Original Article

Relationship of HbA1c with Visual and Anatomical Outcomes of Bevacizumab in Diabetic Macular Edema

Royala Zaka, Yasir Khan, Burhan Abdul Majid Khan, Mirza Zaki-ud-Din Ahmed Sabri, Rabia Qureshi

DOI 10.36351/pjo.v35i4.937 Pak J Ophthalmol 2019, Vol. 35, No. 4

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Correspondence to:

Dr. Royala Zaka

Consultant Ophthalmologist

Prevention of Blindness (POB), Karachi, Pakistan

Email: drroyala@hotmail.com

Purpose: To find relationship of baseline Hemoglobin A1c (HbA1c) with visual outcomes, central macular thickness and number of intravitreal Bevacizumab at 12 months in patients with diabetic macular edema (DME).

Study Design: Quasi experimental study.

Place and Duration of Study: Prevention of blindness (POB) Hospital, Karachi, Pakistan between October 2018 and September 2019.

Material and Methods: Two hundred and eighty patients with Diabetic macular edema (DME) presenting to the eye OPD of POB, who did not receive any treatment for DME were recruited. Patients who had concurrent retinal disease and were treated with intravitreal injections and/or laser were excluded. All patients were evaluated with history, ophthalmological examination and SD-OCT for central subfield macular thickness. Patients received 3 intravitreal injections of Bevacizumab one month apart. OCT was done after 3 months and retreatment for diabetic macular edema was based on the persistence of macular thickness more than 300 microns. All the data was analyzed using SPSS version 20.

Results: There were 280 patients, 53.2% were males and 46.8% were females. Patients were divided into 3 groups; patients with HbA₁C < 7.0, 7.1 – 8.0 and
> 8.0. Central macular thickness decreased significantly from baseline in all 3 groups. Maximum vision improvement was seen in group 1 with HbA₁C < 7.0 and group 2 with 7.1 – 8.0. Significant inverse correlation was seen between HbA₁C and vision at 12 months (r = - 0.40, p < 0.01) and positive correlation with central macular thickness (r = 0.53 p < 0.01).

Conclusion: Initial baseline HbA₁C is strongly related with visual and anatomic outcome at 12 months.

Key Words: Diabetic macular edema; Bevacizumab; Hemoglobin A1C.

Approximately 21 million people are affected by diabetic macular edema worldwide¹. By 2025, the incidence of diabetes in Pakistan will get doubled². The high burden of diabetic complications is associated with uncontrolled diabetes³. Therefore, control of diabetes is the main pillar for prevention and delaying of diabetic complications. In diabetes mellitus, the main reason of visual loss is macular edema⁴. Evidence shows that diabetic macular edema and moderate visual loss can be reduced by tight glycemic control⁵. The Royal College of Ophthalmologists’ Clinical Guidelines for Diabetic Retinopathy” recommends laser alone⁶. Until recently, macular photocoagulation was the treatment of choice for diabetic macular edema. Even with this treatment, macular edema persists in the presence of uncontrolled diabetes⁷. The entire treatment picture has changed with the introduction of anti-vascular endothelial growth factors especially for DME⁸.

Not only we have seen the relationship of HbA₁C with visual and anatomical outcome like previous studies, but also seen the relationship of baseline HbA¹C with frequency or number of Anti-VEGF injections in diabetic macular edema. The frequency of Anti-VEGF injections is an important aspect to know as in the developing country like Pakistan, the cost is one of the main issues. The rationale of our study was that patients with baseline lower HbA¹C may have better visual and anatomical outcome and may require fewer number of Anti-VEGF injections in one duration as compared with patients having high baseline HbA¹C.

The purpose of our study was to find relationship of baseline Hemoglobin A1c (HbA1c) with visual outcomes, central macular thickness and number of intravitreal Bevacizumab at 12 months in patients with diabetic macular edema (DME).

MATERIAL AND METHODS

This study was done between October 2018 to September 2019 at Prevention of Blindness, a charity based hospital where approximately 100 patients receive Anti-VEGF injections weekly for different ocular conditions. Ethical approval was taken before the start of study.

Two hundred and eighty patients diagnosed with diabetic macular edema with initial HbA¹C of less than or more than 7.0, who received at least three Anti-VEGF injections were recruited for the study. They were followed up for 12 months. The exclusion criteria of our study was those individuals who had concomitant retinal disease or who had macular edema due to reasons other than diabetes or had previous treatment with pan-retinal photocoagulation or macular photocoagulation or macular ischemia or did not have baseline HbA¹C or those who were lost to follow-up.

All patients were evaluated starting from the history and comprehensive ophthalmological examination that included best corrected visual acuity using Snellen chart, biomicroscopy to diagnose clinically significant macular edema and OCT optical coherence tomography (SD-OCT) with a central subfield macular thickness (CSMT) measurement to quantify, document and follow-up the macular thickness. The patients whose visual acuity was affected by disruptive anatomy of macula due to the intracystic spaces involving the macula or had more than 300 micron macular thickness on OCT were given intravitreal injections of Bevacizumab. Patients received 3 intravitreal injections at one-month interval. OCT was done after 3 months and retreatment for diabetic macular edema was based on the persistence of macular thickness more than 300 microns.

Patients were followed monthly and HbA₁C was recorded 3 to 4 monthly interval until 12 months. Consent was taken from all the patients after brief explanation about the study, treatment and follow-up. All the data was entered in SPSS version 20, Paired t-test, test of proportion and Pearson correlation coefficient were used for statistical analysis.

RESULTS

Out of 280 patients, 149 (53.2%) were males and 131 (46.8%) were females. Twenty (7.1%) patients had HbA₁C of < 7.0, 187 (66.8%) had 7.1-8.0 and 73 (26.1%) patients had > 8.0 HbA₁c (Table1). Central macular thickness was significantly decreased on 12 months from baseline (p < 0.01). Number of injections given were more according to HbA₁c (< 7.0, 7.1 – 8.0 and > 8.0) but statistically not significant (p > 0.05). Increase in visual acuity was more in patients with HbA1c of < 7.0 as compared to the patients with higher HbA₁C (Table 2). Initial baseline HbA₁C was strongly related with visual and anatomic outcome at 12 months.

Table 1: Demographic characteristics (n = 280).

	Frequency	Percent
Gender
Male	149	53.2
Female	131	46.8
Age in years
Under 50	27	9.6
50-59	158	56.4
60 & above	95	33.9
Range	44–73
Mean ± S.D	58.1 ± 6.11
HbA1c
Group 1 (HbA1c ≤ 7.0)	20	7.1
Group 2 (HbA1c 7.1-8.0)	187	66.8
Group 3 (HbA1c > 8.0)	73	26.1

Table 2: Comparison of HbA1c with CMT, Number of injection and Visual status.

	HbA1c <=7.0 (n=20) n, Mean ± S.D	HbA1c 7.1-8.0 (n=187) n, Mean ± S.D	HbA1c > 8.0 (n=73) n, Mean ± S.D
HbA1c
Base line (Day 0)	19, 6.93 ± 0.09	163, 7.49 ± 0.25	67, 9.37 ± 1.24
At 12 months	19, 7.17 ± 0.31	163, 7.38 ± 0.44	67, 8.64 ± 1.43
P-value	0.005	0.003	0.001
Duration of DM (Years)	20, 10.0 ± 2.51	180, 13.7 ± 4.71*	73, 16.4 ± 4.46* º
CMT Right
Base line (Day 0)	19, 365 ± 72.1	161, 353 ± 81.7	67, 424 ± 138.4
At 12 months	19, 287 ± 315	161, 302 ± 60.1	67, 378 ± 135.3
P-value	0.001	0.001	0.001
CMT Left
Base line (Day 0)	19, 292 ± 44.4	159, 324 ± 70.7	67, 389 ± 118.7
At 12 months	19, 272 ± 33.6	159, 294 ± 47.8	67, 357 ± 103.2
P-value	0.043	0.001	0.001
Number of injections used in 12 months
Right	6, 6.67 ± 2.16	87, 7.39 ± 1.49	52, 7.94 ± 1.29
Left	2, 10.00 ± 0.00	62, 8.19 ± 1.04	44, 8.20 ± 1.30
Vision increased on 12 months
Right	16 (94%) out of 17 1 Line 6 (35%) 2 Line 9 (53%) 3 Line 1 (6%)	73 (64%) out of 113 * 1 Line 23 (20%) 2 Line 34 (30%) 3 Line 15 (13%) 4 Line 1 (1%)	24 (41%) out of 59 * º 1 line 13 (22%) 2 line 7 (12%) 3 line 3 (5%) 4 line 1 (2%)
Left	5 (83%) out of 6 3 line 5 (83%)	60 (68%) out of 88* 1 Line 31 (35%) 2 Line 20 (23%) 3 Line 9 (10%)	18 (36%) out of 50 * 1 line 12 (24%) 2 line 2 (4%) 3 line 4 (8%)

Significant from HbA1c <= 7.0 *P < 0.05 Significant from HbA1c 7.1 – 8.0 ºP < 0.05

DISCUSSION

Our study showed that baseline HbA1c has positive correlation with baseline CMT (r = 0.53, p < 0.01) that means if the initial HbA1c is uncontrolled, patients can have high central macular thickness (CMT). We found that in patients with < 7.0, 7.1 to 8.0 and > 8.1 Hba1c, CMT decreased in all patients after Anti-VEGF injections. Our results also correspond to the previous studies in which the patients having low HbA1C showed greater visual improvement with the use of Anti-VEGF injections⁹. Matsuda and colleagues showed that with HbA1C of 7.0 or less there was significant decrease in CMT with the use of Bevacizumab and similar results were seen with the use of another Anti-VEGF Ranibizumab^10,11. Diabetic Retinopathy Research Group Vienna also showed that CMT was decreased at its maximum by using either Bevacizumab or Ranibizumab if the HbA1C was less than 7.0¹².

Diabetic macular edema is the biggest cause of visual loss in diabetic retinopathy and can happen at any stage of diabetic retinopathy¹³. Tight glycemic control < 7.0 can delay or prevent the complications in both type 1 and type 2 diabetes^14,15.

However VIVID and VISTA DME studies showed that there was no relationship of baseline HbA1C with visual and anatomical outcome. The difference in results might be because the Anti-VEGF used was Aflibercept and less or more than 8.0 HbA1C was used in the study¹⁶.

According to Matsuda et al DME with regulated blood glucose can impact the response to Bevacizumab. The patients with a starting HbA1C of 7.0 or less showed more improvement in BCVA during the 12 months of therapy than those with starting HbA1C > 7.0⁹. Pemp and colleagues also described that the visual improvement could be gained at its highest level by using Bevacizumab or Ranibizumab if the baseline HbA1C was < 7.0 at the start of therapy¹².

Pakistan is a developing country where cost matters for everything and same is for the Ani-VEGF injections. Bevacizumab being a cost effective injection could be the reason for the increased number of injections used in our study. We did not compare among different Anti-VEGF injections like Ranibizumab or Aflibercept that might have given results at a lower number of injections as compared with Bevacizumab which is commonly used in our set up. An article showed that bevacizumab in relation with cost effectiveness is superior to other Anti-VEGF injections¹⁷. Another study showed that the cost of Ranibizumab is 20 to 40 folds higher than the cost of Bevacizumab and the treatment of DME is 10 to 15 million Euros higher in Netherland¹⁸. The Bevacizumab is the cost effective choice as compared to Ranibizumab and Aflibercept¹⁹. The other reason of increase number of injections in the group having < 7.0 HbA1C might be the increase in its HbA1C until 12 months.

The DRCR.net compared the efficacy of 3Anti-VEGF at 2 years. Vision improved in all 3 drug groups however, the frequency of injections became half in 2^nd year²⁰. Our follow up was only 1 year so future studies can check this frequency of injections for more than a year.

One study showed that despite different levels of glycemic control during the treatment the baseline HbA1C affects the visual and anatomical outcome however, the required number of Anti-VEGF injections decrease during the course of treatment if the HbA1C remains controlled⁴.

Limitation of our study was the small number of patients and it was a retrospective study. There were also lesser number of patients in group 1. Future studies can be planned to investigate this group further. Only Bevacizumab was used in this study. Other Anti-VEGF like Ranibizumab and Aflibercept can be compared with Bevacizumab in future studies.

CONCLUSION

Baseline HbA1C has a strong relation with visual and anatomic outcome in diabetic macular edema.

REFERENCES

1. Bansal AS, Khurana RN, Wieland MR, Wang P-W, Van Everen SA, Tuomi L. Influence of glycosylated hemoglobin on the efficacy of ranibizumab for diabetic macular edema: a post hoc analysis of the RIDE/RISE trials. Ophthalmology, 2015; 122 (8): 1573-9.

2. Mumtaz SN, FahimMF, Arslan M, Shaikh SA, Kazi U, Memon MS. Prevalence of diabetic retinopathy in Pakistan; A systematic review. Pak J Med Sci. 2018; 34 (2): 493–500.

3. Fasil A, Biadgo B, Abebe M. Glycemic control and diabetes complications among diabetes mellitus patients attending at University of Gondar Hospital, Northwest Ethiopia. Diabetes, metabolic syndrome and obesity: targets and therapy.Diabetes Metab Syndr Obes. 2019;
12: 75–83.

4. Nezhad GS, Razeghinejad R, Janghorbani M, Mohamadian A, Jalalpour MH, Bazdar S. Prevalence, Incidence and Ecological Determinants of Diabetic Retinopathy in Iran: Systematic Review and Meta-analysis. J Ophthalmic Vis Res. 2019; 14 (3): 321-335.

5. Chew EY, Davis MD, Danis RP, Lovato JF, Perdue LH, Greven C, et al. The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study. Ophthalmology 2014; 121 (12): 2443-51.

6. Jafri AS, Aziz-ur-Rehman AHM, Memon S. Outcomes of intravitreal bevacizumab and macular photocoagulation for treatment of diabetic macular edema in a tertiary care eye hospital, Karachi. Pak J Med Sci. 2017; 33 (5): 1215.

7. Do DV, Shah SM, Sung JU, Haller JA, Nguyen QD. Persistent diabetic macular edema is associated with elevated hemoglobin A1C. American journal of Ophthalmology, 2005; 139 (4): 620-3.

8. Ajlan RS, Silva PS, Sun JK. Vascular endothelial growth factor and diabetic retinal disease. Semin Ophthalmol. 2016; 31 (1-2): 40-8.

9. Singh RP, Habbu K, Ehlers JP, Lansang MC, Hill L, Stoilov I. The Impact of Systemic Factors on Clinical Response to Ranibizumab for Diabetic Macular Edema. Ophthalmology, 2016; 123 (7): 1581-7.

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. J Diabetes Complications, 2014; 28 (2): 166-70.

11. Ozturk BT, Kerimoglu H, Adam M, Gunduz K, Okudan S. Glucose regulation influences treatment outcome in ranibizumab treatment for diabetic macular edema. J Diabetes Complications, 2011; 25 (5): 98-302.

12. Pemp B, Deak G, Prager S. Diabetic Retinopathy Research Group Vienna Distribution of intraretinal exudates in diabetic macular edema during anti-vascular endothelial growth factor therapy observed by spectral domain optical coherence tomography and fundus photography. Retina, 2014; 34 (12): 2407-15.

13. Midena E, Gillies M, Katz TA, Metzig C, Lu C, Ogura Y. Impact of Baseline Central Retinal Thickness on Outcomes in the VIVID-DME and VISTA-DME Studies. J Ophthalmol. 2018; 29: 3640135.

14. Nathan DM, McGee P, Steffes MW, Lachin JM, group DEr. Relationship of glycated albumin to blood glucose and HbA1c values and to retinopathy, nephropathy, and cardiovascular outcomes in the DCCT/EDIC study. Diabetes, 2014; 63 (1): 282-90.

15. Clarke PM, Gray AM, Briggs A, Farmer AJ, Fenn P, Stevens RJ, et al. A model to estimate the lifetime health outcomes of patients with type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS no. 68). Diabetologia. 2004; 47
(10): 1747-59.

16. Singh RP, Wykoff CC, Brown DM, Larsen M, Terasaki H, Silva FQ, et al. Outcomes of diabetic macular edema patients by baseline hemoglobin A1c: analyses from VISTA and VIVID. Ophthalmology Retina, 2017; 1 (5): 382-8.

17. Heier JS, Bressler NM, Avery RL, Bakri SJ, Boyer DS, Brown DM, et al. Comparison of aflibercept, bevacizumab, and ranibizumab for treatment of diabetic macular edema: extrapolation of data to clinical practice. JAMA Ophthalmol. 2016; 134 (1): 95-9.

18. Schauwvlieghe AME, Dijkman G, Hooymans JM, Verbraak FD, Hoyng CB, Dijkgraaf MGW, et al. Comparing the effectiveness and costs of bevacizumab to ranibizumab in patients with diabetic macular edema: a randomized clinical trial (the BRDME study). BMC Ophthalmol. 2015; 15 (1): 71.

19. Ross EL, Hutton DW, Stein JD, Bressler NM, Jampol LM, Glassman AR. Cost-effectiveness of aflibercept, bevacizumab, and ranibizumab for diabetic macular edema treatment: analysis from the diabetic retinopathy clinical research network comparative effectiveness trial. JAMA Ophthalmol. 2016; 134 (8): 888-96.

20. Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology, 2016; 123 (6): 1351-9.

Author’s Affiliation

Dr. Royala Zaka

Consultant Ophthalmologist