Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss among people aged over 50, especially in developed countries [
Substantial evidence suggested that lutein and its isomer zeaxanthin, also known as macular pigment (MP), might prevent the progression of AMD resulting from photooxidative damage [
Some intervention studies have shown putative functional benefits of lutein/zeaxanthin supplementation by increasing MPOD and visual functions; however, the evidence is limited and inconclusive [
Therefore, we conducted this 2-year randomized, placebo-controlled, double-blinded dose-ranging trial to determine the effects of lutein/zeaxanthin on serum concentration, MPOD, and visual performances in early AMD patients and to use the results to discuss the daily lutein/zeaxanthin dosage currently used for long-term treatment.
Subjects with AMD aged over 50 years were recruited in Beijing, China. Inclusion criteria included a clinical diagnosis of early AMD (defined as the presence of soft drusen, presence of retinal pigmentary abnormalities with no signs of late AMD, or both) according to the Age-Related Eye Disease Study System [
All subjects were screened for eligibility based on the protocol criteria. Diagnosis of early AMD was confirmed by 2 ophthalmologists using funduscope and fundus photographs. After enrollment, subject information on characteristics and demographics was collected using questionnaires and examinations. Serum total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), and glucose were measured within 2 days of collection by Beijing Laweekse Health Laboratory using an autoanalyzer.
In this 2-year randomized, double-blinded, placebo-controlled trial, all subjects were randomly assigned to take either 10 mg lutein, 20 mg lutein, lutein (10 mg) + zeaxanthin (10 mg), or a placebo daily. All the supplements were packaged identically with the same labels. Serum lutein/zeaxanthin concentrations, MPOD, and visual performance indices including best-spectacle corrected visual acuity (BCVA), contrast sensitivity (CS), and flash recovery time (FRT) were quantified at baseline, 24 weeks, 48 weeks, and 2 years. All clinical examinations were performed by the qualified ophthalmic technicians in Peking University Eye Center, Peking University Third Hospital. Vision-related quality of life (VFQ-25) was measured at baseline, 48 weeks, and 2 years. Diet stability was assessed using a validated 120-item food frequency questionnaire conducted at baseline, 48 weeks, and 2 years. All subjects, examiners, and study staff were masked to treatment assignment.
Subjects were required to maintain their normal dietary and living habits and were asked to visit our office monthly to collect capsules of the following month and to return the remaining capsules from the month together with the daily checklist. They were encouraged to report any adverse effects immediately and were asked specifically about adverse events such as carotenoderma during visits.
Serum concentrations of lutein and zeaxanthin were extracted and analyzed using a modified high-performance liquid chromatograph (HPLC) method, which is discussed in detail elsewhere [
MPOD was determined using a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph II, Heidelberg Engineering Inc., Heidelberg, Germany) and has been detailed elsewhere [
After diopter correction, BCVA was measured according to the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, and the results were converted to the logarithm of the minimum angle of resolution (logMAR) [
FRT was recorded using a macular adaptometer (MDD-2; Avenue Optical Flash LLC, Lighthouse Point, FL), which included a xenon arc, and flash filtered for infrared, ultraviolet, visible short wavelengths and was delivered through an aperture in a hand-held tube. Technicians pressed a push button to activate the flash and the timer and pressed it again to stop the timer when the first stimuli of vision recovery were reported by the subject. The time was recorded as FRT [
VFQ-25 was our primary patient-reported outcome to evaluate qualitative changes in visual function and health-related quality of life. Scores were calculated with a 0 to 100 scale where higher scores indicate better functioning [
Sample size estimations indicated that 26 patients per group were needed to be able to distinguish a 30% difference for MPOD change in treatment groups (5% significance level, power 80%), and a total of 112 patients were enrolled assuming a dropout rate of 10%. As for randomization, the sequence was computer generated in a 1 : 1 : 1 : 1 ratio within permuted blocks of size 8.
Baseline comparisons among groups were assessed using ANOVA or the chi-square analysis. Skewed data was logarithmically transformed for analysis. Differences between baseline and follow-up measurements within a group were assessed using paired
Of the 334 screened participants, 112 subjects met all the criteria and were subsequently enrolled and randomized. Four subjects (3.6%) were excluded from the analysis due to their failure to attend scheduled examinations. Subject characteristics were well balanced across groups at baseline (Table
Baseline characteristics of subjects with early age-related macular degenerationa,b.
Placebo ( |
10 mg lutein ( |
20 mg lutein |
10 mg lutein + 10 mg zeaxanthin ( | |
---|---|---|---|---|
Age (y) | 69.0 ± 7.5 | 69.7 ± 8.3 | 69.3 ± 6.9 | 68.5 ± 6.9 |
Sex, male [ |
11 (39.3) | 9 (34.6) | 14 (51.9) | 12 (44.4) |
Education (y) | 12.2 ± 2.8 | 10.8 ± 2.7 | 12.2 ± 2.9 | 10.5 ± 4.1 |
BMI (kg/m2) | 24.8 ± 3.0 | 24.1 ± 3.4 | 25.1 ± 3.3 | 24.6 ± 3.6 |
Serum lipids (mmol/L) | ||||
Total cholesterol | 5.022 ± 1.756 | 4.984 ± 1.068 | 5.091 ± 0.883 | 5.247 ± 0.952 |
Triglyceride | 1.571 ± 1.575 | 1.538 ± 0.684 | 1.491 ± 0.821 | 1.777 ± 0.791 |
HDL cholesterol | 1.388 ± 0.438 | 1.386 ± 0.319 | 1.408 ± 0.258 | 1.481 ± 0.291 |
LDL cholesterol | 3.091 ± 0.606 | 3.190 ± 0.746 | 3.203 ± 0.605 | 3.338 ± 0.605 |
Early cataracts [ |
6 (21.4) | 6 (23.0) | 5 (18.5) | 8 (29.6) |
MPOD (D.U.) | 0.315 ± 0.144 | 0.307 ± 0.142 | 0.315 ± 0.122 | 0.320 ± 0.118 |
Serum concentration ( |
||||
Lutein | 0.337 ± 0.397 | 0.319 ± 0.250 | 0.308 ± 0.231 | 0.251 ± 0.260 |
Zeaxanthin | 0.066 ± 0.075 | 0.048 ± 0.050 | 0.050 ± 0.042 | 0.046 ± 0.055 |
bFor continuous variables, all values are mean ± SDs. For categorical variables, all values are
cCataracts diagnosed and graded according to the Lens Opacities Classification System III.
Serum and macular concentrations of lutein/zeaxanthin in all the active treatment groups progressively increased (all
Changes in serum lutein concentration (a) and macular pigment optical density (b) at baseline, 24 weeks, 48 weeks, and 2 years in patients with early age-related macular degeneration, treated with 10 mg/d lutein, 20 mg/d lutein, lutein (10 mg/d) + zeaxanthin (10 mg/d), or placebo. Values are expressed as group mean ± SEMs. Significant increase was observed in all non-placebo groups compared to that of baseline or placebo group (all
Likewise, the effect of 20 mg lutein on increasing MPOD was more effective at the first 24 weeks (increased by 25.4%,
Changes of CS among groups are shown in Table
Changes of contrast sensitivity among different groups during the interventiona.
Placebo |
10 mg lutein |
20 mg lutein |
10 mg lutein + 10 mg zeaxanthin ( | |
---|---|---|---|---|
Contrast sensitivity, log | ||||
3 cycles/degree | ||||
Baseline | 1.22 ± 0.37 | 1.26 ± 0.36 | 1.24 ± 0.39 | 1.25 ± 0.32 |
24 weeks | 1.22 ± 0.34 | 1.32 ± 0.39 | 1.34 ± 0.29 | 1.34 ± 0.34 |
48 weeks | 1.13 ± 0.36 | 1.45 ± 0.37† | 1.47 ± 0.39**† | 1.40 ± 0.31* |
2 years | 1.25 ± 0.32 | 1.47 ± 0.34* | 1.32 ± 0.25† | 1.39 ± 0.39* |
6 cycles/degree | ||||
Baseline | 1.40 ± 0.39 | 1.41 ± 0.34 | 1.40 ± 0.39 | 1.45 ± 0.38 |
24 weeks | 1.34 ± 0.34 | 1.47 ± 0.35 | 1.52 ± 0.37 | 1.51 ± 0.383 |
48 weeks | 1.30 ± 0.31 | 1.57 ± 0.37 | 1.62 ± 0.36*** | 1.52 ± 0.38 |
2 years | 1.25 ± 0.30 | 1.50 ± 0.33 | 1.54 ± 0.36† | 1.50 ± 0.36 |
|
||||
Baseline | 0.97 ± 0.37 | 1.02 ± 0.33 | 1.00 ± 0.34 | 1.06 ± 0.36 |
24 weeks | 1.02 ± 0.36 | 1.06 ± 0.42 | 1.06 ± 0.38 | 1.09 ± 0.35 |
48 weeks | 0.91 ± 0.32 | 1.07 ± 0.35 | 1.12 ± 0.38 | 1.16 ± 0.40 |
2 years | 0.87 ± 0.33 | 1.10 ± 0.35 | 1.05 ± 0.36 | 1.09 ± 0.35 |
18 cycles/degree | ||||
Baseline | 0.50 ± 0.35 | 0.57 ± 0.39 | 0.49 ± 0.35 | 0.53 ± 0.37 |
24 weeks | 0.52 ± 0.36 | 0.60 ± 0.42 | 0.57 ± 0.38 | 0.63 ± 0.35 |
48 weeks | 0.39 ± 0.28 | 0.62 ± 0.34 | 0.63 ± 0.38 | 0.68 ± 0.42 |
2 years | 0.40 ± 0.34 | 0.59 ± 0.45 | 0.65 ± 0.39 | 0.74 ± 0.33*† |
All values are mean ± SDs. Mean values were significantly different from baseline within the same group:
aRepeated-measures analyses of the above variables did not reveal any differential treatment effects, and the only significant time effect was observed at 3 cycles/degree (
Changes of visual performance among different groups during the interventiona.
Placebo |
10 mg lutein |
20 mg lutein |
10 mg lutein + 10 mg zeaxanthin ( | |
---|---|---|---|---|
Best-corrected visual acuity, |
||||
Baseline | 0.34 ± 0.19 | 0.31 ± 0.21 | 0.31 ± 0.21 | 0.32 ± 0.25 |
24 weeks | 0.33 ± 0.25 | 0.32 ± 0.21 | 0.27 ± 0.17 | 0.28 ± 0.30 |
48 weeks | 0.34 ± 0.22 | 0.28 ± 0.22 | 0.26 ± 0.20 | 0.27 ± 0.35 |
2 years | 0.30 ± 0.25 | 0.26 ± 0.15 | 0.28 ± 0.16 | 0.27 ± 0.24 |
Photorecovery time, sec | ||||
Baseline | 18.57 ± 16.78 | 16.68 ± 14.22 | 15.86 ± 11.17 | 17.38 ± 12.00 |
24 weeks | 19.02 ± 10.59 | 18.90 ± 17.71 | 14.13 ± 8.11 | 16.41 ± 14.69 |
48 weeks | 19.70 ± 12.16 | 15.50 ± 11.27 | 14.61 ± 13.43 | 17.80 ± 16.48 |
2 years | 24.41 ± 14.40 | 15.00 ± 8.40† | 15.36 ± 12.75† | 15.67 ± 11.04 |
VFQ25 score | ||||
Baseline | 76.04 ± 18.09 | 75.46 ± 14.60 | 75.58 ± 15.35 | 74.26 ± 14.46 |
48 weeks | 74.97 ± 17.10 | 75.02 ± 13.01 | 72.56 ± 14.46 | 76.32 ± 11.20 |
2 years | 77.31 ± 17.05 | 79.61 ± 13.52 | 76.65 ± 16.32 | 80.13 ± 11.73** |
All values are mean ± SDs.
Mean values were significantly different from baseline within the same group:
Mean values were significantly different from those of the placebo control group:
aRepeated-measures analyses of the above variables did not reveal any differential treatment or time effects.
The VFQ25 scores did not show any significant change over the first 48 weeks; however, they slightly increased at 2 years, especially in the lutein + zeaxanthin group (increased by 7.9%,
This trial demonstrated that 2 years of lutein/zeaxanthin supplementation increased serum lutein/zeaxanthin concentrations, MPOD, and visual performances in patients with early AMD, without leading to any detectable adverse effect. More interestingly, we found that though body lutein/zeaxanthin concentrations and visual performances increased the most after receiving 20 mg lutein within the first 48 weeks, the increases of MPOD and visual functions (BCVA and CS) were similar between the 10 mg lutein and the 20 mg lutein groups at 2 years. Additionally, our results indicate that a combined equal dose of lutein and zeaxanthin might be more effective in improving CS at 18 cycles/degree and patient-reported visual performance (VFQ25 scores).
Consistent with previous studies, lutein/zeaxanthin supplementation increased their serum concentrations dose-dependently [
In this study, a tendency of increase in BCVA and FRT was observed in all the active treatment groups (
However, CS is a more sensitive visual indicator compared to BCVA and FRT, which could provide additional information at the very beginning of visual dysfunction. Significant increases of CS were indeed detected at different spatial frequencies at 48 weeks and 2 years in all the active treatment groups, which is in line with other studies [
We noticed that the change of MPOD and visual functions from baseline was smaller in this study compared to similar studies [
It should be noted that no significant improvement of VFQ25 score was observed until the second year, and the only significant change was seen in the lutein + zeaxanthin group. Similarly, in Richer’s study, the VFQ25 score increased by only 2% after 12 months of lutein and/or zeaxanthin supplementation [
There are some noteworthy limitations in this study. First, the high selective criteria for subjects may affect generalization. Second, since the progression of AMD from early stage to late stage is much longer than our intervention period, our study could not use late AMD as the ultimate outcome and, therefore, is not powered adequately to find a reduction in late AMD incidence. Larger-scale and longer-term studies should be undertaken to focus on the effects of lutein and/or zeaxanthin on early AMD, and more sensitive measurements should be used.
In conclusion, our study has shown that lutein/zeaxanthin supplementation could increase their serum concentrations, MPOD, and reverse visual impairment in subjects with early AMD. Most interestingly, our findings suggest that supplementation with either 10 mg or 20 mg lutein could be equally effective after 2 years. Thus, it might be advisable for early AMD patients to take a lower dosage (10 mg/d) for long-term treatment.
None of the authors declared any conflict of interests regarding the publication of this paper.
Each author (1) contributed to the conception and design, acquisition of data, analysis, and interpretation of data and (2) revised the paper critically for important intellectual content and final approval of the version to be published.
The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (Grant no. 81273063).