Diabetes is associated with a number of met- abolic abnormalities, including hyperglycemia, dyslipidemia, hypertension, and oxidative stress. Release of inflammatory proteins and programmed destruction (apoptosis) of capillary endothelial cells and retinal ganglion cells may lead to a breakdown of the blood-retinal barrier, with vascular leakage, hypoxia, and retinal neovascularization—the hallmarks of diabetic retinopathy (DR). Accompanying deficits in visual function due to retinal neurodegeneration, including contrast sensitivity, visual field (VF) sensitivity, color vision, and electrophysiology, are common (see Figure 1).
These pathways synergistically result in retinal injury (both vasculopathy and neurodegeneration). Though early maintenance of relatively normal blood glucose abrogates this vicious cycle, many patients do not achieve optimal glycemia before this metabolic cascade is initiated. As every major diabetes clinical trial has shown, metabolic memory from a period of poor glycemic control after diabetes onset increases the long-term risk of microvascular complications, particularly DR, despite improved glucose control over time.
Now that we’ve established a framework for sev-eral biologic targets against DR, let’s take a look at a variety of specific micronutrients and dosages that may be beneficial based on human reports and interventional trials.
Vitamins and Minerals
Deficiencies of some B vitamins as well as vitamins C, D, and E have been reported in diabetes, probably because they are depleted secondary to increased oxidative stress.2 Some studies show that vitamin C supplementation can improve islet cell function in patients with type 2 diabetes, and it may be useful for the early prevention of diabetes and the treatment of complications,3 including macular ischemia in proliferative DR (PDR).4 However,
optometrists should be aware that high-dose vitamin C (>500 mg) can interfere with the accuracy of continuous glucose monitoring systems that help patients control their glucose levels, especially those who are using insulin therapy. Thus, limiting supplemental vitamin C to <500 mg/d is recommended for these patients.
Vitamin D deficiency has been implicated in the development of diabetes, especially in those who have vitamin D receptor mutations.5,6 Serum vitamin D status has been shown to be linked to the presence/severity of DR,7 and serum vitamin D levels <18.6 ng/mL were highly associated with PDR in one analysis, likely because vitamin D inhibits vascular endothelial growth factor (VEGF8).
I recommend that patients who have diabetes be tested for serum 25-hydroxyvitamin D3 status and achieve serum vitamin D levels >50 ng/ml and <80 ng/ml by sunlight exposure and/or oral supplementation of at least 5000 IU (125 mcg) of vitamin D3 per day in most adults, in tandem with vitamin K2. This is because vitamins D and K have synergistic bone and cardiovascular benefits.
Observational analysis has also linked deficiencies of vitamins B1, B6, B9, and B12 to a higher incidence of DR.9,10 Of particular interest is the finding that benfotiamine, a fat-soluble derivative of vitamin B1 (thiamine) significantly reduced advanced glycation end products, hexosamine and polyol pathway activity in patients who have type 1 diabetes,11 striking at the heart of mechanisms causing retinal injury (see Figure 1). I recommended 150 mg benfotiamine with meals to my DR patients.
Though vitamin A deficiency appears no more common in diabetes, a large population analysis in Korea reveals that subjects with higher levels of serum vitamin A were dramatically less likely to develop DR after all controls, with maximal protection in males younger than age 60.12
Some mineral deficiencies are also more common in patients who have diabetes, especially chromium, magnesium, and zinc; each of which play a role in normal insulin production and sensitiv-ity.13 Interestingly, a recent 2007 to 2018 analysis of the National Health and Nutrition Examination Survey shows higher total calcium, magnesium, zinc, and copper intake was inversely associated with the risk of DR in adults.14 Another analysis shows that 50% of patients with type 2 diabetes were zinc-deficient, which was also linked with a higher odds of having PDR.15 Patients with sight-threatening DR had significantly lower serum magnesium levels than those with milder DR and no DR in one study,16 an effect possibly explained by the anti-hypertensive effects of magnesium.17 Finally, 50 mcg daily of chromium polynictinate resulted in better HbA1c (-0.4%) and reduced the number of anti-VEGF injections (-1) over 6 months in patients with diabetic macular edema.18
Fatty Acids: Fish Oil
Fish oil supplementation was linked with a statistically significant (2.1/1.6 mm Hg) reduction in blood pressure in the meta-analysis and decrease of inflammatory biomarkers in cross-sectional analyses of the Nurses Health Study and the Multi-Ethnic Study of Atherosclerosis.19,20 Higher serum docosahexaenoic acid (DHA) and Eicosapentaenoic acid + DHA was strongly linked with less frequent (-17%) and severe DR (-38%) in post hoc analysis of 1356 patients with type 2 diabetes.21 The PREDIMED trial shows a 48% reduced risk of sight-threatening DR in those taking 500 mg of long-chain omega-3 polyunsaturated fatty acids from fish (2 servings of oily fish per week).22
Plant-Derived Compounds
A number of plant-based compounds have potential benefit in diabetes and DR.
Bark from French Maritime Pine, Pinus pinaster, contains anthocyanidins that bind to collagen/elastin fibers to improve capillary fragility. In small clinical trials, this bark reduced HbA1c, blood pressure, blood lipids, and inflammatory proteins linked to DR.23 Several studies suggest that this bark improves capillary leakage and slows DR progression in patients who have diabetes.24 It was also shown to improve retinal blood flow, reduce retinal thickening, and improve visual acuity (VA) in patients who had early DME.25 For 20 years, I have been recommending the oral form (120 mg/d) in DR/DME patients with good effect.
Curcumin is a component of the Indian spice, Turmeric. It suppresses NF-kB (reducing inflammation) but is quickly metabolized. Lecithinized curcumin improves retinal blood flow, retinal edema, and VA in DR patients over 4 weeks of supplementation.26 Recently, curcumin combined with black pepper (to enhance bioavailability), artemisia (an antimalarial), and bromelain (degrades advanced glycation end products) reduced central retinal thickness on ocular coherence tomography (OCT) by >30 µm and improved VA by 5 letters/1 line on the Early Treatment Diabetic Retinopathy Study scale. It also improved deep capillary plexus vessel density on OCT-angiography in a small number of patients who had mild to moderate DME.27
Lutein, zeaxanthin, and mesozeaxanthin—the latter of which is produced endogenously in the retina from lutein—are xanthophyll carotenoids (yellow pigments) and constitute the primary components of the macular pigment. A higher serum ratio of nonprovitamin A carotenoids (lutein, zeaxanthin, lycopene) to provitamin A carotenoids (alpha-carotene, beta-carotene, and beta-cryptoxanthin) was associated with a two-thirds reduction in the risk of DR among patients with type 2 diabetes after adjustment for confounding variables, including HbA1c level, hypertension, and disease duration.28
Moreover, macular pigment optical density has been reported to be lower in patients with type 2 diabetes compared with age-matched controls, and even lower in patients with vs without retinopathy; inversely correlated with glycosylated hemoglobin and lutein (6 mg/d) and zeaxanthin (0.5 mg/d) supplementation over 3 months, increasing MPOD, VA, contrast sensitivity, and foveal thickness in subjects who had NPDR compared to controls (n=60).29
A number of other plant-based nutraceuticals have been shown to have benefit in cellular and animal models of DR. These include astaxanthin (another carotenoid pigment), and various other polyphenols (resveratrol, epigallocatechin, quercetin, and rutin).30 Of particular interest to me are quercetin, rutin, and nicotinamide (vitamin B3), all of which are shown to reduce poly(ADP)ribose polymerase (PARP) in cell models, the master switch that facilitates oxidative damage in bloodvessel complications caused by diabetes, including DR.31,32
Multicomponent Supplements
Several multicomponent supplements are available to mitigate the pathogenesis of DR, though few have been studied in clinical trials, and none have been shown to prevent severe disease in human beings.
My advice: Look at the ingredients and specific amounts contained in these products to aid in deciding whether any specific formula makes biologic and clinical sense for particular patients.
I recommend a broad-spectrum vitamin and mineral supplement that contains adequate xanthophylls, like lutein and zeaxanthin (at least 10 mg daily), quercetin, and nicotinamide.
I also recommend extra oral Pinus pinaster, and benfotiamine (see above for dosages), and I have begun recommending micronized curcumin, along with a Mediterranean-type diet.
For my early patients with DR using insulin, I recommend minimizing hypoglycemia with managing diabetes and using a continuous glucose monitor. Hypoglycemia is an emerging risk factor for progression from mild NPDR, to more severe disease.33
The dietary habits of many of our patients are suboptimal. Nutritional supplements have the potential to help but, as my mentor Larry Alexander, OD, used to say, “supplements are not going to counteract the harmful effects of a crappy diet and lifestyle.” True that.
I tell my patients who have diabetes and DR that specific micronutrients may be beneficial, and I give them specific recommendations based on scientific evidence. That said, I also tell them they should still quit smoking, exercise regularly, and try to eat a healthy (Mediterranean-type) diet.
Final Thoughts
The supplements and dosages discussed have very few, if any, drug interactions but, of course, patient intolerance or allergy is something to keep top of mind. It’s also important to remember that fat-soluble supplements, like vitamin D, benfotiamine, and lutein, may require higher dosages to achieve biological effects in overweight patients because they are stored in adipose tissue. Finally, treat patients the same as you would want to be treated.
References
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