Accounting for 8.7% of blindness worldwide, age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. It poses a substantial global burden expected to grow as the population continues to age¹. Many studies have investigated risk factors for AMD, including increased age, current smoking, family history of AMD, higher BMI, cardiovascular disease, and hypertension^2-5. 

One potential risk factor is diabetic retinopathy (DR), the most common complication of diabetes mellitus (DM) characterized by retinal microvascular lesions. Affecting approximately 33% of all patients with DM, DR is projected to affect 191 million people worldwide by 2030.⁶ 

Although most literature supports that DM is a risk factor for AMD,⁷ the role of DR in AMD development remains controversial. Despite distinct pathogenesis and risk factors, many have investigated whether these retinal disorders exhibit protective or predisposing relationships. Focusing on the bidirectional influences, this review examines the literature of the relationship between AMD and DR. A better understanding of this relationship will inform management of patients at risk and therapeutic strategies.

Diabetic Retinopathy as a Risk Factor for Macular Degeneration

Multiple retrospective studies have shown that diagnosis of DR increases likelihood of concurrent AMD diagnosis. For example, a study of 6,621 patients found that DM with both nonproliferative and proliferative DR increased risk of incident diagnosis of dry and wet AMD; DM without retinopathy, however, had no effect on any type of AMD,⁸ suggesting that the retinal pathology, not DM itself, predisposes to AMD. 

Another study of nearly 350,000 patients across 15 years in Taiwan had similar findings: it found a significant correlation between concurrent dry and wet AMD diagnoses among diabetic patients with DR, in comparison to diabetic patients without DR.⁹ A third study of almost 15,000 patients found that prevalence of dry AMD in patients with DM with and without DR was significantly different, at 20.8% and 16.0%, respectively.¹⁰

Although large, population-based sample sizes were indeed a strength, these studies also have important limitations. First, the retrospective nature of these studies precluded calculation of incidence of AMD development. They were also unable to measure some important risk factors such as socioeconomic factors, BMI, family history, and visual acuity, because they were not always included in the databases used. Finally, because early AMD is often asymptomatic, AMD diagnosis may not have been made at the time of data collection. 

Diabetic Retinopathy as a Protective Factor Against Macular Degeneration

Other studies demonstrate that DR is a protective factor for AMD. One study based in Kentucky found that, across over 20,000 patients, the prevalence of AMD in patients with DR was significantly lower than in patients without DR (9.3% vs 19.1%, respectively).¹¹ Another investigation yielded similar results among nearly 5,500 subjects: AMD was present in 9.6% vs 15.6% of DM patients with and without DR, respectively.¹² Interestingly, increased levels of high-density lipoprotein (HDL) protected for AMD in patients with DM.

In a smaller study of 1,739 patients, the 5-year prevalence of AMD in DR patients was 9%, whereas in diabetic patients without DR it was found to be 11.5%. This study also found the prevalence of AMD to be inversely proportional to severity of DR.¹³

Although these studies demonstrate that DR is protective against AMD, an important confounding factor may be that patients actively getting treatment with photocoagulation or injections could have long-term protective effects against AMD. Other limitations include cross-sectional study designs and potential selection bias due to non–population-based subject designs.

Macular Degeneration as a Protective Factor Against Diabetic Retinopathy

Only one study has published that AMD is a protective factor against developing DR. In this retrospective case-cohort study of 43,153 diabetic patients, DR prevalence was 11.4% in AMD patients vs 23% in non-AMD patients.¹⁴ Both dry and wet AMD appeared to statistically decrease the risk of the development of DR. Here, the investigators hypothesized that damage to the outer retina in AMD may alter the response of retinal tissue to ischemia found in DR; thus, the tissue may adapt accordingly and become more resistant to DR-related changes.

An important limitation of this study was that it was conducted at a tertiary care center and was unable to be generalized to the population. Also, due to missing datapoints, such as HbA_1c, across records, some data had to be extrapolated in analysis. Notably, no current studies have shown AMD to be a risk factor for DR development. Although the effects of DR on AMD have been well studied, albeit with variable findings, the effects of AMD on DR remain a gap in the literature.

Clinical Implications

With such inconsistencies in the literature, it is important to keep in mind the implications of these findings. If DR were a risk factor for AMD, patients with DR may benefit from more frequent AMD screening. In addition, physicians may start early counseling of AMD prevention and start patients on preventative measures such as smoking cessation and initiation of AREDS2.

Notably, there have been technological developments based on telemedicine and machine learning that allow concurrent screening even in the primary care setting; these tools offer high sensitivity and specificity for both DR (97.0% and 96.3%, respectively) and AMD (86.6% and 92.1%, respectively).¹⁵ Moreover, these technologies have been shown not only to be at least as effective as traditional in-person testing, but also to have the potential to be more cost-effective.^16,17 As these technologies are refined, both physicians and public health programs may consider implementing these them to streamline care and detect pathology earlier.

In addition to considering screening measures, physicians should also explain the complex relationship between DR and AMD to their patients upon diagnosis of either. Patients should understand the importance of periodic eye exams to monitor disease development or progression; they should understand modifiable risk factors, such as blood glucose levels, hypertension, smoking, and exercise, to minimize risk and future consequences.

Finally, future research should further investigate risk-adjusted likelihoods of developing DR or AMD and also explore potential mechanisms behind this relationship. Although DR and AMD are distinct pathologies, they are partially mediated by common lipid and inflammatory pathways.^18,19 Elucidating these shared cellular mechanisms may reveal potential overlapping therapeutic targets.

Conclusion

Overall, the literature on the association between DR and AMD remains highly inconclusive. Despite large-scale, population-based studies, the effects of DR on subsequent AMD diagnosis are uncertain. Notably, there is a relative lack of research on the impact of AMD diagnosis on DR. Because studies conducted thus far have been cross-sectional, retrospective studies, prospective studies should be designed to account for all important risk factors and enable calculation of incidence. Physicians should be cognizant of the uncertainty surrounding DR and AMD and counsel patients appropriately.

Deborah Li, BA, is a medical student at Renaissance School of Medicine at Stony Brook University. She reports no relevant disclosures. Reach her at deborah.li@stonybrookmedicine.edu.

Nicholas Fazio, BS, is a medical student at Renaissance School of Medicine at Stony Brook University. He reports no relevant disclosures.

Michael Wolek, MD, is an ophthalmology resident at University Hospitals at Case Western Reserve University in Cleveland, Ohio. He reports no relevant disclosures.

Khurram M. Chaudhary, MD, is a retina specialist at Stony Brook University Hospital in Stony Brook, New York. He reports no relevant disclosures.

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