Studies weigh efficacy of omega-3 fatty acids in combating diabetes-related issues

Image Credit: AdobeStock/Alina

Controversy surrounds the potential benefits of omega-3 polyunsaturated fatty acid (PUFA) supplementation for a variety of ophthalmic conditions linked to diabetes, including ocular surface disease and diabetic retinopathy. For example, the phase 3 DREAM study found no benefit on ocular surface parameters in patients with dry eye using 3000 mg omega-3 PUFA (2000 mg eicosapentaenoic acid [EPA] and 1000 mg docosahexaenoic acid [DHA]) for 12 months compared to placebo olive oil consumption¹ and no worsening of symptomatology following discontinuation of omega-3 PUFA for a year,² whereas another study showed significantly improved tear breakup time (TBUT) and meibomian gland dysfunction using 600 mg of EPA plus 1640 mg of DHA compared with 3000 mg of olive oil placebo.³ Another study limited to patients with diabetes and dry eye found that omega-3 PUFA supplementation reduced Ocular Surface Disease Index scores, TBUT, and conjunctival squamous metaplasia using 750 mg of EPA and 750 mg of DHA.⁴ These conflicting results suggest that dose of EPA and DHA, ratio of EPA to DHA, patient characteristics, and/or use of olive oil placebo may affect outcomes.

Studies examining the effects of omega-3 PUFA on diabetic retinopathy have also found conflicting results. In a 3-year human trial registered through EndraCT, 1000 mg DHA plus antioxidants significantly reduced optical coherence tomography central subfield thickness when added to ranibizumab therapy for diabetic macular edema and increased 5- and 10-letter ETDRS gains.⁵ More recently, a prospective sub-analysis of adults over age 40 with type 2 diabetes in the placebo-controlled ASCEND trial found that daily, oral omega-3 fatty acid supplementation, using 460 mg EPA and 360 mg DHA for more than 6 years, was no better than placebo at reducing time to “referable retinopathy” (an amalgamated primary outcome of pre-proliferative diabetic retinopathy [DR], proliferative DR, and/or diabetic macular edema) in 7360 participants in England and Wales.⁶

ASCEND was designed to assess cardiovascular event (MI, stroke, CABG, CV death) risk reduction with omega-3 PUFA and was not expressly powered to assess DR outcomes with high certainty. Nonetheless, time to referable disease in those with no DR at baseline and time to worsening DR grading (secondary outcomes), as well as loss of 15 or more ETDRS letters (tertiary outcome), were similarly unaffected by omega-3 supplementation vs placebo. The authors note that lack of racial/ethnic diversity and under-representation of female participants in the cohort, which was 96% White and 62% male, may have affected both cardiovascular and retinopathy outcomes. They also stipulate the possibility that omega-3 FA dose, ratio of EPA to DHA, and/or duration of treatment may have affected the lack of benefit withg respect to DR.

It is important to note that the EndraCT and ASCEND-Eye studies assessed different dosing regimens and outcomes, so it could be that omega-3 PUFA retinal benefits only accrue with higher dose and more severe disease at baseline, as in the DME-specific trial.

Regarding dose, cardiovascular outcomes in ASCEND also were not significantly better in the omega-3 fatty acid arm⁷; 100 mg daily aspirin reduced serious vascular events by 12% but increased serious bleeding events by 29%. This finding, as I have discussed in another recently published article for Elsevier,⁸ differs from some prospective trials of high-dose omega-3 FA, such as the Phase 3 REDUCE-IT trial, which showed a 25% risk reduction for these very same major adverse cardiovascular events in higher-risk patients with both type 2 diabetes and hypertriglyceridemia over 5 years’ median follow-up and daily use of 4 g EPA,⁹ with a 40% risk observed in non-White patients. As I discuss, this suggests that dose does matter when assessing vascular outcomes, particularly in non-White populations. Moreover, a dose response meta-analysis of omega-3 fatty acid supplementation in 2021 concluded that cardiovascular disease risk reduction was directly proportionate to daily dose ranging from 450 to 5500 mg in subjects both with and without diabetes.¹⁰

It is critical to realize that bioavailability of supplemented omega-3 fatty acid was not assessed in ASCEND nor ASCEND-Eye. Neither serum levels nor, perhaps more importantly, red blood cell membrane omega-3 fatty acid saturation (omega-3 index) were assessed. This is important since Individual response to any given dose is variable¹¹ [and there is evidence that an omega-3 RBC index value greater than 6% confers cardiovascular protection, especially against sudden cardiac death, compared with levels less than 4%.¹²

As I discussed in my previous article, there does not appear to be published evidence regarding the relationship between DR incidence/progression and omega-3 red blood cell index levels.⁸ However, future studies incorporating this relatively simple assay may aid eye care providers with respect to omega-3 fatty acid supplementation and dose given the lack of efficacy seen in ASCEND-Eye. I also made note that the PREDIMED trialconducted in Spain did show that dietary intake of marine-sourced, long-chain omega-3 fatty acids (equivalent to 500 mg daily or 2 weekly servings of oily fish) was associated with a 48% reduction in sight-threatening DR incidence over 6 years in patients older than 55 years with type 2 diabetes compared with those not achieving this level of intake.¹³

Figure. Ω-3 Fatty Acid vs Diabetic Retinopathy

The ASCEND-Eye prospective trial in the UK found no benefit against referable diabetic retinopathy with 1 g daily of ω-3 fatty acid supplementation over 6 years, whereas the PREDIMED trial did find significant protection against sight-threatening diabetic retinopathy, as seen in this patient with proliferative diabetic retinopathy. (Image courtesy of A. Paul Chous, OD, MA, FAAO.)

Of course, fish oil supplements are not fish, so it may be that other constituents of fish and/or substitution of dietary fish for other foods that can have more harmful health ramifications may have conferred this benefit (Figure 1). Omega-3 PUFA are found at high levels in both the brain and its extension, the retina. Diabetes is known to result in so-called advanced lipoxidation endproducts (ALE) that occur when glucose nonenzymatically binds to fatty acids, thereby destabilizing phospholipid membranes within the neurovascular retina, a process which is implicated in the pathogenesis of DR.¹⁴ As such, the development of methods for rapidly assessing retinal omega-3 PUFA content and ALE deposition in clinical settings holds promise for assessing which patients are most likely to benefit from increased intake of fish and/or PUFA supplements.

References:

1. Dry Eye Assessment and Management Study Research Group; Asbell PA, Maguire MG, Pistilli M, et al. n-3 fatty acid supplementation for the treatment of dry eye disease. N Engl J Med. 2018;378(18):1681-1690. doi:10.1056/NEJMoa1709691

2. Hussain M, Shtein RM, Pistilli M, Maguire MG, Oydanich M, Asbell PA; DREAM Study Research Group. The Dry Eye Assessment and Management (DREAM) extension study - a randomized clinical trial of withdrawal of supplementation with omega-3 fatty acid in patients with dry eye disease. Ocul Surf. 2020;18(1):47-55. doi:10.1016/j.jtos.2019.08.002

3. Jo YJ, Lee JS. Effects of dietary high dose DHA omega-3 supplement in dry eye with meibomian gland dysfunction. Int J Ophthalmol. 2021;14(11):1700-1706. doi:10.18240/ijo.2021.11.08

4. Georgakopoulos CD, Makri OE, Pagoulatos D, et al. Effect of omega-3 fatty acids dietary supplementation on ocular surface and tear film in diabetic patients with dry eye. J Am Coll Nutr. 2017;36(1):38-43. doi:10.1080/07315724.2016.1170643

5. Lafuente M, Ortín L, Argente M, et al. Three-year outcomes in a randomized single-blind controlled trial of intravitreal ranibizumab and oral supplementation with docosahexaenoic acid and antioxidants for diabetic macular edema. Retina. 2019;39(6):1083-1090. doi:10.1097/IAE.0000000000002114

6. Sammons EL, Buck G, Bowman LJ, et al; ASCEND Study Collaborative Group. ASCEND-Eye: effects of omega-3 fatty acids on diabetic retinopathy. Ophthalmology. Published online December 3, 2023. doi:10.1016/j.ophtha.2023.11.030

7. ASCEND Study Collaborative Group; Bowman L, Mafham M, Wallendszus K, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018;379(16):1540-1550. doi:10.1056/NEJMoa1804989

8. Chous AP. Effects of Omega-3 Fatty Acid Supplementation in Patients With Diabetic Retinopathy. Ophthalmology. December 25, 2023.

9. Bhatt DL, Steg PG, Miller M, et al. REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. doi:10.1056/NEJMoa1812792

10. Bernasconi AA, Wiest MM, Lavie CJ, Milani RV, Laukkanen JA. Effect of omega-3 dosage on cardiovascular outcomes: an updated meta-analysis and meta-regression of interventional trials. Mayo Clin Proc. 2021;96(2):304-313. doi:10.1016/j.mayocp.2020.08.034

11. Acar N, Merle BMJ, Ajana S, et al; Biomarkers of Lipid Status And metabolism in Retinal ageing (BLISAR) Study Group. Predicting the retinal content in omega-3 fatty acids for age-related macular-degeneration. Clin Transl Med. 2021 Jul;11(7):e404. doi: 10.1002/ctm2.404

12. Von Schacky C. Omega-3 index and sudden cardiac death. Nutrients. 2010;2(3):375-388. doi:10.3390/nu2030375

13. Chew EY. Dietary intake of omega-3 fatty acids from fish and risk of diabetic retinopathy. JAMA. 2017;317(21):2226-2227. doi:10.1001/jama.2017.1926

14. Augustine J, Troendle EP, Barabas P, McAleese CA, Friedel T, Stitt AW, Curtis TM. The Role of Lipoxidation in the Pathogenesis of Diabetic Retinopathy. Front Endocrinol (Lausanne). 2021 Feb 18;11:621938. doi: 10.3389/fendo.2020.621938