Device innovation or systemic risk management?—rethinking priorities in diabetic percutaneous coronary intervention

The global burden of diabetes mellitus (DM) continues to rise, and with it the prevalence of coronary artery disease (CAD) and the need for coronary revascularization (1). Notably, even with optimal control of traditional cardiovascular risk factors, patients with type 2 diabetes continue to exhibit a substantial residual risk (21% higher) of cardiovascular events compared with individuals without diabetes (2), making effective treatment of CAD essential. Percutaneous coronary intervention (PCI) plays a central role in this population and now accounts for nearly 40% of all PCI procedures (3). However, outcomes after PCI remain worse than in non-diabetic individuals (4), largely due to more diffuse and complex atherosclerosis, greater small vessel involvement (5), and diabetes-specific pathophysiological mechanisms (6), including endothelial-to-mesenchymal transition, which promotes endothelial dysfunction, oxidative stress, altered flow dynamics, and enhanced vascular smooth muscle proliferation in response to injury. Together with potential device-related limitations, such as polymer biocompatibility and variability in drug response (7), these factors create a persistent pro-atherogenic milieu. In this context, device innovation alone is unlikely to overcome this challenging scenario; a unified approach encompassing optimal medical therapy and healthy lifestyle habits is imperative.

DM is a well-established independent predictor of stent failure (4) and major adverse cardiovascular events (MACEs) following PCI (8). Despite the substantial reduction in target lesion revascularization achieved with drug-eluting stents (DES) compared with bare-metal stents (9), and ongoing improvements in stent technology, patients with diabetes continue to exhibit a disproportionately higher risk of adverse events than their non-diabetic counterparts (4,10). Notably, rates of cardiac death, myocardial infarction, and repeat revascularization remain significantly higher in diabetic patients, particularly in those requiring insulin therapy (11). This unfavorable risk profile extends across different device platforms, including biodegradable polymer DES (12) and drug-coated balloons (13), underscoring the persistent vulnerability of this population despite contemporary revascularization strategies.

Over the past decade, multiple randomized trials have explored whether refinements in DES design could translate into better outcomes in this high-risk population. The original TUXEDO trial (14) demonstrated a clear superiority of durable polymer everolimus-eluting stents (EES) over first-generation paclitaxel-eluting platforms, establishing EES as the benchmark. However, as comparisons shifted to contemporary DES technologies, differences became less pronounced. In TUXEDO-2 India trial (15), recently presented preliminary data suggest that an ultrathin biodegradable-polymer sirolimus-eluting stent (SES) achieved clinical outcomes comparable to those of the everolimus-eluting XIENCE platform, a finding consistent with prior meta-analyses showing no meaningful differences among modern DES platforms, including biodegradable and durable polymer devices, in patients with diabetes (16).

In parallel, novel strategies have sought to enhance local drug delivery to overcome the particular biological challenges of diabetes, including diffuse CAD and extensive coronary calcification, which may result in heterogeneous drug diffusion, as well as a reduced responsiveness of diabetic endothelial cells to mTOR inhibitors. In the SUGAR trial (17), a polymer-free amphilimus-eluting stent (Cre8 EVO), designed to improve intracellular drug uptake and concentration by releasing sirolimus from discrete reservoirs using a lipid-based carrier, demonstrated early superiority over a zotarolimus-eluting stent at 1 year; however, this benefit was not sustained at longer follow-up, with no significant differences observed at 2 years (18).

Beyond stent-based approaches, drug-coated balloons have also been investigated as an alternative revascularization strategy, with some meta-analyses suggesting potential benefits in selected subsets such as small-vessel disease (19-20). However, these findings are limited by heterogeneity and the inclusion of earlier-generation comparators (first-generation DES or bare metal stents).

Taken together, these data suggest that, in the era of contemporary DES technology, incremental modifications in device design alone have yielded only modest or transient improvements in outcomes among patients with diabetes.

In this context, a novel device for PCI was evaluated in the ABILITY Diabetes Global trial (21). The Abluminus DES+ is a thin-strut, cobalt-chromium SES platform in which the antiproliferative drug is delivered not only from a biodegradable polymer coating on the abluminal surface of the stent, but also from the exposed segments of the delivery balloon. This hybrid design aims to enhance drug distribution along the treated segment, including stent edges, thereby addressing the risk of geographic miss and restenosis while potentially facilitating vascular healing. The trial was designed as a non-inferiority study comparing the efficacy and safety of the Abluminus DES+ with the durable-polymer everolimus-eluting XIENCE stent in a large cohort of patients with diabetes undergoing PCI in the context of chronic coronary syndromes or non-ST-elevation acute coronary syndromes.

At 12 months, Abluminus DES+ failed to meet the criteria for non-inferiority and was associated with significantly higher rates of ischemia-driven target lesion revascularization [Kaplan-Meier estimate 4.8% vs. 2.1%; absolute risk difference 2.7%, 95% confidence interval (CI): 1.3–4.1%] and target lesion failure (9.7% vs. 6.2%; absolute difference 3.5%, 95% CI: 1.5–5.5%) compared with XIENCE. Differences in target lesion failure were driven by an excess of target-lesion revascularization and myocardial infarction in the Abluminus DES+ arm, without differences in cardiovascular or all-cause mortality and no further divergence beyond the first year. Importantly, the direction and magnitude of the effect were consistent across both per-protocol and intention-to-treat analyses, supporting the robustness of the findings. These results are further aligned with previous imaging data (optical coherence tomography) showing no reduction in neointimal proliferation with Abluminus DES+ compared with durable-polymer EES in diabetic patients (22).

The study has several notable strengths. It represents the largest randomized trial to date conducted exclusively in patients with diabetes undergoing PCI, enrolling more than 3,000 patients across 74 centers in 16 countries, thereby enhancing its generalizability. In addition, the 24-month follow-up is particularly relevant, given prior evidence suggesting that early differences between devices may not be sustained over time, as observed in the SUGAR trial. Finally, the use of the everolimus-eluting XIENCE stent as a comparator provides a robust and clinically meaningful benchmark in this high-risk population.

Nevertheless, several limitations should be considered when interpreting the results. Although the study included a substantial proportion of complex lesions (one third of cases), procedural optimization appears suboptimal, with intravascular imaging used in only 10–15% of cases—a recurring and somewhat disheartening pattern across contemporary PCI trials. Time and again, we stumble over the same stone: despite robust evidence (23,24) demonstrating a consistent survival benefit of intravascular imaging guidance across multiple high-risk settings, we continue to overlook what has proven to be one of the most impactful prognostic drivers in interventional cardiology. Optimizing how we prepare the plaque and how to deploy existing technology may ultimately matter more than the technology itself. Post-dilatation practices were not reported separately for each treatment group, limiting insights into potential differences in procedural strategy. Also, protocol deviations were not negligible (10% of patients did not receive implantation according to the instructions for use). Finally, the open-label design introduces the possibility of operator-related bias, which cannot be fully excluded.

On other grounds, we should highlight the fine performance of the comparator: in other words, the combination of the durable fluoropolymer with everolimus is known to be a reference standard. Although technology moved towards biodegradable, mostly abluminal polymers with sirolimus as the drug of choice, not all evidence aligns. Indeed, some meta-analyses have suggested modestly improved outcomes with everolimus-eluting stents compared with sirolimus-eluting platforms in diabetic populations (25). Previous meta-analyses have shown comparable efficacy between biodegradable- and durable-polymer DES in both all-comers (26) and diabetic populations (16).

Adherence to dual antiplatelet therapy was high and balanced between groups. Most notably, landmark analyses demonstrated that the excess risk with DES+ was confined to the early post-PCI period, with no divergence beyond 12 months. Taken together, these findings strongly support a predominantly early, procedure-related mechanism rather than a delayed biological effect related to drug or polymer characteristics.

The choice of a non-inferiority (with sequential superiority testing) design in ABILITY Diabetes Global is methodologically defensible given the excellent performance of contemporary everolimus-eluting stents, which have become a benchmark in modern PCI. However, the observed XIENCE event rates were lower than those used to prespecify the margins. For target lesion failure, the 3.0% margin was set against an expected 9.0% rate (33% relative tolerance), but the observed rate was 6.2%, so the same absolute margin actually represents a 48% relative increase. For ischemia-driven target lesion revascularization the mismatch is more pronounced: against an observed XIENCE rate of 2.1%, the prespecified 2.8% margin corresponds to a >130% relative increase—a margin wider than the comparator’s entire event rate. This gap between prespecified and observed event rates is worth acknowledging when interpreting the absolute margins in the contemporary DES era. These margins correspond to allowing an approximately 30–40% relative increase in lesion-related events, a threshold that may be considered clinically meaningful in the contemporary DES era. Moreover, the per-protocol analysis—arguably as informative as the intention-to-treat in device trials where adherence and implantation technique are critical determinants of outcome—closely mirrors the primary results. This consistency across analytical approaches strengthens the conclusion that the experimental device confers no additional clinical benefit and may, in fact, be associated with worse short-term outcomes, reinforcing the translational relevance of these findings.

These findings also prompt a broader reflection on the determinants of outcomes in diabetic patients undergoing PCI. Poor glycemic control has been consistently associated with an increased risk of stent failure, particularly driven by in-stent restenosis (27). However, emerging evidence suggests that the benefits of contemporary glucose-lowering therapies extend beyond glycemic control itself. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been associated with a reduced incidence of restenosis-related events independently of glycemic levels (28), while glucagon-like peptide-1 receptor agonists (GLP-1 RA) have been linked to lower rates of MACE, restenosis, and disease progression in observational and cohort studies (29). Moreover, combined use of these agents appears to confer additive cardiovascular benefit (30). According to the current guidelines, SGLT2i or GLP-1 RA are recommended in patients with type 2 DM and CAD with a grade of recommendation I, level of evidence A (31). However, only approximately 5% and 12% of patients of ABILITY Diabetes Global were treated with GLP-1RA and iSGLT2, respectively. This likely reflects the fact that guideline recommendations for these glucose-lowering agents were consolidated after the study enrollment period, highlighting a gap between evidence and real-world adoption that may have influenced outcomes.

In conclusion, multiple device- and procedure-based strategies have been explored to mitigate the excess risk of restenosis and target lesion failure in diabetic patients undergoing PCI. Collectively, these data suggest that, in the era of mature DES technology, further improvements are unlikely to be achieved through iterations in drug or polymer design alone. Rather, future progress could depend on optimizing early device-vessel interaction and procedural strategy—including routine use of intravascular imaging—and, equally important, intensifying systemic cardiovascular risk management including the use of contemporary glucose-lowering therapies and aggressive lipid-lowering therapy to reduce the persistent burden of ischemic and recurrent events in this high-risk population.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Cardiovascular Diagnosis and Therapy. The article has undergone external peer review.

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2026-0183/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2026-0183/coif). R.O.L. reports holding a Rio Hortega research-training contract (CM24/00142) funded by the Instituto de Salud Carlos III (ISCIII), Spain. P.S. has received speaker fees from Abbott, Boston Scientific, and Shockwave. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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