Pycnogenol® For Diabetes Mellitus
Biologic Rationale And EvidenceWritten by A. Paul Chous, MA, OD, FAAO Friday, 01 February 2013
Pycnogenol® is a patented extract of bark from the French maritime pine tree, Pinus pinaster, subspecies Atlanticus des Villar. Ingestion and topical application of pine bark and needle preparations for medicinal purposes dates back several centuries, with the first described use by the French explorer Jacques Cartier as a remedy for his scurvy afflicted crew on the St Lawrence River near Quebec in 15351. Nearly four centuries later, the French researcher, Jacques Masquelier isolated an ascorbate-enhancing flavanol (polyphenolic antioxidant containing catechins) he called oligoprocyanidin2 (OPC) from French Maritime Pine and patented the extraction process, later dubbing the end product Pycnogenol®.
The US Pharmacopeia 28 specifies the content of Pycnogenol® as 65-75% procyanidins (tannin compounds) made up of catechin and epicatechin sub-units (plant metabolites consisting of two benzene rings and a dihydropyran ring with a hydroxyl group bound to the third carbon atom –see figure 1 below). The remaining 25-35% consists of polyphenolic monomers. Catechins are commonly found in cocoa and green tea, and some sub-classes (like EGCG) have been shown to block induction and activity of Vascular Endothelial Growth Factor in cell models3 and in the skin of human subjects.4
Figure 1 – chemical structure of Pycnogenol procyanidins
Because of its antioxidant and anti-inflammatory properties, Pycnogenol® has attracted some attention for its potential in the management of a number of clinical entities. Evidence suggests that Pycnogenol® also improves endothelial dysfunction and inhibits the angiotensin system in hypertension5. Moreover, its anti-diabetic activity as a function of blocking the digestive enzyme, alpha-glucosidase has garnered interest from diabetes researchers6. Since its patenting, more than 250 scientific papers have been published examining the biochemistry and potential clinical utility of Pycnogenol®, including more than 30 small RCCTs (see Table 1). Five human studies have looked specifically at application in diabetes, including two studies evaluating diabetic retinopathy.
Table 1 – RCCTs Showing Benefit of Pycnogenol® Supplementation in Subjects without Diabetes
- Reduced LDL-C and increased HDL-C & plasma ORAC in healthy adults (Lipids 2002;37(10):931-4)
- Improved cognition in elderly patients (J. Psychopharmacol 2008;22(5):553-62)
- Lowered blood pressure in hypertensive patients on nifedipine (Life Sci 2004;74(7):855-62)
- Increased kidney cortical blood flow and decreased serum creatinine, urinary albumin, CRP and diastolic BP in hypertensive patients with Metabolic Syndrome on an ACEI (J Cardiovasc Pharmacol Ther 2010;15(1):41-6
- Resored normal erectile function in combination with L-arginine in patients with mild-moderate ED (Int J Impot Res 2008;20(2):173-80
- Improved cochlear blood flow and symptoms in pts with idiopathic tinnitus (Panminerva Med 2010;52(2suppl):63-7)
- Improved gum bleeding and plaque formation in pts with periodontitis (Phytomedicine 2002;9(5):410-13)
- Improved symptoms of allergic rhinitis (including ocular itching) when started at least 5 weeks prior to seasonal exposure (Phytother Res 2010;24(8):1115-9)
- Significantly improved lung function and symptoms in children with asthma (J Asthma 2004;41(8):825-32)
- Improved jet lag symptoms (Minerva Cardioangiol 2008:56(5suppl):3-9)
- Reduced leg edema in CVI (Phytomedicine 2000;7(5):383-8)
- Reduced pain scores and GI complications in osteoarthritis (Phytother Res 207:22(4):518-23 and 22(8):1087-92)
- Marked reduction in hemorrhoid symptoms (Phytother Res 2010:24(3):438-44)
- Increased sperm count of infertile males (Phytother Res 2009:23(3):297-302)
- Significant reduction in pain scores for women with dysmennorhea (J Reprod Med 2008;53(5):338-46) and pregnancy pain (Phytotgher Res 2006;20(3):232-4)
- Reduced Disease Activity Index in Lupus (Phytother Res 2001:15(8):698-704)
- Reduced nausea, vomiting, diarrhea in patients receiving chemotherapy (Panminerva Med 2008:\;50(3):227-34)
- Reduced hyperactivity and improved attention in children with ADHD (Eur Child Adolesc Psychiatry 2006;15(6):329-35
- Lowered IOP & improved blood flow in combination with Bilberry in pts with OHTN (Mol Vis 2008;14:1288-92)
Chous AP, Diabetes Du Jour, Vision Expo West, Las Vegas, 2011
Why might Pycnogenol® benefit patients with diabetes? In addition to limiting post-prandial hyperglycemia by blocking digestion of starches in the small intestine, it appears to decrease oxidative stress caused by acute and chronic hyperglycemia,7 to decrease the inflammatory cytokines COX-1 and COX-2,8 and to positively affect a number of co-morbidities associated with diabetes, including hypertension, kidney dysfunction, dyslipidemia, periodontal disease, erectile dysfunction and chronic venous insufficiency (inferred benefit - see Table 1 and Figure 2).
Figure 2 - Metabolic abnormalities commonly associated with diabetes, with RCCTs showing benefit in patients without diabetes circled in red (inferred benefit)
In addition, Pycnogenol’s procyanidins are highly bioavailable9, a feature of added significance given nutritional malabsorption more common in diabetes10. In the retina, supplementation inhibits production of matrix metallproteinases (MMPs) that cause apoptosis and degrade vascular collagen leading to breakdown of the blood-retinal barrier11, as happens in diabetic retinopathy; as such, Pycnogenol® serves to ‘seal’ leaky capillaries and may inhibit neovascularization as DR progresses.12
Clinical studies in diabetes patients show that Pycnogenol® lowers glycosylated hemoglobin and blood pressure, and improves dyslipidemia. One RCCT in type 2 diabetes (n=77) found that 100mg/day over twelve weeks lowered mean HbA1c 0.6% and serum endothelin-1by 50% compared to usual care (both p < .01).13 Another small RCCT of type 2 patients with hypertension treated by ACE inhibitor drugs +/- 125 mg /day Pycnogenol® for twelve weeks (n=44) found mean reductions in HbA1c of 0.8% (p < .05), mean fasting blood glucose of 24 mg/dl (p < .0001) and LDL cholesterol of 12.7 mg/dl (p < .001) in the supplement group only. In addition, 58% of supplemented subjects were able to halve their ACEI dose and still achieve target blood pressure.14 In another RCCT of diabetes-related lower limb ulceration (n=120), subjects treated with oral, topical, and oral plus topical Pycnogenol® in addition to standard ulcer medications showed significant improvement in ulcer size and symptomatology when compared with standard ulcer medications alone; 89% showed complete resolution of ulceration at 6 weeks with addition of topical + oral Pycnogenol® versus 61% of controls (p < .001).15
Pooled analysis of application in diabetic retinopathy includes 5 clinical trials conducted in France and Germany, of varying quality (n= 1289), with two small RCCTs, suggesting that Pycnogenol® ‘unequivocally’ retards progression of the disease. The largest cohort was a multi-site field study with no controls and no report of patients’ metabolic status (n= 1169).16 A more recent Italian RCCT using 125 mg/day for 90 days in subjects with mild to moderate diabetic macular edema (n=46) showed significant reduction in retinal edema via dilated ophthalmoscopy and high resolution ultrasound, as well as a 25% increase in retinal blood flow through the central retinal artery using laser Doppler ultrasound. In addition, Snellen visual acuity improved only in supplemented subjects (n = 24), with a mean change from 14/20 to 17/20.17 These positive findings clearly need to be replicated in larger, well-designed studies that employ spectral domain OCT, assurance of comparable metabolic control and diverse ethnic composition.
Adverse events reported with Pycnogenol® use include transient GI upset and flatulence (common effects of the FDA-approved alpha-glucosidase inhibitor agents like Precose® and Glyset, ® but relatively uncommon with Pycnogenol®) and the potential for hypoglycemia in patients using insulin or oral agents that increase endogenous insulin production (sulfonylurea secretagogues like glyburide and glimepiride).
I have been using Pycnogenol® for my patients with mild-moderate NPDR and/or DME for the last 9 years in my practice and have seen some marked improvements in glucose control and retinal status with few to no side effects. Good candidates for supplementation include patients with pre-diabetes, diabetes patients with sub-optimal glycemic control (HbA1c > 6.5% for those without established cardiovascular disease and > 7.8% in those with CVD or short life expectancy), patients with NPDR or DME, patients with hypertension, patients with microalbuminuria (30-299 mg albumin/gram of creatinine), patients with erectile dysfunction or periodontal disease (both risk factors for DR and DR progression), and those patients with diabetes who are interested in prevention. The caveat about glycosylated hemoglobin in patients with diagnosed CVD or shortened lifespan stems from results of the ACCORD trial conducted in the US, which showed increased mortality in patients with CVD and poor glucose control who attempted tight control, possibly as a function of acute hypoglycemia and/or higher habitual cardiac glucose requirements, although two other large trials have failed to replicate this deleterious effect on mortality.18 Patients with diabetes should be encouraged to more regularly check their blood glucose levels at home when initiating use of Pycnogenol® or any supplement.
- Stephens HB. Jacques Cartier and His Four Voyages to Canada. British Library, Historical Print Editions (March 28, 2011)
- Camilleri M. Gastrointestinal problems in diabetes. Endocrinol Metab Clin North Am. Jun 1996;25(2):361-78.
- Michaud J, Masquelier J, Roudge AM. [Synthesis of natural procyanidines]. Ann Pharm Fr. 1973 May;31(5):385-395.
- Jung YD, Kim MS, Shin BA, et al. EGCG, a major component of green tea, inhibits tumour growth by inhibiting VEGF induction in human colon carcinoma cells. Br J Cancer. 2001 Mar 23;84(6):844-850.
- Domingo DS, Camouse MM, Hsia AH, et al. Anti-angiogenic effects of epigallocatechin-3-gallate in human skin. Int J Clin Exp Pathol. 2010 Aug 5;3(7):705-709.
- Liu X, Wei J, Tan F, et al. Pycnogenol, French maritime pine bark extract, improves endothelial function of hypertensive patients. Life Sci. 2004 Jan 2;74(7):855-862.
- Schäfer A, Högger P. Oligomeric procyanidins of French maritime pine bark extract (Pycnogenol) effectively inhibit alpha-glucosidase. Diabetes Res Clin Pract. 2007 Jul;77(1):41-46.
- Maimoona A, Naeem I, Saddiqe Z, Jameel K. A review on biological, nutraceutical and clinical aspects of French maritime pine bark extract. J Ethnopharmacol. 2011 Jan 27;133(2):261-277.
- Schäfer A, Chovanová Z, Muchová J, et al. Inhibition of COX-1 and COX-2 activity by plasma of human volunteers after ingestion of French maritime pine bark extract (Pycnogenol). Biomed Pharmacother. 2006 Jan;60(1):5-9.
- D'Andrea G. Pycnogenol: a blend of procyanidins with multifaceted therapeutic applications? Fitoterapia. 2010 Oct;81(7):724-736.
- Grimm T, Schäfer A, Högger P. Antioxidant activity and inhibition of matrix metalloproteinases by metabolites of maritime pine bark extract (pycnogenol). Free Radic Biol Med. 2004 Mar 15;36(6):811-822.
- Kowluru RA, Zhong Q, Santos JM. Matrix metalloproteinases in diabetic retinopathy: potential role of MMP-9. Expert Opin Investig Drugs. 2012 Jun;21(6):797-805.
- Liu X, Wei J, Tan F, et al. Antidiabetic effect of Pycnogenol French maritime pine bark extract in patients with diabetes type II. Life Sci. 2004 Oct 8;75(21):2505-2513.
- Zibadi S, Rohdewald PJ, Park D, Watson RR. Reduction of cardiovascular risk factors in subjects with type 2 diabetes by Pycnogenol supplementation. Nutr Res. 2008 May;28(5):315-320.
- Belcaro G, Cesarone MR, Errichi BM, et al. Diabetic ulcers: microcirculatory improvement and faster healing with pycnogenol. Clin Appl Thromb Hemost. 2006 Jul;12(3):318-323.
- Schönlau F, Rohdewald P. Pycnogenol for diabetic retinopathy. A review. Int Ophthalmol. 2001;24(3):161-171.
- Steigerwalt R, Belcaro G, Cesarone MR, et al. Pycnogenol improves microcirculation, retinal edema, and visual acuity in early diabetic retinopathy. J Ocul Pharmacol Ther. 2009 Dec;25(6):537-540.
- Dhar GC.Intensive glycemic control: implications of the accord, advance, and VADT trials for family physicians. Can Fam Physician. 2009 Aug;55(8):803-804.
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About the Author(s)
Dr. Paul Chous was diagnosed with Type 1 diabetes mellitus at age five. He completed his undergraduate education at Brown University and UC Irvine, and then received his Masters and Doctorate of Optometry degrees with highest honors from UC Berkeley. Paul has a private practice specializing in diabetes eye care and education in Tacoma, WA
Dr. Chous won the American Diabetes Association’s Distinguished Public Service Award in 1998. He is the author of Diabetic Eye Disease: Lessons From a Diabetic Eye Doctor (Fairwood Press, Seattle, 2003), which was included in the “Top 12 Diabetes Books” by Diabetes Update magazine in 2004. He is a feature writer for the web sites dLife – Your Diabetes Life (http://www.dLife.com) and Diabetes In Control (http://www.diabetesincontrol.com), anophthalmic consultant to Children With Diabetes (http://www.childrenwithdiabetes.org) and the Diabetes Exercise and Sports Association (http://www.DESA.org), Section Editor of the Kestrel Diabetes Sourcebook, AOA representative to the National Diabetes Education Program (http://www.ndep.nih.gov), and an adjunct instructor at NOVA Southeastern University College of Optometry in Fort Lauderdale, FL.