The Link Between Diabetes and Age-Related Macular Degeneration (AMD)

👁️ Control Blood Sugar: Stop Vision Loss

When it comes to diabetes and eye health, most people think of diabetic retinopathy. But another serious condition—age-related macular degeneration (AMD)—is increasingly linked to blood sugar issues, especially in older adults.

AMD is a leading cause of vision loss after age 60. And while it starts silently in its dry form, it can progress to wetAMD—an aggressive, sight-threatening condition marked by abnormal blood vessel growth and fluid leakage in the retina.

🔄 Relationship between Diabetes and AMD

We now know that diabetes significantly raises the risk of AMD, especially its late-stage and wet forms. And emerging evidence suggests the link is bidirectional: if you already have AMD—particularly dry AMD—developing diabetes can dramatically increase your risk of vision loss.

📊 Summary: Glycemic Status, Diabetes Duration, and AMD Risk

A large study confirmed a clear relationship between blood sugar status and AMD risk:

Both dry and wet AMD rates increased with higher blood sugar levels and longer diabetes duration.
The risk of dry AMD rose significantly in people with both early (<5 years) and long-standing (≥5 years) diabetes.
Wet AMD risk increased sharply even with new-onset diabetes, and continued rising as diabetes duration increased.
Among men and smokers with diabetes, the risk of wet AMD was particularly high.
People under age 65 with poor glycemic control were especially vulnerable.

🚨 Key Takeaway:

Even early or newly diagnosed diabetes is a serious risk factor for developing AMD—especially its wet form. The shared pathways—like inflammation, VEGF overexpression, and oxidative stress—create a retinal environment primed for damage.

🔬 What This Means If You Already Have Dry AMD

If you’ve been diagnosed with dry AMD, it’s not just your eye health you need to watch—it’s your metabolic health too. Avoiding or delaying the onset of type 2 diabetes can significantly reduce your chances of progressing to wet AMD.

✅ What You Can Do:

Maintain a healthy weight and waistline
Follow a low-glycemic, anti-inflammatory diet (e.g., Mediterranean)
Limit refined carbs and sugars
Stay physically active
Avoid smoking
Monitor blood pressure and cholesterol

👁️ For Diabetic Patients: Go Beyond Retinopathy Screening

If you already have diabetes, especially if it was diagnosed before age 65 or requires insulin, ask your eye doctor to screen for AMD as well as diabetic retinopathy. This is particularly important for those with:

Poor glycemic control
Longer disease duration
Coexisting conditions like hypertension or chronic kidney disease

📌 Bottom Line

Whether you're managing AMD, diabetes, or both, the science is clear: these conditions are deeply connected. If you have dry AMD, avoiding diabetes could help preserve your sight. If you have diabetes, especially newly diagnosed, you're at increased risk for developing both dry and wet AMD.

Early action, regular screenings, and healthy lifestyle changes can make all the difference.

Would like to learn more, read here:

The Interplay of Diabetes Mellitus and Age-Related Macular Degeneration: An Epidemiological and Mechanistic Review

Executive Summary

This report provides a comprehensive review of the intricate relationship between diabetes mellitus (DM) and age-related macular degeneration (AMD), two leading causes of vision impairment globally. The analysis consolidates robust epidemiological evidence demonstrating that DM is a significant risk factor for AMD, particularly its advanced and neovascular forms. This association is further modulated by factors such as the duration of diabetes, the necessity for insulin therapy, and the presence of diabetic retinopathy (DR). A critical observation highlights that a younger age at DM diagnosis is independently associated with a greater risk of ocular complications, including AMD, irrespective of glycemic control or disease duration. The report delves into the shared pathophysiological mechanisms underpinning both conditions, identifying chronic inflammation, oxidative stress, the accumulation of advanced glycation end-products (AGEs), and the pivotal role of vascular endothelial growth factor (VEGF) as common drivers of retinal damage. These convergent pathways not only explain the heightened AMD risk in diabetic individuals but also suggest potential synergistic therapeutic and preventive strategies. The findings underscore the clinical imperative for integrated eye health screening for diabetic patients, extending beyond traditional DR surveillance to include comprehensive AMD assessment, and emphasize the potential for systemic pharmacological agents to offer dual ocular benefits.

1. Introduction: Understanding Age-Related Macular Degeneration and Diabetes Mellitus

1.1. Age-Related Macular Degeneration (AMD): A Global Health Challenge

Age-related macular degeneration stands as the foremost cause of irreversible vision loss among the elderly in developed nations, profoundly impacting global public health. This progressive neurodegenerative disorder of the retina affects approximately one in eight individuals aged 60 years and above. Projections indicate a substantial increase in its prevalence, with global estimates rising from 200 million in 2020 to nearly 300 million by 2040, and affecting an estimated 5.4 million Americans by 2050. This escalating burden imposes significant socioeconomic costs on healthcare systems worldwide.

AMD is broadly categorized into early and late stages. Early-stage AMD is often asymptomatic, meaning individuals may experience no noticeable changes in their vision. In contrast, the late stage of AMD is frequently associated with severe vision loss. Late AMD further subdivides into two principal forms: neovascular AMD (nAMD), also known as wet AMD, and geographic atrophy (GA), commonly referred to as dry AMD. Dry AMD represents the majority of cases, accounting for 80-90% of diagnoses, and is characterized by the slow degeneration and death of retinal cells. Wet AMD, while less common (10-20% of cases), is considerably more severe and often progresses from dry AMD. It is responsible for up to 90% of AMD-related legal blindness due to the abnormal growth and leakage of new, fragile blood vessels beneath the retina. The pathogenesis of AMD is multifactorial, involving a complex interplay of age, genetic predispositions, ocular dysfunctions, systemic diseases, dietary habits, smoking, and various environmental factors.

1.2. Diabetes Mellitus (DM) and its Ocular Complications

Diabetes mellitus is a widespread endocrine disorder with profound and often serious systemic ramifications, including a significant impact on ocular health. Diabetic Retinopathy (DR) represents the primary ophthalmic complication of DM. It is characterized by sustained high blood sugar levels that damage and obstruct the delicate blood vessels within the eyes. This vascular compromise can lead to the formation of new, often aberrant and leaky, blood vessels that subsequently inflict damage upon the retina and/or optic nerve, resulting in impaired vision. Notably, diabetes is recognized as the leading cause of new vision loss among Americans aged 18-74 years.

1.3. Rationale for Exploring the Association between DM and AMD

Although diabetic retinopathy and age-related macular degeneration are distinct clinical entities, a compelling rationale exists for investigating the potential role of diabetes in the development and progression of AMD. This interest stems from their shared risk factors and overlapping pathological processes. Historical research on this association has, however, yielded inconsistent results, with some studies reporting positive correlations, others finding no significant effect, and a few even suggesting an inverse relationship. Given the increasing prevalence of both diabetes and AMD in aging populations, a clear and comprehensive understanding of their interrelationship is crucial for developing effective preventive strategies and optimizing treatment approaches.

A significant implication of the relationship between diabetes and AMD is the potential for an under-recognized burden of early AMD in diabetic patients. Since early AMD is frequently asymptomatic, individuals with diabetes, who are already at an elevated risk for AMD, may experience a prolonged period during which AMD progresses undetected. This silent progression can lead to more advanced, irreversible vision loss by the time symptoms become apparent, exacerbating the overall socioeconomic impact of these combined ocular pathologies. This highlights a critical need for integrated and proactive screening approaches for both DR and AMD in diabetic individuals to facilitate earlier detection and intervention.

2. Epidemiological Evidence: Diabetes as a Risk Factor for AMD

2.1. Overall Association of Diabetes with AMD

Recent meta-analyses provide substantial evidence supporting diabetes as a significant risk factor for age-related macular degeneration. A systematic review and meta-analysis published in 2014, which synthesized data from 24 articles encompassing 27 study populations, reported consistent associations across various study designs. Specifically, an analysis of 7 cohort studies indicated that diabetes was a risk factor for AMD (Odds Ratio, 1.05; 95% Confidence Interval [CI], 1.00–1.14). Results from 9 cross-sectional studies revealed a consistent association (OR, 1.21; 95% CI, 1.00–1.45), and similar associations were detected in 11 case-control studies (OR, 1.29; 95% CI, 1.13–1.49).

An updated meta-analysis published in 2025, which reviewed studies up to January 2024, further solidified this association. This more recent and comprehensive analysis identified diabetes as a statistically significant predictor for AMD occurrence, with an OR of 1.44 (95% CI = 1.3-1.6, P <.00001). This finding strengthens the conclusion of a positive link between diabetes and AMD. Despite this growing body of evidence, it is important to acknowledge that some earlier reports have presented conflicting results, with some finding no correlation or even an inverse relationship between diabetes and AMD. These inconsistencies underscore the complex and multifactorial nature of AMD pathogenesis and suggest the potential for confounding factors or variations in study methodologies to influence observed associations.

2.2. Differential Impact on Early vs. Late AMD

The epidemiological evidence consistently suggests that the association between diabetes and AMD is more pronounced for late-stage AMD compared to its early forms. Cross-sectional studies, for instance, indicated a stronger association for late AMD (OR, 1.48; 95% CI, 1.44–1.51). Similarly, case-control studies showed a clear link to late AMD (OR, 1.16; 95% CI, 1.11–1.21). One cohort study even reported a substantial risk factor for late AMD (OR, 1.81; 95% CI, 1.10–2.98). Conversely, some meta-analyses found no significant association between diabetes and early AMD. This differential impact suggests that diabetes may play a more critical role in the progression of AMD to its advanced, vision-threatening stages rather than in its initial development.

2.3. Specific Associations with Dry vs. Wet AMD

A significant nationwide population-based cohort study conducted in South Korea (Lee et al., 2023) provided detailed insights into the impact of glycemic status on both dry and wet AMD. This study demonstrated that the incidence of both dry and wet AMD increased among diabetes patients compared to subjects with normal glycemic status. For dry AMD, the adjusted Hazard Ratio (HR) was 1.192 (95% CI: 1.141-1.245) for subjects with diabetes for less than 5 years, and 1.294 (95% CI: 1.242-1.349) for those with diabetes for 5 years or more. For wet AMD, the adjusted HR was 1.103 (95% CI: 1.011-1.203) for new-onset diabetes, 1.252 (95% CI: 1.167-1.344) for diabetes less than 5 years, and 1.506 (95% CI: 1.413-1.605) for diabetes 5 years or more. Pooled Odds Ratios (ORs) for neovascular AMD (nAMD) from meta-analyses were 1.10 (95% CI, 0.96–1.26) from cohort studies, 1.48 (95% CI, 1.44–1.51) from cross-sectional studies, and 1.15 (95% CI, 1.11–1.21) from case-control studies.

However, some studies present conflicting findings regarding specific AMD subtypes. For instance, the Beaver Mountain Eye Study found a doubled prevalence of wet AMD in diabetic individuals but no association with early AMD or geographic atrophy (GA), while the Australian Blue Mountains Eye Study linked diabetes only to GA, not wet or early AMD. These inconsistencies highlight the complexity of the relationship and suggest that other factors or study methodologies might influence the observed associations.

2.4. Influence of Diabetes Duration, New-Onset Diabetes, and Insulin Use

The duration of diabetes appears to be a critical factor in AMD risk. The Korean cohort study (Lee et al., 2023) demonstrated that the risk of both dry and wet AMD significantly increased when the duration of diabetes was 5 years or more. Intriguingly, the risk of wet AMD was also elevated even in patients with new-onset diabetes (HR 1.103; 95% CI: 1.011-1.203). This finding suggests that even relatively short-term exposure to high blood glucose levels, if untreated, could initiate the vision-threatening condition of wet AMD, emphasizing the urgency of early blood glucose management.

Further supporting the impact of diabetes severity and management, a nationwide cohort study specifically on a diabetic population (Hwang et al., 2023) identified several diabetes-related factors associated with an increased likelihood of developing exudative (wet) AMD. A longer duration of diabetes (5 years or more) was associated with a Hazard Ratio of 1.13 (95% CI, 1.07-1.18). The administration of insulin for diabetes control was linked to an HR of 1.16 (95% CI, 1.07-1.25), a finding that often indicates more severe or poorly controlled diabetes. Furthermore, the presence of vision-threatening diabetic retinopathy (DR) was identified as a strong independent risk factor, with an HR of 1.40 (95% CI, 1.23-1.61). Notably, these associations, particularly for insulin usage and vision-threatening DR, were more pronounced in younger individuals (<65 years old) , suggesting that in older age groups, the influence of age on AMD might become a more dominant factor.

The epidemiological data consistently show that diabetes is a risk factor for AMD, particularly its late stages. This risk is not static but appears to intensify with the progression and management complexity of diabetes. The explicit demonstration that the risk for both dry and wet AMD increases with a longer duration of diabetes, coupled with the independent association of insulin use and vision-threatening DR with increased exudative AMD risk, points to a cumulative damage model. This suggests that prolonged exposure to the metabolic dysregulation of diabetes, rather than just the initial diagnosis, contributes to the heightened vulnerability of the retina to AMD, especially its more aggressive forms. This understanding implies that beyond initial diagnosis, the trajectory and severity of a patient's diabetes are critical determinants of their AMD risk. It reinforces the importance of sustained, rigorous diabetes management throughout the disease course, not only to prevent DR but also to mitigate the long-term risk of AMD. Patients with long-standing diabetes, particularly those requiring insulin or already manifesting DR, should therefore be considered a high-risk subgroup for AMD and warrant enhanced ophthalmic surveillance.

2.5. The Independent Role of Diabetic Retinopathy (DR) in AMD Risk

Beyond systemic diabetes, the presence of diabetic retinopathy (DR) itself appears to be a significant independent risk factor for AMD. A nationwide population-based study in Taiwan revealed that individuals with DR faced a substantially greater risk of overall AMD (adjusted HR of 3.50; 95% CI = 3.10–3.95), non-exudative AMD (aHR 2.92; 95% CI = 2.08–4.09), and exudative AMD (aHR 3.92; 95% CI = 2.51–6.14) compared to those without retinopathy.The study concluded that the ocular pathologies inherent to DR might have a more significant impact on AMD progression than systemic vascular comorbidities alone.

Further evidence from Medicare data (2013) indicated that nonproliferative diabetic retinopathy (NPDR) significantly increased the risk of both dry and wet AMD, while proliferative diabetic retinopathy (PDR) was associated specifically with an increased risk of wet AMD. However, the Kailuan Eye Study in China suggested that DR, but not diabetes alone, was a statistically significant risk factor for dry AMD but not wet AMD, after adjustments. This particular finding introduces a nuance, indicating that the relationship between DR and specific AMD subtypes might vary across populations or be influenced by other factors.

The observation that the ocular pathologies inherent to DR might have a more significant impact on AMD progression than systemic vascular comorbidities alone suggests a direct, localized connection through DR. This means that the damage mechanisms within the retina caused by DR, such as vascular changes, inflammation, and hypoxia, create a local environment that predisposes the eye to AMD, almost as a secondary retinal insult. This implies that the relationship between DR and AMD is not simply a correlation due to shared systemic risk factors but involves a direct pathophysiological interplay within the ocular microenvironment. Consequently, effective management and prevention of DR could have a significant, independent protective effect against AMD development or progression, reinforcing the need for early and aggressive DR treatment as a strategy for overall retinal health.

2.6. Impact of Age at Diabetes Diagnosis on Ocular Disease Risk

A pivotal study utilizing UK Biobank data (Ye et al., 2024, discussed in Liu et al., 2025) highlighted a strong and surprising link between an earlier age at diabetes diagnosis and a subsequent increased risk of major age-related ocular diseases, including AMD, cataracts, and glaucoma. Crucially, this association was found to be independent of concurrent glycemic control (HbA1c levels) and disease duration.

Specifically for AMD, individuals with type 2 diabetes (T2D) diagnosed at younger ages (<45 years, HR 2.71; 45-49 years, HR 2.57; 50-54 years, HR 1.85; 55-59 years, HR 1.53) had a higher risk of AMD, with the relative risk decreasing as the age at diabetes diagnosis increased. Type 1 diabetes (T1D) showed an even more pronounced increased risk of AMD (HR 4.12). This finding challenges the long-held belief that diabetic complications are primarily a function of cumulative hyperglycemia or disease longevity. Instead, it suggests that the age of onset itself is a crucial, independent parameter, possibly reflecting more severe underlying immune and metabolic dysfunction initiated early in the disease course.

This observation implies that the initial metabolic disruption in younger individuals might trigger irreversible cellular or molecular changes, or lead to a more aggressive disease phenotype, that predisposes them to ocular complications like AMD regardless of subsequent diabetes management. This could involve early epigenetic modifications or a more severe initial inflammatory or oxidative insult that "primes" the ocular tissues for future degeneration. This has significant implications for public health and clinical screening, suggesting that individuals diagnosed with diabetes at a younger age, even if their glycemic control is subsequently optimized, should be considered a uniquely high-risk group for AMD and other ocular complications. This calls for intensified, perhaps lifelong, ophthalmic surveillance for these patients, and emphasizes the importance of early diagnosis of diabetes itself as a critical window for intervention to prevent these long-term "priming" effects on ocular health. It also opens new avenues for research into the specific biological mechanisms underlying this "early onset vulnerability."

Table 1: Summary of Key Epidemiological Associations between Diabetes and AMD

Association Category	Specific Finding (Hazard Ratio or Odds Ratio with 95% CI)	Study Type / Source
Overall AMD Risk	OR 1.05 (1.00–1.14)	Meta-analysis (7 cohort studies)
	OR 1.21 (1.00–1.45)	Meta-analysis (9 cross-sectional studies)
	OR 1.29 (1.13–1.49)	Meta-analysis (11 case-control studies)
	OR 1.44 (1.3-1.6, P <.00001)	Updated Meta-analysis (2025)
Late AMD Risk	OR 1.48 (1.44–1.51)	Meta-analysis (cross-sectional studies)
	OR 1.16 (1.11–1.21)	Meta-analysis (case-control studies)
	OR 1.81 (1.10–2.98)	Meta-analysis (cohort studies)
Dry AMD Risk by Diabetes Duration	HR 1.192 (1.141-1.245) for diabetes < 5 years	Korean Cohort Study (Lee et al., 2023)
	HR 1.294 (1.242-1.349) for diabetes ≥ 5 years	Korean Cohort Study (Lee et al., 2023)
Wet AMD Risk by Diabetes Status/Duration/Insulin Use	HR 1.103 (1.011-1.203) for new-onset diabetes	Korean Cohort Study (Lee et al., 2023)
	HR 1.252 (1.167-1.344) for diabetes < 5 years	Korean Cohort Study (Lee et al., 2023)
	HR 1.506 (1.413-1.605) for diabetes ≥ 5 years	Korean Cohort Study (Lee et al., 2023)
	HR 1.13 (1.07-1.18) for duration ≥ 5 years	Korean Cohort Study (Hwang et al., 2023)
	HR 1.16 (1.07-1.25) for insulin use	Korean Cohort Study (Hwang et al., 2023)
	HR 1.40 (1.23-1.61) for vision-threatening DR	Korean Cohort Study (Hwang et al., 2023)
AMD Risk in Presence of DR	aHR 3.50 (3.10–3.95) for overall AMD	Taiwanese Population Study
	aHR 2.92 (2.08–4.09) for non-exudative AMD	Taiwanese Population Study
	aHR 3.92 (2.51–6.14) for exudative AMD	Taiwanese Population Study
AMD Risk by Age at Diabetes Diagnosis	HR 2.71 (1.49-4.93) for T2D diagnosed < 45 years	UK Biobank Study (Ye et al., 2024)
	HR 4.12 (1.99-8.53) for T1D	UK Biobank Study (Ye et al., 2024)

3. Shared Pathophysiological Mechanisms Linking Diabetes and AMD

The increasing recognition of diabetes as a risk factor for AMD has prompted deeper investigation into their shared underlying biological pathways. A convergence of mechanisms, primarily involving inflammation, oxidative stress, advanced glycation end-products (AGEs), and vascular endothelial growth factor (VEGF), appears to link these two distinct ocular pathologies.

3.1. The Central Role of Chronic Inflammation

Chronic inflammation constitutes a fundamental commonality in the pathogenesis of both AMD and diabetes. High blood sugar levels, often exacerbated by diets rich in refined carbohydrates, are known to promote systemic inflammation in diabetic individuals, thereby increasing the susceptibility to both conditions.

In AMD, chronic low-grade inflammation is a crucial driver of disease progression. This inflammatory state leads to damage of the retinal pigment epithelium (RPE), photoreceptor cells, and choroidal vessels, which can ultimately culminate in geographic atrophy. The complement system, an integral part of the innate immune response, is particularly implicated in the inflammatory processes observed in AMD.

In diabetic retinopathy (DR), the hyperglycemic environment directly activates various inflammatory cells and significantly increases the production of pro-inflammatory cytokines. These include Interleukin-1β (IL-1β), IL-6, IL-18, Tumor Necrosis Factor-α (TNF-α), and macrophage migration inhibitory factor (MIF). This inflammatory cascade contributes to the breakdown of the blood-retinal barrier, vascular damage, and neuroinflammation within the retina.

A critical observation is that diabetic macular edema (DME), DR, and AMD are all recognized as low-grade inflammatory conditions, sharing common microscopic inflammatory signs. These include changes in retinal vascular diameter (vessel dilation), alterations in blood flow, exudation of plasma proteins, and the adhesion, accumulation, and migration of leukocytes within the retinal vasculature. This adherence and migration of immune cells induce vascular dysfunction through increased production of reactive oxygen species (ROS) and lipid peroxidation, leading to a subtle breakdown of the blood-retinal barrier and premature endothelial cell injury and death. When these two conditions co-exist, the systemic inflammatory state induced by diabetes likely exacerbates and amplifies the localized inflammatory processes within the retina that are characteristic of AMD. This synergistic effect suggests that the diabetic inflammatory milieu primes the ocular tissues, making them more susceptible to AMD initiation and progression, and potentially accelerating the disease course. This highlights that effective management of systemic inflammation in diabetic patients, potentially through lifestyle modifications or anti-inflammatory agents, could offer a dual protective benefit against both diabetic complications and AMD, underscoring the interconnectedness of systemic and ocular health.

3.2. Oxidative Stress and Reactive Oxygen Species (ROS)

The retina is inherently vulnerable to oxidative damage due to its high oxygen consumption and constant exposure to light. This vulnerability leads to the accumulation of oxidative damage, resulting in cellular dysfunction and death, which is a significant contributor to AMD pathogenesis.

Oxidative stress is a central pathophysiological factor in the development of both microvascular and cardiovascular complications of diabetes. The metabolic abnormalities associated with diabetes lead to an overproduction of mitochondrial superoxide in endothelial cells of both large and small vessels. This increased superoxide production activates multiple pathways that exacerbate oxidative stress, including the polyol pathway, increased formation of AGEs, and activation of protein kinase C.

Hyperglycemia in diabetes directly promotes oxidative stress through various pathways, enhancing ROS generation. This heightened oxidative burden leads to endothelial dysfunction and vascular inflammation, which are common underlying mechanisms in both DR and AMD. Increased intracellular ROS also contributes to defective angiogenesis, activates pro-inflammatory pathways, and can induce long-lasting epigenetic changes, a phenomenon known as 'hyperglycemic memory'. This "hyperglycemic memory" implies that even if a diabetic patient achieves excellent glycemic control, the historical burden of high blood sugar could continue to perpetuate pro-inflammatory and oxidative processes within the retina. This persistent, sub-clinical cellular damage could render the retinal tissues chronically vulnerable, making them more susceptible to AMD development or accelerated progression, even years after the initial metabolic insult. This profound observation underscores the immense importance of early and sustained glycemic control in diabetes, not just for immediate health but for preventing long-term, potentially irreversible cellular "memory" effects that predispose to AMD. It also highlights the critical role of primary prevention and early intervention strategies in mitigating AMD risk in diabetic populations, as established damage might be challenging to fully reverse.

3.3. Advanced Glycation End-products (AGEs) and their Contribution

Advanced Glycation End-products (AGEs) are harmful compounds formed by the non-enzymatic reaction of glucose and other glycating compounds with proteins and lipids. In diabetes, AGEs accumulate in increased amounts within the extracellular matrix and various tissues throughout the body.

AGEs contribute to tissue damage through several mechanisms: they alter protein function, cause abnormal interactions with the extracellular matrix, and bind to the Receptor for AGEs (RAGE) on cell surfaces. This binding to RAGE is particularly detrimental as it induces the production of ROS and activates the transcription factor nuclear factor kappa B (NFκB), leading to multiple pathological changes in gene expression and amplifying inflammatory responses. The deposition of AGEs in key ocular tissues, including the retinal pigment epithelium (RPE) and photoreceptors, is implicated in the pathogenesis of both DR and AMD. Furthermore, animal studies have shown that AGEs can prevent the clearance of drusen, a hallmark of AMD , suggesting a direct link in waste product accumulation. This indicates that the metabolic environment created by diabetes might exacerbate or contribute to the cellular and molecular processes that lead to the formation and accumulation of drusen and other waste products, thereby accelerating AMD pathogenesis.

3.4. The Pivotal Role of Vascular Endothelial Growth Factor (VEGF)

The formation of new, often leaky, blood vessels (neovascularization) is a critical pathological process in both diabetic retinopathy (DR) and wet (neovascular) AMD. Both conditions are profoundly influenced by Vascular Endothelial Growth Factor (VEGF), a potent signaling molecule that promotes angiogenesis and increases vascular permeability.

In wet AMD, nAMD is characterized by abnormal angiogenesis within the choroid, subretinal space, and retina, which is primarily driven by VEGF. This leads to fragile, leaky vessels, fluid leakage, and ultimately scarring and severe central vision impairment. In DR, hyperglycemia-induced oxidative stress, inflammation, and increased glycosylation products all contribute to VEGF overexpression. This elevated VEGF promotes retinal neovascularization and intraretinal fluid accumulation, leading to complications like diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR).

VEGF is a key factor with a dominant role in DME, DR, and AMD, contributing significantly to the breakdown of the blood-retinal barrier and increased vascular permeability in all three conditions. The remarkable effectiveness of anti-VEGF drugs in treating both wet AMD and DR provides strong evidence for a common underlying angiogenic pathway and shared biological connection between these disorders. Hypoxia and ischemia, common consequences of vascular damage in both conditions, are potent stimulators of VEGF upregulation. The direct observation that both wet AMD and DR are characterized by pathological neovascularization and fluid leakage, and that VEGF is the key molecular driver in both conditions, establishes a clear causal link. The fact that anti-VEGF drugs are effective in treating both wet AMD and DR is a strong validation of this shared mechanism and represents a significant therapeutic convergence. This reinforces the strategic importance of anti-VEGF therapies as a cornerstone treatment for neovascular forms of both conditions. It also suggests that future research into novel anti-angiogenic targets or combination therapies that modulate VEGF pathways could yield significant benefits for both patient populations. However, the mention that anti-VEGF-A treatment can lead to increased levels of other angiogenic biomarkers suggests a potential compensatory mechanism, implying that targeting VEGF-A alone might not always be sufficient for complete disease control, thus necessitating exploration of broader therapeutic strategies that address the entire VEGF family or related pathways.

3.5. Disruption of the Blood-Retinal Barrier and Vascular Changes

A critical shared pathophysiological process in DME, DR, and AMD is the breakdown of the blood-retinal barrier (BRB) and a subsequent increase in vascular permeability. This compromise allows fluid and protein deposits to accumulate in the retinal tissue, leading to macular edema. In DR, hyperglycemia directly contributes to endothelial dysfunction and vascular leakage, disrupting the integrity of retinal blood vessels. In AMD, particularly the wet form, choroidal neovascularization results in the growth of new, fragile vessels that are prone to bleeding and leaking fluid, causing the macula to bulge or lift due to edema. The chronic inflammatory and oxidative stress pathways prevalent in both diabetes and AMD contribute significantly to endothelial cell injury and dysfunction. This leads to compromised vascular integrity, which manifests as BRB breakdown and increased vascular permeability, a critical and shared pathological step in the progression of both diseases.

3.6. Accumulation of Drusen and Waste Products

Waste buildups in retinal cells are broadly associated with the progression of both DR and AMD. Drusen, which are yellow deposits primarily composed of lipids, proteins, and cellular debris, are considered a hallmark of AMD. They accumulate in the interface between the retinal pigment epithelium (RPE) and Bruch's membrane. These deposits are not merely passive accumulations; they actively play a role in inhibiting the transport of essential metabolites to the choroid vessels, and their molecular components can initiate inflammation through the complement cascade. Abnormal lipid cycling and accumulation in the retina, particularly contributing to drusen formation, is a recognized feature of AMD. While drusen are most characteristic of AMD, the general concept of waste product accumulation (e.g., lipofuscin) and impaired cellular clearance in retinal cells is noted as a shared feature influenced by the systemic conditions of high blood sugar and inflammation. This suggests that the metabolic environment created by diabetes might exacerbate or contribute to the cellular and molecular processes that lead to the formation and accumulation of drusen and other waste products, thereby accelerating AMD pathogenesis.

4. Clinical Implications and Potential Management Strategies

The comprehensive understanding of the epidemiological associations and shared pathophysiological mechanisms between diabetes and AMD has significant clinical implications, guiding strategies for early detection, prevention, and management.

4.1. Importance of Early Screening and Diagnosis in Diabetic Patients for AMD

Given the robust epidemiological evidence linking diabetes to an increased risk of AMD, especially its late and wet forms , and considering that early AMD is frequently asymptomatic , proactive and early screening for AMD in diabetic patients is paramount. This is particularly critical because the risk for both dry and wet AMD demonstrably increases with the duration of diabetes. The observation that even new-onset diabetes is associated with an increased risk of wet AMD further underscores the necessity for immediate and vigilant eye care following a diabetes diagnosis. This emphasizes that early blood glucose management is not only crucial for preventing DR but also for mitigating the risk of vision-threatening AMD.

The strong evidence establishing diabetes as a significant risk factor for AMD, particularly its more severe forms, coupled with the asymptomatic nature of early AMD, necessitates a fundamental shift in the approach to diabetic eye care. Current clinical practice predominantly emphasizes DR screening in diabetic patients. However, the data strongly suggests that AMD risk is also significantly elevated and influenced by factors like diabetes duration, insulin use, and even new-onset diabetes. This calls for a transition from a DR-centric screening approach to a more comprehensive "diabetic eye health" paradigm. A holistic eye examination for diabetic patients should explicitly include screening for AMD, not just DR, ideally from the point of diabetes diagnosis. This integrated approach would facilitate earlier detection of AMD, especially its asymptomatic early stages, and potentially prevent severe, irreversible vision loss. This implies a re-evaluation and potential update of clinical guidelines for diabetic eye care, suggesting that healthcare providers should educate diabetic patients about their heightened risk for both DR and AMD, and that advanced imaging techniques capable of detecting early AMD signs should be considered as part of routine diabetic eye examinations. This integration could lead to a more proactive and preventative approach to managing ocular complications in diabetic patients, ultimately improving long-term visual outcomes.

4.2. Lifestyle Interventions

Several lifestyle modifications are consistently recommended to mitigate the risk of developing both DR and AMD, and to generally protect against age-related vision loss.

Adopting a balanced diet is crucial for controlling blood sugar and inflammation, which are shared pathophysiological drivers of both conditions. This includes consuming a variety of fruits and vegetables, incorporating sources of omega-3 fatty acids, and consistently monitoring blood sugar levels for diagnosed diabetic patients. Specifically, adherence to a Mediterranean diet, rich in vegetables, fruits, legumes, whole grains, and nuts, has been linked to a lower risk of both early and late AMD. Furthermore, a low glycemic index diet was found to be protective against AMD changes in animal models and, in a post-hoc analysis of the AREDS study, was associated with a significant reduction in progression to advanced AMD. Conversely, diets with a high glycemic index and even daily consumption of 100% fruit juice have been associated with an increased risk of advanced AMD.

Engaging in moderate physical activity is a general recommendation for overall health and is suggested to contribute to reducing AMD risk. Smoking, both current and former, is a well-established and modifiable risk factor for early AMD and its progression. Complete avoidance of smoking is strongly advised to protect ocular health.

4.3. The Significance of Glycemic Control

Maintaining healthy blood sugar levels is a cornerstone of managing diabetes and is paramount for improving overall eye health and reducing the risk of both DR and AMD. The findings that high blood glucose levels, even in new-onset diabetes, can induce wet AMD strongly emphasize the importance of early and effective blood glucose management.

However, a nuanced finding from a UK Biobank study (Ye et al., 2024, discussed in Liu et al., 2025) indicates that a younger age at diabetes diagnosis is linked to increased ocular disease risk independent of concurrent glycemic control and disease duration. While optimal glycemic control remains vital for preventing progression and complications, this observation adds a critical layer of complexity. It suggests that the initial metabolic insult in early-onset diabetes may have long-lasting, perhaps irreversible, effects that predispose to AMD, even with subsequent good management. This highlights that once established, the damage from chronic oxidative stress and advanced glycation end-products might be challenging to fully reverse, emphasizing the critical role of primary prevention and early intervention strategies in mitigating AMD risk in diabetic populations.

4.4. Pharmacological Approaches

The efficacy of anti-VEGF drugs in treating both wet AMD and proliferative diabetic retinopathy (DR) underscores a shared biological connection and a common therapeutic target. This class of drugs remains a cornerstone of treatment for the neovascular forms of both diseases, highlighting the importance of VEGF in their pathogenesis.

Emerging evidence suggests a potential role for SGLT2 inhibitors in mitigating AMD risk in diabetic patients. A multinational retrospective cohort study found that patients with type 2 diabetes (T2DM) prescribed SGLT2 inhibitors experienced significantly lower risks of overall AMD (Hazard Ratio 0.71; 95% CI, 0.58–0.85) and dry AMD (HR 0.61; 95% CI, 0.46–0.80) compared to those prescribed DPP-4 inhibitors. This protective effect may be attributed to SGLT2 inhibitors' complement inactivation, anti-inflammatory, and antioxidative properties, which align with the shared pathophysiological mechanisms of diabetes and AMD.

A systematic review and meta-analysis of 9 observational studies (totaling over 1.4 million participants) found that metformin use was associated with a significant reduction in the odds of overall AMD (pooled OR 0.81; 95% CI = 0.70–0.93). While subgroup analyses did not show a statistically significant association with dry or wet AMD specifically, this suggests a potential protective effect of metformin against overall AMD development in diabetic patients. Metformin's known antioxidative, anti-inflammatory, and antiangiogenic activities within ocular tissue are hypothesized to contribute to this observed benefit. The effectiveness of anti-VEGF therapies for both wet AMD and DR already demonstrates a shared therapeutic pathway. Extending this, the data on SGLT2 inhibitors reducing overall and dry AMD risk in T2DM patients and metformin being associated with lower odds of AMD is highly significant. These are systemic diabetes medications that appear to offer ocular benefits. Their mechanisms of action (anti-inflammatory, antioxidative, complement inactivation) align perfectly with the shared pathophysiological links between diabetes and AMD. This suggests that certain existing diabetes drugs might be "repurposed" not just for glycemic control but also for AMD prevention or mitigation, offering a synergistic treatment strategy. This opens exciting avenues for future research and clinical application, implying that optimizing systemic diabetes management with specific drug classes could provide a dual benefit for both systemic metabolic control and ocular health, potentially reducing the overall burden of diabetic eye disease. This could lead to more integrated pharmaceutical strategies, where a single medication or combination therapy addresses both the underlying diabetic condition and its associated AMD risk, potentially improving adherence and patient outcomes. It also highlights the potential for novel drug discovery by investigating the ocular effects of other systemic medications.

5. Conclusion and Future Research Directions

5.1. Conclusion

This report has comprehensively reviewed the robust epidemiological evidence demonstrating a significant and increasingly recognized association between diabetes mellitus and age-related macular degeneration, particularly its late and neovascular forms. The risk of AMD is influenced by various diabetes-related factors, including disease duration, the use of insulin, and the presence of diabetic retinopathy. A critical observation that emerged is the strong link between an earlier age at diabetes diagnosis and a larger relative risk of AMD, independent of glycemic control and disease duration, suggesting a unique "early onset vulnerability" that merits further investigation.

The intricate biological interplay between these two prevalent eye diseases is underscored by their shared pathophysiological mechanisms, including chronic inflammation, heightened oxidative stress, the accumulation of advanced glycation end-products, and the pivotal role of vascular endothelial growth factor. These common pathways explain why diabetes can predispose individuals to AMD and why certain therapeutic strategies may offer dual benefits.

Clinically, these findings emphasize the critical need for an integrated approach to eye care for diabetic patients, moving beyond a sole focus on diabetic retinopathy to include comprehensive screening for AMD. Furthermore, the potential of lifestyle interventions (e.g., diet, physical activity, smoking cessation) and certain pharmacological agents (e.g., anti-VEGF therapies, SGLT2 inhibitors, metformin) to offer synergistic benefits in managing both diabetes and AMD risk is a promising area for clinical practice.

5.2. Future Research Directions

Future research should focus on several key areas to further elucidate and address the complex relationship between diabetes and AMD:

Pharmacological Validation: Further large-scale, prospective clinical trials are needed to definitively confirm the protective associations observed for certain pharmacological agents, such as metformin and SGLT2 inhibitors, with AMD risk in diabetic patients. These trials should assess long-term outcomes and optimal dosing strategies.
Mechanistic Elucidation of Early Onset: Research should prioritize elucidating the precise molecular pathways and potential genetic or epigenetic predispositions that mediate the strong link between early-onset diabetes and increased AMD risk, particularly its independence from glycemic control and disease duration. This could involve in-depth investigations into "hyperglycemic memory" and its long-term impact on retinal cellular health and vulnerability.
Combined Therapeutic Approaches: Studies on the efficacy and safety of combined therapeutic approaches, simultaneously targeting systemic metabolic control in diabetes and specific AMD pathways, are warranted. This could involve novel drug combinations or integrated treatment regimens.
Addressing Epidemiological Inconsistencies: Future epidemiological studies should aim to resolve the inconsistencies observed regarding the association of diabetes with specific AMD subtypes (e.g., dry vs. wet, GA vs. nAMD) across different populations. This will help refine risk stratification and enable more personalized management strategies.
Role of Microbiota and Other Systemic Factors: Further exploration of the role of the gut microbiota and other systemic health factors (e.g., hypertension, dyslipidemia, cardiovascular disease) in influencing both diabetes and AMD pathogenesis could reveal novel therapeutic targets and preventive strategies.