre-specified subgroup analysis was performed in patients with IDDM. Finally, a sensitivity outcome analysis was conducted excluding patients from the SCB group who had undergone hybrid PCI or bailout stenting.
All reported P-values were 2-sided, and a P < 0.05 was considered statistically significant. Statistical analyses were conducted using Stata, version 17 (Stata Corp, College Station, TX).
Results
A total of 1,838 patients were included in the present analysis, of whom 599 in the SCB-based PCI cohort and 1,239 in the DES-only cohort . The DES cohort comprised 423 patients (34.1%) treated with the Ultimaster BP-SES, 491 (39.7%) treated with the Cre8 PF-AES and 325 (26.2%) treated with the BioFreedom PF-BES.
Baseline characteristics
Table 1 summarizes baseline clinical characteristics. Patients in the SCB group were younger (66 ± 11 vs. 68 ± 10 years, p < 0.001), more frequently male (80.8% vs. 76.3%, p = 0.028), and had a higher prevalence of prior PCI (48.7% vs. 38.9%, p < 0.001) and CKD (29.4% vs. 20.6%, p < 0.001) than those in the DES group. IDDM was present in 26.9% vs. 25.1% (p = 0.43). Clinical presentation differed, with chronic coronary syndrome more common in the DES group, whereas ACS and myocardial infarction were more frequent in the SCB group.
Table 1.
Baseline clinical characteristics
| SCB-based PCI (N = 599) |
DES-only PCI (N = 1239) |
p-value | |
|---|---|---|---|
| Male sex | 484 (80.8%) | 944 (76.3%) | 0.028 |
| Age (years), mean (SD) | 66.3 (10.8) | 68.5 (9.6) | < 0.001 |
| HbA1c (%), mean (SD) | 7.1 (1.4) | 6.9 (3.8) | 0.54 |
| Insulin-dependent diabetes mellitus | 159 (26.9%) | 311 (25.1%) | 0.43 |
| Hypertension | 465 (77.6%) | 1028 (83.0%) | 0.005 |
| Hyperlipidemia | 463 (77.3%) | 822 (66.4%) | < 0.001 |
| Prior CABG | 52 (8.7%) | 134 (10.8%) | 0.15 |
| Prior PCI | 292 (48.7%) | 482 (38.9%) | < 0.001 |
| Previous MI | 211 (35.2%) | 328 (26.5%) | < 0.001 |
| Stage ≥3 CKD | 176 (29.4%) | 255 (20.6%) | < 0.001 |
| LVEF (%), mean (SD) | 51.8 (9.7) | 50.7 (10.3) | 0.023 |
| Clinical presentation | |||
| Silent or stable angina | 354 (59.1%) | 831 (67.1%) | < 0.001 |
| NSTE-ACS | 186 (31.1%) | 319 (25.8%) | 0.017 |
| STEMI | 59 (9.8%) | 88 (7.1%) | 0.042 |
| Antithrombotic therapy at discharge | |||
| Aspirin | 589 (98.3%) | 1236 (99.8%) | < 0.001 |
| P2Y12 inhibitor | 592 (98.8%) | 1,153 (93.1%) | < 0.001 |
| Clopidogrel | 389 (65.7%) | 933 (80.9%) | |
| Ticagrelor | 32 (5.4%) | 163 (14.1%) | |
| Prasugrel | 171 (28.9%) | 57 (4.9%) | |
| DAPT duration (months), median (IQR) | 12.0 (6.0, 12.0) | 6.0 (4.0, 12.0) | < 0.001 |
CABG, coronary artery bypass grafting; CKD, chronic kidney disease; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSTE-ACS, non-ST segment elevation myocardial infarction; PCI, percutaneous coronary intervention; SCB, sirolimus-coated balloon; SD, standard deviation; STEMI, ST-segment elevation myocardial infarction
Baseline angiographic features are reported in Table 2. The proportion of type B2/C lesions was higher in the DES than the SCB cohort (58.9% vs. 64.3%, p = 0.025), driven by more frequent left main and ostial involvement. Conversely, moderate-to-severe calcifications and bifurcation lesions were more common in the SCB group. Mean lesion length was 25 mm in both groups, while mean reference vessel diameter was smaller in the SCB group (2.5 ± 0.5 vs. 3.1 ± 0.5 mm, p < 0.001). In the SCB cohort, 11.9% of patients underwent upfront hybrid PCI and 7.7% required bailout DES implantation.
Table 2.
Baseline angiographic characteristics
| SCB-based PCI (N = 599) |
DES-only PCI (N = 1239) |
p-value | |
|---|---|---|---|
| N. of Lesions, mean (SD) | 1.1 (0.4) | 1.4 (0.8) | < 0.001 |
| Left main involvement | 5 (0.8%) | 61 (4.9%) | < 0.001 |
| Ostial lesion | 18 (3.0%) | 140 (11.3%) | < 0.001 |
| Moderate to severe calcification | 184 (30.7%) | 234 (18.9%) | < 0.001 |
| Chronic total occlusion | 48 (8.0%) | 73 (5.9%) | 0.086 |
| Bifurcation involvement | 95 (47.3%) | 260 (21.0%) | < 0.001 |
| Type B2 or C lesion | 353 (58.9%) | 797 (64.3%) | 0.025 |
| Lesion length (mm), median (IQR) | 25.0 (20.0, 40.0) | 25.0 (18.0, 40.0) | 0.33 |
| Reference vessel diameter (mm), mean (SD) | 2.5 (0.5) | 3.1 (0.5) | < 0.001 |
| Intravascular imaging | < 0.001 | ||
| IVUS | 41 (7.1%) | 29 (3.2%) | |
| OCT | 3 (0.5%) | 0 (0.0%) | |
| Total number of DCBs per lesion, mean (SD) | 1.1 (0.5) | – | < 0.001 |
| Max DCB diameter, mean (SD) | 2.4 (0.4) | – | |
| Total DCB length, mean (SD) | 29.1 (19.2) | – | |
| Hybrid PCI | 71 (11.9%) | – | |
| Bailout stenting | 46 (7.7%) | – | |
| Total stent length (mm), mean (SD) | 7.9 (18.8) | 32.5 (22.7) | < 0.001 |
DCB, drug-coated balloon; DES, drug-eluting stent; IQR, inter-quartile range; IVUS, intravascular ultrasound; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; SCB, sirolimus-coated balloon; SD, standard deviation
PS matching resulted in 157 matched pairs. SMDs were < 10% for all covariates included in the PS model, except for CKD (SMD 19%), intravascular imaging use (SMD 16%), and reference vessel diameter (SMD 17%) (Supplementary Tables 2–3).
Clinical outcomes at 2 years
At 2-year follow-up, the cumulative incidence of TLF was 9.1% in the SCB group and 9.9% in the DES group (adj. HR 0.88, 95% CI 0.43–1.81, p = 0.736) (Fig. 1; Table 3). Risks of TLR (adj. HR 1.28, 95% CI 0.39–4.17, p = 0.679), TV-MI (adj. HR 1.21, 95% CI 0.19–7.84, p = 0.844) and cardiac death (adj. HR 2.03, 95% CI 0.63–6.50, p = 0.232) were also comparable between the two groups. TVF occurred in 9.9% vs. 11.9% of patients (adj. HR 0.93, 95% CI 0.47–1.85, p = 0.845) (Fig. 1; Table 3). Kaplan–Meier curves for TLF and TVF are shown in Supplementary Fig. 1. Results were consistent when excluding patients who underwent hybrid PCI or bailout stenting from the SCB group (Supplementary Table 4).
Fig. 1.
Clinical outcomes at 2 years. The cumulative incidence of study endpoints at 2-year follow-up is displayed for the sirolimus-coated balloon (SCB)-based PCI group (red) and the drug-eluting stent (DES)-only PCI group (blue). Propensity score (PS)-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) are provided to compare clinical outcomes between the two treatment strategies
Table 3.
Clinical outcomes at 2 years
| SCB-based PCI (N = 599) |
DES-only PCI (N = 1239) |
Log-rank p-value |
PS-adjusted hazard ratio (95% CI)* |
PS-adjusted p-value* |
|
|---|---|---|---|---|---|
| Target lesion failure | 65 (9.1%) | 77 (9.9%) | 0.489 | 0.88 (0.43–1.81) | 0.736 |
| Cardiac death | 15 (2.1%) | 30 (3.3%) | 0.164 | 2.03 (0.63–6.50) | 0.232 |
| Target vessel MI | 11 (1.9%) | 14 (2.3%) | 0.529 | 1.21 (0.19–7.84) | 0.844 |
| Target lesion revascularization | 50 (6.7%) | 43 (3.8%) | < 0.001 | 1.28 (0.39–4.17) | 0.679 |
| Target vessel failure | 69 (9.9%) | 92 (11.9%) | 0.931 | 0.93 (0.47–1.85) | 0.845 |
| Target vessel revascularization | 56 (7.6%) | 60 (3.9%) | 0.001 | 1.93 (0.72–5.12) | 0.189 |
| Stent/Lesion thrombosis | 1 (0.2%) | 9 (0.7%) | 0.134 | 1.51 (0.06–36.85) | 0.799 |
All percentages are Kaplan-Meier estimates at the specific time point and thus do not equal the number of patients divided by the total number of patients in the treatment group
*Variables included in the model for PS calculation: sex, age, hypertension, dyslipidemia, prior PCI, CKD, LVEF, clinical presentation, LM involvement, ostial lesion, total lesion length, maximal lesion size, type B2 or C lesion, use of intravascular imaging, moderate-severe calcification, CTO, bifurcation
CI, confidence intervals; DES, drug-eluting stent; PCI, percutaneous coronary intervention; PS, propensity score; SCB, sirolimus-coated balloon
In the PS-matched cohort, 2-year TLF risk was also similar between the SCB and DES arms (HR 0.77, 95% CI 0.37–1.60, p = 0.485) (Supplementary Table 5).
Subgroup analysis
Results of the exploratory subgroup analysis for 2-year TLF are shown in Fig. 2. SCB-based PCI showed a signal of lower TLF risk in patients with CKD (7.9% vs. 13.3%; adj. HR 0.35, 95% CI 0.08–1.54; p for interaction = 0.042) and in those with long lesions (≥ 30 mm: 9.0% vs. 14.7%; adj. HR 0.41, 95% CI 0.16–1.05). In contrast, DES-only PCI was associated with lower TLF rates in patients with short lesions (< 30 mm: 9.4% vs. 5.2%; adj.HR 3.07, 95% CI 0.96–9.76; p for interaction = 0.003). A non-significant trend was also observed in favour of SCB among patients with moderate-to-severe calcification (p for interaction = 0.082).
Fig. 2.
Subgroup analysis for 2-year TLF. The forest plot shows the hazard ratios (HRs) with 95% confidence intervals for the primary endpoint across prespecified subgroups. Interaction p-values are displayed. HRs < 1.0 favour SCB-based PCI, whereas HRs > 1.0 favour DES-only PCI. p-values < 0.05 are indicated in bold
Among patients with IDDM, both TLF (6.8% vs. 14.2%, log-rank p = 0.087) and TVF (8.1% vs. 16.1%, log-rank p = 0.050) were numerically lower with SCB compared with DES, although not statistically significant after PS adjustment (TLF: adj. HR 0.56, 95% CI 0.11–2.73, p = 0.472; TVF: adj. HR 0.38, 95% CI 0.09–1.63, p = 0.193) (Supplementary Table 6).
Discussion
The SIMPLE-DM pooled analysis represents, to date, the first investigation directly comparing a SCB-based strategy with DES-only PCI in diabetic patients with de novo CAD. Our principal findings can be summarized as follows:
SCB-based PCI yielded similar 2-year outcomes to DES-only PCI, with no significant differences in TLF (9.1% vs. 9.9%) and TVF (9.9% vs. 11.9%).
SCB demonstrated comparable safety to contemporary DES, as evidenced by low and similar rates of cardiac death, TV-MI, and stent/lesion thrombosis.
In a secondary exploratory analysis, subgroup signals suggested differential treatment effects according to lesion and clinical complexity, with numerically lower TLF rates with SCB-based PCI in patients with CKD, longer or calcified lesions, and lower TLF rates with DES-only PCI in patients with short lesions.
DM is one of the strongest predictors of poor long-term outcomes after PCI, driven by both accelerated atherosclerosis progression in untreated segments and an increased risk of stent-related adverse events [27]. This unfavorable prognosis reflects not only the pro-thrombotic milieu and increased platelet reactivity of DM but also the persistent vascular injury, inflammation, and delayed healing induced by permanent metallic scaffolds [28]. While DES markedly reduced mortality, MI, and revascularization rates compared with bare-metal stents in diabetics [29], their outcomes remain suboptimal, with a TVF risk ranging from 7 to 12% at 1 year and steadily increasing up to 10 years after PCI [30, 31].
Against this background, a “leave-nothing-behind” strategy using DCB offers a conceptually attractive option in DM, restoring vessel patency while avoiding the chronic stimulus of a metallic implant. Prior studies in diabetic subsets have been limited mostly to PCB for small-vessel disease, often compared against first-generation DES. The BELLO (Balloon Elution and Late Loss Optimization) and BASKET-SMALL (Basel Stent Kosten Effektivitäts Trial Drug Eluting Balloons vs. Drug Eluting Stents in Small Vessel Interventions) 2 trials suggested favorable outcomes with DCB [32–34], while the more recent NOvara-BIella-TREnto (NOBITRE) registry reported higher TVR rates with PCB compared to new-generation DES [35].
SIMPLE-DM expands this evidence by comparing the outcomes of SCB-based PCI for de novo CAD in diabetic patients against a clinically relevant and contemporary benchmark, represented by a pooled analysis of three widely adopted DES platforms. Indeed, no class effect exists for DCB, underscoring the need for device-specific studies evaluating clinical outcomes according to the eluted antiproliferative agent and the specific coating technology. The SCB strategy relied on the recently introduced Magic Touch SCB, used as a DCB-only approach in more than 80% of cases, after accounting for both planned hybrid procedures and bailout stenting. Despite the numerically lower event rates observed in the DES cohort compared with previous literature, SCB-based PCI achieved comparable 2-year clinical outcomes, with no differences in terms of hard endpoints such as cardiac death and TV-MI. The numerically higher incidence of repeat revascularization in the SCB arm—attenuated after PS adjustment—likely reflects both baseline imbalances in clinical and angiographic characteristics and a greater propensity for angiographic follow-up in earlier SCB-treated patients.
Importantly, the lower risk of TLF observed in patients with CKD and in those with longer or calcified lesions treated with SCB compared to DES might support the concept that reducing metal burden may provide incremental benefit with increasing patient and lesion complexity, as also suggested by recent observational studies [11–13, 20, 36]. CKD is characterized by increased oxidative stress, persistent inflammation, and accelerated vascular calcification, all of which promote neointimal hyperplasia and in-stent neoatherosclerosis [37, 38]. Likewise, lesion length and calcification represent key angiographic determinants of stent failure, frequently leading to stent undersizing, malapposition, and eccentric expansion [39, 40]. Similarly, IDDM patients showed numerically lower event rates with SCB-based compared to DES-only PCI, which may reflect both their poorer response to DES and the greater extent of diffuse, recalcitrant CAD in this subset [33]. Therefore, it is plausible that DCB should not be universally preferred over DES in all diabetic patients but may be particularly advantageous in selected high-risk subsets. However, these findings were derived from exploratory, underpowered subgroup analyses and should currently be regarded as hypothesis-generating only.
Finally, SIMPLE-DM is the first study to directly compare clinical outcomes of SCB and DES in diabetic patients. In the first-generation DES era, sirolimus-eluting stents proved superior to paclitaxel-eluting stents in this population, reducing restenosis and repeat revascularization rates due to their more favorable pharmacokinetic profile [41–43]. Conversely, in the SPIRIT (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) III and IV trials, the advantage of everolimus-eluting over paclitaxel-eluting stents was markedly attenuated in patients with DM, possibly due to a downregulation of the mTOR signaling pathway—targeted by sirolimus and its derivatives [44, 45]. In the DCB setting, the performance of SCB is highly dependent on carrier technology, given the hydrophilic nature of sirolimus [8, 18]. The Magic Touch SCB incorporates sirolimus within phospholipid bilayer nanoparticles, enabling controlled transfer of the drug to the vessel wall according to Fick’s law of diffusion. Clinical trial evidence on this device currently remains limited to the TRANSFORM I (A Prospective Randomized Trial Comparing Sirolimus-Coated Balloon With Paclitaxel-Coated Balloon in De Novo Small Vessels) trial, which failed to demonstrate non-inferiority versus the SeQuent Please NEO PCB in terms of 6-month angiographic net lumen gain [46]. However, the prospective real-world EASTBOURNE registry reported encouraging clinical results, with 1-year TLR rates of 1.6% in non-diabetics and 2.3% in diabetics [47, 48]. The ongoing TRANSFORM II trial, comparing Magic Touch SCB with the Xience everolimus-eluting stent and including a pre-specified DM subgroup, is expected to provide pivotal insights into the role of this new technology in diabetic patients [49].
Limitations
First, as a pooled analysis of observational registries, all procedural decisions were left to operator discretion, introducing potential selection bias. In particular, DCB in contemporary practice are mainly used for selected clinical and angiographic indications (e.g., small vessels, long lesions, bifurcations, high bleeding risk patients) [9]. Second, substantial baseline imbalances in clinical and angiographic characteristics were observed between the SCB and DES groups, largely reflecting heterogeneity in enrolment periods, study designs, and procedural practices across the five pooled registries. Although we applied complementary PS–based methods (adjustment and matching with and without double-adjustment) to mitigate between-group imbalance and observed satisfactory post-matching balance, the influence of unmeasured confounders inherent to non-randomized pooled analyses cannot be excluded [26]. Third, owing to the retrospective study design and the procedural requirements of DCB-based PCI, patients with suboptimal lesion preparation, in whom DCB angioplasty was not feasible, were not included in the SCB arm. Fourth, information on time from DM diagnosis, post-discharge medications, body mass index and granular CKD staging, including dialysis status, were not consistently available across registries. Fifth, the 2-year follow-up may have been insufficient to capture late adverse events. Sixth, in the exploratory subgroup analysis for TLF, the relatively small sample size of individual subgroups may have increased the risk of both type I and type II error. Finally, although second-generation DES remain widely used in contemporary clinical practice, the DES-only PCI cohort in this study was limited to patients treated with third-generation DES, which may limit the generalizability of the findings. Accordingly, the results of the present study should be regarded as hypothesis-generating rather than definitive.
Conclusions
In this observational analysis of all-comer patients with DM undergoing PCI for de novo CAD, an SCB-based strategy was associated with favourable 2-year clinical outcomes in routine clinical practice. After adjustment for measured confounders, outcomes with SCB-based PCI appeared broadly comparable to those observed with contemporary DES-only PCI. Exploratory subgroup analyses highlighted signals of incremental benefit in the highest-risk subsets, including patients with IDDM, CKD, and longer and more severely calcified lesions, although these results should be regarded as hypothesis-generating. Dedicated randomized clinical trials with long-term follow-up are needed to confirm our findings and define the role of DCB-based PCI as a potential metal-free revascularization strategy for diabetic patients with complex CAD.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The publication fee for this work was covered by the Italian Ministry of Health’s "Ricerca Corrente" funding to the IRCCS Humanitas Research Hospital.
Abbreviations
- CAD
Coronary artery disease
- DCB
Drug-coated balloon
- DES
Drug-eluting stent
- DM
Diabetes Mellitus
- IDDM
Insulin-dependent diabetes mellitus
- MACE
Major adverse cardiovascular events
- PCB
Paclitaxel coated balloon
- PCI
Percutaneous coronary intervention
- SCB
Sirolimus-coated balloon
- TLF
Target lesion failure
- TLR
Target lesion revascularization
- TVF
Target vessel failure
- TVR
Target vessel revascularization
- TV-MI
Target vessel myocardial infarction
Author contributions
MG, FG conception, design, acquisition, statistical analysis, and interpretation of data for the work; drafting the work and revising it critically for important intellectual content. PPL, MC conception, design, acquisition, and interpretation of data for the work and revising it critically for important intellectual content. FLC, FT, MF, GC, MLR, VB, BR, DR, AM, GG, CB, AL, GGS, CG, GS provided help and advice on content selection, interpretation, and organization. BC, AC data interpretation and critical revision of the work for important intellectual content; substantially edited and revised the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.
Funding
none.
Data availability
The data that support the findings of this study are available on reasonable request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.
Declarations
Ethics approval and consent to participate
All studies complied with the Declaration of Helsinki, were conducted in accordance with local Institutional Review Board requirements, and all patients provided informed consent for the procedure and subsequent data collection.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Mauro Gitto and Gaia Filiberti: Co first authors.
References
- 1.Ong KL, Stafford LK, McLaughlin SA, et al. Global, regional, and National burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the global burden of disease study 2021. Lancet. 2023;402(10397):203–34. 10.1016/S0140-6736(23)01301-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Nowbar AN, Gitto M, Howard JP, Francis DP, Al-Lamee R. Mortality from ischemic heart disease. Circ Cardiovasc Qual Outcomes. 2019;12(6):e005375. 10.1161/CIRCOUTCOMES.118.005375. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.del Val D, Berta B, Roleder T, et al. Vulnerable plaque features and adverse events in patients with diabetes mellitus: a post hoc analysis of the COMBINE OCT-FFR trial. EuroIntervention. 2024;20(11):e707–17. 10.4244/EIJ-D-23-00628. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.The BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360(24):2503–15. 10.1056/NEJMoa0805796. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Roumeliotis A, Siasos G, Dangas G, et al. Significance of diabetes mellitus status in patients undergoing percutaneous left main coronary artery intervention. Catheter Cardiovasc Interv. 2024;104(4):723–32. 10.1002/CCD.31179. [DOI] [PubMed] [Google Scholar]
- 6.Dangas GD, Farkouh ME, Sleeper LA, et al. Long-term outcome of PCI versus CABG in insulin and non-insulin-treated diabetic patients: results from the FREEDOM trial. J Am Coll Cardiol. 2014;64(12):1189–97. 10.1016/J.JACC.2014.06.1182. [DOI] [PubMed] [Google Scholar]
- 7.Thomas A, Gitto M, Shah S, et al. Antiplatelet strategies following PCI: A review of trials informing current and future therapies. J Soc Cardiovasc Angiography Interventions. 2023;2(3):100607. 10.1016/J.JSCAI.2023.100607. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Leone PP, Gitto M, Gao C, Sanz Sánchez J, Latib A, Colombo A. Rethinking coronary artery metal implants. Prog Cardiovasc Dis Published Online. 2025. 10.1016/J.PCAD.2025.07.005. [DOI] [PubMed] [Google Scholar]
- 9.Camaj A, Leone PP, Kini A, Sharma SK. Sirolimus- vs Paclitaxel-Coated balloons: it is only the start. JACC Cardiovasc Interv. 2024;17(4):580. 10.1016/J.JCIN.2023.12.021. [DOI] [PubMed] [Google Scholar]
- 10.Colombo A, Leone PP. Redefining the way to perform percutaneous coronary intervention: a view in search of evidence. Eur Heart J. 2023;44(41):4321–3. 10.1093/EURHEARTJ/EHAD215. [DOI] [PubMed] [Google Scholar]
- 11.Leone PP, Oliva A, Regazzoli D, et al. Immediate and follow-up outcomes of drug-coated balloon angioplasty in de Novo long lesions on large coronary arteries. EuroIntervention. 2023;19(11):e923–5. 10.4244/EIJ-D-23-00502. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Gitto M, Sticchi A, Chiarito M, et al. Drug-Coated balloon angioplasty for de Novo lesions on the left anterior descending Artery. Circ cardiovasc interv. Published Online Oct. 2023;24:e013232. 10.1161/CIRCINTERVENTIONS.123.013232. [DOI] [PubMed] [Google Scholar]
- 13.Gitto M, Leone PP, Gioia F, et al. Coronary artery dissection in Drug-Coated balloon angioplasty: Incidence, Predictors, and clinical outcomes. Am J Cardiol. 2024;239:28–35. 10.1016/J.AMJCARD.2024.12.008. [DOI] [PubMed] [Google Scholar]
- 14.Shin ES, Jun EJ, Kim S, et al. Clinical impact of Drug-Coated Balloon–Based percutaneous coronary intervention in patients with multivessel coronary artery disease. JACC Cardiovasc Interv. 2023;16(3):292–9. 10.1016/J.JCIN.2022.10.049. [DOI] [PubMed] [Google Scholar]
- 15.Leone PP, Mangieri A, Regazzoli D, et al. Drug-Coated balloon angioplasty guided by postpercutaneous coronary intervention pressure gradient: the REDUCE-STENT retrospective registry. Cardiovasc Interventions. 2023;16(3):363–5. 10.1016/J.JCIN.2022.09.054. [DOI] [PubMed] [Google Scholar]
- 16.Fezzi S, Giacoppo D, Fahrni G et al Individual patient data meta-analysis of paclitaxel-coated balloons vs. drug-eluting stents for small-vessel coronary artery disease: the ANDROMEDA study. Eur Heart J 2025. 10.1093/EURHEARTJ/EHAF002. [DOI] [PubMed] [Google Scholar]
- 17.Giacoppo D, Alfonso F, Xu B, et al. Drug-Coated balloon angioplasty versus Drug-Eluting stent implantation in patients with coronary stent restenosis. J Am Coll Cardiol. 2020;75(21):2664–78. 10.1016/J.JACC.2020.04.006. [DOI] [PubMed] [Google Scholar]
- 18.Leone PP, Calamita G, Gitto M et al Sirolimus- versus paclitaxel-coated balloons for treatment of coronary artery disease. Am J Cardiol. 2025. 10.1016/J.AMJCARD.2025.07.004. [DOI] [PubMed] [Google Scholar]
- 19.Cortese B, Testa L, Heang TM, et al. Sirolimus-Coated balloon in an All-Comer population of coronary artery disease patients: the EASTBOURNE prospective registry. JACC Cardiovasc Interv. 2023;16(14):1794–803. 10.1016/J.JCIN.2023.05.005. [DOI] [PubMed] [Google Scholar]
- 20.Tartaglia F, Gitto M, Leone PP et al. Validation of complex PCI criteria in drug-coated balloon angioplasty. Clin Res Cardiol. 2025. 10.1007/S00392-025-02664-X [DOI] [PubMed] [Google Scholar]
- 21.Godino C, Beneduce A, Ferrante G, et al. One-year clinical outcome of biodegradable polymer sirolimus-eluting stent in all-comers population. Insight from the ULISSE registry (ULtimaster Italian multicenter all comers stent rEgistry). Int J Cardiol. 2018;260:36–41. 10.1016/J.IJCARD.2018.02.014. [DOI] [PubMed] [Google Scholar]
- 22.Colombo A, Godino C, Donahue M, et al. One-year clinical outcome of amphilimus polymer-free drug-eluting stent in diabetes mellitus patients: insight from the ASTUTE registry (AmphilimuS iTalian mUlticenTre rEgistry). Int J Cardiol. 2016;214:113–20. 10.1016/J.IJCARD.2016.03.088. [DOI] [PubMed] [Google Scholar]
- 23.Sardella G, Stefanini GG, Briguori C, et al. Safety and efficacy of polymer-free biolimus-eluting stents in all-comer patients: the RUDI-FREE study. EuroIntervention. 2018;14(7):772–9. 10.4244/EIJ-D-18-00148. [DOI] [PubMed] [Google Scholar]
- 24.Mangieri A, Testa L, Heang TM, et al. Safety and efficacy of single antiplatelet therapy in a large cohort of patients treated with sirolimus-coated balloon: post hoc analysis from the prospective EASTBOURNE registry. Cardiovasc Revasc Med. 2025;74:52–6. 10.1016/J.CARREV.2024.07.024. [DOI] [PubMed] [Google Scholar]
- 25.Garcia-Garcia HM, McFadden EP, Farb A, et al. Standardized end point definitions for coronary intervention trials: the academic research consortium-2 consensus document. Circulation. 2018;137(24):2635–50. 10.1161/CIRCULATIONAHA.117.029289/FORMAT/EPUB. [DOI] [PubMed] [Google Scholar]
- 26.Elze MC, Gregson J, Baber U, et al. Comparison of propensity score methods and covariate adjustment: evaluation in 4 cardiovascular studies. J Am Coll Cardiol. 2017;69(3):345–57. 10.1016/J.JACC.2016.10.060. [DOI] [PubMed] [Google Scholar]
- 27.Stefanini GG, Alfonso F, Barbato E, et al. Management of myocardial revascularisation failure: an expert consensus document of the EAPCI. EuroIntervention. 2020;16(11):e875–90. 10.4244/EIJ-D-20-00487. [DOI] [PubMed] [Google Scholar]
- 28.Chiarito M, Mehran R. Drug-eluting stents in diabetic patients: are we still treading water? Catheter Cardiovasc Interv. 2020;96(2):253–4. 10.1002/CCD.29164. [DOI] [PubMed] [Google Scholar]
- 29.Yang Y, Hyun J, Lee J, et al. Effectiveness and safety of contemporary Drug-Eluting stents in patients with diabetes mellitus. JACC Asia. 2021;1(2):173–84. 10.1016/J.JACASI.2021.07.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Jeong YJ, Ahn JM, Hyun J, et al Ten-year outcomes after Drug-Eluting stents or bypass surgery for left main coronary disease in patients with and without diabetes mellitus: the PRECOMBAT extended Follow-Up study. J Am Heart Assoc. 2021;10(14):e019834. 10.1161/JAHA.120.019834. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Romaguera R, Salinas P, Gomez-Lara J, et al. Amphilimus- vs. zotarolimus-eluting stents in patients with diabetes mellitus and coronary artery disease: the SUGAR trial. Eur Heart J. 2022;43(13):1320–30. 10.1093/EURHEARTJ/EHAB790. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Giannini F, Latib A, Jabbour RJ, et al. Comparison of Paclitaxel drug-eluting balloon and Paclitaxel-eluting stent in small coronary vessels in diabetic and nondiabetic patients - results from the BELLO (balloon elution and late loss optimization) trial. Cardiovasc Revasc Med. 2017;18(1):4–9. 10.1016/J.CARREV.2016.12.008. [DOI] [PubMed] [Google Scholar]
- 33.Jeger RV, Farah A, Ohlow MA, et al. Long-term efficacy and safety of drug-coated balloons versus drug-eluting stents for small coronary artery disease (BASKET-SMALL 2): 3-year follow-up of a randomised, non-inferiority trial. Lancet. 2020;396(10261):1504–10. 10.1016/S0140-6736(20)32173-5. [DOI] [PubMed] [Google Scholar]
- 34.Li K, Cui K, Dan X, Feng J, Pu X The comparative short-term efficacy and safety of drug-coated balloon vs. drug-eluting stent for treating small-vessel coronary artery lesions in diabetic patients. Front Public Health. 2022. 10.3389/FPUBH.2022.1036766. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Verdoia M, Zilio F, Gioscia R, et al. Prognostic impact of Drug-Coated balloons in patients with diabetes mellitus: A Propensity-Matched study. Am J Cardiol. 2023;206:73–8. 10.1016/J.AMJCARD.2023.08.113. [DOI] [PubMed] [Google Scholar]
- 36.Colombo A, Leone PP, Ploumen EH, von Birgelen C. Drug-coated balloons as a first choice for patients with de Novo lesions: pros and cons. EuroIntervention. 2024;20(2):e120–2. 10.4244/EIJ-E-23-00034. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Gao Y, Gu N, Zhou Y, Wang Y, Zhao R, Shi B Study on the relationship between in-stent neoatherosclerosis and chronic kidney disease: an optical coherence tomography study. Sci Rep. 2025. 10.1038/S41598-025-05441-Y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Bangalore S, Guo Y, Samadashvili Z, Blecker S, Xu J, Hannan EL. Revascularization in patients with multivessel coronary artery disease and chronic kidney disease: Everolimus-Eluting stents versus coronary artery bypass graft surgery. J Am Coll Cardiol. 2015;66(11):1209–20. 10.1016/J.JACC.2015.06.1334. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Torii S, Jinnouchi H, Sakamoto A, et al. Vascular responses to coronary calcification following implantation of newer-generation drug-eluting stents in humans: impact on healing. Eur Heart J. 2020;41(6):786–A796. 10.1093/EURHEARTJ/EHZ850. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Kong MG, Han JK, Kang JH, et al. Clinical outcomes of long stenting in the drug-eluting stent era: Patient-level pooled analysis from the GRAND-DES registry. EuroIntervention. 2021;16(16):1318–25. 10.4244/EIJ-D-19-00296. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Lee SW, Park SW, Kim YH, et al. A randomized comparison of sirolimus- versus Paclitaxel-eluting stent implantation in patients with diabetes mellitus. J Am Coll Cardiol. 2008;52(9):727–33. 10.1016/J.JACC.2008.04.056. [DOI] [PubMed] [Google Scholar]
- 42.Kufner S, De Waha A, Tomai F, et al. A meta-analysis of specifically designed randomized trials of sirolimus-eluting versus paclitaxel-eluting stents in diabetic patients with coronary artery disease. Am Heart J. 2011;162(4):740–7. 10.1016/J.AHJ.2011.07.003. [DOI] [PubMed] [Google Scholar]
- 43.Billinger M, Beutler J, Taghetchian KR, et al. Two-year clinical outcome after implantation of sirolimus-eluting and paclitaxel-eluting stents in diabetic patients. Eur Heart J. 2008;29(6):718–25. 10.1093/EURHEARTJ/EHN021. [DOI] [PubMed] [Google Scholar]
- 44.Kereiakes DJ, Cutlip DE, Applegate RJ, et al. Outcomes in diabetic and nondiabetic patients treated with everolimus- or paclitaxel-eluting stents: results from the SPIRIT IV clinical trial (Clinical evaluation of the XIENCE V everolimus eluting coronary stent System). J Am Coll Cardiol. 2010;56(25):2084–9. 10.1016/J.JACC.2010.10.006. [DOI] [PubMed] [Google Scholar]
- 45.Stone GW, Midei M, Newman W, et al. Comparison of an everolimus-eluting stent and a paclitaxel-eluting stent in patients with coronary artery disease: a randomized trial. JAMA. 2008;299(16):1903–13. 10.1001/JAMA.299.16.1903. [DOI] [PubMed] [Google Scholar]
- 46.Ninomiya K, Serruys PW, Colombo A, et al. A prospective randomized trial comparing Sirolimus-Coated balloon with Paclitaxel-Coated balloon in de Novo small vessels. JACC Cardiovasc Interv. 2023;16(23):2884–96. 10.1016/J.JCIN.2023.09.026. [DOI] [PubMed] [Google Scholar]
- 47.Leone PP, Heang TM, Yan LC, et al. Two-year outcomes of sirolimus-coated balloon angioplasty for coronary artery disease: the EASTBOURNE registry. EuroIntervention. 2024;20(13):e831–3. 10.4244/EIJ-D-23-00966. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Caiazzo G, Oliva A, Testa L et al Sirolimus-coated balloon in all-comer population of coronary artery disease patients: the EASTBOURNE DIABETES prospective registry. Cardiovasc Diabetol. 2024. 10.1186/S12933-024-02139-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Greco A, Sciahbasi A, Abizaid A, et al. Sirolimus-coated balloon versus everolimus-eluting stent in de Novo coronary artery disease: rationale and design of the TRANSFORM II randomized clinical trial. Catheter Cardiovasc Interv. 2022;100(4):544–52. 10.1002/CCD.30358. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available on reasonable request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.