Diabetes-Associated Dry Eye Disease: A Clinical Update

LEARNING OBJECTIVES

On completion of this CPD activity, participants should:

1. Understand the pathophysiology of DED within the context of diabetes,

2. Be aware of key strategies for assessment of DED,

3. Be aware of key active ingredients in current treatment options, and

4. Realise the importance of holistic strategies to safeguard vision and wellbeing.

Dry eye disease (DED) is classified as a multifactorial disorder of the ocular surface characterised by a loss of homeostasis of the tear film, manifesting through symptoms of discomfort, visual disturbances, and tear film instability. Individuals with diabetes mellitus experience a markedly higher prevalence of DED compared to individuals without diabetes, with studies reporting rates as high as 54.3%.¹

This increased susceptibility is attributed to the intricate interplay of metabolic disturbances inherent in diabetes. Chronic hyperglycaemia, a hallmark of diabetes, contributes to an array of ocular surface abnormalities, including tear film dysfunction, meibomian gland dysfunction (MGD), and corneal nerve damage, all of which exacerbate DED symptoms.² Hyperglycaemia induces chronic inflammation and oxidative stress, leading to a reduction in goblet cell density and an increase in tear film osmolarity, both critical factors in DED pathogenesis. Additionally, advanced glycation end products (AGEs) alter the structure and function of the lacrimal gland, reducing tear production, where a correlation exists between the severity of diabetic retinopathy and DED, suggesting a shared pathophysiological pathway involving microvascular damage and inflammation.³

The clinical significance of DED in individuals living with diabetes transcends mere ocular discomfort. It is associated with an increased risk of serious complications such as diabetic retinopathy and corneal neuropathy. Research indicates that prolonged hyperglycaemia results in oxidative stress, elevated inflammatory mediators, and microvascular changes that aggravate tear film instability, further complicating the clinical picture.⁴ Therefore, early detection and proactive management of DED, incorporating strategies to mitigate hyperglycaemia and its associated complications, are pivotal in preventing these complications and enhancing the quality of life for individuals living with diabetes.

Pathophysiology of DED in Diabetes

The pathophysiology of DED in diabetes is multifaceted, incorporating several interrelated mechanisms.

Tear Film Dysfunction

Chronic hyperglycaemia may lead to autonomic neuropathy, adversely affecting the lacrimal gland’s function. This impairment results in reduced tear production and increased tear film osmolarity, creating an imbalance that compromises the protective function of the tear film. This imbalance leads to augmented friction between the eyelid and cornea, ultimately resulting in ocular surface damage and patient discomfort.⁵ Furthermore, studies have shown that chronic hyperglycaemia can disrupt the aquaporin channels in the lacrimal gland, reducing water transport and contributing to aqueous tear deficiency. Additionally, alterations in the composition of tear proteins, including a reduction in lactoferrin and lysozyme, compromise the antimicrobial and lubricating functions of the tear film. Glycation end-products and oxidative stress impact protein secretion in the lacrimal gland, diminishing tear stability and compounding dry eye symptoms.⁶

Meibomian Gland Dysfunction

MGD is a common condition in individuals with diabetes, with observable histopathological alterations in glandular structure and function. Lipid secretion from the meibomian glands becomes impaired, resulting in increased tear evaporation and subsequent instability of the tear film. A study by Lemp et al. indicated that individuals with diabetes demonstrated significantly higher rates of meibomian gland dropout compared to individuals without diabetes.⁷ Beyond structural changes, studies have also identified alterations in the lipid composition of meibum in individuals with diabetes, with a decrease in polar lipids and an increase in non-polar lipids, contributing to increased tear evaporation and evaporative dry eye.⁸ Moreover, inflammation within the meibomian glands, driven by pro-inflammatory cytokines, further disrupts lipid production and exacerbates MGD.⁹ This dysfunction of the lipid layer constitutes a critical aspect of the evaporative subtype of DED, necessitating focussed management strategies specifically tailored for this population.

Inflammatory Cascade

The ocular surface in individuals with diabetes is frequently subjected to a state of chronic low-grade inflammation. Elevated blood glucose levels stimulate the production of pro-inflammatory cytokines such as interleukin-1β, tumour necrosis factor-alpha, and matrix metalloproteinase-9 (MMP-9).

Such inflammatory responses lead to epithelial cell damage, increased tear film instability, and impaired wound healing mechanisms.¹⁰ Specifically, MMP-9 has been identified as a key mediator in the breakdown of the corneal epithelial barrier and the disruption of tight junctions, contributing to ocular surface damage.¹¹ Moreover, the hyperglycaemic environment promotes the activation of the NF-κB pathway (nuclear factor kappa-light-chain-enhancer of activated B cells), which further amplifies the production of pro-inflammatory cytokines and perpetuates the inflammatory cycle.⁶ Oxidative stress-induced mitochondrial dysfunction plays a crucial role in amplifying the inflammatory pathways, leading to sustained damage to the ocular surface.¹²

Corneal Nerve Damage

Diabetic neuropathy extends to the corneal nerves, diminishing corneal sensitivity and thereby impairing the blink reflex, which is essential for adequate tear distribution and ocular surface hydration. Subsequently, individuals with diabetes may experience significant ocular surface damage without perceiving corresponding symptoms, complicating timely diagnosis and management.¹ Recent studies utilising in vivo confocal microscopy have documented considerable corneal nerve fibre loss and increased immune cell infiltration in individuals with diabetes, correlating these findings with the severity of DED.² Furthermore, studies have shown that the loss of corneal nerve fibres can lead to a reduction in the production of trophic factors, such as nerve growth factor (NGF), which are essential for maintaining corneal epithelial integrity and tear production.¹⁴ Additionally, alterations in the expression of transient receptor potential (TRP) channels in corneal nerves contribute to the altered sensory perception and reduced blink reflex in individuals with diabetes.⁵

Moreover, robust evidence demonstrates a significant correlation between corneal nerve damage, dry eye severity, and the reduction of specific biomarkers such as corneal nerve fibre density (CNFD) and tear neurotrophins like substance P and calcitonin gene-related peptide (CGRP).^15,16 These alterations are not only indicative of ocular surface pathology but also serve as potential predictors for systemic complications like peripheral neuropathy and diabetic nephropathy. Notably, decreased CNFD and tear neurotrophin levels have been shown to precede clinical manifestations of systemic neuropathy and renal dysfunction, highlighting the potential for early detection and risk stratification.¹⁷

Therefore, the detection, monitoring, and management of corneal nerve damage in individuals with diabetes are crucial, necessitating a collaborative healthcare approach involving ophthalmologists, endocrinologists, optometrists, and other specialists to optimise patient outcomes and potentially mitigate the progression of systemic complications.

 

 

 

Clinical Considerations and Assessment

A thorough assessment of DED in people living with diabetes necessitates a multifaceted approach, integrating subjective reporting with a range of objective clinical and specialised investigations.⁴ Given the potential for underreporting of symptoms due to diabetic neuropathy affecting corneal sensitivity, a comprehensive evaluation is crucial.¹⁵ This evaluation should encompass a detailed history, including duration of diabetes, glycaemic control, presence of other diabetic complications, and a thorough ocular examination.

Subjective Assessment

Subjective assessment involves gathering information directly from the individual about their experience.

Standardised questionnaires, such as the Ocular Surface Disease Index (OSDI)⁹ and the Dry Eye Questionnaire 5 (DEQ-5), are essential tools for quantifying the patient’s subjective experience. These questionnaires explore the frequency and severity of symptoms such as dryness, grittiness, burning, blurred vision, and eye fatigue. However, clinicians must be mindful of the potential for underreporting in diabetic patients due to corneal neuropathy, which can diminish the perception of ocular surface discomfort.⁶ Therefore, while crucial for understanding the patient’s perspective, these questionnaires should not be the sole basis for diagnosis in this population. The correlation between subjective symptoms and objective signs can be weaker in diabetic individuals.

Objective Clinical Assessments

Objective clinical assessments can usually be performed by the clinician during a standard eye examination.

Tear film break-up time (TBUT). Assesses tear film stability using fluorescein dye and a cobalt blue light. A reduced TBUT, typically less than 10 seconds, indicates an unstable tear film and is a common finding in diabetic DED.¹⁰

Schirmer’s test. Measures reflex tear production using filter paper strips. Strips are placed in the lower conjunctival sac for five minutes, and the amount of wetting is recorded. While useful, results in diabetic patients may be influenced by neurotrophic effects, potentially leading to falsely low readings.

Tear osmolarity testing. Measures the salt concentration of tears, a key indicator of DED severity. Elevated tear osmolarity (typically >308 mOsm/L) reflects an imbalance in the tear film and is common in diabetic DED due to reduced tear production and increased evaporation.

Ocular surface staining. Application of vital dyes (fluorescein, lissamine green) to visualise epithelial damage on the cornea and conjunctiva.⁴ Increased staining, particularly in the interpalpebral region, is frequently observed in diabetic patients and indicates ocular surface compromise.

Additional Objective Assessments

These tests often require specific equipment that may be available in a well-equipped optometry or ophthalmology practice.

Meibography. Imaging of the meibomian glands to assess their structure and identify dysfunction (MGD), which is prevalent in diabetic DED. MGD contributes to evaporative dry eye.

Non-invasive tear break-up time (NIBUT). Assessment of tear film stability without fluorescein, using specialised instruments like interferometers or video keratographs where it can provide a more physiological assessment of tear film stability as it avoids the potential disruption caused by fluorescein instillation.

Tear lipid layer assessment (interferometry). Visualisation and assessment of the tear lipid layer thickness and patterns, important in evaluating evaporative dry eye. The lipid layer helps to reduce tear evaporation, and abnormalities are common in DED.

Corneal sensitivity testing (esthesiometry). Quantitative measurement of corneal nerve sensitivity using a Cochet-Bonnet esthesiometer or similar device. Reduced sensitivity is indicative of diabetic corneal neuropathy,¹⁵ which can impact tear production and the perception of dryness.

Point-of-care diagnostic tests. Rapid in-office tests for biomarkers like MMP-9, an inflammatory marker elevated in dry eye disease, which can indicate ocular surface inflammation.¹⁰

Advanced Assessments

These tests often involve laboratory analysis of tear samples or highly specialised imaging techniques.

Conjunctival goblet cell density assessment (impression cytology/confocal microscopy). Quantification of mucin-producing goblet cells, often requiring laboratory processing of samples or advanced imaging. Goblet cell loss leads to reduced mucin production, affecting tear film stability.

Analysis of tear biomarkers (cytokines, growth factors, proteins). Laboratory analysis of collected tear samples to identify and quantify specific inflammatory, neurotrophic, or other protein markers.

In vivo confocal microscopy (IVCM). High-resolution imaging of the cornea and conjunctiva at a cellular level, providing detailed information on corneal nerves, epithelial cells, and inflammatory infiltrates, revealing structural and functional changes associated with neuropathy.¹⁵

Active Ingredients in Dry Eye Drops: A Focus on Aetiology

Aqueous Deficient Dry Eye

Aqueous deficient dry eye, characterised by insufficient tear production, necessitates artificial tear formulations that primarily aim to augment lubrication, prolong tear film retention, and protect the delicate ocular surface.

High-molecular-weight sodium hyaluronate. Composed of a linear polysaccharide, this active ingredient possesses viscoelastic and hygroscopic properties, enabling the formation of a long-lasting, lubricating film across the ocular surface. This sustained lubrication alleviates symptoms and contributes to corneal epithelial healing, potentially by facilitating cell migration and mitigating inflammation.¹⁸ Studies, including a systematic review and meta-analysis by Aragona et al., have highlighted the efficacy of sodium hyaluronate in improving tear film break-up time, Schirmer test scores, and subjective symptoms of dry eye.¹⁹ Additionally, sodium hyaluronate has demonstrated effectiveness in providing relief and supporting ocular surface health where its bioadhesive characteristics extend its residence time on the eye,²⁰ indicating its utility in managing moderate to severe aqueous deficient dry eye. For individuals with diabetes who commonly experience dry eye symptoms – including dryness, burning, redness, pain, and ocular irritation – ocular lubricants with sodium hyaluronate can be a valuable component of their management.

Polyvinyl alcohol (PVA) and povidone. These synthetic polymers increase both the viscosity and the wettability of the ocular surface, improving tear film spread and providing lubrication to reduce dryness and discomfort. These ingredients are well-established in artificial tears and have shown benefit in alleviating dry eye symptoms.

Polyethylene glycol (PEG) and propylene glycol (PG). These function primarily as humectants, drawing and retaining moisture on the ocular surface to help relieve dry eye symptoms.²¹ Their main action is hydration rather than significant enhancement of tear film stability or direct reduction of evaporation. Some individuals may experience transient stinging. Despite this, they are widely used and have demonstrated effectiveness in improving subjective comfort.

Carboxymethylcellulose (CMC) and hydroxypropyl methylcellulose (HPMC). These cellulose-derived polymers, commonly employing viscosity-enhancing agents, contribute to a longer retention time of the tear film, providing lubrication and alleviating dryness.²¹ However, their lower molecular weight and weaker bioadhesive properties, compared to high-molecular-weight sodium hyaluronate, may lead to a shorter duration of action. The increased viscosity can also result in temporary blurred vision.²¹ Nevertheless, CMC and HPMC have demonstrated efficacy in managing symptoms of aqueous deficient dry eye in various studies.²²

Evaporative Dry Eye

Evaporative dry eye, often associated with MGD, results from a deficient lipid layer, leading to increased tear evaporation and ocular surface discomfort. Formulations for this condition aim to supplement or stabilise the lipid layer and, in some cases, address inflammation.

Perfluorohexyloctane. This inert, highly spreadable, and oxygen-permeable liquid facilitates rapid and uniform distribution of lipid components, across the ocular surface. This single ingredient lubricant is preservative-free, phosphate-free, and water-free, representing a formulation option for dry eye relief. This provides quick coverage without significant visual disturbance, and its oxygen permeability is advantageous for corneal health. The lubricant itself spreads across the tear film, mimicking meibomian lipids and reducing evaporation. Clinical trials have demonstrated improvements in evaporative dry eye symptoms associated with MGD within a timeframe as short as two weeks.²³ Perfluorohexyoctane is designed to stabilise and thicken the outer tear film, allowing for replenishment of the underlying aqueous layer with natural tears.

Phospholipids (e.g., phosphatidylcholine). These natural components of meibomian secretions can integrate into the tear film’s lipid layer, enhancing its structure and function. They improve tear film stability and reduce evaporation, and may also enhance spreadability. While long-term efficacy and precise mechanisms are still being researched, some studies suggest phospholipid-containing drops can improve tear film parameters and reduce symptoms associated with evaporative dry eye.²⁴

Omega 3 fatty acids (topical). Topical and systemic omega 3 fatty acids, particularly EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), may offer a safe option for managing dry eye disease and chronic ocular surface inflammation.²⁵ These fatty acids have been shown to resolve the inflammatory process and modulate angiogenesis, which can be beneficial in addressing the underlying causes of dry eye, especially in conditions like diabetes, where inflammation plays a significant role.²⁶ Topical application of omega 3 fatty acids is explored for modulating inflammation and potentially improving meibomian gland function.²⁶ They may reduce inflammation and improve secretion quality, contributing to a more stable lipid layer over time.

Current and Future Treatments

Considering the heightened vulnerability of individuals with diabetes to ocular surface complications, the preferred prescribing treatment strategy for dry eye disease emphasises a multi-faceted approach, prioritising gentle and regenerative therapies. Preservative-free formulations are paramount to minimise potential irritation and toxicity. Sodium hyaluronate emerges as a strong first-line option due to its demonstrated ability to hydrate, promote corneal healing, and support nerve health.²⁵ Furthermore, mice model studies show the combined topical application of pigment epithelium-derived factor (PEDF) and DHA holds significant promise for neurotrophic support and tear production enhancement.²⁸ When addressing evaporative dry eye stemming from meibomian gland dysfunction, perfluorohexyloctane offers a valuable targeted treatment by improving the tear film’s lipid layer and aiding in the clearance of meibomian gland blockages.²¹ It is also important to assess any associated inflammatory signs, which would need to be treated accordingly on a case-by-case basis. Ultimately, a holistic treatment plan, often incorporating non-pharmacological interventions like warm compresses (around 35°C)²⁹ and lid hygiene, alongside carefully selected topical agents with specific active ingredients such as sodium hyaluronate and, when indicated, perfluorohexyloctane, represents the most judicious approach to alleviating DED symptoms and preserving ocular health in individuals living with diabetes.

Dr Amira Howari BOptom (Hons) GradCertOcTher MOptom (UNSW) is a senior clinical optometrist; healthcare industry and motivational keynote speaker; a Diabetes Australia and KeepSight Ambassador; and former Optometry Australia Councillor (NSW/ACT).

Dr Howari has worked in corporate and independent optometry, ophthalmology, and pharmaceutical settings; and at the University of New South Wales as a guest lecturer and clinical supervisor. She currently serves as a member of the Diabetes and Endocrine Network – Agency of Clinical Innovation (NSW Health).

 

 

 

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