Br J Ophthalmol. 2016 Feb;100(2):227-34. doi: 10.1136/bjophthalmol-2014-306534.
The Diabetes Visual Function Supplement Study (DiVFuSS).
- 1Private Practice, Tacoma, Washington, USA.
- 2Captain James A Lovell Federal Heath Care Center, North Chicago, Illinois, USA.
- 3Private Practice, Olathe, Kansas, USA.
- 4Kresge Eye Institute, Wayne State University, Detroit, Michigan, USA.
BACKGROUND: Diabetes is known to affect visual function before onset of retinopathy (diabetic retinopathy (DR)). Protection of visual function may signal disruption of mechanisms underlying DR.
METHODS: This was a 6-month randomised, controlled clinical trial of patients with type 1 and type 2 diabetes with no retinopathy or mild to moderate non-proliferative retinopathy assigned to twice daily consumption of placebo or a novel, multi-component formula containing xanthophyll pigments, antioxidants and selected botanical extracts. Measurement of contrast sensitivity, macular pigment optical density, colour discrimination, 5-2 macular threshold perimetry, Diabetic Peripheral Neuropathy Symptoms, foveal and retinal nerve fibre layer thickness, glycohaemoglobin (HbA1c), serum lipids, 25-OH-vitamin D, tumour necrosis factor α (TNF-a) and high-sensitivity C reactive protein (hsCRP) were taken at baseline and 6 months. Outcomes were assessed by differences between and within groups at baseline and at study conclusion using meand ± SDs and t tests (p<0.05) for continuous variables.
RESULTS: There were no significant intergroup differences at baseline. At 6 months, subjects on active supplement compared with placebo had significantly better visual function on all measures (p values ranging from 0.008 to <0.0001), significant improvements in most serum lipids (p values ranging from 0.01 to 0.0004), hsCRP (p=0.01) and diabetic peripheral neuropathy (Fisher’s exact test, p=0.0024) No significant changes in retinal thickness, HbA1c, total cholesterol or TNF-α were found between the groups.
CONCLUSIONS: This study provides strong evidence of clinically meaningful improvements in visual function, hsCRP and peripheral neuropathy in patients with diabetes, both with and without retinopathy, and without affecting glycaemic control.
TRIAL REGISTRATION NUMBER: www.ClinicalTrials.gov Identifier: NCT01646047.
KEYWORDS: Clinical Trial; Colour vision; Field of vision; Macula; Retina
Previous research has shown that both diabetes and early diabetic retinopathy affect real-world visual function, including patients’ ability to see low contrast targets (like a pedestrian wearing gray clothes on a cloudy day) as well as color perception and visual field (peripheral vision) sensitivity., These changes in visual function may precede clinically observable retinopathy and are considered markers of early retinal dysfunction. The Age-Related Eye Disease Studies (AREDS and AREDS2) demonstrated that a multi-component nutritional supplement containing vitamins C, E, zinc, plus the macular carotenoids lutein and zeaxanthin significantly reduces the risk of moderate “dry” (non-exudative) age-related macular degeneration from progressing to the “wet” (neovascular) form of the disease most likely to cause severe vision loss, and multiple other studies have demonstrated improved visual function in AMD patients supplemented with macular carotenoids. Our group was interested to see if a multi-component supplement could improve visual function in patients with diabetes, some with and some without non-proliferative diabetic retinopathy (DR) at baseline.
We selected constituents for our test formula based on previous research using animal models and limited human studies to disrupt the biological processes underlying DR (reactive oxygen species, mitochondrial DNA damage, apoptosis of retinal capillary cells with attendant hypoxia and vascular leakage). In addition to measuring visual function in two groups randomized to receive the test formula or placebo, we also assessed retinal edema, serum lipids, high-sensitivity C-reactive protein, glycosylated hemoglobin and diabetic peripheral neuropathy symptoms at baseline and after six months.
No significant baseline differences were found between the placebo and supplement groups (between 1/3 to 1/2 of subjects in each group had mild to moderate non-proliferative DR by design, and there were no cases of macular edema). Subjects receiving the supplement compared to placebo were found to have significantly better visual function on all measures after six months, significantly higher macular pigment optical density (MPOD – a measure of lutein and zeaxanthin concentration at the center of the macula), significantly reduced neuropathy symptoms in those with symptoms at baseline, significantly reduced hsCRP, LDL-C and triglycerides, significantly (but modestly) increased HDL-C and no appreciable change in A1c values (see figure 1 below). At unmasking, four subjects were found to have reduced DR severity on supplement (see figure 2 below). There were no adverse events reported.
Figure 1 – DiVFuSS: Mean changes in visual function (averaged for both eyes), serum lipids, high-sensitivity C-reactive protein (hsCRP), glycosylated hemoglobin (HbA1c), and diabetic peripheral neuropathy symptom score (DPNSS) in supplemented (Suppl) versus placebo (Plac) groups at 6 months. Note that all improvements occurred despite minimal positive impact on HbA1c in the supplemented group (boxed). Adapted from Chous AP, Richer SP, Gerson JD, Kowluru RA. Br J Ophthalmol. 2016 Feb; 100(2):227-34.
Significance of Our Findings
Our study suggests that clinically meaningful improvements can be achieved in visual function and biomarkers associated with diabetes and DR in patients who have no overt retinopathy as well as those with early retinopathy and, in particular, without affecting blood glucose control (figure 3). Previous work using the same formula in an animal model showed reduction in oxidative stress, mitochondrial DNA damage, VEGF, nfKb, and retinal capillary apoptosis with no significant difference in glycemic control between supplemented and non-supplemented animals at 9-12 months, suggesting a biological link between human and animal findings.
The typical algorithm for prevention of vision loss from diabetes-related eye disease is as follows: (1) Get & maintain good blood sugar, pressure and lipid control; (2) Get annual dilated eye examinations; (3) Receive laser photocoagulation or anti-vascular endothelial growth factor (anti-VEGF) therapy by a series of intraocular injections if and when patients develop vision threatening diabetic retinopathy (proliferative retinopathy and or diabetic macular edema involving the central area of the macula). Although these treatments save vision, unfortunately this “counsel, watch, and wait to treat” approach does not always result in optimal outcomes and without significant expenditure of resources.
Figure 2: Subject #38 at baseline (left) and 6 months (right) after taking the DiVFuSS supplement. Note reduction of retinal hard exudate and temporal microaneurysm formation, indicating a reduction in diabetic retinopathy severity (image courtesy of A. Paul Chous, O.D.)
Evidence suggests that about 20% of newly diagnosed type 2 patients have some degree of DR already, and that early, tight control of blood glucose (as reflected by its 3-month average, HbA1c) lowers both the incidence and progression of DR. Still, about 50% of patients have HbA1c levels above 7%, and while good metabolic control lowers the risk of diabetes complications, a significant percentage of patients who achieve good control still ultimately need destructive photocoagulation or a series of injections into the eyes to mitigate the risk of severe vision loss. Diabetic retinopathy remains a leading cause of new blindness globally. This begs the question, we think – Is there anything more we can do for our patients with diabetes?
Of course, this is a relatively small study, and it remains to be seen if the test formula results in reduced incidence or progression of DR over time, or in patients with more advanced stages of DR. However, we believe our test formula (now commercially available) gives us an additional strategy for improving patients’ vision and possibly reducing their long-term risk independently of good long-term metabolic control. This has great potential impact for patients with diabetes who develop DR despite good diabetes control, for those who are unable to achieve good control, and for those interested in prevention. In fact, our findings suggest we can do more for our patients than “counsel, watch, and wait to treat.”
Figure 3: Clinically Significant Findings With The DiVFuSS Formula
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