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Grape Seed Procyanidin Extracts Effect on Diabetic Retinopathy


The leading cause of visual impairment in people with diabetes is diabetic macular edema (DME). DME is characterized by swelling of the retina and hard exudates (HEs), which are lipid deposits in the retina. HEs are often treated by invasive procedures such as macular photocoagulation and intravitreal (into the back of the eye) injections of drugs. However, these treatments have a short duration of action and can cause serious complications. Non-invasive, long-lasting treatments for HEs are needed to prevent vision loss.

Grape (Vitis vinifera, Vitaceae) seed procyanidin extract (GSPE) has been shown to reduce capillary permeability and fragility. Procyanidins are flavonoids that possess antioxidant and anti-inflammatory activities. In in vitro studies, GSPE has been shown to inhibit the vascular endothelial growth factor signaling pathway, the main pathway responsible for diabetic retinopathy (retina damage) progression. The purpose of this randomized, double-blind, placebo-controlled trial was to assess the effectiveness and safety of GSPE in the treatment of HEs associated with non-proliferative diabetic retinopathy in patients with type 2 diabetes mellitus (T2DM). The effects of GSPE were also compared to calcium dobesilate (CD), an oral medication widely used for diabetic retinopathy.

The trial enrolled patients at 12 hospitals in South Korea from November 2012 to January 2015. Patients were included if they were 40-78 years old; had T2DM that was well-controlled with drugs for at least three months; hemoglobin A1c ≤ 9%; DME with HEs with central subfield mean thickness (CSMT) ≤ 300 µm; and best-corrected visual acuity (BCVA), a measure of vision impairment, ≥ 20/40.

Patients were excluded if they had laser therapy, intravitreal injections, or intraocular surgery within six months of enrollment or another macular disease, severe hypertension, severe renal insufficiency, or were taking sulodexide, kallidinogenase, or bilberry (Vaccinium myrtillus, Ericaceae) extract.

Patients (N = 124) were randomly assigned to receive 150 mg/day GSPE (Entelon®; Hanlim Pharm; Seoul, South Korea), 750 mg/day CD (Doxium®; Ilsung Pharmaceuticals; Seoul, South Korea), or placebo (content not provided) in an approximately 2:2:1 ratio. The daily dose was divided into three capsules, and the intervention lasted 12 months.

Comprehensive eye exams were conducted at baseline and during study visits at months three, six, nine, and 12. The eye exams assessed BCVA, intraocular pressure, total macular volume, and CSMT using optical coherence tomography and the Early Treatment Diabetic Retinopathy Study map. Adverse events (AEs) were recorded at each study visit. Blood was drawn at baseline and 12 months for safety monitoring.

Patients were randomly assigned to the GSPE group (n = 51), CD group (n = 47), or placebo group (n = 26). Sixteen patients did not complete the first study visit, so the intent-to-treat population included 108 patients. An additional 22 patients (nine in the GSPE group, seven in the CD group, and six in the placebo group) did not complete the trial because of poor compliance or protocol violations. There were no significant differences in baseline characteristics among the three groups.

The rate of treatment success, which was defined as a decrease in HE grade severity of more than two grades at month 12, was highest in the GSPE group (43.90%), followed by the CD group (14.29%) and the placebo group (8.00%). The success rate was significantly higher in the GSPE group compared to the CD group (P = 0.0029) and the placebo group (P = 0.0021).

Changes in macular thickness were not significantly different among the three groups at month 12. Total macular volume decreased in the GSPE group at months nine and 12; however, there was no statistically significant difference among the three groups overall. Furthermore, no significant changes in BCVA or progression of diabetic retinopathy were observed among the groups. Four patients in the GSPE group and two patients in the CD group had gastrointestinal AEs that may have been related to the treatments. There were no statistically or clinically relevant differences in vital signs and blood values among the groups after the intervention.

The authors concluded that GSPE therapy for one year improved HEs in patients with non-proliferative diabetic retinopathy. GSPE was more effective than CD in reducing HEs. Although GSPE did not affect visual acuity in this population, the authors suggested that GSPE can be considered as adjunct therapy in patients with a larger number of central HEs that impair their vision or in patients who do not want to have intravitreal injections.

GSPE’s mechanism of action in reducing HEs is not known. In human and animal studies, procyanidins have been shown to reduce blood cholesterol and the size of cholesterol deposits in arteries. However, no significant changes in blood lipid levels occurred in the GSPE group in this study.

According to the authors, limitations of the study were that the sample size was relatively small, the study population had only mildly increased macular thickness, and blood levels of GSPE were not measured.