Sulodexide and its multifaceted role in the multiverse of vascular diseases

SULODEXIDE AND VASCULAR AGING

Vascular aging, characterized by arterial stiffening, endothelial dysfunction, chronic inflammation, and impaired remodeling, is a key contributor to cardiovascular diseases such as hypertension and atherosclerosis.^1-3

Sulodexide, a combination of fast-moving heparin and dermatan sulfate, has demonstrated significant endothelial-protective properties. These include restoring the glycocalyx, enhancing nitric oxide-mediated vasodilation, and reducing vascular inflammation and oxidative stress.^4-5 Additionally, sulodexide has been shown to slow endothelial senescence, thereby maintaining vascular elasticity and function.^6-7

Dr Reyes highlighted clinical trials confirming these benefits, with one study reporting significant reductions in blood pressure (10.2/5.4 mmHg, P<0.001).⁸

SULODEXIDE IN ARTERIAL AND VENOUS THROMBOSIS

Dr Reyes also emphasized a unified approach to arterial and venous thrombosis, as both conditions share endothelial dysfunction as a common pathway.⁹ Sulodexide, a glycosaminoglycan with antithrombotic properties, exerts dual antiplatelet and anticoagulant effects.¹⁰

The IPO-V2 study reported significant reductions in post-myocardial infarction cardiovascular events, including left ventricular thrombosis and mortality.¹¹ Furthermore, the TUN-EndCOV study highlighted improved endothelial function in long COVID-19 patients treated with sulodexide (Figure 1).¹² By protecting the endothelium and preventing both arterial and venous thrombotic events, sulodexide offers a comprehensive strategy for managing cardiovascular and thrombotic diseases.



SULODEXIDE IN PERIPHERAL VASCULAR DISEASES.

Peripheral vascular diseases, including chronic venous disease (CVD) and peripheral artery disease (PAD), are often overlooked despite their significant health burden. In the Philippines, five out of ten individuals suffer from chronic venous insufficiency (CVI), a severe form of CVD, while PAD increases the risk of cardiovascular death, myocardial infarction, and hospitalization due to atherothrombotic events.^13,14

Dr Arellano emphasized that CVD management, based on the CEAP classification, includes both conservative and interventional approaches. For C0 to C6 stages, conservative treatment, including pharmacotherapy, is preferred. Sulodexide has demonstrated significant benefits in CVD management, with clinical studies highlighting its venoactive properties. These include improved ulcer healing, alleviation of major symptoms (e.g., pain, heaviness, edema), and enhanced quality of life.^15-18 A 2024 study further supports its role in reducing proinflammatory markers and endothelial cell activation, potentially preventing CVD progression.¹⁹

For venous thromboembolism (VTE), sulodexide’s anticoagulant properties have proven highly effective. The SURVET study showed a 50% reduction in recurrent VTE (HR 0.49, 95%CI 0.27–0.92).²⁰ A meta-analysis confirmed a 49% reduction in recurrent VTE (RR 0.51) and a 59% reduction in superficial vein thrombosis (RR 0.41).²¹ Additionally, sulodexide reduced all-cause mortality by 33% (OR 0.67, 95% CI 0.52–0.85) and cardiovascular mortality by 56% (OR 0.44, 95% CI 0.22–0.89), with no significant increase in bleeding risk (Figure 2).²² Dr Arellano also noted that various clinical guidelines include sulodexide as part of VTE management.



PAD, one of the most underdiagnosed, underestimated, and undertreated forms of atherosclerotic cardiovascular disease, is a sign of widespread atherosclerosis. Dr Arellano stressed that PAD treatment has two key goals: preventing cardiovascular disease progression and improving patients’ quality of life by relieving intermittent claudication. Sulodexide has emerged as a promising adjunct therapy in PAD management. The SUAVIS trial demonstrated that sulodexide doubled pain-free walking distance in 23.8% of patients versus 9.2% in the placebo group, with a 65% increase from baseline.²³

A meta-analysis reported a 36% increase in pain-free walking distance and improved ankle-brachial index.²⁴ Furthermore, sulodexide demonstrated an 84-meter increase in pain-free walking distance (60% greater than comparators) and a 316-meter increase in maximal walking distance (2.4× vs. comparators).²⁵

MANAGEMENT OF GLYCOCALYX DYSFUNCTION IN DIABETES MELLITUES (DM) AND ITS COMPLICATIONS

In 2021, over 7 million people were affected by DM, with its macrovascular and microvascular complications remaining a significant burden. DM is the leading cause of diabetic retinopathy and nephropathy.²⁶ Dr Gomez highlighted how metabolic abnormalities in DM accelerate atherogenesis through a prothrombotic state, endothelial dysfunction, and vascular inflammation—all key targets of sulodexide.²⁷ However, she noted that many physicians still perceive sulodexide solely as an antithrombotic agent, overlooking its broader vascular benefits.

A six-year follow-up study found that impaired endothelial glycocalyx predicts adverse outcomes even in individuals without overt cardiovascular disease.²⁸ Thus, Dr Gomez emphasized the need for early intervention to prevent further endothelial dysfunction. Among the best practices in preventing cardiovascular complications in diabetic patients is the restoration of glycocalyx integrity, a role that sulodexide has been shown to fulfill.^27,29

Sulodexide has demonstrated efficacy in DM patients with peripheral artery disease and venous ulcers.²⁵ In reducing albuminuria for both types 1 and2 DM, a randomized controlled trial showed a statistically significant reduction versus the comparator.³⁰ Additionally, in non-proliferative diabetic retinopathy, sulodexide has been associated with decreased severity of hard exudates and a lower risk of retinal hemorrhages and intraretinal microvascularabnormality.³¹

EXPERT INSIGHTS: PANEL DISCUSSION

Panel of Experts: (from left) Dr Gilbert Vilela, Dr Rosella Arellano, Dr Honolina Gomez, Dr Raymond Rosales, Dr Ivan Villespin, Dr Lynn Gomez, Dr Jesus Tamesis Jr., and Dr Eugenio Reyes.

The meeting concluded with an enriching panel discussion moderated by Dr Gilbert Villela, featuring the speakers and other specialists, including Dr Raymond Rosales (neurologist), Dr Ivan Villespin (pulmonary vascular specialist), Dr Lynn Gomez (nephrologist), and Dr Jesus Tamesis Jr. (neuro-ophthalmologist).

Retinopathy: Dr Tamesis noted improvements in patients with ischemic extra-ocular palsies and cavernous sinus fistulas treated with sulodexide.

Nephrology: Dr Lynn Gomez emphasized its role in restoring the glomerular basement membrane matrix and improving endothelial function in diabetic patients with proteinuria or eGFR <40.

Neurology: Dr Rosales highlighted sulodexide’s potential in preserving the glycocalyx, which may explain its benefits in cerebral small vessel disease and blood-brain barrier (BBB) integrity specially in cases of COVID-19.

Pulmonary vascular disease: Dr Villespin reiterated its role as prophylaxis in high-risk cases, offering a safer alternative for thromboprophylaxis in high-bleeding-risk patients.

Diabetes and obesity: Dr Honolina Gomez noted that sulodexide may help prevent vascular complications in obese patients on GLP-1 receptor antagonists or those with contraindications to SGLT2 inhibitors.

SULODEXIDE AS A CORNERSTONE IN VASCULAR DISEASE MANAGEMENT

From vascular aging and thrombosis to peripheral vascular diseases and diabetes-related complications, sulodexide’s endothelial-protective, anti-inflammatory, and antithrombotic properties make it a versatile therapeutic option. Its proven efficacy in improving outcomes—such as reducing blood pressure, enhancing walking distance in PAD, and restoring glycocalyx integrity in diabetes with a low bleeding risk—positions sulodexide as a cornerstone in vascular care.

The expert panel emphasized sulodexide’s role in bridging treatment gaps, particularly for high-risk patients with comorbidities or contraindications toother therapies. As research advances, sulodexide’s potential continues to grow, offering hope for better patient outcomes and a reduced global burden of vascular diseases.