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KESTREL and KITE: 52-Week Results From Two Phase III Pivotal Trials of Brolucizumab for Diabetic Macular Edema.
Brown, DM, Emanuelli, A, Bandello, F, Barranco, JJE, Figueira, J, Souied, E, Wolf, S, Gupta, V, Ngah, NF, Liew, G, et al
American journal of ophthalmology. 2022;:157-172
Abstract
PURPOSE To compare the efficacy and safety of brolucizumab with aflibercept in patients with diabetic macular edema (DME). DESIGN Double-masked, 100-week, multicenter, active-controlled, randomized trials. METHODS Subjects were randomized 1:1:1 to brolucizumab 3 mg/6 mg or aflibercept 2 mg in KESTREL (n = 566) or 1:1 to brolucizumab 6 mg or aflibercept 2 mg in KITE (n = 360). Brolucizumab groups received 5 loading doses every 6 weeks (q6w) followed by 12-week (q12w) dosing, with optional adjustment to every 8 weeks (q8w) if disease activity was identified at predefined assessment visits; aflibercept groups received 5 doses every 4 weeks (q4w) followed by fixed q8w dosing. The primary endpoint was best-corrected visual acuity (BCVA) change from baseline at Week 52; secondary endpoints included the proportion of subjects maintained on q12w dosing, change in Diabetic Retinopathy Severity Scale score, and anatomical and safety outcomes. RESULTS At Week 52, brolucizumab 6 mg was noninferior (NI margin 4 letters) to aflibercept in mean change in BCVA from baseline (KESTREL +9.2 letters vs +10.5 letters; KITE +10.6 letters vs +9.4 letters; P < .001), more subjects achieved central subfield thickness (CSFT) <280 µm, and fewer had persisting subretinal and/or intraretinal fluid vs aflibercept, with more than half of brolucizumab 6 mg subjects maintained on q12w dosing after loading. In KITE, brolucizumab 6 mg showed superior improvements in change of CSFT from baseline over Week 40 to Week 52 vs aflibercept (P = .001). The incidence of ocular serious adverse events was 3.7% (brolucizumab 3 mg), 1.1% (brolucizumab 6 mg), and 2.1% (aflibercept) in KESTREL; and 2.2% (brolucizumab 6 mg) and 1.7% (aflibercept) in KITE. CONCLUSION Brolucizumab 6 mg showed robust visual gains and anatomical improvements with an overall favorable benefit/risk profile in patients with DME.
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Systematic review of diabetic eye disease practice guidelines: more applicability, transparency and development rigor are needed.
Gyawali, R, Toomey, M, Stapleton, F, Zangerl, B, Dillon, L, Ho, KC, Keay, L, Alkhawajah, SMM, Liew, G, Jalbert, I
Journal of clinical epidemiology. 2021;:56-68
Abstract
OBJECTIVES To assess the quality of diabetic eye disease clinical practice guidelines. STUDY DESIGN AND SETTING A systematic search of diabetic eye disease guidelines was conducted on six online databases and guideline repositories. Four reviewers independently rated quality using the Appraisal of Guidelines, Research, and Evaluation (AGREE II) instrument. Aggregate scores (%) for six domains and overall quality assessment were calculated. A "good quality" guideline was one with ≥60% score for "rigor of development" and in at least two other domains. RESULTS Eighteen guidelines met the inclusion criteria, of which 13 were evidence-based guidelines (involved systematic search and grading of evidence). The median scores (interquartile range (IQR)) for "scope and purpose," "stakeholder involvement," "rigor of development," "clarity of presentation," "applicability" and "editorial independence" were 73.6% (54.2%-80.6%), 48.6% (29.2%-71.5%), 60.2% (30.9%-78.1%), 86.6% (76.7%-94.4%), 28.6% (18.0%-37.8%) and 60.2% (30.9%-78.1%), respectively. The median overall score (out of 7) of all guidelines was 5.1 (IQR: 3.7-5.8). Evidence-based guidelines scored significantly higher compared to expert-consensus guidelines. Half (n = 9) of the guidelines (all evidence-based) were of "good quality." CONCLUSION A wide variation in methodological quality exists among diabetic eyecare guidelines, with nine demonstrating "good quality." Future iterations of guidelines could improve by appropriately engaging stakeholders, following a rigorous development process, including support for application in clinical practice and ensuring editorial transparency.
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Diet and risk of visual impairment: a review of dietary factors and risk of common causes of visual impairment.
Broadhead, GK, Hong, T, Bahrami, B, Flood, V, Liew, G, Chang, AA
Nutrition reviews. 2021;(6):636-650
Abstract
Age-related macular degeneration, diabetic retinopathy, cataract, and glaucoma remain the leading causes of visual impairment in developed nations, resulting in a substantial treatment burden on sufferers and health care systems. Despite significant advances in diagnostic testing and therapeutics, population-based strategies to reduce the burden of these diseases remain limited. However, there is some evidence that these diseases may share overlapping risk factors, particularly in regard to dietary intake and antioxidant status, and it is thus possible that dietary modification may reduce both the prevalence and severity of these conditions. In particular, dietary intake of green leafy vegetables, hyperglycemia/glycemia index, and omega-3 fatty acid intake, as well as overall dietary patterns, may affect risk of one or more of these conditions. In this review, we analyse the evidence for dietary intake and the association with these conditions, and provide insights into possible modifications that may thus simultaneously reduce the risk of visual impairment from multiple causes, including improving dietary intake of green leafy vegetables and reducing dietary glycemic index, both of which have been associated with a decreased risk of multiple causes of visual impairment.
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Carbohydrate nutrition variables and risk of disability in instrumental activities of daily living.
Gopinath, B, Flood, VM, Burlutksy, G, Liew, G, Mitchell, P
European journal of nutrition. 2019;58(8):3221-3228
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Plain language summary
In older adults, maintaining independence is determined by the ability to carry out activities of daily living (ADL), such as bathing and walking. Certain features of carbohydrate-rich foods known as the glycaemic index (GI), and glycaemic load (GL) have been implicated in the development of obesity, diabetes, and cardiovascular disease. Other aspects of carbohydrate quality such as fibre intake have been shown to influence the risk of chronic diseases that are more common with ageing. This prospective study aimed to examine the association between the GI and GL of foods consumed, intakes of carbohydrates and fibre, and the ability to perform ADL in older adults. A total of 844 participants from the Blue Mountains Eye Study in Australia, aged 60 years or older were examined from 2002-2004 to 2007-2009. Dietary information was collected using a food-frequency questionnaire, and functional status was assessed using an activities of daily living scale. Participants who reported moderate consumption of dietary fibre (19.1g to 29.6g fibre per day) had a lower risk of experiencing instrumental ADL (IADL) disability compared with those in the lowest group of fibre consumption (19g fibre or less per day); that is, they were more likely to be able to use the telephone, get to places out of walking distance, do housework, take their own medications, and handle money at the 5-year follow-up. There was no added benefit for fibre intake above 19.6g per day. Other baseline carbohydrate nutrition variables, including GI, GL, and total carbohydrate intake, were not associated with ADL disability over the 5 years. The researchers concluded that these findings could inform the development of targeted intervention strategies to encourage a greater intake of fibre-rich foods in older adults, potentially preserving or delaying further deterioration in physical functioning.
Abstract
PURPOSE We aimed to examine the prospective association between dietary glycemic index (GI) and glycemic load (GL) of foods consumed, intakes of carbohydrates and fiber, and the ability to perform activities of daily living (ADL) in older adults. METHODS A total of 844 participants from the Blue Mountains Eye Study aged 60 years or older were examined from 2002-2004 to 2007-2009. Dietary information was collected using a validated, semi-quantitative food-frequency questionnaire. The Older Americans Resources and Services activities of daily living scale were administered to assess the functional status of participants. Multivariable logistic regression analysis was performed. RESULTS After multivariable adjustment, participants who were in the second and third quartiles of energy-adjusted total fiber intake compared to those in the first quartile of intake (reference group) at baseline had reduced risk of incident impaired instrumental activities of daily living (IADL) 5 years later: OR, 0.39 (95% CI 0.22-0.70) and OR 0.54 (95% CI 0.30-0.95), respectively. Analyses that involved dichotomized total fiber intake showed that participants in the upper three quartiles of total fiber intake (> 19 g/day), compared to those in the lowest quartile of intake (≤ 19 g/day) or reference group, had reduced IADL disability risk 5 years later: OR 0.49 (95% CI 0.31-0.79). Non-significant associations were observed with total carbohydrates, GI, and GL and with risk of impaired total and basic ADL at 5-year follow-up. CONCLUSIONS Habitual fiber consumption might be beneficial in leading to improved health status subserving performance of instrumental daily activities, needed to function in the community.
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Profile of a population-based diabetic macular oedema study: the Liverpool Eye and Diabetes Study (Sydney).
Liew, G, Wong, VW, Saw, M, Tsang, TE, Nolan, T, Ong, S, Ho, IV
BMJ open. 2019;(1):e021884
Abstract
PURPOSE The population prevalence of diabetic macular oedema (DME) is unclear. Previous estimates have depended on photographic grading of clinically significant macular oedema, which is subjective and has resulted in widely varying estimates. With the advent of optical coherence tomography (OCT), the presence and severity of DME can now be assessed objectively and accurately. METHODS The Liverpool Eye and Diabetes Study (LEADS) is a cross-sectional population-based study of patients with type 1 and type 2 diabetes in a multi-ethnic region of Sydney, Australia, to determine the population prevalence of OCT-defined DME, how this varies by ethnicity and association with systemic factors. This report describes the rationale, methodology and study aims. RESULTS To date 646 patients out of an expected sample size of 2000 have been recruited. Baseline data are presented for patients with type 1 (n=75, 11.8%) and type 2 (n=562, 88.2%) diabetes recruited to date. Patients with type 1 diabetes were younger (39.5vs60.7 years), with longer duration of diabetes (18.1vs11.7 years), slightly worse glycaemic control (HbA1c 9.0vs8.3), and less likely to have hypertension (30.7vs71.4%), hypercholesterolaemia (33.3vs74.6%) and obesity (31.1vs51.5%, respectively, all p<0.05). CONCLUSIONS The LEADS will provide objective estimates of the population prevalence of DME, how this varies with ethnicity and associations with systemic disease.
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Retinal microvascular changes in microvascular angina: Findings from the Australian Heart Eye Study.
Liew, G, Mitchell, P, Chiha, J, Plant, AJH, White, A, Joachim, N, Wang, S, Burlutsky, G, Kovoor, P, Thiagalingam, A, et al
Microcirculation (New York, N.Y. : 1994). 2019;(6):e12536
Abstract
OBJECTIVE Microvascular changes in microvascular angina are poorly understood due to difficulties in imaging the coronary microcirculation in vivo. The retinal microvasculature may reflect changes in coronary microcirculation. We assessed microvascular changes in the retina in patients with microvascular angina and compared them with patients with angiographically proven coronary artery disease. METHODS We performed retinal photography and coronary angiography on 915 patients. Retinal vessel calibers were measured using a validated computer-assisted method; coronary artery disease was graded from coronary angiograms. Microvascular angina was defined as angina with <25% stenosis in all coronary epicardial arteries. RESULTS A total of 139 patients (15.2%) had microvascular angina, while 776 (84.8%) had coronary artery disease. Participants with microvascular angina and coronary artery disease had similar retinal arteriolar and venular calibers. After adjustment for age, ethnicity, mean arterial pressure, diabetes, current smoking, body mass index, and fellow vessel caliber, women with smaller venules were threefold more likely to have microvascular angina than women with larger venules (multivariable-adjusted odds ratio 3.54, 95% confidence interval 1.35 to 9.24, P < 0.01). This difference was not observed in men. CONCLUSIONS Microvascular angina in women was associated with microvascular changes distinct from those in coronary artery disease.
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New anti-hyperglycaemic agents for type 2 diabetes and their effects on diabetic retinopathy.
Saw, M, Wong, VW, Ho, IV, Liew, G
Eye (London, England). 2019;(12):1842-1851
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Abstract
There has been an increase in the range of non-insulin anti-hyperglycaemic agents used to treat type 2 diabetes. With the globally rising rates of type 2 diabetes and complications such as diabetic retinopathy, it is important for ophthalmologists to be aware of these new agents and their impacts on diabetic retinopathy and diabetic macular oedema. We conducted a review of the literature to determine if there were any beneficial or harmful effects of the currently used anti-hyperglycaemic agents on diabetic retinopathy or diabetic macular oedema. Our review of the current literature found that apart from thiazolidinediones, anti-hyperglycaemic agents have been reported to have beneficial or neutral effects on diabetic eye complications. Thiazolidinediones (pioglitazone is the only one currently available) have been linked to incident or worsening diabetic macular oedema, although the rate is believed to be low. Glucagon-like peptide 1 (GLP1) agonists (incretins) in general are beneficial except semaglutide which is associated with increased rates of diabetic retinopathy complications. These results have implications for selection of anti-hyperglycaemic agents for patients with diabetic retinopathy or macular oedema. Further studies need to be conducted to identify if reported beneficial effects are independent of the impact of glycaemic control. Early worsening of retinopathy with tight glycaemic control should also be noted in interpretation of future studies.
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Early atherosclerosis is associated with retinal microvascular changes in adolescents with type 1 diabetes.
Peña, AS, Liew, G, Anderson, J, Giles, LC, Gent, R, Wong, TY, Couper, JJ
Pediatric diabetes. 2018;(8):1467-1470
Abstract
BACKGROUND/OBJECTIVE Adolescents with type 1 diabetes have early macrovascular changes (increased intima-media thickness [IMT]) and early retinal changes that predict clinical disease in adulthood. We hypothesized that early changes in the macrovascular and retinal microvascular beds develop in parallel before retinopathy develops. We therefore aimed to investigate the relationship between changes in atherosclerosis (carotid and aortic IMT) and retinal vascular geometry cross-sectionally and longitudinally in adolescents with type 1 diabetes. METHODS Ninety adolescents with type 1 diabetes (41 boys, aged 13.6 ± 3.5 years) who were enrolled in a randomized controlled trial had evaluations at baseline; 41 randomized to placebo were also investigated at 12 months for carotid and aortic IMT using ultrasound and retinal vascular geometry was measured from retinal photographs. RESULTS There were significant associations between thicker mean/maximum carotid IMT and wider retinal arteriolar and venular calibers; for every 0.1 mm increase in mean carotid IMT, retinal arteriolar caliber increased by 7.90 μm (95% confidence interval [CI] 4.50, 11.30, P < 0.0001) and venular caliber by 9.61 μm (95% CI 4.16, 15.06, P = 0.0008). Increased mean aortic IMT was associated with increased arteriolar tortuosity (2.61, 95% CI 0.50, 4.71, P = 0.02). CONCLUSIONS The early changes of atherosclerosis are associated with retinal microvascular changes in adolescents with type 1 diabetes. This supports parallel adverse changes in the macro and microvascular circulations from early adolescence in type 1 diabetes, and highlights the importance of early intervention.
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A spectrum of retinal vasculature measures and coronary artery disease.
Wang, SB, Mitchell, P, Liew, G, Wong, TY, Phan, K, Thiagalingam, A, Joachim, N, Burlutsky, G, Gopinath, B
Atherosclerosis. 2018;:215-224
Abstract
BACKGROUND AND AIMS We aimed to comprehensively describe a spectrum of retinal vessel measures including fractal dimension (Df) and their associations with indices of coronary artery disease (CAD) extent and severity, as well as hypertension and diabetes. METHODS The Australian Heart Eye Study (AHES) is an observational study that surveyed 1680 participants presenting to a tertiary referral hospital for the evaluation of potential CAD by coronary angiography. A range of newer retinal vessel geometric measures (Df, curvature tortuosity, and branching angle) were quantified from retinal photographs using semi-automated software, the Singapore 'I' Vessel Assessment (SIVA) tool. A combined retinal score was constructed, aiming to assess the joint effect of multiple retinal vessel parameters on CAD, comprising of those variables that were most strongly significant in multivariate analysis - Df, arteriolar curvature tortuosity, and retinal arteriolar calibre. CAD was objectively quantified using a range of measures obtained from coronary angiography. RESULTS A total of 1187 participants had complete data on retinal vessel measurements and coronary vessel evaluation. Retinal vascular Df and curvature tortuosity decreased with increasing age; women had significantly lower Df than men (p<0.003). Straighter retinal vessels were associated with CAD extent and Gensini scores in multivariable analysis (p<0.02). Accounting for media opacity by sub-group analysis in pseudophakic patients, the combined retinal score was associated with stenosis greater than 50% in any coronary artery segment (vessel score) and obstructive coronary stenosis in all three main coronary arteries (segment score) (p = 0.01). Lower Df and narrower arteriolar branching angle were associated with CAD vessel score (p<0.03). In sex-stratified multivariate analyses, straighter arterioles were associated with greater odds of CAD in men, and narrower venular branching angle was associated with CAD in women. CONCLUSIONS A range of retinal vessel measures were associated with CAD extent and severity. A sparser retinal microvascular network (smaller Df) was associated with older age and female gender. After accounting for the impact of media opacity, retinal vessel measures were associated with more diffuse and severe CAD.
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Age-related macular degeneration.
Mitchell, P, Liew, G, Gopinath, B, Wong, TY
Lancet (London, England). 2018;(10153):1147-1159
Abstract
Age-related macular degeneration is a leading cause of visual impairment and severe vision loss. Clinically, it is classified as early-stage (medium-sized drusen and retinal pigmentary changes) to late-stage (neovascular and atrophic). Age-related macular degeneration is a multifactorial disorder, with dysregulation in the complement, lipid, angiogenic, inflammatory, and extracellular matrix pathways implicated in its pathogenesis. More than 50 genetic susceptibility loci have been identified, of which the most important are in the CFH and ARMS2 genes. The major non-genetic risk factors are smoking and low dietary intake of antioxidants (zinc and carotenoids). Progression from early-stage to late-stage disease can be slowed with high-dose zinc and antioxidant vitamin supplements. Intravitreal anti-vascular endothelial growth factor therapy (eg, ranibizumab, aflibercept, or bevacizumab) is highly effective at treating neovascular age-related macular degeneration, and has markedly decreased the prevalence of visual impairment in populations worldwide. Currently, no proven therapies for atrophic disease are available, but several agents are being investigated in clinical trials. Future progress is likely to be from improved efforts in prevention and risk-factor modification, personalised medicine targeting specific pathways, newer anti-vascular endothelial growth factor agents or other agents, and regenerative therapies.