Home West London Diabetic macular oedema treated with Aflibercept

Diabetic macular oedema treated with Aflibercept



Diabetic macular oedema (DMO) is a number one explanation for sight impairment within the working age inhabitants with roughly 21 million people affected worldwide.1 Currently, the primary line remedy for centre-involving DMO includes intravitreal anti-vascular Endothelial Growth Factor (VEGF). Despite a number of landmark research demonstrating efficacy of anti-VEGF within the remedy of DMO, it’s recognised {that a} subset of sufferers don’t reply favourably.2 Identifying components which affect remedy response is necessary as it might allow us to doubtlessly modify these components thereby enhancing response, individualise remedy regimens and prognosticate outcomes.

Post-hoc analyses of a number of RCTs resembling DRSS Protocol I,3 RESTORE,4 RESOLVE,5 READ26,7 and BOLT,8 RISE/RIDE9 have beforehand recognized youthful age, male intercourse, higher baseline greatest corrected visible acuity (BCVA) and presence of subretinal fluid as beneficial predictors of visible acuity.3,6–9 Meanwhile, length of diabetes mellitus, worse baseline diabetic retinopathy, presence of epiretinal membrane (ERM) or floor wrinkling have been proven to adversely have an effect on practical and anatomical outcomes;3,4,9 while intraretinal cysts (IRC), HbA1c, renal failure and hypercholesterolaemia haven’t been demonstrated to impact remedy response.3,8,9

In many populations, together with the UK, the prevalence of diabetes and diabetic retinopathy is increased in ethnic minorities.10–13 North West London (NWL) is a area of London recognized to be one of the vital ethnically numerous within the nation.14

In all eye departments in North West London, intravitreal aflibercept is the first-line remedy for centre-involving macular oedema as described in our earlier research.15 The licence for aflibercept for the DMO indication was authorised by the European Medicines Agency in June 2014 and it obtained the UK’s National Institute for Health and Care Excellence (NICE) approval in July 2015 based mostly on encouraging outcomes from the pivotal VIVID and VISTA research.16 Our latest report confirmed that the real-world efficacy of aflibercept in treatment-naive sufferers with DMO in North West London was decrease than reported within the landmark scientific trials, with a imply acquire of +4 letters at 12 months in comparison with +10.7 within the trials. We be aware that the imply variety of injections in our inhabitants was decrease (6.2 within the NWL cohort versus 8.7 and eight.4 in VIVID and VISTA) as is commonly the case in the actual world with clinic capability pressures and decrease affected person adherence than in scientific trials.15 We additionally demonstrated that the imply visible acuity acquire in our inhabitants was increased within the subgroup of sufferers with baseline BCVA lower than 70 letters (imply acquire of +7.4 ETDRS letters), with a lot of our sufferers having increased visible acuity at baseline than was allowed within the registration trials.15 However, we needed to go additional to research baseline ocular and systemic components which will predict poorer visible and anatomical outcomes. Our aim was to establish sufferers which may be significantly vulnerable to poor visible and anatomical outcomes to allow higher counselling on initiation of remedy, information higher individualisation of remedy and supply alerts to direct additional potential research. This research is necessary as earlier real-world research haven’t included a inhabitants as numerous as routinely treated in North West London.


The methodology of this research has been beforehand described.15 In abstract, we carried out this retrospective, multicentre cohort research at three North West London Hospitals between January 2016 and July 2018 with knowledge analysed between June 2020 and July 2020. The research was authorised prospectively by the Research and Development departments of all three hospitals (London North West University Healthcare NHS Trust Research and Development reference no. SE19/016, Imperial College NHS Trust service analysis reference no. 381 and Hillingdon Hospital service analysis reference no. 1018 and the research adopted the tenets of the Declaration of Helsinki.

Treatment-naive diabetic macular oedema sufferers initiated on intravitreal aflibercept and adopted up for at the least 12 months had been included within the research. Both Type 1 and Type 2 diabetes mellitus sufferers of all ages, gender and ethnicity on oral hypoglycaemics and/or insulin had been included within the research. For sufferers with bilateral remedy, each eyes had been included. Patients had been initiated on aflibercept based mostly on the presence of centre-involving DMO outlined as central subfield thickness (CSFT) at initiation over 400 µm, though the CSFT could possibly be lower than <400 µm if there was an space higher than 400 µm within the central 3000 µm of the ETDRS grid.

The exclusion standards had been cataract surgical procedure inside 3 months of commencing intravitreal aflibercept, different macular illnesses resembling retinal vein occlusion or age-related macular degeneration, epiretinal membranes higher than stage 3 and the presence of macular oedema of different aetiology.

The remedy protocol in all three hospitals was in alignment with 2014 EU abstract of product traits label for aflibercept which is loading part of 5 month-to-month intravitreal aflibercept (except remedy success after three injections outlined as 20/20 imaginative and prescient or CSFT<250 μm), adopted by ongoing injections each 8 weeks till stability was achieved. Stability was outlined as in Protocol T as no enchancment or worsening in visible acuity or central macular thickness after two consecutive injections.17

Data Collection

Electronic medical information had been reviewed for sufferers’ demographic knowledge, HbA1c values (inside 6 months of first injection), creatinine and eGFR (inside 6 months of first injection), lens standing and retinopathy standing utilizing the UK nationwide screening committee (NSC) grades (R1: gentle and reasonable non-proliferative diabetic retinopathy, R2: extreme non-proliferative diabetic retinopathy, R3A: energetic proliferative diabetic retinopathy, R3S: steady treated proliferative diabetic retinopathy) as documented within the medical information at baseline, complete variety of injections at 12 months and greatest corrected visible acuity (BCVA) at baseline and 12 months. Visual acuity was assessed utilizing ETDRS charts at 4 metres at baseline and in any respect injection visits. SD-OCT was obtained in the usual mode (the improved depth imaging mode was not used for the aim of evaluating DMO): Heidelberg Spectralis, Heidelberg, Germany at Central Middlesex Hospital and Western Eye Hospital and HD OCT Cirrus 5000 (Carl Zeiss AG, Germany) at Hillingdon Hospital. Central subfield thickness CSFT and macular quantity had been calculated robotically by the instrument and recorded at baseline, 3 months, 6 months and 12 months after the primary intravitreal aflibercept. OCT options had been categorised into the next patterns: presence of intraretinal fluid, subretinal fluid, epiretinal membrane (ERM), vitreomacular adhesion (VMA) and gentle vitreomacular traction (VMT). Virtual Caliper operate of Spectral Domain-OCT was used for measurement of width and peak of the most important intraretinal cyst. All knowledge had been collected at scheduled time factors ± 1 month to permit for scheduling and capability points inside every hospital.

Statistical Analysis

Data collected from our cohort had been analysed utilizing Microsoft Excel 2010 (Microsoft Corporation, Washington, USA) and SPSS 22.0 (SPSS Inc, Chicago, USA).

Sample measurements had been summarised with imply worth and normal deviation whereas categorical variables had been expressed as frequencies. To assess associations between outcomes and variables, univariate and multivariate logistic regressions had been used with outcomes introduced as regression coefficient with a 95% confidence interval. When selecting candidate variables for multivariable logistic regression, entry choice criterion was set at P ≤ 0.10 and keep criterion set at P ≤ 0.05. A backwards choice process was used to retain solely the statistically vital variables within the remaining mannequin. A p worth of <0.05 was interpreted as statistically vital.


A complete of 270 eyes of 221 sufferers met the inclusion standards for the research and the general efficacy is reported elsewhere and summarised in Table 1. For the current report, resulting from lacking knowledge for some baseline variables, solely 202 eyes had been included within the regression mannequin. The following evaluation contains 202 eyes of the full cohort who had full knowledge of all investigated baseline variables.

Table 1 Baseline Patient Characteristics in Our North West London (NWL) Study Compared with VIVIDa and VISTAb

Predictors of Functional Outcomes

On univariate evaluation, higher baseline BCVA was related with higher BCVA at 12 months. In addition, youthful age, decrease baseline CMT and better HbA1c had been additionally related with higher BCVA at 12 months, having corrected for baseline BCVA (Table 2). In phrases of retinopathy standing, eyes that had obtained earlier PRP (R3S) trended in the direction of decrease BCVA at 12 months, though this didn’t attain statistical significance (P = 0.07). On multivariate evaluation, higher baseline BCVA, decrease baseline CMT, increased HbA1c and absence of epiretinal membrane (ERM) had been related with higher BCVA at 12 months (Table 3). There was no statistically vital affiliation between gender, ethnicity, baseline renal operate (eGFR), baseline macular quantity, lens standing, presence of subretinal fluid, vitreomacular adhesion (VMA) or vitreomacular traction (VMT) with BCVA at 12 months on univariable and multivariable evaluation (Tables 2 and three).

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Table 2 Univariable Analysis of Associations Between Ocular and Systemic Factors with Best Corrected Visual Acuity (BCVA) at 12 Months

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Table 3 Multivariable Analysis of Associations Between Ocular and Systemic Factors with BCVA and CMT at 12 Months

Predictors of Structural Outcomes

On univariate and multivariate evaluation, baseline CMT (P < 0.001) and retinopathy standing (P = 0.007) had been discovered to be considerably related with CMT at 12 months (Tables 4 and three). Patients with R3A standing had lowest CMT values at 12 months (P = 0.007), adopted by R3S, R2 and R1. Ethnicity was discovered to be considerably related with the CMT at 12 months, with Caucasian eyes having increased CMT than different ethnicities, however this didn't attain significance as soon as baseline CMT was corrected for. There was no statistically vital affiliation between gender, HbA1c, renal operate (eGFR), baseline macular quantity, lens standing, measurement of intraretinal cyst, presence of subretinal fluid, vitreomacular adhesion (VMA) or vitreomacular traction (VMT) with CMT values at 12 months(Tables 4 and three).

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Table 4 Univariable Analysis of Associations Between Ocular and Systemic Factors with Central Macular Thickness (CMT) at 12 Months


We beforehand reported the efficacy of aflibercept in treatment-naïve sufferers with diabetic macular oedema in North West London. Our intention within the current report was to establish any ocular or systemic traits which may be predictive of higher practical or anatomical response in our cohort. Such data is helpful to assist design potential research and information service supply. The broad range of our remedy inhabitants cohort inside North West London uniquely allows our knowledge to be broadly relevant in contrast with the essentially homogeneous demographic in randomised managed trials. Identified components related with antagonistic outcomes could kind the idea of a danger stratification instrument for DMO sufferers initiated on intravitreal aflibercept, significantly as a lot of our findings have been beforehand confirmed in potential research.

Within our cohort, we discovered that higher baseline visible acuity was considerably related with higher visible acuity at 12 months. This discovering is constant with post-hoc evaluation of RIDE/RISE which confirmed a correlation between higher baseline BCVA and remaining BCVA of 6/12 or higher and READ2 which confirmed higher baseline BCVA elevated the possibility of fine visible final result outlined as higher than 6/30.7,9 It has been hypothesised that good baseline BCVA regardless of macular oedema means that the fluid has not been current for sufficiently lengthy to confer everlasting harm thereby leading to higher remedy response to intravitreal aflibercept.9

In phrases of affected person’s age, we discovered that 10 years improve in age was related with 1.5 much less ETDRS letters at 12 months. This affiliation was additionally famous in Diabetic Retinopathy Clinical Research Network Protocol I, albeit at a higher impact of 1.9 much less ETDRS letters at 12 months with each 10 years improve in age and the post-hoc evaluation of RIDE/RISE which confirmed that for each 5 years older at baseline, a affected person was much less prone to acquire 15 or extra letters at 24 months3,9 This could also be as a result of the eyes of youthful sufferers could also be extra tolerable to fluid accumulation making them extra amenable to reversible harm.9 In phrases of HbA1c, there was no affiliation with visible outcomes when analysed as a steady variable however when categorised, we discovered that sufferers with HbA1c ≥64 had increased BCVA at 12 months. All revealed research up to now have both discovered no affiliation or a deleterious impact of HbA1c on remedy response to aflibercept and it’s doubtless our discovering on the contrary is confounded by the inclusion of HbA1c degree inside 6 months of baseline as a baseline worth which doesn’t account for fluctuations in HbA1c ranges all through the research interval.8,9

Interestingly, we demonstrated higher anatomical response however a development in the direction of decrease BCVA in sufferers with extra superior diabetic retinopathy. The antagonistic results of proliferative illness on visible outcomes is constant with earlier research together with RIDE/RISE and Protocol T.9,17 Postulated mechanisms for this affiliation embody diabetic macular ischaemia being extra ceaselessly related with extra superior diabetic retinopathy.18 A latest research by Tsai et al. additionally confirmed that elevated severity of diabetic retinopathy was related with decreased deep perifoveal vessel density, bigger superficial and deep foveal avascular zone (FAZ) and lowered retinal sensitivity whereas Samara et al. discovered a correlation between bigger FAZ areas and poorer visible acuities.19,20 On the opposite hand, these eyes doubtless have increased VEGF drive leading to higher anatomical responses.

We excluded eyes that had vitreoretinal interface abnormalities requiring surgical procedure however evaluated the affect of gentle vitreoretinal interface disturbance on practical outcomes. Our discovering that the presence of ERM was related with poorer BCVA mirrors that discovered within the publish hoc evaluation of Protocol I.3 ERM is understood to scale back visible operate independently by distorting the retina and might progress to preretinal macular fibrosis and it’s doubtless that it might limit practical enchancment in DMO through related mechanisms.21

Anatomical Outcomes

In phrases of anatomical outcomes of remedy, baseline CMT and retinopathy standing had been discovered to be related with remaining CMT at 12 months. We discovered that increased baseline CMT resulted in increased remaining CMT regardless of higher absolute fluid discount over a 12-month interval. The higher CMT discount inside this subset of sufferers is as a result of ceiling impact to remedy of sufferers with low baseline CMT. Notwithstanding the higher CMT discount, our research means that sufferers with increased baseline CMT could require extra intensive remedy for optimum anatomical final result at 12 months. Caucasian eyes tended to have increased CMT at 12 months in contrast with different ethnicities earlier than adjusting for baseline CMT. This could also be resulting from findings that eyes of African descent have decrease CMT and broader foveal pits in contrast with Caucasian eyes however additional potential research on anatomical response to remedy of macular oedema throughout ethnicities are warranted.22

Our research is restricted by its retrospective nature. In addition, our knowledge on HbA1c and renal operate was restricted to inside 6 months of baseline and solely documented at this single time level and thus doesn’t bear in mind the fluctuations earlier than the research remedy was began or in the course of the research. Our research additionally lacked the strict visible acuity and OCT acquisition protocols as is the norm in scientific trials however is anticipated inside a real-life pressured health-care setting. The power of our research, nevertheless, lies within the range of our research inhabitants which is a real-world interior London inhabitants with numerous ethnicities and grades of diabetic retinopathy represented. Our outcomes would due to this fact be extra reflective of real-world scientific apply and spotlight that older sufferers, sufferers with decrease BCVA, extra superior retinopathy, epiretinal membrane and better CMT are prone to have worse outcomes when treated with aflibercept for diabetic macular oedema and may gain advantage from immediate and well timed graduation of remedy to maximise outcomes.


In abstract, our research recognized a number of baseline traits related with remedy response to aflibercept in treatment-naive DMO at 12 months. To our data, that is the most important revealed dataset analyzing components influencing remedy response in sufferers treated with aflibercept for diabetic macular oedema inside the UK in a real-world setting. Further work together with giant potential research in numerous populations are required to substantiate our findings with the aim of individualising remedy, and prognosticating outlook.

Data Sharing Statement

The datasets used and/or analysed in the course of the present research can be found from the corresponding creator on cheap request.

Ethics Approval and Consent to Participate

The research was authorised prospectively by the Research and Development departments of all three hospitals (London North West University Healthcare NHS Trust Research and Development reference no. SE19/016, Imperial College NHS Trust service analysis reference no. 381 and Hillingdon Hospital service analysis reference no. 1018 and the research adopted the tenets of the Declaration of Helsinki.


Paul Bassett – Statsconsultancy Ltd for statistical evaluation.

Author Contributions

All authors made vital contributions to the work reported together with conception, research design, execution, acquisition of information, evaluation and interpretation, drafting, revising and critically reviewing the article as proven under. All authors gave remaining approval of the model to be revealed and have agreed on the journal to which the article has been submitted; and comply with be accountable for all points of the work.

Conceptualisation: CD.

Data Curation: CD, AG, SYS, AM, SN.

Formal Analysis: CD, AM.

Investigation: SYS, AM, SN.

Methodology: CD, RCL, SG, EP.

Project Administration: AG, SYS.

Supervision: CD, EP, RCL, SG.

Validation: SYS, AG, CD.

Writing- Original Draft: SYS, AG.

Writing – Review and Editing: CD, AM, EP, RCL, SG.


The authors obtained no particular funding for this work.


CD has obtained journey and assembly grants from Bayer, Novartis and Allergan. She has additionally served on advisory boards for Novartis and Allergan and obtained speaker charges from Novartis. EP has obtained journey and assembly grants from Bayer, Allergan and Alimera Sciences, speaker charges from Allergan and Novartis and has served on advisory board for Alimera Sciences. SG has obtained journey and assembly grants and served on advisory boards for Novartis and Bayer. The authors report no different conflicts of curiosity on this work.


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