Glycemic variability indices associated with diabetic retinopathy in patients with type 2 diabetes mellitus

Objective. To study short-term and long-term glycemic variability (GV) as factors associated with DR, its severity, and the progression of diabetic retinopathy in patients with type 2 diabetes mellitus.

Materials and methods. A retrospective analysis was conducted of 593 patients with type 2 diabetes (419 women (70.66 %) and 174 men (29.32 %), disease duration 10 [6; 15] years) who underwent ophthalmological examination in the Laser Microsurgery Department of the City Clinical Hospital No. 10 for the period 2016-2023 was performed. DR was noted in 165 patients. The study included 428 patients without exudative-hemorrhagic manifestations. The dynamic of disease progression was monitored over a oneyear and three-year period. The GV SD, CV, MAGE, and TIR indices were calculated. Statistical data processing was performed using the Statistica 12 software package.

Results. A GV SD threshold of 0.854 and MAGE 0.967 was established to detect the presence of DR. The SD and MAGE indices were statistically significantly higher in patients with DR (1.253 [0.707; 1.893] vs 0.707 [0.283; 1.414], p = 0.021 and 1.4 [0.9; 2.3] vs 0.9 [0.4; 1.833], p = 0.021). Progression of DR in the first year of observation was associated with higher rates of short-term GV SD (3.8 [2.68; 4.9] vs 1.15 [0.71; 1.4], p = 0.045); CV (41.3 [35.37; 47.1] vs 15.71 [8.14; 16.0], p = 0.045), MAGE (4.9 [2.87; 7.0] vs 1.3 [1.0; 2.0], p = 0.045). Progression of DR in the third year of observation was associated with higher rates of long-term GV SD HbA1c (3.418 [3.042; 5.219] vs 0.202 [0.0; 0.52], p = 0.052).

Conclusion. VG was associated with the presence of DR and its progression, but cannot be used as a sole marker. Further research is needed to establish a comprehensive set of markers that is effective in assessing the risk of DR progression.

1. IDF diabetes atlas. 10th ed. International diabetes federation. Brussels. 2021. Available at: https://www.diabetesatlas.org (accessed: 14.11.2022).

2. Early Treatment Diabetic Retinopathy Study Research Group. Fundus photographic risk factors for progression of diabetic retinopathy ETDRS. J VitreoRetin Dis. 1991; 9(5): 823–833.

3. Zhang Z., Lv D., You Y., et al. Assessing the importance of risk factors for diabetic retinopathy in patients with type 2 diabetes mellitus: results from the classification and regression tree models. J Family Community Med. 2024; 31(3): 197–205.

4. Simo R., Franch-Nadal J., Vlacho B., et al. Rapid reduction of HbA1c and early worsening of Diabetic Retinopathy. Diabetes Care. 2023; 46(9): 1633–1639.

5. Blighe K., Gurudas S., Lee Y., Sivaprasad S. Diabetic retinopathy environment-wide association study (EWAS) in NHANES 2005– 2008. J Clin Med. 2020; 9: 2005–2008.

6. Acan D., Calan M., Er D., et al. The prevalence and systemic risk factors of diabetic macular edema. BMC Ophthalmol. 2018; 18. doi: 10.1186/s12886-018-0753-y.

7. Cardoso C.R.L., Leite N.C., Moram C.B.M., Salles G.F. Long-term visit-to-visit glycemic variability as predictor of micro- and macrovascular complications in patients with type 2 diabetes. Cardiovascular. Diabetol. 2018; 17. doi: 10.1186/s12933-018-0677-0.

8. Lazar S., Ionita I., Reurean-Pintilei D., Timar B. How to Measure Glycemic Variability? Medicina. 2024; 60(1). doi: 10.3390/medicina60010061.

9. Porta M., Kohner E.M. Screening for diabetic retinopathy in Europe. Diabetic Medicine. 1991; 8: 197–198.

10. Dehghani Firouzabadi F., Poopak A., Samimi S., et al. Glycemic profile variability as an independent predictor of diabetic retinopathy in patients with type 2 diabetes. Front Endocrinol (Lausanne). 2024; 7(15). doi: 10.3389/fendo.2024.1383345.

11. Zhou J.J., Koska J., Bahn G., Reaven P. Fasting glucose variation predicts microvascular risk in ACCORD and VADT. J Clin Endocrinol Metab. 2021; 106(4): 1150–1162.

12. Today study group. Long-term outcomes among young adults with type 2 diabetes based on durability of glycemic control. Diabetes care. 2022; 45(11): 2689–2697.

13. Lu J., Ma X., Zhang L., et al. Glycemic variability assessed by continuous glucose monitoring and the risk of diabetic retinopathy in latent autoimmune diabetes of the adult and type 2 diabetes. Diabetes Invest. 2019; 10(3): 753–759.

14. El A., Van Elsen M., Charleer S., et al. Relationship between Time in Range, Glycemic Variability, HbA1c, and complications in adults with type 1 diabetes Mellitus. J Clin Endocrinol Metab. 2022; 107(2): 570–581.

15. Slieker R.C., H van der Heijden A. A. W. H., Nijpels G., et al. Visit-to-visit variability of glycemia and vascular complications. Cardiovasc Diabetol. 2019; 18. doi: 10.1186/s12933-019-0975-1.

16. Hsieh Y.T., Hsieh M.C. Fasting plasma glucose variability is an independent risk factor for diabetic retinopathy and diabetic macular edema in type 2 diabetes. Clin Exp Ophthalmol. 2020; 48(4): 470–476.

17. Dhatariya K., Humberstone A., Hasnat A., et al. The Association between Mean glycated haemoglobin or glycaemic variability and the development of retinopathy in people with diabetes. Diabetes Therapy. 2021; 12(10): 2755–2766.

18. Dai D., Shen Y., Lu J., et al. Association between visit-to-visit variability of glycated albumin and diabetic retinopathy among patients with type 2 diabetes. J Diabetes Complicat. 2021; 35(9). doi: 10.1016/j.jdiacomp.2021.107971.

19. Kim H.U., Park S., Kim Y.K. Long-term HbA1c variability and the development and progression of diabetic retinopathy in subjects with type 2 diabetes. Sci Rep. 2021; 11. doi: 10.1038/s41598-021-84150-8.

20. Danne T., Nimri R., Battelino T., et al. International Consensus on Use of continuous glucose monitoring. Diabetes Care. 2017; 40(12): 1631–1640.

21. Mo Y., Ma X., Lu J., et al. Defining the target value of the coefficient of variation by continuous glucose monitoring in Chinese people with diabetes. J Diabetes Invest. 2021; 12(6): 1025–1034.

22. Monnier L., Colette C., Owens D.R. Glycemic variability: the third component of the dysglycemia in diabetes. Is it important? How to measure it? J Diabetes Sci Technol. 2008; 2 (6): 1094–1100.

23. Wang Y., Lu J., Shen Y., et al. Comparison of glucose time in range and area under curve in range in relation to risk of diabetic retinopathy in type 2 diabetes patients. J Diabetes Investig. 2022; 13(9); 1543–1550.

24. Rosa L., Zajdenverg L., Lopes Souto D., et al. HbA1c variability and long-term glycemic control are linked to diabetic retinopathy and glomerular filtration rate in patients with type 1 diabetes and multiethnic background. J Diabetes Complicat. 2019; 33(9): 610–615.

25. Mao Y., Zhong W. HbA1c variability as an independent risk factor for microvascular complications in type 1 diabetes. J Diabetes Sci Technol. 2024; 18(2): 380–388.

26. Park J.Y., Hwang J.H., Kang M.J., et al. Effects of glycemic variability on the progression of diabetic retinopathy among patients with type 2 diabetes. Retina. 2021; 41(7): 1487–1495.