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Carl Zeiss Case Studies

High-Frequency Deep Sclerotomy A MIGS Procedure for Mild-to-Moderate Glaucoma

iCare COMPASS Automated Perimeter

Clinical

1rem

Authors

A look at how EDOF technology can be categorised into five types

Extended depth-of-focus IOLs: A review 

Over the last 15 years, biosimilars have become a major feature of the health care landscape. Physicians in many disciplines, particularly oncology and immunology, have embraced biosimilars. However, access to educational resources on these powerful biologics can be inconsistent, and in turn, some ophthalmologists who could benefit from the adoption of biosimilars are left in the dark.

The real-world application of biosimilars was the focus of discussion for Martin Zinkernagel, MD, PhD, chair of the Department of Ophthalmology at the University Hospital of Bern, Switzerland, and Paolo Lanzetta, MD, professor of ophthalmology and chairman of the Department of Medicine-Ophthalmology at the University of Udine in Italy. In their discussion, the experts addressed several common questions, framed around the phase 3 clinical trial for biosimilar SB11 (BYOOVIZ) from Biogen. SB11 is approved in Europe and the United Kingdom. Like the reference product ranibizumab (Lucentis), SB11 is approved for the treatment of retinal disease including neovascular age-related macular degeneration (nAMD).

Addressing physicians’ levels of familiarity with biosimilars, Dr Lanzetta attributed much of the variation to regulatory discrepancies. “The uptake of biosimilars varies throughout Europe by country and by product,” he said. “Obviously, variation in the uptake of biosimilars [is] influenced by government involvement, reimbursement issues and tender procurement policies.” Recent survey data have revealed gaps in awareness across Europe and in the United States on the efficacy and safety of biosimilars for retinal diseases, Dr Lanzetta said, especially in terms of “real-world data.”

In a clinical application, Dr Lanzetta said, biosimilars may exhibit minor differences from the reference products, but they aren’t considered to have significant impact on the efficacy or safety profile. Typically, the biosimilar and reference medicine must have the same posology and route of administration, with few exceptions, he added.

Dr Lanzetta also said that in the last 10 years, the European Medicines Agency (EMA) has approved the highest number of biosimilars worldwide.

 “And this means, to us physicians, having both the possibility to have experience on their use in terms of safety and evaluating the efficacy after that,” he explained.

One common misconception about biosimilars is that these therapeutics are interchangeable with the idea of generic medicines. But there is a key indicator that biosimilars are unique: the cost. “While generic medicines are marketed at a significantly lower price than name brand ones, why do we not see the same level of cost savings with biosimilars?” Dr Zinkernagel asked.

Dr Lanzetta explained that biosimilars are developed via a rigorous, complex and highly regulated manufacturing process. “Generics are simple chemical medicines or agents, which is not the case for biosimilars and biologics,” he said. “Unlike generics, biologics, and therefore biosimilars as well, are very complex; they’re very difficult to copy. And the development processes are patented and proprietary to the originators.” The proprietary nature of biologic development, he added, is why biosimilars may have differences from their originators.

Prof Zinkernagel and Dr Lanzetta used data from the SB11 phase 3 trial to expand upon the capabilities of biosimilars. Prof Zinkernagel detailed the study: over 700 patients were included in the randomised, double-masked, parallel-group multicentre trial. Over 52 weeks, investigators evaluated the efficacy and the safety profile of this biosimilar SB11 in comparison with monthly ranibizumab for the treatment of nAMD.

“Patients with neovascular AMD were included, [with a] visual acuity range between 20/40 and 20/200,” Prof Zinkernagel said. “[Patients] were randomised in a 1:1 ratio to either have the originator or the biosimilar every 4 weeks from baseline up to week 48.”

Primary end-points were change from baseline in best corrected visual acuity at week 8 and change from baseline in central subfield thickness at week 4. The pre-specified secondary efficacy end-points included longer-term assessments of change from baseline in visual acuity, and the proportion of participants who lost fewer than 15 letters or who gained 15 or more letters in visual acuity from baseline at weeks 24 and 52.

“Other secondary end-points included, of course, change from baseline in central subfield thickness and central retinal lesion thickness at week 24, as well as change from baseline in choroidal neovascularisation [CNV] size and proportion of participants with active CNV leakage seen via OCT [optical coherence tomography] at week 24,” Prof Zinkernagel continued. Describing the results, he said, “When you look at the visual acuity improvements, it’s really equivalent. You have equivalence between the originator and the biosimilar, and the same holds true for a decrease in central retinal thickness. So the curves are basically the same, and also the secondary end-points.”

Prof Zinkernagel also spoke about the immunogenicity outcomes of the SB11 trial, as immunogenicity reactions have been a common problem in past assessments of anti–vascular endothelial growth factor (VEGF) agents. Along with detrimental effects to visual acuity, immunogenicity reactions can also lead to vasculitis and vitritis.

“Now, in this trial, the overall cumulative incidence of anti-drug antibodies, antibodies reacting against this specific drug up to week 52, was very low,” Prof Zinkernagel said. “For the SB11 biosimilar, it was 4.2%, and for the originator it was 5.5%. So very, very similar.”

He also noted that most antibodies were non-neutralising, which generally indicates a weak antibody response. “Furthermore, no statistical or clinically relevant differences in the incidence of anti-drug antibodies and neutralising antibodies were observed between treatment groups at any of the time points,” Prof Zinkernagel explained.

Dr Lanzetta highlighted the unique potentialities for anti-VEGF therapies as an area where physicians can consider treating patients with a biosimilar. “You can either switch a patient from the originator, obviously, or you can also consider treating with a biosimilar treatment-naive patients who may benefit…from being treated with that reference agent or originator agent,” he said. When to deploy a biosimilar will depend on many factors, including the locality where a patient is being treated. “Europe has different countries, different health care systems,” Dr Lanzetta said. “You may consider treating with the biosimilar patients who may not be strictly adherent to the cost of therapy and the frequency of treatment because of some cost issues.”

Just as education on biosimilars is vital to practitioners, awareness and education resources for patients are vital, too. “We spend a lot of time with our patients in letting them know that biologics did undergo a very rigorous approval process through studies, efficacy and safety studies,” Dr Lanzetta emphasised. This education is vital to getting patients on board with biosimilars, and it sparks enthusiasm about the potential benefits. “Once they do understand that, I think they will be very prone to receive a biosimilar; [it’s] in their interest and in the interest of the community, the whole community of patients, and in the interest of the health care system,” Dr Lanzetta said.

1. Biosimilars in the EU: information guide for healthcare professionals. European Medicines Agency. Updated December 2, 2019. Accessed October 3, 2023. 

https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pd

Editor’s note: A prior version of this article contained a misspelling of the product name BYOOVIZ. It has been corrected. We regret the error.

How biosimilars expand treatment options for patients with retinal disease

Dr Rick Lewis discusses the FLigHT procedure and ViaLase laser at the 2024 European Society of Cataract and Refractive Surgeons (ESCRS) meeting

This year, the European Society of Cataract and Refractive Surgeons holds its congress in Barcelona, Spain. We spoke with Rick Lewis, MD, about the femtosecond laser image-guided high precision trabeculotomy (FLigHT) procedure from ViaLase, the company’s recent CE mark and 36-month results he presented at the meeting.

Editor’s note: The below transcript has been lightly edited for clarity.

 This year, the meeting of the European Society of Cataract and Refractive Surgeons is in Barcelona. Joining me today, I have Dr Rick Lewis, who is the Chief Medical Officer at ViaLase, who's going to talk about what he's bringing to the meeting. Dr Lewis, thank you so much for being here.

 Thank you for the kind introduction. You know, it's a pleasure to be here and share what I think is very exciting data from our initial phase one safety study at ViaLase. We evaluated channel patency, intraocular pressure and safety over a 36-month period in our initial cohort of open angle glaucoma patients, looking at the FLigHT treatment; FLigHT stands for [femtosecond laser] image-guided high precision trabeculotomy. This was a prospective, single-centre study. It wasn't randomised. It was 18 eyes with 12 patients and started back in 2020. We had our prototype machine and were able to create, without any safety issues, a channel in the trabecular meshwork of 200 by 500 microns, and this is a non-incisional trabeculotomy. What separates the approach with ViaLase is that the patient interface, like what you get with IntraLase or LenSx, is applied to the patient's eye after applying topical anesthetic. The procedure takes minutes. There's no incision, there's no restrictions post-op, there's no hyphema, and the patient has a trabeculotomy.

We were able, in the study, to follow them over the course of 3 years. Our data is impressive. We got pressure reductions of almost 7 millimeters. A few patients did need to require medications, but the vast majority did not, and our safety, both initially and at 3 years, was remarkably good. So we're very excited about this.

We're actually in the middle of other studies now, some of our pivotal studies, and we're happy to report that we have applied for and received EU approval, European Union approval, to launch this product in Europe, [either at the] end of this year, or more likely, the first quarter of next year. This will be, again, the FLigHT treatment with ViaLase. So it's an exciting time. We have a number of presentations at this year's ESCRS meeting, including the iNovation session.

This particular abstract will be presented in the scientific programme. We have a series of other meetings, and are very excited to launch this new approach to treating glaucoma.

: I was lucky enough to report on that CE Mark that the ViaLase laser received in the EU just just a few weeks ago. What do you think that that approval, and this procedure, says about the changing landscape of both glaucoma care and refractive care?

 I've been in glaucoma for close to 40 years, and it's always been frustrating. You know, historically, we have treated glaucoma with topical eye drops, which we all know patients are non-compliant and create a significant ocular surface problem for those patients, not only in glaucoma, but for refractive and cataract surgery. The ability to create a trabeculotomy without a corneal incision will add a unique and special opportunity in treating these patients, both early and late in the disease. And I think that represents, truly, like you say, a paradigm shift in the management of this disease. I'm excited by it. And when you look at the technology, most everyone gets excited by it. This is very unique, and it isn't even the creation of the trabeculotomy. It's our imaging system, both gonioscopic imaging and OCT imaging, that allows very precise placement. With a commercialised device, we will be able to place one, two, three or even four channels. And there is very little risk involved in this, and it avoids all the problems that happen with intraocular trabeculotomy. So a very exciting opportunity. And again, between this and some of the other laser treatments, I think the paradigm of using medications early will probably be changed.

: The other major aspect of the FLigHT procedure that makes it so unique is that it's something that extends treatment to patients regardless of their lens status. What do you think is so important about accessibility, especially for patients in Europe?

: Well, you know, the issue with lens status has to do, of course, with all the approved MIGS treatments. In any area, whether it's Europe or North America, the approval process demanded that a cataract surgery be done in conjunction with most of the device-related MIGS procedures. Well, not everybody, of course, has cataracts, or perhaps has had cataract surgery in the past, and cannot be a combined procedure. The opportunity here to do it in phakic eyes and pseudophakic eyes, in primary glaucoma and secondary glaucoma, in a variety of age groups, whether it's...an ideal treatment in the future for early juvenile-onset glaucoma, and certainly even in the elderly. Because the risk factor is significantly reduced. Now, we don't have data yet on some of these secondary glaucomas, but the opportunity is obvious and will certainly be pursued.

: I know that you and I have discussed how we're both turning our European conference travel into vacations this year, because we're smart! But the ESCRS is 

 a big congress. Tell me a little bit about what you're looking forward to discussing or debating with your colleagues there.

: You know, ophthalmology is such an exciting field, and there's so many things going on at all these different levels. You know, whether it's cornea, refractive or cataract, the new lenses, the laser-adjusted lenses, the ability to treat glaucoma with non-pharmaceutical ways, you know, the cornea treatment, there's exciting areas of replacing cornea. You learn so much at these meetings, and just getting to see your colleagues and hear the latest presentations, I feel very fortunate that I'm in ophthalmology. I can't think of a more exciting field than this.

: Well, I feel very fortunate that you've joined me this morning to discuss the meeting, and I'm sure that our viewers will feel the same. Thank you so much for your time and safe travels!

Rick Lewis, MD, speaks about a non-pharmaceutical approach to treating glaucoma with laser technology

ESCRS 2024: 36-month results following femtosecond laser image-guided high precision trabeculotomy (FLigHT)

Retina surgeons have no shortage of cases—the packed schedules and last-minute add-ons we see on our calendars testify to this fact. Because we are so busy ensuring that our cases are performed safely and effectively, we sometimes overlook how the surgical suite changes around us. Let us use this time to pause and consider how evolutions in digital technology are changing our operating rooms (ORs) and to look ahead at how forthcoming innovations could affect the way we operate.

Heads-up 3D displays in the surgical suite represent a significant advancement in surgical technology over the past decade. Many modern ORs have adopted these advanced visualisation platforms to enhance surgical precision and comfort.

I have used heads-up 3D displays in the OR for 8 years and realised several of the benefits outlined by my colleagues in the literature and on the podium. The ergonomic benefits of sitting upright quickly become apparent. The ability to easily apply filters and enhance contrast, allowing improved visualisation of tissue planes and through media opacities (e.g., haemorrhages that block a full posterior view), means a more precise surgical technique. Surgeons in teaching settings may find they can better instruct residents and fellows as they share an identical view.

For similar reasons, surgical assistants may be better able to anticipate surgical steps and increase procedural efficiency. These benefits quickly become self-evident when a surgeon adopts heads-up 3D displays.

We have even seen incremental innovations to heads-up technology since its introduction. This suggests that the innovators are only beginning to improve our ORs. Ergonomic improvements have taken hold: for example, an articulating C-arm allows users to look directly in front of them, eliminating the need to turn their heads to look past the scope’s column.

Also, surgeons now have the option to use digital binoculars on some platforms in addition to (or instead of) a heads-up display screen, allowing greater optionality for visualisation based on surgeon preference. Adjustments such as these flatten the learning curve for trainees and attendings, easing the pathway to adoption.

The benefits of a heads-up 3D display are not merely anecdotal and matters of convenience. Data from studies have shown that heads-up 3D visualisation is associated with improved outcomes compared with standard-of-care approaches in some cases. Reddy et al compared macular hole surgery outcomes in cases performed by trainee surgeons who did or did not use heads-up 3D visualisation and found that the macular hole closure rate was significantly higher in the group that used heads-up 3D displays (86% vs 60%; 

 Similarly, Kim et al reported that using heads-up 3D displays in cases of epiretinal membrane (ERM) surgery was associated with decreased rates of ERM recurrence and dissociated optic nerve fibre layer presence compared with conventional visualisation.

Many of us in retina share this enthusiasm for the potential of heads-up 3D displays to reshape ophthalmology. Razavi et al recently published an editorial that explored the promise of this technology to expand access to care.

 They pointed to how heads-up displays could allow teleophthalmology to leverage remote assistance from specialists and could be used in a virtual reality landscape to expand access to training and education not limited by geographic constraints.

Intraoperative optical coherence tomography

The ability to quickly characterise pathologic conditions in the OR can make a difference in surgical decision-making and postoperative follow-up requirements.

Take, for instance, a case in which you peel a thick membrane only to uncover a macular hole with morphology that appears different after the peel. Is it a lamellar macular hole? Is it a full-thickness macular hole? With intraoperative optical coherence tomography (OCT), surgeons receive immediate imaging data that would otherwise be unavailable and can adjust their surgical approach in real time.

The effects of intraoperative OCT on surgery have been described extensively in the literature, particularly in the DISCOVER study (NCT02423213) led by Ehlers. Huang et al reviewed 41 patients from DISCOVER who underwent vitrectomy for conditions related to vitreomacular traction (VMT). The use of intraoperative OCT affected surgical decision-making in approximately 19% of patients.

Yee et al reported on 84 eyes in DISCOVER that underwent macular hole repair.

In 51% of cases, surgeons reported that intraoperative OCT provided useful information, such as confirmation of VMT release and the identification of occult residual membranes. In 12% of cases, intraoperative OCT specifically altered surgical decision-making.

Surgeons wishing to reduce the need for staining ERMs might consider embracing intraoperative OCT in their digital OR. Lorusso et al compared 2 cohorts that underwent ERM peeling, with the first group undergoing conventional peeling and the second undergoing peeling assisted by intraoperative OCT.

 They found that intraoperative OCT reduced the application of Brilliant Blue G, with 75% of cases in the conventional group requiring staining and 8% of the patients in the intraoperative OCT group requiring staining. Given these findings, surgeons seeking tools that can help them better perceive the surgical field and subsequently make more informed decisions may consider adding intraoperative OCT to their digital OR.

Robotics, software, artificial intelligence and the future of technology

We have heard plenty about software, robotics, and artificial intelligence (AI) in the consumer space. In the simplest sense, we envision manufacturers embracing robotics to complete rote tasks with greater precision, better safety, and reduced costs. The software we interact with has woven itself into the fabric of our lives to the point that we no longer consciously recognise its presence. And for all the speculation about how AI will affect our lives, we have reaped the benefits of AI-based systems for years, empowering educators, professionals, and domain experts to maximise their contributions.

But what impact, if any, might these innovations have on a modern OR? Given the careful and deliberate pace at which retina surgeons adopt new hardware, one might assume that innovations in these fields will make their way into the surgical suite in a decade or so, and even then, only in small steps. If retina surgeons do not adopt a new vitrectomy platform, how could they benefit from AI improvements—whatever they are—integrated into the latest hardware models?

However, upgrades to software can occur irrespective of whether new hardware is purchased. Incremental updates to surgical platforms will likely start introducing AI frameworks that already exist (eg, predictive models for macular hole closure) while returning high-quality data so that the algorithms driving such models can refine their precision. One can imagine a scenario in the
not-too-distant future where surgical preparation includes guidance from an AI model nourished by data from thousands of retina specialists.

We should expect innovation on the instrumentation front, too. For instance, forceps that correct for surgeon motion errors or hand tremors could leverage robotics engineering. Is there a possibility of robots executing fully automated vitrectomies in our lifetime? Perhaps, but my bet is that fully automated surgeries will go more the way of the flying car (a nice-to-have reserved for the realm of science fiction) than the way of the smartphone (a piece of technology foretold by science fiction and that proliferated in large part because of its affordability and breadth of capabilities).

Retina specialists have a history of embracing surgical innovations, and even those of us who are firmly late adopters have been converted after seeing that patient outcomes have improved following the embrace of new technologies. Although it remains to be seen exactly how future standards of care will adopt innovations rooted in robotics, software and AI, we can safely say that a new, evolving standard of care that includes enhanced visualisation from a heads-up 3D display and intraoperative OCT imaging has raised the floor for the next generation of retina specialists.

Today, we look back on retinal surgeries of the 1970s with a mix of awe and disbelief. We cannot envision working that way. Perhaps in the 2070s, newly minted retina fellows will look at our current surgical standards the same way.

1. Reddy S, Mallikarjun K, Mohamed A, et al. Comparing clinical outcomes of macular hole surgeries performed by trainee surgeons using a 3D heads-up display viewing system versus a standard operating microscope. 

. 2021;41(8):2649-2655. doi:10.1007/s10792-021-01792-3

2. Kim DJ, Kim DG, Park KH. Three-dimensional heads-up vitrectomy versus conventional microscopic vitrectomy for patients with epiretinal membrane. 

. 2023;43(6):1010-1018. doi:10.1097/IAE.0000000000003762

3. Razavi P, Cakir B, Baldwin G, D’Amico DJ, Miller JB. Heads-up three-
dimensional viewing systems in vitreoretinal surgery: an updated perspective. 

 2023;17:2539-2552. doi:10.2147/OPTH.S424229

4. Huang HJ, Sevgi DD, Srivastava SK, Reese J, Ehlers JP. Vitreomacular traction surgery from the DISCOVER study: intraoperative OCT utility, ellipsoid zone dynamics, and outcomes. 

. 2021;52(10):544-550.
doi:10.3928/23258160-20210913-01

5. Yee P, Sevgi DD, Abraham J, et al. iOCT-assisted macular hole surgery: outcomes and utility from the DISCOVER study. 

. 2021;105(3):403-409. doi:10.1136/
bjophthalmol-2020-316045

6. Lorusso M, Micelli Ferrari L, Gisotti EN, et al. Success of iOCT in surgical management of ERM peeling. 

. 2022;32(5):3116-3120.
doi:10.1177/11206721221085383

Barakat is the founder and director of the Retina Macula Institute of Arizona in Scottsdale. He reports the following relevant disclosures: He is a consultant/speaker for Alcon and Bausch + Lomb.

The future of the tech-forward surgical suite

The digital OR: Retina care of tomorrow

Monogenic obesity is a rare and severe disease most often resulting from 

) mutations that disrupt the neuronal pathways in the hypothalamus and prefrontal cortex. Following 6 months of treatment with semaglutide, a glucagon like peptide-1 (GLP-1) receptor agonist, the investigators observed that two siblings with monogenic obesity, had evidence of corneal nerve regeneration.

First author Hoda Gad, BSc, MSc, PhD from the Research Department, Weill Cornell Medicine-Qatar, Doha, Qatar, reported their findings in 

According to the researchers, patients with monogenic obesity present with impaired satiety and hyperphagia in early childhood with severe early-onset obesity due to dysregulation of the central leptin-melanocortin neuronal pathways.

They explained that changes in lifestyle in patients with 

 and even bariatric surgery provided limited long-term benefit.

However, use of GLP-1 receptor agonists can achieve beneficial changes in weight, blood pressure and lipids with a decrease in reactive oxygen species (ROS) and inflammation, which could impact neurons,

Specifically, they reported that GLP-1R-mediated extracellular signal-regulated kinase signalling in diabetic rodents protected large motor fibre function and small fibre structure by a mechanism independent of glycaemic control.

 They also previously reported corneal nerve regeneration after bariatric surgery12 and with the once-weekly GLP-1 agonist exenatide,

 and in 14 patients with type 2 diabetes semaglutide or dulaglutide improved nerve area and sural nerve amplitude.

In this case report, Gad and colleagues performed corneal confocal microscopy to assess for evidence of nerve regeneration after treatment with semaglutide in siblings with an 

 gene mutation, a 10-year-old boy (weight, 100.3 kg; body mass index [BMI], 39.7 kg/m2) and his 8-year-old sister (weight, 58.6 kg; BMI, 32.2 kg/m2) (

Their respective baseline haemoglobin A1c (HbA1c) values were 5.8% and 5.6%, the total cholesterol 4.4 and 3.4 mmol/L, low-density lipoprotein 2.3 and 2.0 mmol/L, high-density lipoprotein 2.1 and 1.0 mmol/L, and triglycerides 1.0 and 1.4 mmol/L. Both children exhibited intense hyperphagia, impaired satiety and severe, early-onset obesity.

The siblings had a heterozygous missense variant c.508A>G, p.Ille170Val in the 

gene, a rare variant with minor allele frequency in gnomAD of 0.00009. They both were treated with semaglutide 0.5 mg weekly for 1 month and then 1.0 mg weekly for 5 months.

Corneal confocal microscopy showed corneal small nerve fibre degeneration in the two siblings before treatment.

The authors reported, “We also showed that 6 months of treatment with semaglutide was associated with small nerve fibre regeneration, but with no major effect on weight, HbA1c, and lipids, which argues for alternate mechanisms beyond an improvement in weight and glycemia as a basis for nerve regeneration in these two children with 

The investigators observed nerve regeneration (

) evidenced by increases in corneal nerve fibre density of 13.9% in the brother and 14.7% in the sister; corneal nerve branch density, 110.2% and 58.7%, respectively, and corneal nerve fibre length, 21.5% and 44.0%, respectively.

Hypothesis for nerve regeneration without other changes

The investigators explained that obesity is a risk factor for small fibre neuropathy,

and they had reported previously that nerve regeneration occurred with an improvement in weight and metabolic parameters after bariatric surgery.

 GLP-1 receptor agonists also reduce weight and improve many neuropathy risk factors including hyperglycaemia, blood pressure and hyperlipidemia.

 Previous case reports on use of the daily GLP-1 agonist liraglutide have shown reduced weight and improved glycaemia.

 However, their recent cohort study showed no major impact of liraglutide on weight or HbA1c in obese children.

It is noteworthy, Gad and colleagues explained, that GLP-1 therapies activate sirtuin

 which may be associated with the nerve regeneration seen in the patients under discussion, independent of weight and glycaemia changes. In addition, GLP-1 receptors are expressed in the dorsal root ganglion and peripheral nerves,

 and in an animal model of type 1 diabetes mellitus, GLP-1 treatment led to intraepidermal nerve fibre regeneration without weight or glucose changes.

Further, adults with type 2 diabetes mellitus treated with once-weekly exenatide and pioglitazone had small nerve fibre regeneration, despite an increase in weight.

They concluded, “We believe that our study provides novel insights into the complications associated with 

 gene mutation as evidenced by subclinical neurodegeneration. Furthermore, we show nerve regeneration after treatment with semaglutide, without an improvement in weight or glycemia, indicating an independent effect of GLP-1 therapy, which merits further study.”

1. Gad H, Mohammed I, Dauleh H, et al. Case report: Nerve fiber regeneration in children with melanocortin 4 receptor gene mutation related obesity treated with semaglutide. 

 2024;15:1385463; doi:10.3389/fendo.2024.1385463

2. Mohammed I, Haris B, Al-Barazenji T, et al. Understanding the genetics of early-onset obesity in a cohort of children from Qatar. 

. 2023;108:3201–13;
doi: 10.1210/clinem/dgad366

3. Huvenne H, Dubern B, Clement K, Poitou C. Rare genetic forms of obesity: clinical approach and current treatments in 2016. 

4. Reinehr T, Hebebrand J, Friedel S, et al. Lifestyle intervention in obese children with variations in the melanocortin 4 receptor gene. 

 2009;17:382–9.
doi: 10.1038/oby.2008.422

5. Hainerova I, Larsen LH, Holst B, et al. Melanocortin 4 receptor mutations in obese Czech children: studies of prevalence, phenotype development, weight reduction response, and functional analysis. 

 2007;92:3689–96; doi: 10.1210/jc.2007-0352

6. Trier C, Hollensted M, Schnurr TM, et al. Obesity treatment effect in Danish children and adolescents carrying Melanocortin-4 Receptor mutations. 

 2021;45:66–76; doi: 10.1038/s41366-020- 00673-6

7. Vos N, Oussaada SM, Cooiman MI, et al. Bariatric surgery for monogenic non-syndromic and syndromic obesity disorders. 

2020;20:44; doi: 10.1007/s11892-020-01327-7

8. Poitou C, PuderL, Dubern B, et al. Long-term outcomes of bariatric surgery in patients with bi-allelic mutations in the POMC, LEPR, and MC4R genes. 

 2021;17:1449–56; doi: 10.1016/ j.soard.2021.04.020

9. Cooiman MI, Alsters SIM, Duquesnoy M, et al. Long-term weight outcome after bariatric surgery in patients with melanocortin-4 receptor gene variants: a case-control study of 105 patients. 

 2022;32:837–44; doi: 10.1007/s11695-021-05869-x

10. Goldney J, Sargeant JA, Davies MJ. Incretins and microvascular complications of diabetes: neuropathy, nephropathy, retinopathy and microangiopathy. 

 (2023) 66:1832–45; doi: 10.1007/s00125-023-05988-3

11. Jolivalt CG, Fineman M, Deacon CF, Carr RD, Calcutt NA. GLP-1 signals via ERK in peripheral nerve and prevents nerve dysfunction in diabetic mice. 

 2011;13:990–1000; doi: 10.1111/j.1463-1326.2011.01431.x

12. Adam S, Azmi S, Ho JH, et al. Improvements in diabetic neuropathy and nephropathy after bariatric surgery: a prospective cohort study. 

 2021;31:554–63. doi: 10.1007/s11695-020-05052-8

13. Ponirakis G, Abdul-Ghani MA, Jayyousi A, et al. Effect of treatment with exenatide and pioglitazone or basal-bolus insulin on diabetic neuropathy: a substudy of the Qatar Study. 

 2020;8:e001420. doi: 10.1136/bmjdrc-2020-001420

14. Dhanapalaratnam R, Issar T, Lee ATK, et al. Glucagon-like peptide-1 receptor agonists reverse nerve morphological abnormalities in diabetic peripheral neuropathy. 

 2024;67:561–6; doi: 10.1007/s00125-023-06072-6

15. Herman RM, Brower JB, Stoddard DG, et al. Prevalence of somatic small fiber neuropathy in obesity. 

 2007;31:226–35; doi: 10.1038/sj.ijo.0803418

16. Johnson SA, Shouman K, Shelly S, et al. Small fiber neuropathy incidence, prevalence, longitudinal impairments, and disability. 

 2021;97:e2236–e47; doi: 10.1212/WNL.0000000000012894

17. Azmi S, Ferdousi M, Liu Y, et al. Bariatric surgery leads to an improvement in small nerve fiber damage in subjects with obesity. 

2021;45:631–8; doi: 10.1038/s41366-020-00727-9

18. Iqbal Z, Kalteniece A, Ferdousi M, et al. Corneal keratocyte density and corneal nerves are reduced in patients with severe obesity and improve after bariatric surgery. 

19. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. 

 2021;384:989–1002; doi: 10.1056/NEJMoa2032183

20. Iepsen EW, Zhang J, Thomsen HS, et al. Patients with obesity caused by melanocortin-4 receptor mutations can be treated with a glucagon-like peptide-1 receptor agonist. 

2018;28:23–32.e3; doi: 10.1016/j.cmet.2018.05.008

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A case report demonstrates independent effect of GLP-1 receptor agonist

Dr Jorge L. Alió and Dr Elinor Megiddo-Barnir

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