Management of patients with diabetic macular oedema and good visual acuity: new findings from protocol v

As we observe a dramatic increase in diabetes prevalence worldwide, diabetes-associated eye complications are rapidly emerging as a global health issue that may threaten patients’ visual

acuity [1]. Even though treatment of diabetic retinopathy (DR) can reduce the risk of visual loss by 60% [2], this disorder still remains the leading cause of blindness among working-age

adults. Diabetic macular oedema (DMO) is a major cause of vision decrease in these patients and may occur at any stage of DR. In 1985, the Early Treatment Diabetic Retinopathy Study reported

on the use of laser photocoagulation to treat DMO [3]. The latter trial enrolled 1122 patients with DMO and demonstrated that the laser treatment effects in a reduced risk of moderate

vision loss. Until the introduction of intravitreal anti-vascular endothelial growth factor (VEGF) injections, laser had been thus considered as the treatment of choice for eyes with DMO.

Since 2010, several evidences have suggested that anti-VEGF agents may be considered as an effective and safe treatment in eyes with DMO and impaired vision [4,5,6,7,8]. To simplify,

anti-VEGF therapies demonstrated a better improvement in visual acuity in comparison with focal/grid laser therapy. Nonetheless, the anti-VEGF treatment was also displayed to produce an

amelioration in DR severity [9], even without an enhancement in retinal perfusion [10]. Of note, in a number of cases the anti-VEGF treatment may be ineffective and in these cases a switch

to other treatments, including intravitreal dexamethasone, was proved to be potentially effective, especially in presence of definite imaging biomarkers [11]. Thanks to the support of the

National Eye Institute, National Institutes of Health, the Diabetic Retinopathy Clinical Research (DRCR) Retina Network has organized and realized different important clinical trials which

delineated guidelines for patients with DMO. In detail, in a study on 854 eyes with DMO, they provided evidence that intravitreal ranibizumab is superior in gaining visual acuity, with 30%

of eyes increasing by three lines of visual acuity and 50% increasing by two lines at 1 year [4]. Successively, the DRCR Retina Network compared the three available anti-VEGF drugs in 660

DMO eyes with moderate to severe visual impairment [12, 13]. The latter clinical trial demonstrated that all the three agents cause VA improvement from baseline to 1 and 2 years with a

decreased number of injections in the second year [12, 13]. However, aflibercept was displayed to be more efficacious at improving vision at 1 year in eyes with severe visual impairment

(20/50 to 20/320 Snellen equivalent) [12, 14]. Among these eyes with worse baseline visual acuity, aflibercept had superior visual outcomes at 2 years compared with bevacizumab, while

superiority of aflibercept over ranibizumab, noted at 1 year, was no longer displayed [13, 14]. Limited data was however available on the most appropriate therapeutic approach for eyes with

DMO and good visual acuity. This aspect is crucial, assuming that these patients represent a main portion of DR population [15]. Recently, the DRCR Retina Network investigators reported

significant results from Protocol V which specifically sought to address this critical debate [16]. This study included patients with centre-involved DMO and good visual acuity (20/25 or

better) who were divided into three arms: prompt laser photocoagulation, prompt aflibercept therapy, or observation. Furthermore, this trial allowed eyes randomized to observation or laser

to receive aflibercept rescue if visual acuity decreased from baseline by ≥10 letters at one visit or by 5–9 letters at two following visits [16]. This study concluded that the proportion of

eyes experiencing a reduction in visual acuity by five letters at 2 years was similar independently on the assigned group [16]. Moreover, data from this trial also demonstrated that prompt

treatment with aflibercept does not cause a significant reduction in the risk of a five letter or more loss, as this outcome was reached in 19%, 17%, and 16% in the observation, laser and

aflibercept groups, respectively [16]. Importantly, ~10% of patients within the observation group experienced a two-step improvement in visual acuity, which was similar to that exhibited in

the other two groups [16]. Taking all these results together, the investigators concluded that postponing treatment in centre-involved DMO and good visual acuity does not effect in a worse

prognosis, as compared with prompt laser or intravitreal treatment. Assuming that the cost of the drugs would be avoided, these results may have a huge impact on cost and burden of care

delivery for patients and the health care system. Nonetheless, a reduction of the psychological burden for patients and their families would also be obtained. Importantly, we might avoid

treatment-related unnecessary risks to patients, including the injection procedure itself. All these aspects emphasize the importance of these results and clinicians must recognize their

relevance and accordingly employ a conservative management in patients with DMO and good visual acuity, at least until there is recorded reduction in visual acuity. To completely comprehend

these evidences from Protocol V, it is worth noting that included patients in this trial were characterized by a good metabolic and blood pressure control, as well as they routinely attended

their follow-up visits. Although it might be said that these subjects do not necessarily reflect the profile of diabetic patients in real-world practice, the OBTAIN study recently reported

on real-world data and similarly showed that visual acuity is maintained over a 1 year of follow-up in DMO patients with good visual acuity [17]. However, future studies are needed to reveal

whether this conservative management might impact clinic attendance and long-term follow-up care among these patients. Finally, future developments of more lasting and less invasive

therapies might encourage to consider starting treatment earlier. Moreover, further development of novel-emerging therapies for DMO [18], including subthreshold laser treatment whose

beneficial effect has already been demonstrated [19], may also modify the treatment threshold for these patients. Also, new discovered imaging biomarkers might allow the identification of a

sub-group of patients with DMO and good visual acuity who may actually benefit from an early treatment. REFERENCES * Querques G. Eye complications of diabetes. Acta Diabetol.

2019;56:971–971. http://www.ncbi.nlm.nih.gov/pubmed/31201573. Accessed 12 Aug 2019. Article  Google Scholar  * American Diabetes Association AD. Standards of medical care in diabetes–2010.

Diabetes Care. 2010;33:S11–61. http://www.ncbi.nlm.nih.gov/pubmed/20042772. Accessed 2 Jun 2019. Article  Google Scholar  * Photocoagulation for diabetic macular edema: early treatment

diabetic retinopathy study report number 1 early treatment diabetic retinopathy study research group. Arch Ophthalmol. 1985;103:1796–806. * Elman MJ, Aiello LP, Beck RW, Bressler NM,

Bressler SB, Edwards AR, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema - the diabetic retinopathy

clinical research network. Ophthalmology. 2011;118:609–14. Article  Google Scholar  * Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, et al. A prospective

randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT Study). 12-month data: report 2. Ophthalmology. 2010;117:1078–e2. Article 

Google Scholar  * Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL, Friedman SM, et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt

laser for diabetic macular edema. Ophthalmology. 2011;118:609–14. Article  Google Scholar  * Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The RESTORE

study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615–25. Article  Google Scholar  * Nguyen QD, Brown DM,

Marcus DM, Boyer DS, Patel S, Feiner L, et al. Ranibizumab for diabetic macular edema: Results from 2 phase iii randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789–801. Article 

Google Scholar  * Ip MS, Zhang J, Ehrlich JS. The clinical importance of changes in diabetic retinopathy severity score. Ophthalmology. 2017;124:596–603. Article  Google Scholar  * Bonnin S,

Dupas B, Lavia C, Erginay A, Dhundass M, Couturier A, et al. Anti–vascular endothelial growth factor therapy can improve diabetic retinopathy score without change in retinal perfusion.

Retina. 2019;39:426–34. Article  CAS  Google Scholar  * Cavalleri M, Cicinelli MV, Parravano M, Varano M, De Geronimo D, Sacconi R, et al. Prognostic role of optical coherence tomography

after switch to dexamethasone in diabetic macular edema. Acta Diabetol. 2019: 1–9. http://link.springer.com/10.1007/s00592-019-01389-4. Accessed 12 Aug 2019. * Diabetic Retinopathy Clinical

Research Network, Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193–203.

http://www.ncbi.nlm.nih.gov/pubmed/25692915. Accessed 11 Aug 2019. Article  Google Scholar  * Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, et al. Aflibercept,

bevacizumab, or ranibizumab for diabetic macular edema. Ophthalmology. 2016;123:1351–9. https://linkinghub.elsevier.com/retrieve/pii/S0161642016002062. Accessed 11 Aug 2019. Article  Google

Scholar  * Ashraf M, Souka A, Adelman R, Forster SH. Aflibercept in diabetic macular edema: evaluating efficacy as a primary and secondary therapeutic option. Eye. 2016;30:1531–41. Article 

CAS  Google Scholar  * Bressler NM, Varma R, Doan QV, Gleeson M, Danese M, Bower JK, et al. Underuse of the health care system by persons with diabetes mellitus and diabetic macular edema in

the United States. JAMA Ophthalmol. 2014;132:168–73. Article  Google Scholar  * Baker CW, Glassman AR, Beaulieu WT, Antoszyk AN, Browning DJ, Chalam KV, et al. Effect of initial management

with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized

clinical trial. JAMA. 2019;321:1880–94. Article  CAS  Google Scholar  * Busch C, Fraser-Bell S, Zur D, Rodríguez-Valdés PJ, Cebeci Z, Lupidi M, et al. Real-world outcomes of observation and

treatment in diabetic macular edema with very good visual acuity: the OBTAIN study. Acta Diabetol. 2019;56:777–84. Article  Google Scholar  * Sacconi R, Giuffrè C, Corbelli E, Borrelli E,

Querques G, Bandello F. Emerging therapies in the management of macular edema: a review. F1000Research 2019;8:1413 https://f1000research.com/articles/8-1413/v1. Accessed 12 Aug 2019. Article

  Google Scholar  * Mansouri A, Sampat KM, Malik KJ, Steiner JN, Glaser BM. Efficacy of subthreshold micropulse laser in the treatment of diabetic macular edema is influenced by

pre-treatment central foveal thickness. Eye. 2014;28:1418–24. Article  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Ophthalmology,

University Vita-Salute, IRCCS Ospedale San Raffaele, Milan, Italy Giuseppe Querques, Enrico Borrelli, Riccardo Sacconi & Francesco Bandello Authors * Giuseppe Querques View author

publications You can also search for this author inPubMed Google Scholar * Enrico Borrelli View author publications You can also search for this author inPubMed Google Scholar * Riccardo

Sacconi View author publications You can also search for this author inPubMed Google Scholar * Francesco Bandello View author publications You can also search for this author inPubMed Google

Scholar CORRESPONDING AUTHOR Correspondence to Giuseppe Querques. ETHICS DECLARATIONS CONFLICT OF INTEREST FB is a consultant for: Alcon (Fort Worth,Texas,USA), Alimera Sciences

(Alpharetta, Georgia, USA), Allergan Inc (Irvine, California,USA), Bayer Shering-Pharma (Berlin, Germany), Bausch and Lomb (Rochester, New York, USA), Genentech (San Francisco, California,

USA), Hoffmann-La-Roche (Basel, Switzerland), NovagaliPharma (Évry, France), Novartis (Basel, Switzerland), Sanofi-Aventis (Paris, France), Thea (Clermont-Ferrand, France), Thrombogenics

(Heverlee,Belgium), and Zeiss (Dublin, USA). GQ is a consultant for: Alimera Sciences (Alpharetta, Georgia, USA), Allergan Inc (Irvine, California, USA), Amgen (Thousand Oaks,USA), Bayer

Shering-Pharma (Berlin, Germany), Bausch and Lomb (Rochester, New York, USA), Heidelberg (Germany), KBH (Chengdu; China), Hoffmann-La-Roche (Basel, Switzerland), LEH Pharma (London, UK),

Lumithera (Poulsbo; USA), Novartis (Basel, Switzerland), Topcon (Tokyo, Japan), Sandoz (Berlin, Germany), Sifi (Catania, Italy), Sooft-Fidea (Abano, Italy), Thea (Clermont-Ferrand, France),

and Zeiss (Dublin, USA). The remaining authors declare that they have no conflict of intetrest. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to

jurisdictional claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Querques, G., Borrelli, E.,

Sacconi, R. _et al._ Management of patients with diabetic macular oedema and good visual acuity: new findings from Protocol V. _Eye_ 34, 792–794 (2020).

https://doi.org/10.1038/s41433-019-0658-x Download citation * Received: 28 August 2019 * Accepted: 28 August 2019 * Published: 29 October 2019 * Issue Date: May 2020 * DOI:

https://doi.org/10.1038/s41433-019-0658-x SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not

currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative