
==== Front
Medicine (Baltimore)
Medicine (Baltimore)
MD
Medicine
0025-7974
1536-5964
Lippincott Williams & Wilkins Hagerstown, MD

39029073
MD-D-23-11592
00075
10.1097/MD.0000000000039026
3
4300
Research Article
Observational Study
Retinopathy risk factors in patients with type 2 diabetes on liraglutide
https://orcid.org/0000-0002-6796-9428
Mahzari Moeber M. MBBS abc*
Alanazy Abdulmalik M. alanazy201@ksau-hs.edu.sa
ab
Feroz Zeeshan PhD ferozz@ksau-hs.edu.sa
bd
Almani Khalid M. almani394@ksau-hs.edu.sa
ab
Alghamdi Meshari A. alghamdi105@ksau-hs.edu.sa
ab
Almadani Abdulaziz S. almadani312@ksau-hs.edu.sa
ab
Alzahrani Majed K. alzahrani339@ksau-hs.edu.sa
ab
Alibrahim Ahmed R. MD alibrahim.md@gmail.com
bc
Badri Motasim PhD badrim@ksau-hs.edu.sa
be
a College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
b King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
c Department of Medicine, Ministry of the National Guard-Health Affairs, Riyadh, Saudi Arabia
d Basic Sciences Department, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
e Department of Epidemiology and Biostatistics, College of Public Health and Health Informatics, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
* Correspondence: Moeber M. Mahzari, King Saud bin Abdulaziz University for Health Sciences, 3130, P.O. Box 3660, Riyadh, 11481, Kingdom of Saudi Arabia (e-mail: Moeber@hotmail.com, MahzariM@ksau-hs.edu.sa).
19 7 2024
19 7 2024
103 29 e3902623 12 2023
30 5 2024
01 7 2024
Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Liraglutide, a glucagon-like peptide 1 receptor agonist, effectively treats type 2 diabetes(T2D) by lowering glucose levels, suppressing glucagon release, and promoting insulin secretion. Liraglutide has been shown to reduce body weight and glycated hemoglobin (HbA1c) levels and improve cardiovascular outcomes. However, evidence regarding the association between liraglutide and diabetic retinopathy in the Middle East is insufficient. Therefore, this study aimed to investigate the characteristics and risk factors of diabetic retinopathy in patients with T2D treated with liraglutide in Saudi Arabia. This retrospective cohort study was conducted on patients (≥14 years) with T2D treated with liraglutide between 2015 and 2021, who had a documented retinopathy assessment at baseline before liraglutide initiation and during follow-up, at King Abdulaziz Medical City (KAMC), Riyadh. Data collection included demographic information, retinopathy status, body mass index (BMI), and HbA1c level at baseline and follow-up after liraglutide use. The study included 181 patients with a mean age of 58.2 (9.8) years. Of these, 72.9% were females. At baseline, the median weight (interquartile range) was 88 (77–100) kg, diabetes duration was 19 (13–23.5) years, and HbA1c level was 9% (8–10%). Total of 69.6% were on insulin, 22.7% were on oral hypoglycemic agents, and 7.7% were on no other medications in addition to liraglutide. After a median of 2 years follow-up, both HbA1c level and weight decreased significantly (P < .001). Seventy-one of the 87 patients (81.6%) without retinopathy at baseline continued to show no retinopathy. Among patients with retinopathy at baseline, 25.5% showed improvement and 44.7% showed no change. In the multivariate binary mixed effect analysis, factors significantly associated with retinopathy were: use of insulin (odds ratio [OR]:2.68; 95% confidence interval [CI]: 1.18–6.09, P = .019), older age (OR:1.03; 95% CI: 1.00–1.06; P = .022), higher HbA1c level (OR:1.17; 95% CI: 1.02–1.34; P = .024), Hypertension (OR:2.56; 95% CI: 1.13–5.76; P=<.0001) and longer diabetes duration (OR:1.04; 95% CI: 1.00–1.08; P = .024). In conclusion, liraglutide use caused significant reductions in the HbA1c level and weight of patients with T2D. Most patients showed no change in retinopathy status after liraglutide use.

liraglutide
retinopathy
type 2 diabetes
OPEN-ACCESSTRUE
==== Body
pmc1. Introduction

Type 2 diabetes mellitus (T2D) is a highly prevalent disease affecting approximately 10% of adults worldwide.[1] Saudi Arabia has one of the highest prevalence rates of T2D, affecting approximately 16% of the population.[2,3] T2D poses challenges in terms of glycemic control and complications. Despite significant advancements in treatment, most patients still have poor disease control.[4] Poorly controlled T2D is associated with increased morbidity and mortality, mainly due to microvascular and macrovascular complications.[5] Retinopathy is a common complication, affecting at least one-third of patients with T2D and leading to high morbidity.[6]

Several drug classes are effective in the glycemic control of patients with T2D. These include glucagon-like peptide 1 receptor agonists (GLP-1RAs), which suppress glucagon and stimulate insulin secretion.[7] In fact, patients taking liraglutide, a GLP-1RA, not only have controlled blood glucose levels but also experience a reduction in their body weight and have better cardiovascular outcomes.[8]

To the best of our knowledge, the effects of liraglutide on diabetic retinopathy have not been adequately studied. In 2016, the long-term effects of liraglutide in patients with T2D were examined using the LEADER study.[9] After a median follow-up of nearly 4 years, it was concluded that the liraglutide group had a reduction in the study primary outcomes: cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. However, the incidence of retinopathy was higher in the liraglutide group, although the difference was not statistically significant. A cohort study conducted in the United Kingdom from 2007 to 2015 reported that GLP-1RAs reduced the incidence of diabetic retinopathy events by 33% compared with insulin.[10] In addition, a study on the effect of topical liraglutide on the retina concluded that it prevented retinal neurodegeneration.[11] Liraglutide was found to promote the activation of the protein kinase B pathway, which is important for the maintenance of retinal neurons.[12,13]

Currently, GLP-1RAs, including liraglutide, are widely used to treat patients with T2D. As diabetic retinopathy is a well-known microvascular consequence of T2D, it is critical to determine the relationship between liraglutide and retinopathy. Few studies have been conducted on diabetic retinopathy in patients taking liraglutide in the Middle East. Therefore, this study aimed to investigate the characteristics and risk factors of diabetic retinopathy in patients with T2D treated with liraglutide in King Abdulaziz Medical City (KAMC), Riyadh, Saudi Arabia.

2. Material and methods

This retrospective cohort study was conducted at KAMC, Riyadh. The study population included adult and adolescent patients (≥14 years) with T2D, treated with liraglutide between 2015 and 2021, who had a documented retinopathy assessment at baseline before liraglutide initiation and during follow-up. Patients treated with a GLP-1RA other than liraglutide or those whose retinopathy status was not assessed by an ophthalmologist were excluded. Data were collected by reviewing patients’ medical records using a structured data collection form. The data included demographic information, duration of diabetes, medication, glycated hemoglobin (HbA1c) level, weight, and retinopathy status at baseline and during follow-up. The retinopathy status at baseline and follow-up was recorded from the ophthalmology clinical records. At baseline, retinopathy status was categorized according to whether the patient had retinopathy (of any type) or not. At follow-up, retinopathy status was categorized as improved, worsened, or unchanged in patients with retinopathy at baseline, whereas it was categorized as either developed or not developed in patients without retinopathy at baseline.

2.1. Statistical methods

Descriptive statistics were used to summarize the data. Categorical data are expressed as frequencies (%) and continuous data as means and standard deviations (SDs) or medians and interquartile ranges (IQRs). The χ2 test was used to compare categorical data and the Wilcoxon test for continuous data. A longitudinal binary mixed-effects analysis was performed to identify factors associated with retinopathy. These factors included age, sex, weight, HbA1c level, duration of diabetes, hypertension and anti-hyperglycemic medications, in addition to liraglutide. The variables found to be significant in the univariate analysis were used to fit the final multivariate model. Data were analyzed using IBM SPSS version 27.0 (IBM, Armonk, NY, USA). All tests were 2-sided and a P value of <.05 was considered significant.

2.2. Ethical considerations

Ethical approval was obtained from the Institutional Review Board of King Abdullah International Medical Research Center, Riyadh, Saudi Arabia on July 14, 2021 (approval number: SP21R/254/05; Memo. Ref. No. IRBC/1474/21). The need for informed consent was waived due to the retrospective nature of the study.

3. Results

This study included 181 patients with T2D who received liraglutide. The mean age (SD) was 58.2 (9.8) years, and 72.9% of the patients were female. Retinopathy was present in 94 (51.9%) patients at baseline, before liraglutide initiation. At baseline, the median weight (IQR) was 88 (77–100) kg, diabetes duration was 19 (13–23.5) years, HbA1c level was 9% (8–10%), and body mass index (BMI) was 35 (31–40) kg/m2. Majority of the study sample had hypertension on treatment 162 (89.5%) and dyslipidemia on statin therapy 177 (97.8%). The majority 126 (69.6%) of the patients were taking insulin, 41 (22.7%) were taking oral hypoglycemic agents, and 14 (7.7%) were taking no other medications in addition to liraglutide. The median follow-up time was 2 years (Table 1).

Table 1 Patients’ demographic and clinical characteristics.

Characteristic		
Gender
 Male, n(%)	
49 (27.1)	
 Female, n(%)	132 (72.9)	
Age (yr), Mean (SD)	58.2 (9.8)	
Patients with retinopathy at baseline, n(%)	94 (51.9)	
Hypertension, n(%)	162 (89.5)	
Dyslipidemia, n(%)	177 (97.8)	
Follow-up duration, yr, Median (IQR)	2 (2–3)	
Duration of diabetes, Median (IQR)	19 (13–23.5)	
Weight, kg, Median (IQR)	88 (77–100)	
BMI, Median (IQR)	35 (31–40)	
HbA1c, Median (IQR)	9 (8–10)	
Anti-hyperglycemic Medications in addition to liraglutide, n(%)		
 Insulin	126 (69.6)	
 Oral hypoglycemic agents	41 (22,7)	
 No other medications	14 (7.7)	
BMI = body mass index, IQR = interquartile range, SD = standard deviation.

The entire study population showed a significant reduction in HbA1c levels during follow-up, with a median of 8% compared with 9% at baseline (P < .001; Fig. 1). Weight also showed a significant reduction during follow-up, with a median of 87 kg compared with 89 kg at baseline (P < .001; Fig. 2).

Figure 1. Comparison of HbA1c levels at baseline and follow-up visit (Wilcoxon test P < .001) HbA1c = glycated hemoglobin.

Figure 2. Comparison of body weight at baseline and follow-up visit (Wilcoxon test P < .001).

Table 2 shows a comparison of patients with and without retinopathy, both at baseline and during follow-up, according to demographic and clinical variables. At baseline, patients with retinopathy were slightly older [median age: 61 (IQR: 55.5–65) vs 58 (IQR: 50–64), respectively; P = .043] and had a longer duration of diabetes, 20 (15–25) vs 15 (10–22) years, respectively; P = .004) compared with those without retinopathy. More patients with retinopathy had hypertension compared to patients without retinopathy, 91 (96.8%) vs 71 (81.6%), P = .001. Sex distribution, median BMI, and median HbA1c level did not differ significantly between the 2 groups. Similar results were obtained at follow-up. In addition, the HbA1c level median was similar in the 2 groups but the IQR was significantly higher in those with retinopathy [8 (8–10) vs 8 (7–9)], respectively; P = .015). Also, all patients with retinopathy,110 (100%), had dyslipidemia vs 67 (94.4%) of the patients without retinopathy, P = .012.

Table 2 Comparison of patients with and without retinopathy.

Characteristic	Baseline retinopathy status	Follow-up retinopathy status	
Retinopathy	No retinopathy	P	Retinopathy	No retinopathy	P	
Age	61 (55.5–65)	58 (50–64)	.043	61 (56–65)	56 (50–64)	.043	
Gender, n(%)	.542			.542	
 Male	26 (27.7)	23 (26.4)	28 (25.5)	21 (29.6)	
 Female	68 (72.3)	64 (73.6)	82 (74.5)	50 (70.4)	
Duration of diabetes	20 (15–25)	15.5 (10–22)	.004	20 (15–25)	16 (10–22)	.004	
BMI (kg/m2)	37 (32–40)	35 (31–40)	.453	36 (32–40)	34 (31.8–38)	.263	
Hypertension	
 Yes	91 (96.8)	71 (81.6)	.001	103 (93.6)	59 (83.1)	.024	
 No	3 (3.2)	16 (18.4)		7 (6.4)	12 (16.9)		
Dyslipidemia	
 Yes	94 (100)	83 (95.4)	.051	110 (100)	67 (94.4)	.012	
 No	0	4 (4.6)		0	4 (5.6)		
HbA1c (%)	9 (8–10)	9 (8–10)	.429	8 (8–10)	8 (7–9)	.015	
Unless otherwise stated, numbers are Median (IQR)

BMI = body mass index.

During follow-up, 71 (81.6%) of the 87 patients who had no retinopathy at baseline continued to have no retinopathy, whereas 16 (18.4%) developed retinopathy.

Among the patients with retinopathy at baseline: 24 (25.5%) showed improvement, 42 (44.7%) showed no change, and the remaining 28 (29.8%) showed worsening retinopathy status.

In the univariate mixed-effects binary analysis, the factors significantly associated with retinopathy were: age, HbA1c level, duration of diabetes, hypertension and insulin. Similarly, in the final multivariate analysis, the factors that were independently associated with retinopathy were insulin use (odds ratio [OR]:2.68; 95% confidence interval [CI]: 1.18–6.09; P = .019), age (OR:1.03; 95% CI: 1.00–1.06; P = .022), HbA1c level (OR:1.17; 95% CI: 1.02–1.34; P = .024), hypertension (OR:2.56; 95% CI: 1.13–5.76; P=<.0001), and diabetes duration (OR:1.04; 95% CI: 1.00–1.08; P = .024) (Table 3).

Table 3 Longitudinal binary mixed effect analysis for factors associated with retinopathy.

Factor	Univariate analysis	Multivariate analysis	
OR(95%CI)	P	OR(95%CI)	P	
Age	1.04 (1.00–1.07)	<.0001	1.03 (1.00–1.06)	.022	
HbA1c	1.17 (1.04–1.33)	.010	1.17 (1.02–1.34)	.024	
Hypertension	4.18 (1.96–8.89)	<.0001	2.56 (1.13–5.76)	<.0001	
Diabetes duration	1.06 (1.03–1.09)	<.0001	1.04 (1.00–1.08)	.024	
Anti-hyperglycemic medications in addition to liraglutide	
 Insulin	2.28 (1.03–5.03)	.041	2.68 (1.18–6.09)	.019	
 Oral hypoglycemic agents	0.90 (0.38–2.14)	.81	1.22 (0.50–3.02)	.663	
 No other medications	1		1		
OR = Odds ratio. P = Wald test.

4. Discussion

GLP-1RAs lead to significant weight loss and HbA1c reduction in patients with T2D. In this study, the median weight loss with liraglutide was 2 kg, and the median HbA1c reduction was 1%, which is consistent with previous studies.[8,9,14] GLP-1RAs, particularly liraglutide, have beneficial effects beyond glycemic control and cardiovascular benefits. Rizza et al demonstrated that liraglutide in combination with degludec insulin increases the beneficial gut microbiome Alistipes. This microbiome has been linked to healthy aging, appetite control, reduction of neuroinflammation with cognitive improvement, and normalization of glucose homeostasis.[15] Although these effects are beyond the scope of this study, the association of this combination with beneficial effects on diabetic complications such as retinopathy should be further studied.

Diabetic retinopathy is a common complication of T2D, affecting 22% to 36% of patients with T2D worldwide[6] and 30% to 40% in Saudi Arabia.[16,17] In contrast, in this study, half of the cohort had retinopathy at baseline, which may be due to the older age and longer duration of diabetes in the cohort.

Some studies have reported that patients with T2D treated with GLP-1RAs, including liraglutide, may be at risk of retinopathy progression.[9,18] In contrast, other studies confirmed the safety and even a possible protective effect of liraglutide against retinopathy.[19–21] However, it is important to note that these studies differed in terms of study design, sample size, and follow-up duration, which may explain these conflicting results.

In this study, although more patients developed retinopathy during follow-up, the difference was not statistically significant. The majority of patients who did not have retinopathy at baseline also did not have retinopathy after an average of 2 years of liraglutide treatment. Moreover, most patients who had retinopathy at baseline showed improvement or no change in their retinopathy status. To some extent, our findings confirm the safety of liraglutide from the perspective of retinopathy. However, the study was limited in its ability to draw firm conclusions regarding the association between liraglutide and retinopathy because the study design was retrospective and there was no control arm.

Previous studies have shown that the risk factors for developing retinopathy include older age, insulin use, longer duration of diabetes, poor glycemic control, hypertension and rapid decline in HbA1c.[16,22] This study also found that older age, higher HbA1c levels, longer duration of diabetes, hypertension and insulin use were significantly associated with retinopathy in the group of patients taking liraglutide. Dyslipidemia with high LDL cholesterol and triglycerides have been also associated with the development of diabetic retinopathy.[23] In this study, majority of the study sample (98%) had dyslipidemia and were on statin therapy, and all the patients with retinopathy either at baseline or at follow-up had dyslipidemia.

In the LEADER study, retinopathy was not significantly higher in patients taking liraglutide. However, the study was not powered to evaluate retinopathy outcomes; therefore, the risk factors for retinopathy were not described.[9] A limited number of studies have examined the association between retinopathy and liraglutide. A few systematic reviews and meta-analyses have assessed the effects of different GLP-1RAs on retinopathy. For example, a meta-analysis that included 6 studies on different GLP-1RAs, including the LEADER trial of liraglutide, showed no overall association between retinopathy and GLP-1RAs; however, there was substantial heterogeneity within the studies. Nonetheless, this metanalysis showed that poor glycemic control at baseline and a rapid and dramatic reduction in HbA1c were risk factors for the development of retinopathy. In contrast, studies with longer follow-up periods showed a protective effect of GLP-1RAs on retinopathy after transient worsening at 6–12 months, independent of the change in HbA1c.[10] In this study, patients with retinopathy had significantly higher range of HbA1c levels at follow-up, confirming that persistent poor glycemic control is a risk factor for the progression of retinopathy. Hence, patients who start liraglutide therapy with high HbA1c levels at baseline and continue to have relatively poor glycemic control at follow-up, are likely to be at a higher risk for retinopathy.

Our study showed that patients taking insulin and liraglutide had a higher risk of retinopathy than those taking liraglutide alone or liraglutide and an oral hypoglycemic agent. The risk of retinopathy associated with insulin use is well established.[24] Similar to the effects of GLP-1RAs, rapid improvements in blood glucose levels have been identified as a likely cause of diabetic retinopathy in insulin-treated patients.[24] Similar to the results of our study, insulin use with GLP-1RAs has been associated with an increased risk of retinopathy.[10]

In conclusion, we found that the majority of patients with T2D who received liraglutide experienced an improvement or no change in their retinopathy status. Older age, poor glycemic control, longer duration of diabetes, hypertension and possibly dyslipidemia, are associated with a higher risk of developing and worsening retinopathy.

To the best of our knowledge, this is the first study to examine retinopathy associated with liraglutide use in Saudi Arabia and the Middle East. However, this study had some limitations that should be considered, including its single-center and retrospective design, the variable and relatively short follow-up period, and the possibility of variation between ophthalmologist assessments of retinopathy. Therefore, the study findings cannot be generalized to the entire population of patients with T2D. Future prospective studies investigating the effects of liraglutide and potential risk factors for retinopathy are needed.

5. Conclusion

Liraglutide significantly reduced the body weight and HbA1c levels of patients with T2D. Furthermore, the retinopathy status improved or remained unchanged with liraglutide use in most patients. Moreover, we found that older age, poor glycemic control, longer duration of diabetes and hypertension were risk factors for retinopathy in patients taking liraglutide. Future multi-center prospective studies are needed to further investigate the characteristics and association between liraglutide use and diabetic retinopathy.

Acknowledgments

We are grateful to Ms. Atika Al Sudairi of the Office of Research for her assistance during the copy-editing phase. We would like to thank Editage (www.editage.com) for their writing support on the manuscript.

Author contributions

Conceptualization: Moeber M. Mahzari, Abdulmalik M. Alanazy, Zeeshan Feroz, Khalid M. Almani, Meshari A. Alghamdi, Abdulaziz S. Almadani, Majed K. Alzahrani, Ahmed R. Alibrahim.

Data curation: Moeber M. Mahzari, Abdulmalik M. Alanazy, Khalid M. Almani, Meshari A. Alghamdi, Abdulaziz S. Almadani, Majed K. Alzahrani, Ahmed R. Alibrahim.

Formal analysis: Moeber M. Mahzari, Abdulmalik M. Alanazy, Motasim Badri.

Investigation: Moeber M. Mahzari, Abdulmalik M. Alanazy, Khalid M. Almani, Meshari A. Alghamdi, Abdulaziz S. Almadani, Majed K. Alzahrani, Ahmed R. Alibrahim, Motasim Badri.

Methodology: Moeber M. Mahzari, Abdulmalik M. Alanazy, Khalid M. Almani, Meshari A. Alghamdi, Abdulaziz S. Almadani, Majed K. Alzahrani, Ahmed R. Alibrahim, Motasim Badri.

Project administration: Moeber M. Mahzari, Abdulmalik M. Alanazy, Zeeshan Feroz.

Resources: Moeber M. Mahzari, Abdulmalik M. Alanazy.

Software: Moeber M. Mahzari, Abdulmalik M. Alanazy.

Supervision: Moeber M. Mahzari, Zeeshan Feroz, Motasim Badri.

Validation: Moeber M. Mahzari, Abdulmalik M. Alanazy, Zeeshan Feroz, Khalid M. Almani, Meshari A. Alghamdi, Abdulaziz S. Almadani, Majed K. Alzahrani, Ahmed R. Alibrahim, Motasim Badri.

Visualization: Moeber M. Mahzari, Abdulmalik M. Alanazy, Zeeshan Feroz, Khalid M. Almani, Meshari A. Alghamdi, Abdulaziz S. Almadani, Majed K. Alzahrani, Ahmed R. Alibrahim, Motasim Badri.

Writing – original draft: Moeber M. Mahzari, Abdulmalik M. Alanazy, Khalid M. Almani, Meshari A. Alghamdi, Abdulaziz S. Almadani, Majed K. Alzahrani, Ahmed R. Alibrahim.

Writing – review & editing: Moeber M. Mahzari, Zeeshan Feroz, Motasim Badri.

Abbreviations:

BMI body mass index

GLP-1RAs glucagon-like peptide 1 receptor agonists

HbA1c hemoglobin A1c

IQRs interquartile ranges

KAMC King Abdulaziz Medical City

SDs standard deviations

T2D type 2 diabetes

The requirement for written consent was waived due to the retrospective nature of the study.

Ethical approval was obtained from the Institutional Review Board of the King Abdullah International Medical Research Center (reference number: SP21R/254/05, date 14/7/2021).

The authors have no conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

How to cite this article: Mahzari MM, Alanazy AM, Feroz Z, Almani KM, Alghamdi MA, Almadani AS, Alzahrani MK, Alibrahim AR, Badri M. Retinopathy risk factors in patients with type 2 diabetes on liraglutide. Medicine 2024;103:29(e39026).
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