Short-term impact of glycaemic control and intravitreal ranibizumab treatment on serum cytokine levels and diabetic macular edema in patients with unregulated blood glucose

Yıl 2022, Cilt: 32 Sayı: 6, 774 - 780, 31.12.2022

Emine Tınkır Kayıtmazbatır , Gülfidan Bitirgen , Günhal Şatırtav , İbrahim Kılınc , Mustafa Kulaksızoğlu , Bülent Savut , Hürkan Kerimoğlu

https://doi.org/10.54005/geneltip.1191169

Öz

Objective: To evaluate the short-term effect of glycaemic control and intravitreal ranibizumab treatment on diabetic macular edema (DME) and to assess the correlation between HbA1c and certain serum cytokines.
Design: A prospective study of 43 participants with HbA1c levels exceeding 53 mmol/mol (7%) and with DME, as detected by spectral domain optical coherence tomography (SDOCT).
Subjects: Participants were grouped according to their initial best corrected distance visual acuity (BCVA). Group 1 was treated with three monthly doses of intravitreal ranibizumab (0.5 mg) injections, and Group 2 was followed without treatment.
Methods: Serum cytokine levels, including interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1(MCP-1), and vascular endothelial growth factor (VEGF) were analysed at the beginning and at the end of 3 months, using enzyme-linked immunosorbent assays (ELISA).
Results: A significant decrease in macular thicknesses (except for one quadrant) was observed in Group. Changes in serum cytokine levels were not correlated with HbA1c decrease. Serum VEGF level was significantly increased in Group 1, despite the intravitreal treatment.
Conclusion: Short-term glycaemic control alone had limited value in the treatment of DME. The therapeutic effect of intravitreal treatment on DME supports the role of the local cytokine milieu in the pathophysiology.

Anahtar Kelimeler

Diabetes Mellitus, Type 2, Glycaemic Control, Glycated Haemoglobin A1c, Macular Edema, Serum Cytokines, Vascular Endothelial Growth Factor

Destekleyen Kurum

Necmettin Erbakan University Scientific Research Projects Department

Proje Numarası

141518017

Teşekkür

We thank Samet Uludag, Yusuf Can Efe, and Ihsan Toran from the Department of Ophthalmology for their help in the registration of the participants. We thank Tevfik Balci, M.D., and Nejla Ozer, M.D., from Department of Medical Biochemistry for their collaboration in delivery and storage of the serum samples. We also thank to Fatih Kara, Associate Professor and Adnan Karaibrahimoglu, Assistant Professor for their contribution for statistical analysis of the data.

Kan şekeri regüle olmayan hastalarda kısa dönem glisemik control ve intravitreal ranibizumab tedavisinin serum sitokin düzeyleri ve diyabetik maküler ödem üzerine etkisi

Öz

Amaç: Glisemik kontrol ve intravitreal ranibizumab tedavisinin diyabetik maküla ödemi (DMÖ) üzerindeki kısa vadeli etkisini ve HbA1c ile belirli serum sitokinleri arasındaki korelasyonu değerlendirmek.
Tasarım: Prospektif çalışmaya HbA1c seviyeleri 53 mmol/mol (%7) üzerinde ve spektral domain optik koherens tomografi (SDOKT) ile DMÖ tespit edilmiş 43 katılımcı dahil edildi.
Katılımcılar: Katılımcılar, başlangıç en iyi düzeltilmiş uzak görme keskinliklerine (EDGK) göre gruplandırıldı. Grup 1, üç doz aylık intravitreal ranibizumab (0.5 mg) enjeksiyonu ile tedavi edilirken, Grup 2’deki katılımcılar intravitreal tedavi uygulanmadan takip edildi.
Yöntem: İnterlökin (IL)-1β, IL-6, IL-8, tümör nekroz faktörü-alfa (TNF-a), monosit kemoatraktan protein-1(MCP-1) ve vasküler endotelyal büyüme faktörü (VEGF) dahil olmak üzere serum sitokin seviyeleri, enzime bağlı immünosorbent testi (ELISA) kullanılarak 3 aylık takibin başında ve sonunda analiz edildi.
Bulgular: Grup 1’in maküla kalınlıklarında (bir kadran hariç) anlamlı azalma gözlendi. Serum sitokin seviyelerindeki değişiklikler HbA1c düşüşü ile korele bulunmadı. Grup 1'de intravitreal tedaviye rağmen serum VEGF düzeyi anlamlı olarak yükseldi.
Sonuç: Kısa süreli glisemik kontrolün tek başına DMÖ tedavisindeki yeri sınırlıdır. İntravitreal tedavinin DMÖ üzerindeki terapötik etkisi, lokal sitokin ortamının patofizyolojideki rolünü desteklemektedir

Anahtar Kelimeler

Diyabetes Mellitus, Tip 2, Glisemik Kontrol, Glikolize Hemoglobin A1c, Maküler Ödem, Serum Sitokinleri, Vasküler Endotelyal Büyüme Faktörü

Proje Numarası

141518017

Kaynakça

• 1. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. The Lancet [Internet]. 2010 [cited 2022 Sep 20];376(9735):124–36. Available from: 10.1016/s0140-6736(09)62124-3
• 2. Browning D, Stewart M, Lee C. Diabetic macular edema: Evidence-based management. Indian J Ophthalmol [Internet]. 2018 [cited 2022 Sep 20];66(12):1736. Available from: 10.4103/ijo.ijo_1240_18
• 3. Hussain RM, Ciulla TA. Treatment strategies for refractory diabetic macular edema: switching anti-VEGF treatments, adopting corticosteroid-based treatments, and combination therapy. Expert Opinion on Biological Therapy [Internet]. 2016 [cited 2022 Sep 20];16(3):365–74. Available from: 10.1517/14712598.2016.1131265
• 4. Schmidt-Erfurth U, Garcia-Arumi J, Bandello F, Berg K, Chakravarthy U, Gerendas BS, et al. Guidelines for the Management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA). Ophthalmologica [Internet]. 2017 [cited 2022 Sep 20];237(4):185–222. Available from: 10.1159/000458539
• 5. Xu L, Lu T, Tuomi L, Jumbe N, Lu J, Eppler S, et al. Pharmacokinetics of Ranibizumab in Patients with Neovascular Age-Related Macular Degeneration: A Population Approach. Invest Ophthalmol Vis Sci [Internet]. 2013 [cited 2022 Sep 20];54(3):1616. Available from: 10.1167/iovs.12-10260
• 6. Lee J-H, Lee W, Kwon OH, Kim J-H. Cytokine profile of peripheral blood in type 2 diabetes mellitus patients with diabetic retinopathy. Ann Clin Lab Sci. 2008;38(4):361–7.
• 7. Iyer SSR, Lagrew MK, Tillit SM, Roohipourmoallai R, Korntner S. The Vitreous Ecosystem in Diabetic Retinopathy: Insight into the Patho-Mechanisms of Disease. IJMS [Internet]. 2021 [cited 2022 Sep 20];22(13):7142. Available from: 10.3390/ijms22137142
• 8. Hillier RJ, Ojaimi E, Wong DT, Mak MYK, Berger AR, Kohly RP, et al. AQUEOUS HUMOR CYTOKINE LEVELS AS BIOMARKERS OF DISEASE SEVERITY IN DIABETIC MACULAR EDEMA. 2017 [cited 2022 Sep 20];37(4):761–9. Available from: 10.1097/IAE.0000000000001210
• 9. Rangasamy S, McGuire P, Das A. Diabetic retinopathy and inflammation: Novel therapeutic targets. Middle East Afr J Ophthalmol [Internet]. 2012 [cited 2022 Sep 20];19(1):52. Available from: 10.4103/0974-9233.92116
• 10. Matsuda S, Tam T, Singh RP, Kaiser PK, Petkovsek D, Carneiro G, et al. The impact of metabolic parameters on clinical response to VEGF inhibitors for diabetic macular edema. Journal of Diabetes and its Complications [Internet]. 2014 [cited 2022 Sep 20];28(2):166–70. Available from: 10.1016/j.jdiacomp.2013.11.009
• 11. Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, Lachin J, Cleary P. The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus. N Engl J Med [Internet]. 1993 [cited 2022 Sep 20];329(14):977–86. Available from: 10.1056/NEJM199309303291401
• 12. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). The Lancet [Internet]. 1998 [cited 2022 Sep 20];352(9131):837–53. Available from: 10.1016/s0140-6736(98)07019-6
• 13. Aiello LP, Cahill MT, Wong JS. Systemic considerations in the management of diabetic retinopathy. American Journal of Ophthalmology [Internet]. 2001 [cited 2022 Sep 20];132(5):760–76. Available from: 10.1016/s0002-9394(01)01124-2
• 14. Giacco F, Brownlee M. Oxidative Stress and Diabetic Complications. Circ Res [Internet]. 2010 [cited 2022 Sep 20];107(9):1058–70. Available from: 10.1161/CIRCRESAHA.110.223545
• 15. Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J, et al. Vascular Endothelial Growth Factor Is a Critical Stimulus for Diabetic Macular Edema. American Journal of Ophthalmology [Internet]. 2006 [cited 2022 Sep 20];142(6):961-969.e4. Available from: 10.1016/j.ajo.2006.06.068
• 16. Celebiler Cavusoglu A, Bilgili S, Alaluf A, Doğan A, Yılmaz F, Aslanca D, et al. Vascular Endothelial Growth Factor Level in the Serum of Diabetic Patients with Retinopathy. Ann Ophthalmol [Internet]. 2007 [cited 2022 Sep 20];39(3):205–8. Available from: 10.1007/s12009-007-0037-2
• 17. Burgos R, Simó R, Audí L, Mateo C, Mesa J, García-Ramírez M, et al. Vitreous levels of vascular endothelial growth factor are not influenced by its serum concentrations in diabetic retinopathy. Diabetologia [Internet]. 1997 [cited 2022 Sep 20];40(9):1107–9. Available from: 10.1007/s001250050794
• 18. Turgut Ozturk B, Bozkurt B, Kerimoglu H, Okka M. Effect of serum cytokines and VEGF levels on diabetic retinopathy and macular thickness. Mol Vis. 2009;15:1906–14.
• 19. Shao EH, Sivagnanavel V, Dabbagh A, Dave R, Tempest-Roe S, Tam FWK, et al. Multiphasic changes in systemic VEGF following intravitreal injections of ranibizumab in a child. Eye [Internet]. 2015 [cited 2022 Sep 20];29(4):569–73. Available from: 10.1038/eye.2014.343
• 20. Gnanasekaran S, Bandala-Sanchez E, Kolic M, Churilov L. The association between intravitreal ranibizumab therapy and serum cytokine concentrations in patients with diabetic macular edema. Mol Vis. 2020;(26):246–56.
• 21. Gordon MS, Margolin K, Talpaz M, Sledge GW, Holmgren E, Benjamin R, et al. Phase I Safety and Pharmacokinetic Study of Recombinant Human Anti-Vascular Endothelial Growth Factor in Patients With Advanced Cancer. JCO [Internet]. 2001 [cited 2022 Sep 20];19(3):843–50. Available from: 10.1200/JCO.2001.19.3.843
• 22. Stefanini MO, Wu FTH, Mac Gabhann F, Popel AS. Increase of Plasma VEGF after Intravenous Administration of Bevacizumab Is Predicted by a Pharmacokinetic Model. Cancer Research [Internet]. 2010 [cited 2022 Sep 20];70(23):9886–94. Available from: 10.1158/0008-5472.can-10-1419