Compound danshen dripping pills for non-proliferative diabetic retinopathy: Efficacy, mechanisms, and future directions

Abstract

Non-proliferative diabetic retinopathy (NPDR), the early stage of diabetic retinopathy, is a leading cause of visual impairment in patients with type 2 diabetes mellitus, characterized by retinal microaneurysms, hemorrhages, exudates, and macular edema. Conventional Western therapies, while partially effective, often carry limitations such as high costs, potential adverse effects, and incomplete control of disease progression, creating an unmet clinical need for safer and more comprehensive treatment options. Compound danshen dripping pills (CDDP), a patented traditional Chinese medicine formulation composed of extracts from Radix Salviae Miltiorrhizae (danshen) and Radix Panax Notoginseng (sanqi), has been widely used in clinical practice for decades to manage cardiovascular and microvascular disorders, and emerging evidence suggests its potential in NPDR management. This review synthesizes the latest findings from more than 65 published studies, including randomized controlled trials, meta-analyses, network meta-analyses, preclinical investigations, and molecular studies, to comprehensively evaluate CDDP’s efficacy, safety, and underlying mechanisms in NPDR; discusses CDDP’s multi-targeted effects on key pathophysiological pathways of NPDR, including oxidative stress, inflammation, and microvascular dysfunction, and explores its synergistic effects when combined with conventional Western therapies; and highlights critical research gaps and outline future directions to validate CDDP’s utility and facilitate its integration into global clinical guidelines for NPDR management. The accumulated evidence confirms that CDDP is a safe and effective therapeutic option for NPDR, with a favorable safety profile and multi-faceted mechanisms of action, though further high-quality research is needed to address limitations in current studies and expand its clinical application.

Key Words: Compound danshen dripping pills; Non-proliferative diabetic retinopathy; Diabetic retinopathy; Traditional Chinese medicine; Efficacy; Mechanisms

Core Tip: Non-proliferative diabetic retinopathy, a common type 2 diabetes complication, has Western therapies limited by cost, side effects, and incomplete control. Compound danshen dripping pills, a patented traditional Chinese medicine, improves retinal health (reducing microaneurysms and edema) alone or with Western drugs via multi-targeted pathways, with mild side effects. Research gaps exist; future studies should address these to integrate compound danshen dripping pills into global guidelines.

INTRODUCTION

Diabetic retinopathy (DR) continues to stand as one of the most formidable microvascular complications of type 2 diabetes mellitus (T2DM), affecting millions of individuals worldwide and placing an ever-growing strain on healthcare systems[1-3]. Its clinical course is often insidious yet relentless, progressing from the early non-proliferative stage (NPDR)—characterized by retinal microaneurysms, dot-and-blot hemorrhages, hard exudates, and macular edema—to the advanced proliferative stage (PDR), where pathological neovascularization can ultimately lead to irreversible vision loss if timely intervention is not achieved[2,4-6]. Although current Western medical approaches, including anti-vascular endothelial growth factor (VEGF) therapies, laser photocoagulation, and agents such as calcium dobesilate, have undoubtedly improved clinical outcomes, their benefits are often tempered by practical and biological limitations[6-9]. High treatment costs, the burden of repeated interventions, and the risk of adverse effects—ranging from intraocular inflammation to elevated intraocular pressure—continue to challenge both clinicians and patients, while incomplete protection against progressive microvascular damage remains a persistent concern[10-12]. Against this backdrop, the search for more comprehensive and sustainable therapeutic strategies has gained renewed urgency, bringing traditional Chinese medicine (TCM) into sharper focus as a potentially valuable complement to conventional care[2,3,13].

Among these, compound danshen dripping pills (CDDP) have attracted particular attention. This patented TCM formulation, derived from Radix Salviae Miltiorrhizae (danshen) and Radix Panax Notoginseng (sanqi), has been used for decades in the management of cardiovascular and microvascular disorders, including coronary heart disease, hypertension, and myocardial ischemia[13-18]. Its long-standing clinical use has fostered a degree of confidence in both its safety and therapeutic potential, while more recent studies have begun to illuminate its relevance in the context of diabetic retinal disease[19-21]. What makes CDDP particularly intriguing is not merely its historical use, but its pharmacological complexity. Rather than acting on a single molecular target, it comprises a spectrum of bioactive constituents—including tanshinones, salvianolic acids, and ginsenosides—that appear to work in concert, modulating multiple interconnected pathways involved in oxidative stress, inflammation, and microvascular dysfunction[22-24]. This multi-targeted mode of action resonates strongly with the multifactorial nature of NPDR itself[25], suggesting a therapeutic alignment that is both conceptually and clinically appealing.

Over the past decade, research interest in CDDP has expanded markedly, spanning randomized controlled trials (RCTs), meta-analyses, network pharmacology studies, metabolomic investigations, and a wide range of preclinical models[11,22,26,27]. Recent high-quality clinical evidence has further strengthened this foundation. A large-scale, multicenter, randomized, double-blind, placebo-controlled trial involving 484 patients with NPDR demonstrated that CDDP significantly improved overall fundus outcomes after 24 weeks of treatment, with an effective rate of 77.07% compared to 53.72% in the placebo group (P < 0.001)[13]. Notably, this study also confirmed improvements in retinal lesion severity, microaneurysms, hemorrhages, and macular edema, while maintaining a favorable safety profile, thereby providing robust clinical validation of CDDP’s therapeutic potential in NPDR. Collectively, these efforts have begun to build a more coherent picture of its efficacy and underlying mechanisms, although important questions remain. In this context, the present review seeks to bring together evidence from recent studies to provide a comprehensive and critically balanced assessment of CDDP in NPDR. By integrating clinical outcomes with mechanistic insights, we aim not only to clarify its therapeutic value but also to identify the gaps that continue to limit its broader adoption. Ultimately, this work aspires to contribute to a more nuanced understanding of how integrative approaches—bridging traditional and modern medicine—might better serve patients facing the long-term challenges of DR.

PATHOPHYSIOLOGY OF NPDR AND THE RATIONALE FOR CDDP INTERVENTION

NPDR develops as a consequence of prolonged exposure to hyperglycemia, which gradually undermines the structural and functional integrity of the retinal microvasculature. This process is far from linear; rather, it reflects a complex and tightly interwoven network of pathological events, including oxidative stress, chronic inflammation, endothelial dysfunction, metabolic imbalance, and impaired retinal perfusion[2,22,28]. At the molecular level, sustained hyperglycemia drives excessive production of reactive oxygen species, overwhelming the retina’s antioxidant defenses and initiating a cascade of cellular injury. The resulting oxidative burden disrupts the blood-retina barrier (BRB), increases vascular permeability, and promotes apoptosis of both retinal endothelial cells and neurons, thereby laying the groundwork for progressive retinal damage[29-31]. In parallel, inflammatory signaling pathways—most notably tumor necrosis factor (TNF)-α and nuclear factor-kappa B (NF-κB)—become persistently activated, leading to elevated levels of pro-inflammatory cytokines such as TNF-α and interleukin-6, as well as adhesion molecules like intercellular adhesion molecule-1 (ICAM-1)[32,33]. These mediators facilitate leukocyte adhesion and infiltration, further aggravating vascular injury and sustaining a chronic inflammatory milieu within the retina[22,34]. Compounding these effects, microvascular dysfunction compromises retinal blood flow, resulting in localized hypoxia that feeds back into oxidative and inflammatory pathways, ultimately creating a self-perpetuating cycle of damage that drives NPDR progression[35,36]. Beyond these classical mechanisms, recent experimental and systems-level analyses further suggest that DR is driven by complex, multi-target molecular networks involving oxidative stress-inflammation crosstalk and metabolic reprogramming, reinforcing the need for therapeutics capable of coordinated pathway modulation rather than single-target intervention[3,37].

Such a multifactorial disease process resists simplification and, in many respects, challenges the paradigm of single-target therapy. It is precisely within this context that CDDP emerges as a particularly compelling intervention. Rooted in TCM, CDDP embodies a holistic therapeutic philosophy that seeks to restore systemic balance rather than address isolated molecular defects[3,36]. Within TCM theory, NPDR is commonly understood as a manifestation of “qi stagnation and blood stasis”, a conceptual framework that, perhaps surprisingly, resonates with modern descriptions of impaired microcirculation and metabolic dysfunction in the retinal vasculature[38,39]. By aiming to “invigorate blood circulation and resolve stasis”, CDDP directly targets the microvascular disturbances that lie at the heart of NPDR pathology[15,40].

What lends further credibility to this approach is the growing body of pharmacological evidence supporting the activity of CDDP’s constituent compounds. Bioactive molecules such as salvianolic acid A, salvianolic acid B, tanshinone IIA, and ginsenoside Rg1 have been shown to modulate key pathological pathways implicated in NPDR, including oxidative stress, inflammatory signaling, and endothelial dysfunction[14,22,23]. Rather than acting in isolation, these compounds appear to exert synergistic effects, offering a broader and more coordinated response to the multifaceted nature of retinal injury. This multi-targeted profile is particularly appealing in a disease where overlapping mechanisms drive progression and where therapeutic redundancy may, in fact, be advantageous. Notably, recent pharmacological studies have also highlighted that key constituents of danshen, particularly tanshinones, can modulate lipid metabolism and cholesterol transport pathways, such as NPC1 L1 inhibition, thereby linking metabolic regulation with vascular protection, a connection that may be especially relevant in metabolically driven retinal injury[41].

Beyond its local effects on the retina, CDDP also appears to exert systemic metabolic benefits, including the regulation of glucose metabolism and improvement of insulin sensitivity—both of which are central to the pathogenesis of DR[42,43]. By simultaneously addressing upstream metabolic disturbances and downstream microvascular damage, CDDP offers a more integrated therapeutic strategy, one that complements rather than replaces conventional Western treatments. This integrative potential is increasingly supported by clinical evidence demonstrating that CDDP, whether used alone or alongside standard therapies, can improve retinal structure and function and alleviate the clinical manifestations of NPDR[11,26,38]. Taken together, these observations suggest that CDDP is not merely an alternative option, but a potentially valuable component of a more comprehensive and patient-centered approach to NPDR management.

CLINICAL EFFICACY OF CDDP IN NPDR: EVIDENCE FROM CLINICAL TRIALS AND META-ANALYSES

CDDP monotherapy: Efficacy in improving retinal outcomes and clinical symptoms

Over the past decade, a growing body of RCTs has begun to paint a consistent and increasingly convincing picture of the clinical value of CDDP as a standalone therapy for NPDR[20,26,27,40,44]. Across different study designs and patient populations, a common thread emerges: CDDP is capable of not only slowing retinal damage but also meaningfully improving visual function. One of the most robust pieces of evidence comes from a randomized, double-blind, placebo-controlled multicenter trial involving 223 patients, in which both mid-dose (540 mg) and high-dose (810 mg) CDDP produced significant improvements in fundus fluorescein angiography (FFA) and fundoscopic findings after 24 weeks of treatment[20]. The magnitude of this effect is difficult to overlook, with “excellent” and “effective” response rates for FFA reaching 74% and 77% in the high- and mid-dose groups, respectively, compared with only 28% in the placebo arm. Similar trends were observed in fundoscopic outcomes, where response rates of 42% and 59% sharply contrasted with the modest 11% seen in controls (P < 0.001), suggesting not only efficacy but a clear dose–response relationship[20].

Building on earlier trials, a recent large-scale superiority RCT further consolidates the clinical evidence base. In a rigorously designed multicenter study including 484 NPDR patients across 16 centers, CDDP administered at 540 mg three times daily for 24 weeks significantly improved fundus outcomes compared with placebo, with a markedly higher overall effective rate (77.07% vs 53.72%, P < 0.001)[13]. Importantly, this trial also demonstrated consistent benefits across multiple clinically relevant endpoints, including reductions in retinal microaneurysms, hemorrhages, and macular edema, alongside improvements in visual acuity and TCM symptom scores, reinforcing both the reproducibility and clinical relevance of CDDP’s therapeutic effects.

Encouragingly, these findings are not isolated. A randomized, double-dummy, double-blind study comparing CDDP with calcium dobesilate in 57 NPDR patients demonstrated that CDDP significantly improved best corrected visual acuity, reduced visual field mean defect (MD), and decreased both hemorrhage area and microaneurysm counts. Notably, its efficacy was comparable to that of calcium dobesilate, a widely used microcirculation-modulating agent, positioning CDDP as a credible alternative rather than merely a complementary option[40].

Evidence from smaller and more targeted studies adds further nuance, particularly in patient subgroups defined by TCM syndromes. In patients characterized by “qi stagnation and blood stasis”, who often exhibit more pronounced microvascular impairment, CDDP appears especially effective. A study involving 81 such patients reported an overall response rate of 87.50% with CDDP, markedly higher than the 63.41% observed with captopril, alongside notable reductions in macular edema and improvements in visual acuity[38]. Similarly, a clinical study of 42 patients (78 eyes) found that three months of CDDP treatment not only improved visual acuity and reduced retinal lesions but also enhanced electrophysiological parameters, including shortening of the P100 latency and improvements in a- and b-wave responses, suggesting functional recovery at the retinal level[45].

When viewed collectively through the lens of meta-analysis, these individual findings coalesce into a coherent and compelling narrative. A meta-analysis of 26 RCTs encompassing 2047 patients demonstrated that CDDP monotherapy significantly improved overall clinical efficacy (risk ratio = 0.54), reduced retinal hemorrhages (weighted mean difference = -0.62), and enhanced visual acuity (weighted mean difference = 0.14)[27]. Another analysis of 13 RCTs reported a 64% reduction in the risk of disease progression (risk ratio = 0.36), alongside meaningful improvements in microaneurysms, hemorrhages, and visual function[19]. While these analyses acknowledge limitations in study quality, including small sample sizes and incomplete blinding, the consistency of benefit across studies lends weight to the overall conclusion. For patients who are unable to tolerate or access conventional therapies, CDDP monotherapy may represent a realistic and effective alternative[19,27].

CDDP combination therapy: Synergistic effects with Western drugs and other agents

If monotherapy establishes the baseline efficacy of CDDP, combination therapy reveals its broader potential within an integrative treatment framework. Increasingly, studies suggest that CDDP does not simply add to the effects of conventional therapies but may amplify them in meaningful and sometimes unexpected ways[46]. A network meta-analysis of 42 RCTs involving 4858 NPDR patients found that the combination of CDDP with calcium dobesilate ranked highest in overall clinical efficacy (surface under the cumulative ranking curve = 88.58%), outperforming both agents used alone and demonstrating superior improvements in visual field parameters[26]. This pattern is reinforced by another network meta-analysis of 23 RCTs, which showed that the combination significantly improved best corrected visual acuity, reduced macular thickness, and lowered VEGF levels compared with calcium dobesilate monotherapy, suggesting a complementary interaction between the two treatments[11].

Beyond standard microcirculation agents, CDDP also appears to integrate effectively with therapies targeting broader metabolic and inflammatory pathways. In a preclinical study using db/db mice, coadministration of CDDP with bezafibrate resulted in greater reductions in vascular leakage, improved retinal thickness, and enhanced antioxidant effects compared with CDDP alone[47]. This synergy likely reflects the convergence of mechanisms, with CDDP modulating oxidative stress and inflammation while bezafibrate addresses lipid metabolism—an increasingly recognized contributor to retinal pathology in NPDR[47]. These synergistic effects are consistent with broader experimental observations showing that CDDP can enhance tissue repair and cellular survival under conditions of oxidative and inflammatory stress, including improved microenvironmental stability and reduced apoptosis in ischemic tissues, suggesting that its combinatorial benefits may extend beyond the retina to systemic microvascular protection[48].

Clinical evidence echoes these findings. A meta-analysis of 8 RCTs involving 524 patients showed that combining CDDP with Western medicine significantly improved overall efficacy (odds ratio = 5.00), reduced visual field deficits, and decreased hemorrhagic plaque area compared with Western medicine alone[49]. A broader synthesis of 167 studies further confirmed these benefits, highlighting consistent improvements in visual acuity and retinal outcomes[49]. Even beyond conventional pharmacology, exploratory studies suggest that CDDP may act synergistically with other bioactive agents, such as Sanghuang, enhancing vascular function and reducing inflammation—an observation that, while preliminary, hints at a wider therapeutic versatility[34].

Taken together, these findings suggest that CDDP is particularly well suited to combination strategies, where its multi-targeted effects can complement more specific interventions. This flexibility may prove especially valuable in patients with complex clinical profiles, including those with dyslipidemia or cardiovascular comorbidities, where a single therapeutic approach is rarely sufficient[11,26].

Safety profile of CDDP in NPDR: Tolerability and adverse events

In clinical practice, efficacy alone is rarely enough; tolerability often determines whether a treatment can be sustained over the long term. In this regard, CDDP distinguishes itself with a safety profile that has remained consistently reassuring across studies of varying scale and duration. In the multicenter trial by Lian et al[20], no clinically significant adverse events (AEs) were observed, even at higher doses of 810 mg/day, suggesting a wide therapeutic window. This finding is echoed in meta-analyses, where CDDP monotherapy did not increase the incidence of AEs, with only mild and transient gastrointestinal symptoms—such as nausea or abdominal discomfort—reported in a small proportion of patients[27]. These findings are further corroborated by recent large-scale clinical data. In the multicenter RCT by An et al[13], no significant differences in AE rates were observed between the CDDP and placebo groups, with laboratory parameters remaining stable throughout the study period. This consistency across both smaller trials and larger, rigorously controlled studies strengthens confidence in the overall safety and tolerability of CDDP in NPDR management.

Combination therapy does not appear to compromise this safety profile. Analyses incorporating multiple RCTs have found no significant increase in AEs when CDDP is used alongside Western medications, and importantly, no serious AEs have been directly attributed to its use[11,50]. Pharmacovigilance studies provide additional reassurance, particularly in patients requiring complex medication regimens. For example, coadministration with warfarin did not significantly alter its pharmacokinetics or pharmacodynamics, nor did CDDP show meaningful interaction with clopidogrel, suggesting compatibility with commonly prescribed cardiovascular therapies[51-53].

Part of this confidence stems from CDDP’s long history of clinical use, which offers a form of real-world validation rarely available for newer agents[15]. That said, it would be premature to regard the safety profile as fully characterized. As with many therapies used in chronic conditions, long-term pharmacovigilance remains essential, particularly in populations with multiple comorbidities or those exposed to polypharmacy[19,54]. Even so, the balance of current evidence suggests that CDDP is not only effective but also remarkably well tolerated, offering a favorable risk–benefit profile when compared with many conventional interventions[26,27].

MECHANISMS OF ACTION OF CDDP IN NPDR: FROM PRECLINICAL STUDIES TO MOLECULAR TARGETS

Antioxidative stress: Mitigating oxidative damage to the retina

Oxidative stress is a central driver of retinal damage in NPDR, and CDDP’s antioxidative properties have been extensively studied as a key mechanism of its therapeutic effect. Preclinical studies have consistently shown that CDDP reduces reactive oxygen species production and enhances antioxidant defense systems in retinal tissues, thereby mitigating oxidative damage and protecting retinal cells from hyperglycemia-induced injury[29,30]. For example, a study in a noise-induced hearing loss mouse model found that CDDP crosses the blood-lymphatic barrier and reduces levels of 4-hydroxynonenal—a marker of lipid peroxidation—by modulating the respiratory chain, highlighting its potent antioxidative activity that is likely relevant to NPDR, as 4-hydroxynonenal accumulation is a key feature of hyperglycemia-induced retinal damage[22,29,30]. Recent transcriptomic and functional studies further suggest that CDDP exerts its antioxidative effects through modulation of mitochondrial respiratory chain activity and redox homeostasis, highlighting a deeper level of metabolic regulation that may underlie its protective effects across different organ systems[30].

CDDP’s antioxidative effects are mediated by its bioactive components, particularly salvianolic acids and tanshinones, which are the primary active constituents of Radix Salviae Miltiorrhizae—a key component of CDDP. Dong et al[22] identified salvianolic acid A, salvianolic acid B, salvianolic acid C, and tanshinone IIA as key active compounds in Salvia miltiorrhiza that reduce oxidative stress by downregulating pro-inflammatory cytokines and inhibiting inflammatory cell adhesion. These compounds also abrogate hyperglycemia-induced phosphorylation of protein kinase B (AKT) 1 and phosphatidylinositol 3-kinase (PI3K), key molecules involved in oxidative stress signaling, further supporting their role in mitigating retinal oxidative damage[22]. Additionally, CDDP has been shown to increase the expression of superoxide dismutase—a key antioxidant enzyme—and reduce malondialdehyde levels in retinal tissues, further reinforcing its role in mitigating oxidative stress and protecting retinal cells[35,55].

In diabetic rat models, CDDP treatment was found to moderate electroretinography abnormalities and reduce retinal cell apoptosis by inhibiting oxidative stress, independently of blood glucose levels, suggesting that its antioxidative effects are direct and not merely a secondary result of improved glycemic control[29]. A gene array analysis in these models showed that CDDP regulates genes involved in the apoptosis pathway, including increasing B-cell lymphoma 2 expression (a pro-survival protein) and decreasing Bax and caspase-3 expression (pro-apoptotic proteins), which are key mediators of oxidative stress-induced cell death[29]. These findings suggest that CDDP’s antioxidative effects play a critical role in protecting retinal cells from hyperglycemia-induced damage, thereby slowing NPDR progression and preserving retinal function[29,30].

Anti-inflammatory effects: Targeting inflammatory pathways in NPDR

Chronic inflammation is another key pathophysiological mechanism in NPDR, and CDDP’s anti-inflammatory properties have been well-documented in preclinical and clinical studies, providing a critical link to its therapeutic efficacy. Network pharmacology and molecular docking studies have shown that CDDP targets key inflammatory pathways such as TNF signaling, NF-κB signaling, and PI3K-AKT signaling—all of which are dysregulated in NPDR and contribute to retinal microvascular damage[22,43]. Tian et al[20] found that CDDP’s active ingredients target lipid and atherosclerosis, PI3K-AKT, and TNF signaling pathways, all of which are involved in NPDR pathogenesis[43], providing a molecular basis for its anti-inflammatory effects and its ability to mitigate retinal damage.

Preclinical studies have confirmed that CDDP reduces the expression of pro-inflammatory mediators such as TNF-α, interleukin-6, and ICAM-1 in retinal tissues, thereby reducing inflammation-induced retinal damage[22,35]. For example, a study in streptozotocin-induced diabetic mice found that CDDP attenuates BRB breakdown by inhibiting retinal inflammation and angiogenesis, with key involvement of the PI3K-AKT, VEGF, TNF, and NF-κB pathways—all of which are critical to the inflammatory response in NPDR[22]. CDDP also reduces leukocyte adhesion to retinal microvascular endothelial cells, a key event in inflammatory-mediated retinal damage, by downregulating CD11b and forkhead box protein O1 expression, further supporting its anti-inflammatory effects[35].

Clinical studies have further supported CDDP’s anti-inflammatory effects in NPDR patients, with meta-analyses showing that CDDP treatment reduces levels of pro-inflammatory cytokines in NPDR patients, correlating with improvements in retinal outcomes[27]. Additionally, a study by Fan et al[43] found that CDDP modulates the toll-like receptor 4/myeloid differentiation primary response 88/NF-κB signaling pathway in diabetic mice, inhibiting neuroinflammation and improving cognitive function—a mechanism that may also be relevant to retinal inflammation in NPDR, as neuroinflammation plays a key role in retinal neuronal damage[43]. These findings collectively suggest that CDDP’s anti-inflammatory effects contribute significantly to its therapeutic efficacy in NPDR, by reducing inflammation-induced retinal damage and improving microvascular function[22,43]. Emerging evidence also points to a role for CDDP in modulating systemic inflammatory axes, including gut-organ signaling pathways, where regulation of microbiota-associated immune responses may contribute to its broader anti-inflammatory profile in diabetes-related complications[43].

Microvascular protection: Improving retinal circulation and barrier function

Impaired retinal microcirculation and BRB breakdown are hallmark features of NPDR, and CDDP’s ability to protect the retinal microvasculature is a key mechanism of its therapeutic effect. Preclinical studies have shown that CDDP improves retinal microcirculation by dilating retinal blood vessels, reducing vascular permeability, and attenuating vascular leakage—all of which are critical to mitigating retinal damage in NPDR[14,35]. Hu et al[14] found that CDDP promotes angiogenesis in zebrafish embryos in a dose-dependent manner, via the VEGF/VEGF receptor and PI3K/AKT signaling pathways, suggesting that it may enhance retinal blood flow in NPDR patients by promoting the formation of functional retinal blood vessels.

CDDP’s microvascular protective effects are also evident in diabetic animal models, which closely mimic the pathophysiology of NPDR. A study in db/db mice found that coadministration of CDDP and bezafibrate reduces vascular leakage and improves retinal thickness, more effectively than CDDP alone, highlighting the synergistic effects of CDDP with other agents in protecting the retinal microvasculature[47]. Another study in streptozotocin-induced diabetic rats found that CDDP prevents BRB breakdown by reversing endothelial barrier dysfunction, a process mediated by its active compounds (salvianolic acid A, salvianolic acid B, and cryptotanshinone)[22]. These compounds interact with key molecules involved in cell-cell junctions, such as zonula occludens-1 and claudin-5, thereby strengthening the BRB and reducing vascular leakage—a key feature of NPDR[22].

Clinical studies have confirmed that CDDP improves retinal microcirculation in NPDR patients, with retrospective RCTs showing that CDDP reduces macular edema and improves visual acuity by enhancing retinal microcirculation[38]. Another study found that CDDP treatment reduces the number of microaneurysms and retinal hemorrhages—key indicators of impaired microcirculation—in NPDR patients, further supporting its microvascular protective effects[45]. Additionally, a network meta-analysis found that CDDP combined with calcium dobesilate significantly improves visual field gray value, a measure of retinal microcirculation, compared to other treatments, highlighting the synergistic effects of the combination in improving retinal blood flow[26]. These findings suggest that CDDP’s microvascular protective effects are critical to its ability to improve retinal outcomes in NPDR, by restoring normal retinal circulation and preserving BRB integrity[14,22]. Consistent with these mechanistic insights, recent clinical observations indicate that CDDP not only improves retinal microcirculation but also exerts neurovascular protective effects, including preservation of retinal ganglion cells and attenuation of vascular permeability, further underscoring its dual vascular-neuronal protective capacity[13].

Modulation of key molecular targets and quality biomarkers

Recent studies have identified key molecular targets of CDDP in NPDR, providing further insight into its mechanisms of action and linking its quality to its therapeutic efficacy. VEGF, a key mediator of angiogenesis and vascular permeability in DR, is a major target of CDDP, with preclinical studies showing that CDDP reduces VEGF expression in retinal tissues, thereby inhibiting angiogenesis and vascular leakage—key events in NPDR progression[11,22,56]. Clinical studies have also confirmed that CDDP lowers VEGF levels in NPDR patients, correlating with improvements in retinal outcomes such as reduced macular edema and improved visual acuity[11,26].

ICAM-1, an adhesion molecule involved in leukocyte infiltration and retinal damage, is another key target of CDDP, with preclinical and clinical studies showing that CDDP reduces ICAM-1 expression in retinal tissues, thereby reducing leukocyte adhesion and inflammation[22,34,57]. Additionally, CDDP targets neurofibromatosis type 2 and protein phosphatase 1 catalytic subunit alpha, which have been identified as quality biomarkers (Q-biomarkers) linking CDDP’s quality to its efficacy in NPDR[58]. Shen et al[58] used a combination of ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry, network pharmacology, and proteomics to identify these biomarkers, which are closely associated with CDDP’s vasodilatory effects and its ability to improve retinal microcirculation.

These Q-biomarkers not only strengthen the link between CDDP’s quality and efficacy but also provide a framework for improving quality control of CDDP, ensuring consistent therapeutic effects in clinical practice—a critical consideration for TCM formulations, which can vary in composition based on ingredient quality and processing[58]. Li et al[50] further supported this by developing a feedforward control method for CDDP’s mixing process based on quality by design, which ensures consistent dynamic viscosity of the formulation—a critical factor in its efficacy and bioavailability. Additionally, pharmacokinetic studies have identified key bioactive components of CDDP, including tanshinol, ginsenoside Rb1, and ginsenoside Rg1, which are absorbed into the bloodstream and reach the retina to exert their therapeutic effects[23,59]. Pharmacokinetic investigations using population-based modeling approaches have further clarified the absorption and disposition characteristics of key active components such as tanshinol and ginsenosides, demonstrating predictable multi-compartment kinetics and supporting their systemic bioavailability and therapeutic relevance[59].

Network pharmacology studies have also shed light on CDDP’s multi-targeted mechanism of action, which aligns with the complex pathophysiology of NPDR. Piao et al[36] used a systems pharmacology approach to identify 18 putative targets of Radix Salviae (a key component of CDDP) in DR, including VEGF, matrix metalloproteinases, and cyclooxygenase-2, which are involved in angiogenesis, inflammation, and apoptosis—all key pathways in NPDR. Zhou et al[60] identified quercetin, luteolin, and apigenin as key active compounds of CDDP that modulate signaling pathways involved in atherosclerosis, a process closely linked to NPDR, further supporting CDDP’s multi-targeted effects. These findings collectively demonstrate that CDDP exerts its therapeutic effects in NPDR through a complex, multi-targeted mechanism that addresses the diverse pathophysiological pathways of the disease, making it well-suited to manage this complex chronic condition[22,36].

SUMMARY OF KEY STUDIES EVALUATING CDDP FOR NPDR

To provide a clear overview of the evidence supporting CDDP’s efficacy in NPDR, Table 1 synthesizes the core evidence from 10 Landmark studies (encompassing retrospective RCTs[27], double-blind placebo-controlled trials[20,40], meta-analyses[26], network meta-analyses, and preclinical investigations) to systematically validate CDDP as a viable therapeutic option for NPDR. Spanning diverse study designs, sample sizes (from 42 participants to 4858 participants), and patient populations including those with TCM “qi stagnation and blood stasis” syndrome[38] and broader NPDR cohorts[11,26,27,49,50], the findings consistently underscore CDDP’s efficacy in improving critical retinal outcomes. As monotherapy, CDDP achieves robust response rates (e.g., 87.50% overall response rate in TCM-syndrome-matched patients, 74%-77% FFA response rate vs 28% in placebo) while reducing macular edema, retinal hemorrhages, and microaneurysms, and enhancing visual acuity and electrophysiological function[27,38]. When combined with conventional agents (e.g., calcium dobesilate[11,26], bezafibrate[47], or Western medicine[49,50]), CDDP exhibits synergistic effects—most notably the highest clinical efficacy rate (surface under the cumulative ranking curve = 88.58%) with calcium dobesilate—and further mitigates vascular leakage, macular thickness, and VEGF levels beyond single-agent therapy.

Table 1 Summary of key studies evaluating compound danshen dripping pills for non-proliferative diabetic retinopathy.

Intervention	Study type	Number of patients/animals	Key outcomes (significant findings)	Safety profile	Ref.
CDDP monotherapy	Retrospective RCT	81 (NPDR, qi stagnation and blood stasis)	ORR: 87.50% vs 63.41% (captopril); reduced macular edema (12.50% vs 31.71%); improved visual acuity	No serious AEs; mild, transient side effects	[38]
CDDP monotherapy	Meta-analysis (26 RCTs)	2047 (NPDR)	RR = 0.54 (curative effect); reduced retinal hemorrhages (WMD = -0.62); improved visual acuity (WMD = 0.14)	No increased AE risk; mild side effects	[27]
CDDP + calcium dobesilate	Network meta-analysis (42 RCTs)	4858 (NPDR)	Highest clinical efficacy rate (SUCRA = 88.58%); improved visual field gray value; reduced macular thickness and VEGF levels	No serious AEs	[11,26]
CDDP + bezafibrate	Preclinical (db/db mice)	NA (animal model)	Reduced vascular leakage; improved retinal thickness; greater anti-oxidative effect than CDDP alone	No toxicity observed	[47]
CDDP + western medicine	Meta-analysis (8 RCTs)	524 (DR, including NPDR)	OR = 5.00 (effective rate); reduced visual field gray value (MD = -0.93); reduced hemorrhagic plaque area (MD = -0.65); improved visual acuity	Favorable safety profile; no serious AEs	[49,50]
CDDP monotherapy	Double-blind, placebo-controlled RCT	223 (NPDR)	FFA response rate: 74%-77% vs 28% (placebo); fundoscopic response rate: 42%-59% vs 11% (placebo)	No clinically significant AEs	[20]
CDDP vs calcium dobesilate	Double-dummy, double-blind RCT	57 (NPDR)	Improved BCVA, and reduced visual field MD, fundus hemorrhage area, and microaneurysm number; no significant difference vs calcium dobesilate	No obvious adverse events with clinical significance	[40]
CDDP monotherapy	Clinical trial	42 patients (78 eyes, NPDR I-III phase)	Improved visual acuity, reduced microhemorrhages and microaneurysms, shortened P100 wave and a/b wave latent period	Well-tolerated, no serious AEs	[45]
CDDP monotherapy	Meta-analysis (13 RCTs)	NA (pooled data from 13 RCTs)	Reduced DR progression risk (RR = 0.36); improved retinal microaneurysms (MD = -4.32) and visual function (MD = -0.12 letter)	No increased AE risk	[19]
CDDP + calcium dobesilate	Network meta-analysis (23 RCTs)	1824 (DR, including NPDR)	Enhanced BCVA; reduced macular thickness and VEGF levels vs calcium dobesilate alone	No serious AEs; safety profile comparable to control	[11]

The table highlights compound danshen dripping pills’s efficacy across different study designs, including monotherapy and combination therapy, and confirms its favorable safety profile across all evaluations. CDDP: Compound danshen dripping pills; RCT: Randomized controlled trial; NPDR: Non-proliferative diabetic retinopathy; ORR: Overall response rate; AEs: Adverse events; RR: Risk ratio; WMD: Weighted mean difference; OR: Odds ratio; SUCRA: Surface under the cumulative ranking curve; VEGF: Vascular endothelial growth factor; NA: Not applicable; FFA: Fundus fluorescein angiography; DR: Diabetic retinopathy; MD: Mean defect; BCVA: Best corrected visual acuity.

Across all evaluations, CDDP maintains a uniformly favorable safety profile: No serious AEs are reported, and mild, transient side effects (e.g., gastrointestinal discomfort) are rare and resolve without treatment discontinuation. Even in meta-analyses pooling thousands of patients and preclinical models, CDDP demonstrates no increased AE risk or toxicity, reinforcing its suitability for long-term NPDR management. Notably, CDDP performs comparably to conventional microcirculation modifiers (e.g., calcium dobesilate) and reduces DR progression risk by 64%, solidifying its role as both a standalone and adjunctive therapy. Collectively, these studies establish CDDP’s consistent efficacy, multi-scenario applicability, and excellent tolerability, laying a rigorous evidence base for its clinical utility in NPDR.

GAPS AND FUTURE RESEARCH DIRECTIONS

Inclusion criteria for CDDP use in NPDR

For CDDP to be used thoughtfully in clinical practice rather than applied in a one-size-fits-all manner, patient selection needs to be grounded in both biological plausibility and real-world clinical experience. At its core, the starting point remains a clear and well-substantiated diagnosis of NPDR. This should be established through standard ophthalmic assessments—fundus examination, FFA, and optical coherence tomography—interpreted in accordance with widely accepted frameworks such as the Early Treatment DR Study classification[57]. Only those patients exhibiting the characteristic features of NPDR, including microaneurysms, dot-and-blot hemorrhages, hard exudates, or macular edema without neovascularization, should be considered primary candidates[2,10]. In contrast, individuals who have already transitioned to PDRs, or who present with aggressive, treatment-refractory disease, are less likely to benefit from CDDP as a standalone therapy and may require it, if at all, as part of a broader combination strategy.

Equally important is the metabolic context in which NPDR develops. Most of the clinical evidence supporting CDDP has been generated in patients with T2DM, and it is within this group that its use feels most justified at present[26,27]. While it is tempting to extrapolate these findings to type 1 diabetes, the absence of robust supporting data urges a degree of restraint. Moreover, CDDP should not be viewed as a substitute for glycemic control; rather, it appears to function best when layered onto a background of relatively stable metabolic status. Patients with markedly uncontrolled hyperglycemia are unlikely to experience meaningful retinal benefit unless systemic metabolic derangements are first addressed[42,43].

From a TCM perspective, the notion of “qi stagnation and blood stasis” offers a useful, if interpretive, lens through which to identify those most likely to respond. Interestingly, this conceptual framework often overlaps with clinical signs of impaired microcirculation and chronic vascular stress seen in NPDR. Patients presenting with symptoms such as blurred vision, ocular fatigue, or peripheral numbness—alongside characteristic tongue and pulse findings—have, in several studies, shown more pronounced responses to CDDP[38,45]. That said, clinical reality is rarely so neatly categorized, and it would be overly restrictive to confine CDDP use solely to those fitting strict TCM syndromic labels. There is a growing sense that its benefits may extend beyond these boundaries, particularly for patients who struggle with tolerance or access to conventional therapies.

Safety considerations, of course, remain non-negotiable. Patients with known hypersensitivity to the herbal components, active bleeding disorders, or those receiving anticoagulant therapy without appropriate monitoring should generally be excluded, given the mild antiplatelet properties associated with CDDP[51,52]. Similarly, individuals with significant hepatic or renal impairment represent a group in whom caution is warranted, not because of clear evidence of harm, but rather due to the absence of reassuring data[54]. Special populations—including pregnant or lactating women, children, and older adults with complex comorbidities—require particularly careful, individualized consideration, as they often fall outside the scope of existing clinical trials.

Taken together, these criteria do not define rigid boundaries so much as they sketch a clinically sensible profile: Patients with confirmed NPDR in the setting of type 2 diabetes, reasonably controlled metabolic status, minimal contraindications, and— where applicable—features suggestive of microvascular stagnation. Applying CDDP within this framework not only enhances the likelihood of benefit but also provides a clearer foundation for future studies aiming to refine patient stratification.

Key research gaps and priorities

While earlier studies were often limited by modest sample sizes, the recent multicenter RCT by An et al[13] represents a significant step forward, providing high-level evidence from a large cohort of 484 patients. Nevertheless, despite this progress, important gaps remain—particularly regarding long-term outcomes, population diversity, and comparative effectiveness against standard-of-care therapies. Despite the encouraging body of evidence surrounding CDDP, there is a lingering sense that the field is still in an early, somewhat fragmented stage of development. One of the most immediate limitations lies in the narrow demographic scope of existing studies. Much of the clinical work has been conducted in Chinese populations, often within the context of TCM diagnostic frameworks. While these studies are valuable, they inevitably raise questions about how well the findings translate across different ethnicities, healthcare systems, and patterns of disease expression[26,38]. Expanding future trials to include more diverse populations is not simply a matter of representation—it is essential for understanding how biological variability and environmental factors may shape treatment response[3,13].

Another recurring concern is the relatively short duration of follow-up in most studies. NPDR is not a condition that unfolds over weeks or months, but rather one that evolves slowly over years[28]. Yet, many trials conclude at 24 weeks, offering only a snapshot of what is, in reality, a long and complex disease trajectory[2,27]. While some more recent studies have extended this window modestly[61], there remains a clear need for longer-term investigations—ideally spanning several years—that can meaningfully assess whether CDDP alters the natural history of the disease, delays progression to PDRs, and preserves vision in a sustained way. Even in the recent large-scale RCT by An et al[13], the intervention period was limited to 24 weeks, underscoring the continued need for longer-term studies to determine whether these encouraging short-term benefits translate into sustained protection against disease progression. Incorporating patient-reported outcomes, such as quality of life, would also bring a much-needed human dimension to these evaluations.

Equally important is the question of how CDDP compares directly with established therapies. At present, most studies position it against placebo or relatively modest comparators such as calcium dobesilate[26,62]. While these comparisons are informative, they fall short of addressing the more pressing clinical question: How does CDDP perform relative to current standards such as anti-VEGF therapy or laser photocoagulation? Without such head-to-head data, it remains difficult to define its precise role—whether as an alternative, an adjunct, or a niche option for specific patient groups[10,26]. Carefully designed comparative trials would go a long way toward clarifying this uncertainty.

On the mechanistic front, there is a noticeable gap between elegant preclinical findings and their validation in human systems. Animal models have provided valuable insights into pathways involving oxidative stress, inflammation, and vascular dysfunction, yet these models inevitably simplify the complexity of human disease[22,30]. Bridging this gap will likely require more translational work—linking molecular signatures in human retinal tissue or circulating biomarkers to clinical outcomes. Such efforts could help move the field beyond descriptive efficacy toward a more precise, mechanism-informed application of CDDP[36,58].

Quality control represents another, often underappreciated challenge. Unlike single-molecule drugs, CDDP is a complex mixture, and its therapeutic consistency depends heavily on the quality of its raw materials and manufacturing processes. While recent advances—such as the identification of quality biomarkers and the application of quality-by-design principles—are encouraging, they are not yet universally implemented[50,58,63]. Achieving reliable standardization will be crucial, particularly if CDDP is to gain broader acceptance beyond regions where TCM practices are already well integrated.

Finally, although the safety profile of CDDP appears reassuring, the current evidence base is still largely built on short-term observations. Long-term pharmacovigilance remains essential, especially in patients with multiple comorbidities who are often taking several medications simultaneously. The potential for subtle drug-drug interactions, cumulative effects, or rare AEs cannot be fully excluded without extended follow-up[51,52,54]. This is particularly relevant for populations that are routinely underrepresented in clinical trials, including older adults and those with organ dysfunction.

In reflecting on these gaps, what emerges is not a sense of limitation, but rather a clear roadmap: Larger, more diverse, and longer-term studies; direct comparisons with established therapies; deeper mechanistic validation in human systems; rigorous quality standardization; and sustained safety monitoring—all of these will be essential steps in moving CDDP from a promising option to a fully integrated component of global NPDR care.

CONCLUSION

NPDR remains a leading cause of visual impairment in patients with T2DM, and current therapeutic options, while effective, are often constrained by cost, tolerability, and incomplete disease control. In this context, CDDP has emerged as a promising complementary approach. Evidence from recent studies indicates that CDDP can meaningfully improve retinal outcomes—including reductions in microaneurysms, hemorrhages, and macular edema—while also supporting visual acuity. These benefits are observed both as monotherapy and, more notably, in combination with conventional treatments, where synergistic effects are frequently reported. Importantly, CDDP demonstrates a favorable safety profile, with predominantly mild and transient AEs. Mechanistically, CDDP exerts multi-targeted effects by attenuating oxidative stress, suppressing inflammation, and preserving retinal microvascular integrity. Its bioactive components act in concert to address key drivers of NPDR progression, aligning both with traditional concepts of “qi stagnation and blood stasis” and modern pathophysiological understanding. Clinically, its use appears most appropriate in patients with confirmed NPDR, underlying T2DM, stable metabolic control, and no major contraindications.

Despite these encouraging findings, important gaps remain, including limited population diversity in existing studies, short follow-up durations, insufficient head-to-head comparisons with standard therapies, and the need for stronger mechanistic validation in human systems. Addressing these challenges through well-designed, large-scale, and long-term studies will be essential. In summary, CDDP represents a safe and multi-faceted therapeutic option for NPDR, with clear potential to complement existing treatments. The recent emergence of large-scale, rigorously conducted randomized trials adds an important layer of confidence to this field, signaling a transition from exploratory use toward evidence-based clinical validation. With further validation, it may become an increasingly valuable component of integrated NPDR management.