Pycnogenol ® Improves Microcirculation,Retinal Edema,and Visual Acuity in Early Diabetic Retinopathy

Abstract

Purpose:

The growing numbers of diabetes cases in the developed world are followed by increasing numbers of people diagnosed with diabetic complications. Diabetic microangiopathies in the eye lead to the development of retinopathy involving gradual loss of vision. Previous studies with Pycnogenol^® showed effectiveness for stopping progression of preproliferative stages of retinopathy. The aim of our study was to show protective effects of Pycnogenol in early stages of retinopathy, characterized by mild to moderate retinal edema in the absence of hemorrhages or hard exudates in the macula center.

Methods:

Following treatment with Pycnogenol (24 patients) for 3 months, retinal edema score (dilated ophthalmology) and retinal thickness (high resolution ultrasound) showed statistically significant improvement as compared to the placebo group (22 patients), which showed negligible changes to baseline. Laser Doppler flow velocity measurements at the central retinal artery showed a statistically significant increase from 34 to 44 cm/s in the Pycnogenol group as compared to marginal effects in the control group.

Results:

The major positive observation of this study is the visual improvement, which was subjectively perceived by 18 out of 24 patients in the Pycnogenol group. Testing of visual acuity using the Snellen chart showed a significant improvement from baseline 14/20 to 17/20 already, after 2 months treatment, whereas no change was found in the control group.

Conclusions:

Pycnogenol taken at this early stage of retinopathy may enhance retinal blood circulation accompanied by regression of edema, which favorably improves vision of patients.

Introduction

Diabetic retinopathy as a major cause of blindness in people with diabetes represents one of the most feared diabetic complications. The variable risk factors are well known, which correlate well with the patient’s glucose control.1 According to the National Institute of Health 40% to 45% of Americans diagnosed with diabetes already have some stage of diabetic retinopathy.

Diabetic retinopathy is a term used for microangiopathies related to the vascular system of the retina caused by diabetes. Retinopathy progresses from nonproliferative or background retinopathy to proliferative retinopathy.

The common pathway involved in the pathogenesis of macular edema is the breakdown of the blood–retinal barrier. The mechanisms involved are multifactorial and complex as recently reviewed by Bhagat and coworkers.2 Chronic hyperglycemia leads to glycation of proteins and accumulation of advanced glycation end products, which in turn lead to proinflammatory processes involving NF-κB activation and subsequent expression of endothelial cell adhesion molecules and the resulting leukocyte adhesion. Matrix metalloproteinases (MMPs) play a decisive role in the remodeling of extracellular matrix and are involved in causing changes to vascular permeability.

French maritime pine bark extract Pycnogenol^® (Horphag Research, UK) has been ascribed a very diverse clinical pharmacology.3 The pharmacologic activities suggest Pycnogenol to possess various modes of action making it suitable to control retinopathy and prevent further damage. Pycnogenol stimulates endothelial nitric oxide to facilitate vasodilatation, which in turn would prevent ischemic conditions that trigger angiogenesis.4 Pycnogenol was shown to have broad antioxidant activity and was shown to act in synergy with Lutein for prevention of lipid oxidation in the eyes.5^,6 Indeed, clinical pharmacologic studies have demonstrated anti-inflammatory activity for Pycnogenol including NF-κB activation inhibition, inhibition of MMP activity and expression.7^,8 Moreover, Pycnogenol inhibits alpha-glucosidase, which was shown to lower blood glucose in diabetes.9^,10

Pycnogenol has been previously investigated for diabetic retinopathy, however, no knowledge is currently available on its efficacy for diabetic macular edema.11 Moreover, none of the previous studies have investigated Pycnogenol for the improvement of early stages of diabetic retinopathy.

Methods

Inclusion criteria

Patients had diabetes mellitus type II for at least 4 years and their blood glucose was well controlled by diet and oral antidiabetic medication (HbA1c <7%). Patients with a moderate degree of diabetic retinopathy were recruited, as judged by the presence of macular edema and retinal swellings and minor presence of exudates and hemorrhages. Potential subjects were investigated for presence of moderate retinal edema during ophthalmologic examination after pupil dilation.

Exclusion criteria

Patients with proliferative retinopathy and presence of vast exudates and progressed hemorrhage and signs of previous hemorrhage were excluded. Patients with any other ophthalmologic conditions than diabetic retinopathy were excluded. Patients with intraocular hypertension, 21 mmHg or higher, were excluded. Patients who had previous surgical or laser treatment or any other invasive intervention were excluded. Patients with systemic hypertension requiring medical treatment were excluded from this study.

Randomization

This study was carried out in double-blind, placebo-controlled fashion. Patients were allocated to treatment groups using randomization by blocks. Block allocation sequences were created by using randomly generated numbers from a computer program. The randomization list covered twice the number of subjects planned to be recruited. Each patient enrolled in the study received the respective lowest randomization number available.

Treatment and observation

The study was performed according to the Declaration of Helsinki. Subjects were treated with three 50 mg Pycnogenol tablets (total 150 mg Pycnogenol) or placebo tablets in the morning after breakfast over a period of 2 months. Tablets were manufactured by Manhattan Drug Company Inc. (New York, USA). The study was planned to include at least 20 patients each for the Pycnogenol and the placebo group.

Patient’s visual acuity was assessed using the standard Snellen Chart. Evaluation of diabetic retinopathy was carried out by ophthalmoscopy following pupil dilation. The retinal blood flow was quantitatively and noninvasively evaluated by color duplex scanning. The retinal thickness was evaluated using resolution ultrasound at 14 MHz from Esaote (Genoa, Italy). Ultrasonography was carried out twice by two experienced physicians and the average value of the two retinal measurements is presented as percent variations compared to baseline values set to 100%.

Statistics

Considering the possible variability of measurements and observations (within such a minute set of observations), even in controlled, standardized conditions and considering interindividual variations, we included at least 20 subjects in each of the study groups.

A percentage of at least 25% female subjects were included in each group. A post-treatment or postobservation variation >5% in signs/symptoms or parameters was considered significant (P < 0.05) to define a variation or improvement determined to treatments or to define differences between groups.

The evaluation of these measurements and observations even in a very standardized clinical/environmental conditions cannot be considered statistically normally distributed. Therefore, nonparametric statistic tests (Mann–Whitney U-test, Tukey test, and the analysis of the variance) among groups were used in the final evaluation and analysis of treatment or follow-up-dependent statistical data.

Data collection and elaboration and the final statistical analysis were independently conducted; the statisticians were not aware of the technical details of retinal measurements but had contributed to the definition and construction of the study protocol.

Results

Forty-six diabetic patients were recruited for this study who presented with a moderate degree of diabetic macular edema. The patients were randomly assigned to either the Pycnogenol treatment group or the placebo control group. The groups had similar demographics and clinical characteristics at baseline. No significant differences in baseline characteristics were observed (Table 1).

Table 1.

Details of Patients

	Pycnogenol group	Placebo group
Age, years	51.2 ± 5.4	52.3 ± 6.1
Male to female ratio	14:10	15:7
HbA1c	6.9 ± 0.1	6.8 ± 0.2
Years of diabetes	6.4 ± 0.6	6.5 ± 0.5

The improvement of retinal thickness as well as edema score (Table 2) was found to be more prominent in those patients with more prominent macular edema. For this reason, we chose to present the data separately for patients with mild retinal edema and more advanced, moderate edema, based on the retinal thickness observed by high resolution ultrasound. Patients with baseline retinal thickness below 500 µm were considered having mild edema, and patients with higher retinal thickness as having moderate edema. Based on this differentiation we found that in the Pycnogenol group 13 patients had mild edema and 11 had moderate macular edema. In the placebo group 12 had mild and 10 had moderate edema, respectively. As shown in Table 3 the retinal thickness of patients with moderate edema decreased significantly as compared to the control group after 2 and 3 months of treatment with Pycnogenol (Table 3). In patients with mild edema retinal thickness decreased as well but did not reach statistical significance. The ophthalmologic investigation did in average show less edema, with 6 out of 11 subjects with moderate edema taking Pycnogenol having mild edema score levels at the end of the study. In contrast, all 22 subjects in the control group remained in the same category of diabetic retinopathy/macular edema score as diagnosed at inclusion. Improvement of edema score in the Pycnogenol group was statistically significantly lower compared to baseline as well as the control group. Only a marginal and nonsignificant effect on retinal thickness was evident in the control group.

Table 2.

An Arbitrary Edema Score Which Was Utilized to Quantify Changes in Edema During the Course of This Clinical Trial

Classification	Score	Dilated ophthalmoscopy findings
Absence of diabetic macular edema	0	No retinal thickening or hard exudates found in posterior pole
Mild diabetic macular edema	2	Defined by limited retinal thickening or hard exudates in posterior pole but distant from the macula
Moderate diabetic macular edema	4	Defined by retinal thickening or hard exudates approaching towards the center of the macula without affecting its center
Severe diabetic macular edema	6	Retinal thickening or hard exudates affecting the center of the macula

Table 3.

Treatment Outcome of Parameters Investigated in This Study in Response to Pycnogenol (Pyc) or Placebo Controls (Ctrl)

		Treatment of mild retinal edema cases			Treatment of moderate retinal edema cases
Months		0	2	3	0	2	3
Visual acuity (Snellen chart)	Pyc	14/20	17/20∗, ,‡	17/20∗	14/20	17/20∗, ,‡	17/20∗, ,‡
Visual acuity (Snellen chart)	Ctrl	14/20	14/20	14/20	14/20	14/20	14/20
Retinal edema score (scale 1–6)	Pyc	2.3 ± 1.2	1.6 ± 0.8∗, ,‡	1.6 ± 0.7∗, ,‡	2.3 ± 1.1	1.5 ± 0.8∗, ,‡	1.5 ± 0.6∗, ,‡
Retinal edema score (scale 1–6)	Ctrl	2.2 ± 1.0	2.1 ± 1.1	2.1 ± 1.1	2.4 ± 0.8	2.3 ± 0.9	2.5 ± 1.1
Retinal flow (cm/s)	Pyc	36 ± 4.1	45 ± 3.8∗, ,‡	48 ± 4.2∗, ,‡	34 ± 3.0	42 ± 3.1∗, ,‡	44 ± 2.8∗, ,‡
Retinal flow (cm/s)	Ctrl	35 ± 3.0	34 ± 2.7	36 ± 3.0	35 ± 2.0	34 ± 3.1	36 ± 2.6
Diastolic flow relative to max systolic flow	Pyc	12% (0–33)	15%∗, ,‡ (2–40)	+15%∗, ,‡ (3–38)	13% (1–21)	16%∗, ,‡ (2–26)	+22%∗, ,‡ (4–29)
Diastolic flow relative to max systolic flow	Ctrl	11% (0–36)	11% (0–38)	11% (1–39)	13% (0–20)	13% (0–20)	12.5% (0–19)
Retinal thickness (µm)	Pyc	478 ± 49	421 ± 46	425 ± 47	544 ± 66	419 ± 33∗, ,‡	408 ± 35∗, ,‡
Retinal thickness (µm)	Ctrl	474 ± 55	465 ± 43	469 ± 52	563 ± 54	546 ± 61	541 ± 63

Patients were subdivided into two categories reflecting the severity retinal edema as outlined in Methods. Diastolic retinal blood flow is given as median and range in round brackets. All other parameters are given as mean values with standard deviation.

^∗Statistically significant difference compared to baseline values within the group. Statistical analysis was carried out as described in Methods.

^‡Statistically significant difference between treatment and placebo group.

The most pronounced improvement due to Pycnogenol was found for visual acuity. Eighteen out of a total of 23 patients taking Pycnogenol reported subjectively perceived visual improvement. Objective evaluation using the Snellen chart confirmed the visual improvement with visual acuity increasing from baseline average 14/20 to average 17/20 already after 2 months treatment with Pycnogenol, whereas no significant change was found in the control group.

Treatment with Pycnogenol significantly improved retinal blood flow, both systolic and diastolic components, expressed as flow velocity at the central retinal artery.

None of the patients dropped out during the 3 months trial. Medication was well tolerated and no side-effects were observed.

Discussion

A series of previous studies has pointed to vision-saving effects of Pycnogenol for patients with preproliferative diabetic retinopathy, as reviewed by Schönlau and Rohdewald.11 A multicenter field study in Germany with 1,169 diabetic retinopathy patients showed that daily intake of 20–160 mg Pycnogenol, according to severity of retinal symptoms, effectively halted progression of vision loss over a 6 months investigational period. Another study found that Pycnogenol significantly lowered retinal bleedings as judged by fluorangiography after 2 months treatment and resulted in a limited improvement of visual acuity.12

Our group recently found important benefits of Pycnogenol for diabetic microangiopathy including those involved in diabetic ulcera.13^,14 The recently demonstrated nitric oxide related improvement of vasodilatation with Pycnogenol is in congruence with the improved retinal blood flow shown in our retinopathy patients.4

The major target is the prevention of diabetic complications by tight blood glucose control through medication, dietary restrictions, and life-style changes involving physical activity. The Diabetes Control and Complications Trial (DCCT) (DCCT Research Group, 1993) and the United Kingdom Prospective Diabetes Study (UKPDS) (Lancet, 1998) have both emphasized the importance of a tight glucose control to reduce diabetic microvascular disease in type I and type II diabetes mellitus. Interestingly, only recently an investigation of 170,000 people with diabetes revealed that the relatively new antidiabetic class of medication known as glitazones significantly increases the risk for macular edema. They found a lowered, yet still present association between macular edema and glitazones even when patient’s glucose was under good control with HbA1c <7%.15 The authors caution that ophthalmologists treating patients with diabetic macular edema should consider the role of glitazones.

Pycnogenol has been intensively investigated since the 1970s to control and reduce edema, especially in venous disease.16⁻20 The mechanism of action involved for decreasing edema with Pycnogenol is complex.3 Pycnogenol was shown to improve endothelial function by stimulating nitric oxide synthase, which explains the improved retinal blood flow velocity. This effect is suggested to explain the decreased capillary filtration. Moreover, the potent inhibition of MMPs shown for Pycnogenol may help to improve capillary integrity.

Retinal edema has been ascribed to cause blurred vision, therefore, the reduced edema found in our patients was expected to improve vision. The degree of visual improvement, however, was impressive as patient’s themselves, 18 out of total 24 taking Pycnogenol, perceived this effect. A multicenter, field study with 1,169 type I and type II diabetes patients, showed that Pycnogenol stopped progression of vision loss, however, no significant improvement of vision occurred in patients.11 These patients had diabetes for an average of 12 years and half of the patients had previously been treated for retinopathy. Our study suggests that Pycnogenol may be especially beneficial for diabetic patients during early stages of retinopathy for stopping progression of the disease and restoring vision lost to this time.

Footnotes

Author Disclosure Statement

No author has a financial support or financial interest in any material or method mentioned.

References

Kohner

E.M.

Microvascular disease: what does the UKPDS tell us about diabetic retinopathy?. Diabet. Med. 25:20–24, 2008.

Bhagat

, Grigorian

R.A.

, Tutela

, et al. Diabetic macular edema: Pathogenesis and treatment. Surv. Ophthalmol. 54:1–32, 2009.

Rohdewald

P.J.

, Pycnogenol®, French Maritime Pine Bark Extract. In: Dekker

, ed. Encyclopedia of Dietary Supplement. Informa Healthcare: New York, NY; 2005 ; pp. 545–553.

Nishioka

, Hidaka

, Nakamura

, et al. Pycnogenol^®, French maritime pine bark extract, augments endothelium-dependent vasodilation in humans. Hypertension Res. 30:775–780, 2007.

Chida

, Suzuki

, Nakanishi-Ueda

, et al. In vitro testing of antioxidants and biochemical end-point in bovine retinal tissue. Ophthalmic Res. 31:407–415, 1999.

Nakanishi-Ueda

, Kamegawa

, Ishigaki

, et al. Inhibitory effect of lutein and Pycnogenol^® on lipid peroxidation in porcine retinal homogenate. J. Clin. Biochem. Nutr. 38:204–210, 2006.

Grimm

, Chovanová

, Muchová

, et al. Inhibition of NF-κB activation and MMP-9 secretion by plasma of human volunteers after ingestion of maritime pine bark extract (Pycnogenol). J. Inflamm. 3:1, 2006.

Grimm

, Schäfer

, and Högger

. Antioxidant activity and inhibition of matrix-metalloproteinases by metabolites of maritime pine bark extract (Pycnogenol^®). Free Rad. Biol. Med. 36:811–822, 2004.

Liu

, Zhou

H.J.

, and Rohdewald

. French maritime pine bark extract Pycnogenol^® dose-dependently lowers glucose in type II diabetes patients. Diabetes Care. 27:839, 2004.

10.

Zibadi

, Rohdewald

P.J.

, Park

, and Watson

R.R

. Reduction of cardiovascular risk factors in subjects with type 2 diabetes by Pycnogenol supplementation. Nutr. Res. 28:315–320, 2008.

11.

Schönlau

, and Rohdewald

. Pycnogenol^® for diabetic retinopathy. A review. Int. Ophthal. 24:161–171, 2002.

12.

Spadea

, and Balestrazzi

. Treatment of vascular retinopathies with Pycnogenol^®. Phytother. Res. 15:219–223, 2001.

13.

Cesarone

M.R.

, Belcaro

, Rohdewald

, et al. Improvement of diabetic microangiopathy with pycnogenol: A prospective, controlled study. Angiology. 57:431–436, 2006.

14.

Belcaro

, Cesarone

M.R.

, Errichi

B.M.

, et al. Diabetic ulcers: Microcirculatory improvement and faster healing with Pycnogenol^®. Clin. Appl. Thromb. Hemost. 12:318–323, 2006.

15.

Fong

D.S.

, and Contreras

. Glitazone use associated with diabetic macular edema. Am. J. Ophthalmol. 147:583–586.e1, 2009.

16.

Arcangeli

. Pycnogenol® in chronic venous insufficiency. Fitoter. 71:236–244, 2000.

17.

Petrassi

, Mastromarino

, and Spartera

. Pycnogenol^® in chronic venous insufficiency. Phytomed. 7:383–388, 2000.

18.

Schmidtke

, and Schoop

. Das hydrostatische Ödem und seine medikamentöse Beeinflussung. Swiss Med. 6:67–69, 1984.

19.

Cesarone

M.R.

, Belcaro

, Rohdewald

, et al. Comparison of pycnogenol and daflon in treating chronic venous insufficiency: A prospective, controlled study. Clin. Appl. Thromb. Hemost. 12:205–212, 2006.

20.

Watson

R.R

. Reduction of cardiovascular disease risk factors by French maritime pine bark extract. Cardiovasc. Rev. Rep. 20:326–329, 1999.