What is the role of diosmin and hesperidin in the treatment of chronic venous insufficiency (CVI)?

Diosmin + Hesperidin in Chronic Venous Insufficiency

Diosmin combined with hesperidin (micronized purified flavonoid fraction, MPFF) is an effective adjunctive pharmacotherapy for chronic venous insufficiency that should be used alongside—not instead of—compression therapy and interventional treatments when indicated. 1

Evidence-Based Role in CVI Management

Primary Treatment Algorithm

MPFF serves as adjunctive medical therapy, not primary treatment, for CVI. The treatment hierarchy remains: 1

• Compression therapy (20-30 mmHg for CEAP C1-C3, 30-40 mmHg for C4-C6) is mandatory initial treatment and must be continued for minimum 3 months before interventional therapy is considered 1
• Endovenous thermal ablation (radiofrequency or laser) remains the primary interventional treatment for saphenous vein reflux when vein diameter ≥4.5mm and reflux duration ≥500ms, with MPFF serving as adjunctive therapy 1
• For CEAP C4-C6 disease, interventional therapy should not be delayed for prolonged compression trials—early thermal ablation prevents progression, with MPFF as adjunctive therapy 1

Clinical Efficacy Data

MPFF demonstrates 30-60% superiority to placebo or standard care in managing CVI symptoms. 2 The largest published trial enrolled 5,052 patients across 23 countries over 2 years, showing: 2, 3

• Significant reduction in CEAP class, edema, and quality of life scores (p=0.0001 for all) irrespective of whether reflux was demonstrable at baseline 2
• 79% of patients and 83% of investigators rated effectiveness as good or excellent after 6 months 2
• Improvement occurred regardless of compression stocking use, though compression remains recommended 2

Specific Clinical Indications

MPFF is particularly beneficial for:

• Venous leg ulcers ≤10cm diameter: MPFF 500mg twice daily plus standard management (compression and local treatment) significantly increases complete healing rates compared to standard management alone over 2-6 months 1
• Symptomatic relief: Consistent improvement in leg heaviness, aching, swelling, and nocturnal cramping 2, 3
• Patients with symptoms but no demonstrable reflux: 57% of symptomatic CVI patients lack venous reflux on Doppler, yet still benefit from MPFF 3

Dosing and Formulation

The micronized formulation is superior to non-micronized diosmin. 2, 4 Standard dosing: 2

• 600mg diosmin (with hesperidin constituents) once or twice daily 2
• Micronization improves bioavailability and clinical outcomes compared to non-micronized forms 4
• Treatment duration typically 6 months for optimal benefit, though improvement begins within weeks 2, 3

Mechanism of Action

MPFF addresses multiple pathophysiologic mechanisms in CVI: 2

• Manages venous inflammation and leukocyte accumulation in deteriorated venous vessel walls 2
• Reduces platelet aggregation and thrombotic components 2
• Improves venous tone and reduces capillary permeability, decreasing edema 2
• Objective measurements show 20-40% improvement in venous reflux, venous/lymphatic flow, and venous pressure compared to placebo 2

Critical Limitations and Pitfalls

MPFF cannot replace mechanical interventions in severe disease. 1 Common errors include:

• Delaying necessary interventional therapy: Compression stockings alone have no proven benefit in preventing post-thrombotic syndrome in recent randomized trials 1
• Using MPFF as monotherapy for advanced disease: Patients with CEAP C4-C6 require interventional treatment; MPFF is adjunctive only 1
• Expecting MPFF to eliminate need for compression: Compression therapy remains mandatory regardless of pharmacotherapy 1

Surveillance Requirements

Long-term monitoring is necessary as recurrence rates are 20-28% at 5 years even with appropriate treatment, necessitating ongoing symptom monitoring 1

Safety Profile

MPFF is generally well-tolerated with minimal adverse effects. 2 The formulation is:

• GRAS (Generally Recognized as Safe) by FDA standards 2
• Suitable for vegans, free of common allergens (no gluten, lactose, tree nuts, peanuts) 2
• Requires physician supervision as a medical food 2

Comparative Evidence

MPFF performs similarly to other venoactive agents. 5 A head-to-head trial showed:

• Pycnogenol and diosmin/hesperidin have similar effects on venous ulcer healing and limb circumference reduction (P<0.0001 for both) 5
• Both treatments significantly decrease affected limb circumference over 90 days 5

Quality of Life Impact

MPFF produces significant, continuous improvement in disease-specific quality of life. 3 The validated CIVIQ questionnaire demonstrated:

• Progressive improvement throughout 6-month treatment in physical, social, and psychological domains 6, 3
• Symptoms more severe at baseline in patients with reflux, but all patients improved regardless of reflux presence 3
• Greater symptom decrease in patients without venous reflux for pain, sensation of swelling, and cramps 3