The present trial among adults with retinitis pigmentosa showed no significant treatment effect on the course of retinal degeneration in central field sensitivity as monitored by the HFA 30-2 program (the primary outcome measure) or in the central macula as monitored by ETDRS acuity (a secondary outcome measure). The trial did, however, show a significant beneficial effect of lutein 12 mg/day on preserving mid-peripheral visual field sensitivity as monitored by the HFA 60-4 program, a secondary outcome measure; the lutein + A group lost on average 27 dB per year versus 34 dB per year in the control + A group (see ). The effect of treatment was the same for patients with initial HFA sensitivities above and below the median, indicating that the observed benefit of lutein on slowing mid-peripheral field loss was not simply limited to those patients with milder disease who retained more sensitivity in this region. No effect of lutein could be detected with respect to preserving the full-field 30-Hz cone ERG (a secondary outcome measure); a possible explanation for the difference between the mid-peripheral HFA findings and the ERG results is that the latter is generated not only by central plus mid-peripheral cones but also by far peripheral cones. Since all the outcome measures were specified a priori and are correlated, no statistical adjustments for multiple comparisons were performed. The detectable benefit of lutein supplementation on preserving mid-peripheral function but not central function in retinitis pigmentosa may reflect an increased requirement for antioxidants in photoreceptor outer segments in a region of the retina where the photoreceptors are most impaired.
The effect of lutein on slowing mid-peripheral field decline was consistent with the observation that the annual rate of decline of mid-peripheral field sensitivity was significantly slower among those in the upper quartile of serum lutein at follow-up versus those in the lower 3 quartiles. Most patients taking lutein 12 mg/day had a serum lutein level above 20 μg/dL which was associated with a decrease in decline of HFA 60-4 sensitivity (see ). Serum lutein levels above 60-70 μg/dL were not associated with greater benefit. The finding that serum lutein levels vary widely among patients taking the same dose of lutein, described by others, 43
was also observed in this study (see ). In addition, patients in the highest quartile of MPOD elevation at follow-up — as a measure of increase in intra-retinal lutein — had a significantly slower rate of decline not only of mid-peripheral field but also of central and mid-peripheral field combined compared with the rate among those in the lower 3 quartiles.
The randomized comparisons ( and ) demonstrating a beneficial effect of lutein on slowing mid-peripheral field sensitivity loss, and the observational data that maximal slowing occurred among those with the highest serum lutein and greatest increase in MPOD (), provide evidence to support the use of lutein supplementation 12 mg/day among adults with typical retinitis pigmentosa also taking vitamin A palmitate 15,000 IU/day and eating 1-2 servings of oily fish per week. It should be noted that no significant adverse effects were found with use of lutein with respect to both general health and lowering serum retinol over the 4 year duration of this trial.
The short-term safety of lutein has been reported in two other studies of retinitis pigmentosa in which patients were given this supplement in higher doses for up to 6 months. 35,44
However, some concern has been raised that long-term lutein supplementation is associated with an increased risk of lung cancer among smokers over age 50 in the general population. 45
The present trial was conducted in current non-smokers and therefore the recommendation for lutein supplementation 12 mg/day is limited to adult patients with typical retinitis pigmentosa who do not smoke. The long-term safety of lutein even in non-smokers remains to be established. Because the highest serum lutein levels were not associated with greater benefit in this study (see ) and because the long-term safety of higher dose lutein supplementation is unknown, patients should not exceed 12 mg/day based on current knowledge.
Patients on vitamin A palmitate 15,000 IU/day, 1-2 three-ounce servings of oily fish per week, and lutein 12 mg/day should be reminded to have a fasting serum vitamin A and liver function profile annually as a precaution. Women who are pregnant or planning to become pregnant should not take high-dose vitamin A supplements because of an increased risk of birth defects. Patients age 49 and over should monitor their bone health because of the slight (0.5 – 1.0%) increased risk of hip fracture among patients on long-term high-dose vitamin A supplementation. 46,47
The benefit of lutein supplementation on the long-term course of mid-peripheral visual field loss among patients also on vitamin A and an oily fish diet can only be estimated. Based on the randomized comparison (see ), a patient age 40 would be expected to lose 27 dB/year of total point score, on average, in the lutein group versus 34 dB/year in the control group (i.e. 7 dB saved per year) over the 4-year interval of this trial. Assuming 60 measurable test locations within the HFA 60-4 program and recognizing that 1 dB=0.1 log10 unit, we calculate that lutein supplementation saved, on average, 2.7% per test location per year of mid-peripheral field sensitivity (i.e. 100 × [10(7dB × 0.1/60)−1] = 2.7%) that is equivalent to 0.12 dB per test location per year (i.e., 0.12 dB = 7 dB/60 test locations). With respect to change in serum lutein (see ), we calculate a saving of 12 dB/year or 4.7% per year (i.e. 100 × [10(12 dB × 0.1/60) −1] = 4.7%) that is equivalent to 0.2 dB per test location per year. With respect to change in MPOD we calculate a saving of 16 dB/year or 6.3% per year (i.e. 100 × [10(16 dB × 0.1/60) −1] = 6.3%) or 0.27 dB per test location per year. Therefore, depending on the analysis, the average yearly saving of mid-peripheral visual field sensitivity during the trial ranged from 2.7% to 6.3% per test location per year.
Over the longer term, taking into account that a patient age 40 has, on average, 375 dB of mid-peripheral sensitivity based on total point scores (see ), the estimated benefit in preserving mid-peripheral field sensitivity based on the randomized comparison would be 3 additional years (i.e., 375/27 = 14 versus 375/34 = 11), based on the serum lutein observational results would be 6 additional years (i.e., 375/21 = 18 versus 375/33 = 12), and based on the MPOD observational results would be 10 additional years (i.e., 375/18 = 21 versus 375/34 = 11). In the latter case an average patient on vitamin A who starts lutein at age 40 could expect to lose mid-peripheral field by age 61 (i.e., 40 + 21), while a patient not on lutein would be expected to lose mid-peripheral field by age 51 (i.e., 40 + 11). Follow-up of patients taking lutein and vitamin A with an oily fish diet for at least 10 years would be needed to confirm the above estimates with respect to preserving mid-peripheral visual field.