Eyes from Type 1 diabetes patients are associated with higher post-operative complications rates than those from Type 2 diabetes patients

doi:10.21203/rs.3.rs-2486010/v1

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Eyes from Type 1 diabetes patients are associated with higher post-operative complications rates than those from Type 2 diabetes patients

https://doi.org/10.21203/rs.3.rs-2486010/v1

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Objective

To assess the effect of the type of diabetes on the formation of pseudophakic cystoid macular edema (PCME) and posterior capsular opacification (PCO) following cataract surgery.

Methods

Cohort study of patients who underwent cataract extraction at the Department of Ophthalmology, Bristol Eye Hospital, Bristol, UK, between 2003 and 2017. The rate of PCME and Nd:YAG laser capsulotomies following cataract surgery were assessed and compared between non-diabetic, type 1 (DM1) and type 2 diabetes (DM2) patients. Multivariate Cox regression controlling for age and gender was used to estimate hazard ratios (HR) for Nd:YAG laser capsulotomies.

Results

Included were 53,471 consecutive cataract surgeries (21,884 male and 31,587 female patients, with a mean age of 74.4 ± 10.9 years). Overall, 42,651 eyes (79.8%) were non-diabetic, 823 eyes (1.5%) of DM1, and 9997 eyes (18.7%) of DM2 patients. The mean follow-up time was 6.8 ± 4.2 years. PCME was found in 0.9% of non-diabetics, 2.1% of DM1, and 1.6% of DM2 patients (P = 0.003 and P < 0.001, respectively). In univariate analysis, the eyes of DM1 (P < 0.001) and DM2 (P = 0.003) patients had significantly higher Nd:YAG laser capsulotomy rates than the eyes of non-diabetic patients. In Cox regression analysis adjusted for the patient's age and gender, DM1 (HR 1.692, 95%CI 1.390–2.059, P < 0.001) and DM2 (HR 1.157, 95%CI 1.075–1.244, P < 0.001) remained significantly predictive for higher Nd:YAG laser capsulotomy rates.

Conclusions

In our large cohort study, DM1 predisposed to high risk for developing PCME and PCO following cataract surgery. These findings could expand our knowledge of the underlying mechanisms, preventive measures and therapeutic targets against late-onset complications.

Health sciences/Diseases/Eye diseases/Lens diseases

Health sciences/Health care/Therapeutics/Surgery

cataract surgery

diabetes

postoperative complications

pseudophakic cystoid macular edema

posterior capsule opacification

uveitis

Nd:YAG laser capsulotomy

Diabetes is one of the most severe chronic diseases worldwide because of its prevalence and negative impact on the quality of life of the affected individuals (1). In cataract surgery, patients with diabetes have an increased risk for several post-operative complications, e.g., impaired corneal recovery, pseudophakic cystoid macular edema (PCME), or endophthalmitis (2). Poor glycemic control, type 1 diabetes (DM1) and the level of diabetic retinopathy (DR) were associated with increased intravitreal levels of vascular permeability factors, the development of macular edema and the incidence of PCME after cataract surgery (3–5).

Posterior capsular opacification (PCO) remains the most common long-term complication of cataract surgery, and morbidity related to PCO is a substantial economic burden (6). This is explained by the costs of the follow-up visits, the procedure itself and managing the associated complications that may appear due to the procedure (6). Moreover, PCO can potentially obscure the fundus view, compromising the observation and timely treatment of posterior segment pathologies, e.g., diabetic retinopathy and macular edema. In the clinical setting, as for registry-based studies, the incidence of Nd:YAG laser capsulotomy is often used as a surrogate marker for PCO formation. During the modern phacoemulsification era, Nd:YAG laser capsulotomy incidence was found to be higher in younger patients (aged below 60 or 70 years), among females, in eyes with hard nucleus or post-vitrectomy status, and those implanted with low-diopter intraocular lenses (IOLs) (7, 8). Importantly, adjustable confounders, such as IOL type and post-operative anti-inflammatory medication, affected the rates of Nd:YAG laser capsulotomy (9–11). The role of diabetes in PCO formation remains controversial (2).

In this large retrospective cohort study from a tertiary center in the UK, we assessed the common late-onset post-operative complications, especially PCO, in DM1 and DM2 patients and non-diabetic controls following cataract surgery.

Study design

This study was a registry-based retrospective cohort study of consecutive adult cataract surgeries performed at the Department of Ophthalmology, Bristol Eye Hospital, Bristol, UK. The study rationale was to investigate the common late-onset post-operative complications, especially PCO, in type 1 and type 2 diabetic patients and non-diabetic controls. Post-operative uveitis, PCME, and PCO were recorded as post-operative complications. In cases of concomitant post-operative uveitis and PCME, the complication was recorded as PCME. This study received the local ethics community approval (CORN/SE/2021–2022/02 and was presented to the local audit authority) and adhered to the tenets of the Declaration of Helsinki.

Data acquisition and subjects

The study included patients who underwent cataract extraction at the Department of Ophthalmology, Bristol Eye Hospital, between 2003 and 2017. Data was collected from the patient medical records system (Medisoft, Ltd, Leeds, UK). Clinical variables were registered for age at surgery and gender, date of cataract surgery and laterality, DM status (no/yes) and type (DM1/DM2), the existence of pseudoexfoliation (no/yes), use of mechanical pupil expansion devices (no/yes), and the Nd:YAG laser capsulotomy treatment status (no/yes) and the date of treatment. All surgeries for patients under 18 years were excluded (N = 112). Among 3688 eyes, diabetes status remained unknown; thus, they were excluded from the data analysis.

Statistical analyses

Data are presented as mean ± standard deviation (SD) or absolute values and proportions. Statistical analysis was performed using IBM SPSS Statistics 27 (IBM SPSS Statistics for Windows, Version 27.0. IBM Corp., Armonk, NY). Qualitative data were analyzed with the Chi-square and Fisher-Freeman-Halton tests, and parametric data were compared with the one-way ANOVA test using Bonferroni correction. Kaplan-Meier curves were generated, and a log-rank test was used to assess Nd:YAG laser capsulotomy-free survival. Multivariate Cox regression controlling for age and gender was used to estimate hazard ratios (HR) for Nd:YAG laser capsulotomies. P-values less than 0.05 were considered statistically significant.

Included were 53,471 consecutive cataract surgeries (21,884 male and 31,587 female surgeries, with a mean age of 74.4 ± 10.9 years). Overall, 42,651 eyes (79.8%) were non-diabetic, 823 eyes (1.5%) of type 1 diabetes (DM1), and 9997 eyes (18.7%) of type 2 diabetes (DM2) patients (Table 1). The mean follow-up time was 6.8 ± 4.2 years.

Table 1

Baseline parameters according to the type of diabetes.
	DM - N = 42651	DM1 N = 823	DM2 N = 9997	P =
Age (years)	74.7 ± 10.9	64.1 ± 14.3	73.9 ± 9.7	< 0.001
Male:Female	16494:26157	438:385	4952:5045	< 0.001
Laterality (R:L)	21774:20877	430:393	5105:4892	0.793
PXF	91 (0.2%)	0 (-)	12 (0.1%)	0.071
Pupil expansion device	625 (1.5%)	17 (2.1%)	172 (1.7%)	0.076
Data are given as mean (± SD) or absolute numbers with proportions. PXF, pseudoexfoliation.

Risk of pseudophakic cystoid macular edema after cataract surgery in type 1 and 2 diabetes patients

PCME was found in 0.9% of non-diabetics, in 2.1% of DM1 (P = 0.003, Table 2), and in 1.6% of DM2 (P < 0.001, Table 2) patients. Furthermore, either post-operative uveitis or PCME was found in 2.6% of non-diabetic, 4.6% of DM1 (P < 0.001, Table 2), and 3.4% of DM2 (P < 0.001, Table 2) patients.

Table 2

Clinical outcomes according to the type of diabetes. Data are given as absolute numbers and proportions. DM; diabetes mellitus, PCME; pseudophakic cystoid macular edema. Qualitative data were analyzed with the two-factor χ² test (two groups) and Fisher-Freeman-Halton test (multiple groups; overall).
Postoperative status	DM - N = 42651	DM1 N = 823	P =	DM2 N = 9997	P =	Overall P =
Uveitis without PCME	715 (1.7%)	21 (2.6%)	0.074	181 (1.8%)	0.345	0.114
PCME	391 (0.9%)	17 (2.1%)	0.003	159 (1.6%)	< 0.001	< 0.001
Uveitis / PCME	1106 (2.6%)	38 (4.6%)	< 0.001	340 (3.4%)	< 0.001	< 0.001

Risk of Nd:YAG laser capsulotomy after cataract surgery in type 1 and 2 diabetes patients

Nd:YAG laser capsulotomy rates between the eyes of non-diabetic, DM1, and DM2 patients were compared by univariate Kaplan-Meier and multivariate Cox regression analyses. In univariate analysis, the eyes of DM1 (P < 0.001, Fig. 1) and DM2 (P = 0.003, Fig. 1) patients had significantly higher Nd:YAG laser capsulotomy rates than the eyes of non-diabetic patients. In Cox regression analysis adjusted for the patient's age and gender, DM1 (HR 1.692, 95% CI 1.390–2.059, P < 0.001, Fig. 2) and DM2 (HR 1.157, 95% CI 1.075–1.244, P < 0.001, Fig. 2) remained significantly predictive for higher Nd:YAG laser capsulotomy rates. When comparing the types of diabetes, Nd:YAG laser capsulotomy rates were significantly higher among patients with type 1 than type 2 disease (HR 1.364, 95% CI 1.116–1.666, P = 0.002).

In our large cohort study, in univariate and multivariate regression analyses of 53,471 eyes with over a 5-year follow-up, DM1 was associated with higher PCME and Nd:YAG laser capsulotomy rates than patients with no diabetes or DM2. It has been reported that the development and severity of PCO increase in DM patients compared to non-diabetic patients (7, 12–16). However, while some studies revealed a higher incidence of PCO in diabetic patients, other studies did not confirm the effect, regardless of the stage of retinopathy (9, 17–24). This is the first report to compare Nd:YAG laser capsulotomy rates between patients with type 1 and type 2 diabetes (Table 3).

Table 3

The incidence or risk of PCO formation related to the type of diabetes.
Author	Country	Year	Effect of diabetes on PCO rate (OR, HR or non-significant)	N= (Total)	N= (Diabetes)	Type of DM (Compared with non-diabetic controls)	Follow-up (Months)
Hecht et al.¹⁰	Finland	2020	Non-significant	25818	10820	Type 1 and 2	22.8 ± 15.7
Chen et al.²³	Taiwan	2019	Lower risk (OR = 0.905, P < 0.05)	25713	NA	Type 1 and 2	12
Wu et al.⁷	China	2018	Higher risk (OR = 1.825, P = 0.035)	652	NA	Type 1 and 2	26.04 ± 8.14
Kossack et al.²²	Germany	2018	Non-significant	3025	920	Type 1 and 2	48
Praveen et al.²¹	India	2014	Non-significant	150	75	Type 1 and 2	48
Nekolová at al.²⁰	Slovakia	2008	Non-significant	140	36	Type 2	84
Ebihara et al.¹⁶	Japan	2006	Higher incidence (P = 0.002 at 6 months; P = 0.03 at 12 months)	84	42	Type 1 and 2	12
Elgohary & Dowler¹⁹	UK	2006	Lower risk (HR = 0.69, P = 0.047)	806	327	Type 1 and 2	48
Hayashi et al.¹⁵	Japan	2002	Higher incidence (P = 0.0139)	200	100	Type 1 and 2	36
Zaczek & Zetterstrom¹⁸	Sweden	1999	Lower incidence (P < 0.05)	52	26	Type 1 and 2	12
Ionides et al.¹⁴	UK	1994	Higher incidence (P = 0.04)	90	263	Type 1 and 2	12
Knorz et al.¹⁷	Germany	1991	Lower incidence (P = 0.05)	939	202	Type 1 and 2	NA
OR; odds ratio, HR; hazard ratio, PCO; posterior capsule opacification. NA = not applicable.

The difference between the two types of diabetes emerging from decades of observations and experiments was formally recognized in 1979 when the definitions for DM1 and DM2 were introduced (25). However, the limitation of a simple distinction between DM1 and DM2 has been increasingly recognized, with subjects showing the coexistence of insulin resistance and immune activation against β-cells. With advancing our cellular and molecular understanding of diabetes, a more pathophysiological classification that overcomes the historical and simple 'glucocentric' view could result in better patient phenotyping and therapeutic approach.

The proliferation of lens epithelial cells and the degree of post-operative inflammation are associated with the development of PCO. The inflammation causes epithelial cells to produce cytokines, which induce collagen production and fibrous metaplasia (16). The mechanisms include, e.g., activation and signaling of reactive oxygen species (ROS), nuclear factor kappa B (NF-κB) pathway and pro-inflammatory and -fibrotic cytokines, namely tumor necrosis factor-alpha (TNFα) and transforming growth factor-beta (TGFβ) (26, 27). Both humoral and cellular immunity involvement in DM type 1 pathogenesis might explain the increased risk of PCO in this subgroup and the effect of steroidal anti-inflammatory treatment to reduce the PCO rate over NSAIDs (non-steroidal anti-inflammatory drugs) alone (10).

The strength of this study is its real-world evidence (RWE) setting based on a large registry and long follow-up time. The limitation of our study includes several confounders, which we did not control. First, complicated surgeries were not identified and excluded from the registry. Surgical manipulation and complications may increase the risk for PCME (28, 29). Second, neither surgeon seniority nor surgical technique, IOL material and other lens properties (i.e., dioptric power and edge and haptic design) were recorded. These factors affect Nd:YAG laser capsulotomy rates (8, 9, 30). Third, we could not extract the data to analyze the effects of DM control, diabetic retinopathy stage, insulin dependence among DM2 patients, or systemic medication on post-operative complications. Recently, we found that diabetes alone did not impair recovery from routine cataract surgery, and systemic vasoactive mediations may have a bearing on the incidence of PCME (31, 32). Fourth, other ocular comorbidities and anti-inflammatory medication for cataract surgery were beyond the scope of the study. Fifth, Nd:YAG laser capsulotomy is a surrogate marker for PCO. It should be acknowledged that the study results may be biased as typical patients with ocular comorbidities (i.e., diabetic posterior segment complications) visit ophthalmic healthcare specialists more frequently. Impaired visual acuity in pseudophakic patients, due to any ground reason, may lead to Nd:YAG laser capsulotomy with lower indication compared to those without any vision-impairing comorbidity. We could not retrieve BCVA before and after the Nd:YAG laser capsulotomies. BCVA (gain and absolute values) is not the optimal parameter to analyze the surgery outcomes or the need for Nd:YAG laser capsulotomy. PCO affects contrast sensitivity, dysphotopsia, and other problems related to the quality of vision, and so does diabetic retinopathy (32). Thus, we would need visual function questionnaires to estimate the morbidity due to PCO. Sixth, pseudoexfoliation syndrome was previously reported as a risk factor for PCME (33, 34). Nevertheless, since its prevalence was low in this patient population and the baseline differences between the groups were non-significant, we omitted PXF as a confounder in the multivariate analysis. Finally, we did not assess glucose variability, glycemic control, and the length of disease in years, which may act as confounders (35).

In conclusion, in our large real-world evidence study, especially the DM1 subtype predisposed to high risk for PCME and Nd:YAG laser capsulotomies. These findings could expand our understanding of the potential mechanisms, preventive measures and therapeutic targets against late-onset complications. Our study provides data to give better risk levels for requiring Nd:YAG laser capsulotomy or for additional treatment against PCME based on the type of DM. Furthermore, we hope our findings will stimulate future prospective and more comprehensive studies to better predict and identify patients at risk so appropriate preventive measures before surgery can be used. The differences between the two types of diabetes should also encourage future clinical studies in determining and representing cataract surgery outcomes regarding the type of diabetes.

Acknowledgments: The authors have neither proprietary nor commercial interests in any medications or materials discussed in this study. Dr. Tuuminen is a scientific adviser (advisory board, honoraria) to Alcon Laboratories, Inc., Allergan, Inc., Bayer AG and Novartis AG, and has received clinical trial support (study medicines) from Bayer AG and Laboratoires Théa.

Conflicts of Interest: No conflicting relationships exist for any author.

Funding: None.

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There is no conflict of interest

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Version 1

posted

You are reading this latest preprint version

Eyes from Type 1 diabetes patients are associated with higher post-operative complications rates than those from Type 2 diabetes patients

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusions

Figures

Introduction

Methods

Study design

Data acquisition and subjects

Statistical analyses

Results

Discussion

Declarations

References

Additional Declarations

Status:

Version 1