Change on glycosylated hemoglob with glucagon-like peptide-1 receptor agonists affecting the progress of diabetes retinopathy in type 2 diabetes– A systematic review and meta-analysis

Change on glycosylated hemoglob with glucagon-like peptide-1 receptor agonists affecting the progress of diabetes retinopathy in type 2 diabetes– A systematic review and meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Change on glycosylated hemoglob with glucagon-like peptide-1 receptor agonists affecting the progress of diabetes retinopathy in type 2 diabetes– A systematic review and meta-analysis wenxuan Wang, jingyi Lu, jing Li, yuchen Ma, xin Wang, fang Zhang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3834867/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background ：Whether glucagon-like peptide-1 receptor agonists(GLP-1RA) has adverse effects on diabetes retinopathy(DR) due to blood glucose control is unclear.The main purpose of this article is to evaluate the effect of GLP-1RA or GLP-1RA combined with insulin on DR by inducing different degrees of glycosylated hemoglob(HbAlc). Methods ：This is a meta-analysis of 20 randomized controlled trial which including a total of 56204 type 2 diabetes(T2DM) patients.We used risk ration(RR) and 95% cofidence intervals(CIs) to estimate the influence of varying descending HbAlc levels in DR. Results ：GLP-1RA does not increase the risk of DR in T2DM,IDegLira was associated with an increased risk of DR (RR 1.69 95% CI 1.11-2.57), while the use of liraglutide did not increase the risk of DR (RR 0.70, 0.48-1.01). In the group with baseline glycation levels＜8.5% in the first 12 weeks, a decrease of over 1.5% in glycated hemoglobin was associated with an increased risk of DR (RR 1.75 95% CI 1.01-3.04), a decrease of 1% -1.5% in glycated hemoglobin reduced the risk of DR (RR 0.59 95% CI 0.37-0.93), and a decrease of＜1% in glycated hemoglobin was not associated with DR (RR 1.25 95% CI 0.93-1.69). In the group with baseline glycation levels ≥ 8.5% in the first 12 weeks, the decrease in glycated hemoglobin by more than 1.5% (RR 0.95 95% CI 0.66-1.38) and less than 1% (RR 0.77 95% CI 0.39-1.51) had no effect on DR. In the group with baseline glycation levels＜8.5% in the first 8 weeks, a decrease of 1% -1.5% in glycated hemoglobin (RR 0.94 95% CI 0.42-2.06), a decrease of less than 1% in glycated hemoglobin (RR 1.26 95% CI 0.62-2.59), and a decrease of more than 1.5% (RR 1.40 95% CI 0.68-2.87) had no effect on DR. In the group with baseline glycation levels ≥ 8.5% in the first 8 weeks, a decrease of less than 1% (RR 0.77 95% CI 0.39-1.51), and a decrease of 1% -1.5% (RR 1.09 95% CI 0.71-1.66) had no effect on DR. In the group with baseline glycation levels＜8.5% in the first 4 weeks, a decrease less than 0.5% (RR1.47 95% CI 0.47-4.58), 0.5% -＜1% (RR0.85 95% CI 0.30-2.46), and 1% -＜1.5% (RR1.40 95% CI 0.68-2.87) in glycated hemoglobin did not affect DR. In the group with baseline glycation levels ≥ 8.5%, a decrease of 0.5% -＜1% (RR0.99 95% CI 0.69-1.41) in glycated hemoglobin did not affect DR.The use of GLP-1RA combined with insulin did not increase the risk of DR (RR 1.24, 95% CI 0.90-1.71),however in the group with baseline glycation levels＜8.5% in the first 12 weeks,a decrease of over 1.5% in glycated hemoglobin was associated with an increased risk of DR (RR 1.75 95% CI 1.01-3.04). Conclusions ：When GLP-1RA is applied in T2DM patients with HbAlc level under 8.5%, controlling the decrease of HbAlc by 1% -1.5% in the first 12 weeks can reduce the risk of DR, and the decrease of HbAlc by more than 1.5% will increase the risk of DR.GLP-1RA combined with insulin does not show the risk of DR. The promoting effect by IDegLira in DR may be mediated by the quick variation of blood glucose. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Background Diabetes is a chronic disease characterized by insulin deficiency and insulin resistance. In 2022, about 537 million adults worldwide sufferred from diabetes, nearly 90% of whom will be type 2 diabetes. Its own and long-term complications are becoming important factors affecting modern people's health and quality of life[1]. Diabetes retinopathy is a complication of diabetes microvascular disease. About 30–40% of diabetes patients can develop into diabetes retinopathy (DR) [2, 3]. Currently, over 100 million people worldwide suffer from DR, especially among adults of working age, which is the main cause of blindness and visual impairment[2, 4] Glucagon like peptide-1 receptor agonist (GLP-1RA), a blood glucose dependent hypoglycemic agent, has advantages such as good blood glucose control, significant weight loss effects, and cardiovascular benefits. There is still significant controversy over whether GLP-1RA has adverse effects on DR. Some trials support the use of GLP-1RA, especially semaglutide, which increases the risk of DR [5, 6], while others show neutral results [7]. Studies have observed that early strengthening of blood glucose control may worsen DR [8–13]. The purpose of this study is to explore the relationship between the change of HbAlc and DR in the early stage of type 2 diabetes treated with different types of GLP-1RA. Methods Result analysis and systematic evaluation of included randomized controlled trials are based on PRISMA. Search strategy and searches From the establishment of the database until March 27, 2023, we searched for eligible literature through Embase, Pubmed, and Cochrane, limiting the language of the literature to English.Our search terms are as follows:“Type 2 diabetes mellitus（All Fields）”，“diabetic retinopathy（All Fields）”，“GLP-1RA（Tile，Abstract or Auther Keywords）”“Glucagon-like peptide-1 receptor agonists”，“Liraglutide”，“Semaglutide”，“Dulaglutide”，“Albiglutide”，“Exenatide”，“Lixisenatide”，“IDegLira”，“IGlarLixi”，“insulin degludec/liraglutide”.In addition, we also supplemented the list of references such as articles, metas, and reviews that meet the search criteria. Data selection One researcher exported the database to NoteExpress, where he deleted duplicate literature, and screened RCTs by reading literature abstracts and methods. If the article lacks specific information on evaluating the outcome indicators of GLP-1RA in the treatment of type 2 diabetes, or if ADA believes that there may be ASCVD or renal function risk, GLP-1RA will be excluded. A complete study selection process is shown in Fig. 1. Data extraction and quality assessment Inclusion criteria: (1) The research type is RCT; (2) The diagnosis of type 2 diabetes of the subjects was clear, and the age was ≥ 18 years old; (3) The intervention measures are GLP-1RA or GLP-1RA combined with insulin mixture, with a duration of ≥ 12 weeks; (4) Outcome indicators: glycated hemoglobin (HbA1c), diabetes retinopathy (DR). Exclusion criteria: (1) Articles without DR related information; (2) Articles where the experiment is suspended, there are no results, or the result data is not standardized and cannot be applied; (3) The control group and experimental group are both articles of GLP-1RA; (4) The subjects included people with non type 2 diabetes;(5)Control groups are DDP-IV. Two researchers independently read the literature title, abstract, and full text, screened the literature based on inclusion and exclusion criteria, extracted relevant data, and used the Cochrane Bias Risk Assessment Tool (ROB) for quality evaluation; Cross check the data results and discuss and resolve any disagreements. Analysis To test the relationship between GLP-1RA and DR by calculating relative risk (RR) and 95% confidence interval (CI). Conduct heterogeneity testing on the included studies, and if there is no heterogeneity (P ≥ 0.05, I 2 ≤ 50%), select a fixed effects model; Instead, select a random effects model and conduct subgroup analysis to analyze the sources of heterogeneity. Use a funnel plot and Egger's test for publication bias analysis. Use ROB for risk bias analysis. with α = 0.05 is used as the inspection level. Results A total of 661 articles were retrieved from four databases (search results from the establishment of the database to March 27, 2023), including 429 Embase articles, 100 Pubmed articles, 132 Cochrane articles, and 352 repetitions. The remaining 309 articles were screened for titles and abstracts, and 150 unrelated articles were selected. The remaining 159 articles were further read in full, with a total of 65 reviews, metas, case studies, conference papers, comments, communications, guidelines, and consensus selected,37 irrelevant study type(retrospective studies, cohort studies, post hoc analysis, real-world studies, animal experiments, and in vitro cell studies), 2 no articles, 14 registered trials or trial protocols and 41 RCTs.There were 41 RCTs, including 18 that did not meet the inclusion and exclusion criteria, and 3 that did not have DR results. A total of 20 RCT studies were finally included, of which 9 were related to semaglutide (5 were oral semaglutide and 4 were subcutaneous injection semaglutide), 4 were related to liraglutide, 1 was dulaglutide, 2 were abiglutide and 1 was exenatide weekly preparation. (Fig. 1)Among them, 12 RCTs’ control groups were placebo, 2 control groups were SGLT-2 inhibitors (empagliflozin,Canagliflozin),3 control groups are insulin (including lispro conbined with insulin glargine or degludec) and the rest of them are glinide,metformin, a-glucosidase inhibitor or thiazolidinedione(Table 2). The number of patients enrolled in 20 RCTs was 56204, including 33825 men (60%) and 22379 women (40%), with an average age of 62.64 years (54.7–66.2 years), an average follow-up time of 75.6w (26w-240w), an average BMI of 31.90 (24.8–35.7), an average HbA1c of 8.30% (7.3% -9.3%), and an average history of diabetes of 12.46 years (3.5–14.9 years)(Table 1). In different categories of GLP-1RA, it was found that IDegLira was associated with an increased risk of DR (RR 1.69 95% CI 1.11–2.57), while the use of semaglutide (RR 1.20 95% CI 0.99–1.44), Abiglutide (RR 0.86 95% CI 0.65–1.13), and liraglutide (RR 0.70,95% CI 0.48–1.01) did not increase the risk of DR(Fig. 2). The use of GLP-1RA combined with insulin did not increase the risk of DR (RR 1.24, 95% CI 0.90–1.71),however in the group with baseline glycation levels＜8.5% in the first 12 weeks,a decrease of over 1.5% in glycated hemoglobin was associated with an increased risk of DR (RR 1.75 95% CI 1.01–3.04)(Fig. 9,Fig. 10). In the group with baseline glycation levels＜8.5% in the first 12 weeks, a decrease of over 1.5% in glycated hemoglobin was associated with an increased risk of DR (RR 1.75 95% CI 1.01–3.04), a decrease of 1% -1.5% in glycated hemoglobin reduced the risk of DR (RR 0.59 95% CI 0.37–0.93), and a decrease of＜1% in glycated hemoglobin was not associated with DR (RR 1.25 95% CI 0.93–1.69). In the group with baseline glycation levels ≥ 8.5% in the first 12 weeks, the decrease in glycated hemoglobin by more than 1.5% (RR 0.95 95% CI 0.66–1.38) and less than 1% (RR 0.77 95% CI 0.39–1.51) had no effect on DR(Fig. 3,Fig. 6). In the group with baseline glycation levels＜8.5% in the first 8 weeks, a decrease of 1% -1.5% in glycated hemoglobin (RR 0.94 95% CI 0.42–2.06), a decrease of less than 1% in glycated hemoglobin (RR 1.26 95% CI 0.62–2.59), and a decrease of more than 1.5% (RR 1.40 95% CI 0.68–2.87) had no effect on DR. In the group with baseline glycation levels ≥ 8.5% in the first 8 weeks, a decrease of less than 1% (RR 0.77 95% CI 0.39–1.51), and a decrease of 1% -1.5% (RR 1.09 95% CI 0.71–1.66) had no effect on DR(Fig. 4,Fig. 7).In the group with baseline glycation levels＜8.5% in the first 4 weeks, a decrease less than 0.5% (RR1.47 95% CI 0.47–4.58), 0.5% -＜1% (RR0.85 95% CI 0.30–2.46), and 1% -＜1.5% (RR1.40 95% CI 0.68–2.87) in glycated hemoglobin did not affect DR. In the group with baseline glycation levels ≥ 8.5%, a decrease of 0.5% -＜1% (RR0.99 95% CI 0.69–1.41) in glycated hemoglobin did not affect DR(Fig. 5,Fig. 8). Begger's analysis showed no publication bias with P＞0.05, and the overall quality of 20 articles in risk assessment was relatively high(Fig. 11,Fig. 12). Discussion In recent years, some large-scale RCT trials of GLP-1RA have been conducted (such as SUSTAIN6) and related meta-analyses have gradually raised concerns about whether the use of GLP-1RA poses DR risk. Our analysis shows that the use of GLP-1RA does not increase the risk. Among different types of GLP-1RA or GLP-1RA combined with insulin, only the combination of insulin and liraglutide shows a significant DR risk. Previous studies have confirmed that rapid blood glucose control can worsen preexisting DR[32]. Compared to traditional therapies such as 1–2 insulin injections per day, dietary control, and exercise, the use of insulin pump intensification therapy leads to a significant increase in early DR deterioration within six months and or one year (OR2.06, P＜0.001).The results of a meta-regression analysis suggest that when using GLP-1RA,HbA1c increases the risk of DR by 6%, 14%, or 8% for every 0.1% decrease in follow-up time within 3 months (P＜0.006), 1 year (P＜0.002), and later[33]. This trend of increased risk is similar to early trials such as DCCT and the Oslostudy, which also prompted us to explore whether GLP-1RA has DR risk or due to the enhanced blood glucose control. With the widely application of smeglutide, more and more attention has been paid to the risk of GLP-1RA to DR. Although this article does not show that smeglutide has a promoting effect on DR, some articles mention that it shows an increase in the risk of DR deterioration or poor blood glucose control in type 2 diabetes in the short term (the first 16 weeks) [34] The deterioration of DR caused by rapid control of early blood sugar often occurs within one year of intensive insulin therapy and appears to be reversible. At the 18th month of follow-up, 51% of patients with type 1 diabetes whose DR worsened could recover, and early good HbAlc control in the average 6.5 years of follow-up would significantly delay DR progress (compared with conventional insulin treatment, DR progress in the insulin pump treatment group slowed by 54%)[12]. Timely and appropriate strengthening of blood glucose control is necessary, because long-term (more than one year) glycosylated hemoglobin higher than 6.5% will aggravate diabetes retinopathy[35]. The main purpose of this article is to discuss whether the initial application of GLP-1RA in type 2 diabetes patients with poorly controlled blood glucose has a new DR or a worsening DR due to the improvement of blood glucose in the first 16 weeks. To explore the appropriate targets for enhanced blood glucose control using GLP-1RA, we conducted a subgroup analysis of the decrease in glycosylated hemoglobin and DR risk in the first 4 weeks, first 8 weeks, and first 12 weeks (no subgroup analysis was conducted in the 16th week, as glycosylated hemoglobin had relatively small changes between the 16th and 12th weeks). The reason for selecting these time nodes was because the included RCT had data for our analysis at this time node.The results showed that in the type 2 diabetes population with poor blood glucose control and lower than 8.5% glycosylated hemoglobin level, a large range of blood glucose control in the first 12 weeks would increase the risk of retinopathy in type 2 diabetes, and appropriate glycosylated hemoglobin control ( 1% -1.5%) could reduce the risk of DR.For people with type 2 diabetes whose baseline glycosylated hemoglobin level is higher than 8.5%, no similar conclusion has been drawn.While the previous 8 weeks and the first 4 weeks did not show any correlation with DR risk or DR benefits, which may be related to the shorter duration of GLP-1RA application. The initial dose of GLP-1RA application in the early stage was relatively small, and gradually increased to the treatment dose over time.Besides HbAlc is usually applied in measuring the average of three months(12 weeks) blood glucose.So there is inaccuracy in measuring blood glucose control levels in the first 8 weeks and the first 4 weeks using glycated hemoglobin. A study investigated GLP-1 receptor (GLP-1R) expression in normal human eyes and eyes of patients with advanced stages of proliferative DR (PDR) by immunohistochemistry with the thoroughly validated monoclonal antibody 3F52 and found GLP-1Rs are rarely expressed in the normal human eye(only detected in single cells in the retinal ganglion cell layer) and appear undetectable in advanced stages of PDR[36].GLP-1Rs were not detected in the retinal and choroid vasculature, the retinal pigment epithelium, or in any other ocular structure which means GLP-1RA may play an insignificant role in diabetes retinopathy.A meta-analysis pointed out that a higher level of glycosylated hemoglobin variation means an increased risk of diabetes retinopathy (HR1.49 (1.19–1.87))[37]. In our meta-analysis we grouped patients with type 2 diabetes mellitus at different baseline levels to obtain different effects of GLP-1RA on DR caused by different degrees of enhanced glucose control.And we confirm that previous studies believed that the potential DR risk of GLP-1RA was derived from enhanced glucose control.At the same time, the goal of strengthening blood glucose control for reference was proposed in our study. TIR% (percentage in range, the time when the blood glucose level is within the target value in one day) was used to measure the early blood glucose control. Compared with measuring glycosylated hemoglobin, it was more timely, and TIR% was related to the microvascular complications of diabetes. TIR%＞70% can reduce DR risk [38–40], but it’s difficult to obtain. Whether it is self-testing blood glucose 7 times a day or using a continuous blood glucose monitor, it increases the difficulty for patients to monitor and control blood glucose. Patients with self-testing blood sugar have poor compliance, and the cost of continuous blood glucose monitors is higher. Regular monitoring of glycated hemoglobin is easier and less expensive, and using this indicator to measure whether blood sugar fortification meets the standard is easier to achieve. A retrospective study provided us with the corresponding relationship between TIR% and HbAlc[38]. Here we raise a general reference goal to measure whether the enhanced blood sugar control is up to the standard through the change of HbAlc indicators.HbAlc should finally be controlled at the corresponding level of TIR%＞70%, that is, HbAlc＜7.57%. For people with type 2 diabetes whose baseline glycosylated hemoglobin level is less than 8.5%, the decrease should be controlled between 1% and 1.5% in the first 12 weeks, and the decrease should not exceed 1.5%. Limits: In the subgroup analysis, due to the different dosages of GLP-1RA, the rate and magnitude of glycated hemoglobin decrease were not stratified for all 20 RCTs; The number of RCT tests with an early decrease of over 1.5% and over 2% in glycated hemoglobin is not enough, and the sample size included in the group still needs to be further expanded; The data on the decrease rate and magnitude of glycated hemoglobin obtained in this article comes from the graph of glycated hemoglobin and time variation in RCT experiments, which may have some errors.Even though the use of IDegLira reduces the total amount of insulin,different dosage of insulin between experiment and control group may have effect on RR. In type 2 diabetes population with unsatisfactory blood glucose control ( HbAlc＜8.5%), GLP-1RA should be used to control the decline of glycosylated hemoglobin between 1% and 1.5% in the first 12 weeks to reduce the risk of diabetes retinopathy. The use of degludec and liraglutide mixture will increase the risk of diabetes retinopathy. The appropriate decline of glycosylated hemoglobin in the first 4 weeks and the first 8 weeks still needs further discussion. Declarations Availability of data and materials The datasets used and/or analyzed during the current study were accessed in 2023 and are available from the pubmed,embase, Cochrane or corresponding author on reasonable request. Ethical Approval not applicable Funding not applicable Author Contribution Wang wenxuan and Lu jingyi wrote the main manuscript text.Li jing、Ma yuchen、Wang xin and Jiang jiajia collected the data. Hao yongmei、Zhang fang and Li chunhui revised the paper.Hao Yongmei was responsible for drafting writing ideas, guiding the writing of articles, and finalizing the manuscript References Ahmad E, Lim S, Lamptey R, Webb DR, Davies MJ. Type 2 diabetes. Lancet. 2022;400(10365):1803-20. Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. 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Vilsboll T, Bain SC, Leiter LA, Lingvay I, Matthews D, Simo R, et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. Diabetes Obes Metab. 2018;20(4):889-97. Laiteerapong N, Ham SA, Gao Y, Moffet HH, Liu JY, Huang ES, et al. The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes & Aging Study). Diabetes Care. 2019;42(3):416-26. Hebsgaard JB, Pyke C, Yildirim E, Knudsen LB, Heegaard S, Kvist PH. Glucagon-like peptide-1 receptor expression in the human eye. Diabetes Obes Metab. 2018;20(9):2304-8. Qu F, Shi Q, Wang Y, Shen Y, Zhou K, Pearson ER, et al. Visit-to-visit glycated hemoglobin A1c variability in adults with type 2 diabetes: a systematic review and meta-analysis. Chin Med J (Engl). 2022;135(19):2294-300. Sheng X, Xiong GH, Yu PF, Liu JP. The Correlation between Time in Range and Diabetic Microvascular Complications Utilizing Information Management Platform. Int J Endocrinol. 2020;2020:8879085. Yapanis M, James S, Craig ME, O'Neal D, Ekinci EI. Complications of Diabetes and Metrics of Glycemic Management Derived From Continuous Glucose Monitoring. J Clin Endocrinol Metab. 2022;107(6):e2221-e36. Lu J, Ma X, Zhou J, Zhang L, Mo Y, Ying L, et al. Association of Time in Range, as Assessed by Continuous Glucose Monitoring, With Diabetic Retinopathy in Type 2 Diabetes. Diabetes Care. 2018;41(11):2370-6. Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1baselinecharacteristic.jpg Table1continuedbaselinecharacteristic.jpg Table2Approximatedecreaseinglycatedhemoglobinwithinthefirst16weeks.jpg Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3834867","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":265559748,"identity":"277ffab3-6b99-4ab9-8300-a1899c5d723a","order_by":0,"name":"wenxuan Wang","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"wenxuan","middleName":"","lastName":"Wang","suffix":""},{"id":265559749,"identity":"fef63e46-7f2a-4e9d-8440-f922bdabead6","order_by":1,"name":"jingyi Lu","email":"","orcid":"","institution":"Hebei Medical 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19:20:19","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":177924,"visible":true,"origin":"","legend":"","description":"","filename":"Table1baselinecharacteristic.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3834867/v1/9f4cb844e0bb3262b4556cf0.jpg"},{"id":49382921,"identity":"9fe09394-d3c6-4b46-bcc1-eb13e09a6ee2","added_by":"auto","created_at":"2024-01-09 19:36:19","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":113977,"visible":true,"origin":"","legend":"","description":"","filename":"Table1continuedbaselinecharacteristic.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3834867/v1/2a198fe2a678db514c937223.jpg"},{"id":49382169,"identity":"7dd77d19-ddc3-4610-bd15-dd6608716acc","added_by":"auto","created_at":"2024-01-09 19:20:19","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":159567,"visible":true,"origin":"","legend":"","description":"","filename":"Table2Approximatedecreaseinglycatedhemoglobinwithinthefirst16weeks.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3834867/v1/a145da4d1973847e76206dd2.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Change on glycosylated hemoglob with glucagon-like peptide-1 receptor agonists affecting the progress of diabetes retinopathy in type 2 diabetes– A systematic review and meta-analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eDiabetes is a chronic disease characterized by insulin deficiency and insulin resistance. In 2022, about 537\u0026nbsp;million adults worldwide sufferred from diabetes, nearly 90% of whom will be type 2 diabetes. Its own and long-term complications are becoming important factors affecting modern people's health and quality of life[1]. Diabetes retinopathy is a complication of diabetes microvascular disease. About 30\u0026ndash;40% of diabetes patients can develop into diabetes retinopathy (DR) [2, 3]. Currently, over 100\u0026nbsp;million people worldwide suffer from DR, especially among adults of working age, which is the main cause of blindness and visual impairment[2, 4] Glucagon like peptide-1 receptor agonist (GLP-1RA), a blood glucose dependent hypoglycemic agent, has advantages such as good blood glucose control, significant weight loss effects, and cardiovascular benefits. There is still significant controversy over whether GLP-1RA has adverse effects on DR. Some trials support the use of GLP-1RA, especially semaglutide, which increases the risk of DR [5, 6], while others show neutral results [7]. Studies have observed that early strengthening of blood glucose control may worsen DR [8\u0026ndash;13]. The purpose of this study is to explore the relationship between the change of HbAlc and DR in the early stage of type 2 diabetes treated with different types of GLP-1RA.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eResult analysis and systematic evaluation of included randomized controlled trials are based on PRISMA.\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eSearch strategy and searches\u003c/h2\u003e\n\u003cp\u003eFrom the establishment of the database until March 27, 2023, we searched for eligible literature through Embase, Pubmed, and Cochrane, limiting the language of the literature to English.Our search terms are as follows:\u0026ldquo;Type 2 diabetes mellitus（All Fields）\u0026rdquo;，\u0026ldquo;diabetic retinopathy（All Fields）\u0026rdquo;，\u0026ldquo;GLP-1RA（Tile，Abstract or Auther Keywords）\u0026rdquo;\u0026ldquo;Glucagon-like peptide-1 receptor agonists\u0026rdquo;，\u0026ldquo;Liraglutide\u0026rdquo;，\u0026ldquo;Semaglutide\u0026rdquo;，\u0026ldquo;Dulaglutide\u0026rdquo;，\u0026ldquo;Albiglutide\u0026rdquo;，\u0026ldquo;Exenatide\u0026rdquo;，\u0026ldquo;Lixisenatide\u0026rdquo;，\u0026ldquo;IDegLira\u0026rdquo;，\u0026ldquo;IGlarLixi\u0026rdquo;，\u0026ldquo;insulin degludec/liraglutide\u0026rdquo;.In addition, we also supplemented the list of references such as articles, metas, and reviews that meet the search criteria.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eData selection\u003c/h2\u003e\n\u003cp\u003eOne researcher exported the database to NoteExpress, where he deleted duplicate literature, and screened RCTs by reading literature abstracts and methods. If the article lacks specific information on evaluating the outcome indicators of GLP-1RA in the treatment of type 2 diabetes, or if ADA believes that there may be ASCVD or renal function risk, GLP-1RA will be excluded. A complete study selection process is shown in Fig.\u0026nbsp;1.\u003c/p\u003e\n\u003cp\u003eData extraction and quality assessment\u003c/p\u003e\n\u003cp\u003eInclusion criteria: (1) The research type is RCT; (2) The diagnosis of type 2 diabetes of the subjects was clear, and the age was \u0026ge;\u0026thinsp;18 years old; (3) The intervention measures are GLP-1RA or GLP-1RA combined with insulin mixture, with a duration of \u0026ge;\u0026thinsp;12 weeks; (4) Outcome indicators: glycated hemoglobin (HbA1c), diabetes retinopathy (DR).\u003c/p\u003e\n\u003cp\u003eExclusion criteria: (1) Articles without DR related information; (2) Articles where the experiment is suspended, there are no results, or the result data is not standardized and cannot be applied; (3) The control group and experimental group are both articles of GLP-1RA; (4) The subjects included people with non type 2 diabetes;(5)Control groups are DDP-IV.\u003c/p\u003e\n\u003cp\u003eTwo researchers independently read the literature title, abstract, and full text, screened the literature based on inclusion and exclusion criteria, extracted relevant data, and used the Cochrane Bias Risk Assessment Tool (ROB) for quality evaluation; Cross check the data results and discuss and resolve any disagreements.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eAnalysis\u003c/h2\u003e\n\u003cp\u003eTo test the relationship between GLP-1RA and DR by calculating relative risk (RR) and 95% confidence interval (CI). Conduct heterogeneity testing on the included studies, and if there is no heterogeneity (P\u0026thinsp;\u0026ge;\u0026thinsp;0.05, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026le;\u0026thinsp;50%), select a fixed effects model; Instead, select a random effects model and conduct subgroup analysis to analyze the sources of heterogeneity. Use a funnel plot and Egger's test for publication bias analysis. Use ROB for risk bias analysis. with \u0026alpha;\u0026thinsp;=\u0026thinsp;0.05 is used as the inspection level.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 661 articles were retrieved from four databases (search results from the establishment of the database to March 27, 2023), including 429 Embase articles, 100 Pubmed articles, 132 Cochrane articles, and 352 repetitions. The remaining 309 articles were screened for titles and abstracts, and 150 unrelated articles were selected. The remaining 159 articles were further read in full, with a total of 65 reviews, metas, case studies, conference papers, comments, communications, guidelines, and consensus selected,37 irrelevant study type(retrospective studies, cohort studies, post hoc analysis, real-world studies, animal experiments, and in vitro cell studies), 2 no articles, 14 registered trials or trial protocols and 41 RCTs.There were 41 RCTs, including 18 that did not meet the inclusion and exclusion criteria, and 3 that did not have DR results. A total of 20 RCT studies were finally included, of which 9 were related to semaglutide (5 were oral semaglutide and 4 were subcutaneous injection semaglutide), 4 were related to liraglutide, 1 was dulaglutide, 2 were abiglutide and 1 was exenatide weekly preparation. (Fig.\u0026nbsp;1)Among them, 12 RCTs\u0026rsquo; control groups were placebo, 2 control groups were SGLT-2 inhibitors (empagliflozin,Canagliflozin),3 control groups are insulin (including lispro conbined with insulin glargine or degludec) and the rest of them are glinide,metformin, a-glucosidase inhibitor or thiazolidinedione(Table\u0026nbsp;2).\u003c/p\u003e\n\u003cp\u003eThe number of patients enrolled in 20 RCTs was 56204, including 33825 men (60%) and 22379 women (40%), with an average age of 62.64 years (54.7\u0026ndash;66.2 years), an average follow-up time of 75.6w (26w-240w), an average BMI of 31.90 (24.8\u0026ndash;35.7), an average HbA1c of 8.30% (7.3% -9.3%), and an average history of diabetes of 12.46 years (3.5\u0026ndash;14.9 years)(Table\u0026nbsp;1).\u003c/p\u003e\n\u003cp\u003eIn different categories of GLP-1RA, it was found that IDegLira was associated with an increased risk of DR (RR 1.69 95% CI 1.11\u0026ndash;2.57), while the use of semaglutide (RR 1.20 95% CI 0.99\u0026ndash;1.44), Abiglutide (RR 0.86 95% CI 0.65\u0026ndash;1.13), and liraglutide (RR 0.70,95% CI 0.48\u0026ndash;1.01) did not increase the risk of DR(Fig.\u0026nbsp;2). The use of GLP-1RA combined with insulin did not increase the risk of DR (RR 1.24, 95% CI 0.90\u0026ndash;1.71),however in the group with baseline glycation levels＜8.5% in the first 12 weeks,a decrease of over 1.5% in glycated hemoglobin was associated with an increased risk of DR (RR 1.75 95% CI 1.01\u0026ndash;3.04)(Fig.\u0026nbsp;9,Fig.\u0026nbsp;10). In the group with baseline glycation levels＜8.5% in the first 12 weeks, a decrease of over 1.5% in glycated hemoglobin was associated with an increased risk of DR (RR 1.75 95% CI 1.01\u0026ndash;3.04), a decrease of 1% -1.5% in glycated hemoglobin reduced the risk of DR (RR 0.59 95% CI 0.37\u0026ndash;0.93), and a decrease of＜1% in glycated hemoglobin was not associated with DR (RR 1.25 95% CI 0.93\u0026ndash;1.69). In the group with baseline glycation levels\u0026thinsp;\u0026ge;\u0026thinsp;8.5% in the first 12 weeks, the decrease in glycated hemoglobin by more than 1.5% (RR 0.95 95% CI 0.66\u0026ndash;1.38) and less than 1% (RR 0.77 95% CI 0.39\u0026ndash;1.51) had no effect on DR(Fig.\u0026nbsp;3,Fig.\u0026nbsp;6).\u003c/p\u003e\n\u003cp\u003eIn the group with baseline glycation levels＜8.5% in the first 8 weeks, a decrease of 1% -1.5% in glycated hemoglobin (RR 0.94 95% CI 0.42\u0026ndash;2.06), a decrease of less than 1% in glycated hemoglobin (RR 1.26 95% CI 0.62\u0026ndash;2.59), and a decrease of more than 1.5% (RR 1.40 95% CI 0.68\u0026ndash;2.87) had no effect on DR. In the group with baseline glycation levels\u0026thinsp;\u0026ge;\u0026thinsp;8.5% in the first 8 weeks, a decrease of less than 1% (RR 0.77 95% CI 0.39\u0026ndash;1.51), and a decrease of 1% -1.5% (RR 1.09 95% CI 0.71\u0026ndash;1.66) had no effect on DR(Fig.\u0026nbsp;4,Fig.\u0026nbsp;7).In the group with baseline glycation levels＜8.5% in the first 4 weeks, a decrease less than 0.5% (RR1.47 95% CI 0.47\u0026ndash;4.58), 0.5% -＜1% (RR0.85 95% CI 0.30\u0026ndash;2.46), and 1% -＜1.5% (RR1.40 95% CI 0.68\u0026ndash;2.87) in glycated hemoglobin did not affect DR. In the group with baseline glycation levels\u0026thinsp;\u0026ge;\u0026thinsp;8.5%, a decrease of 0.5% -＜1% (RR0.99 95% CI 0.69\u0026ndash;1.41) in glycated hemoglobin did not affect DR(Fig.\u0026nbsp;5,Fig.\u0026nbsp;8).\u003c/p\u003e\n\u003cp\u003eBegger's analysis showed no publication bias with P＞0.05, and the overall quality of 20 articles in risk assessment was relatively high(Fig.\u0026nbsp;11,Fig.\u0026nbsp;12).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn recent years, some large-scale RCT trials of GLP-1RA have been conducted (such as SUSTAIN6) and related meta-analyses have gradually raised concerns about whether the use of GLP-1RA poses DR risk. Our analysis shows that the use of GLP-1RA does not increase the risk. Among different types of GLP-1RA or GLP-1RA combined with insulin, only the combination of insulin and liraglutide shows a significant DR risk. Previous studies have confirmed that rapid blood glucose control can worsen preexisting DR[32]. Compared to traditional therapies such as 1\u0026ndash;2 insulin injections per day, dietary control, and exercise, the use of insulin pump intensification therapy leads to a significant increase in early DR deterioration within six months and or one year (OR2.06, P＜0.001).The results of a meta-regression analysis suggest that when using GLP-1RA,HbA1c increases the risk of DR by 6%, 14%, or 8% for every 0.1% decrease in follow-up time within 3 months (P＜0.006), 1 year (P＜0.002), and later[33]. This trend of increased risk is similar to early trials such as DCCT and the Oslostudy, which also prompted us to explore whether GLP-1RA has DR risk or due to the enhanced blood glucose control. With the widely application of smeglutide, more and more attention has been paid to the risk of GLP-1RA to DR. Although this article does not show that smeglutide has a promoting effect on DR, some articles mention that it shows an increase in the risk of DR deterioration or poor blood glucose control in type 2 diabetes in the short term (the first 16 weeks) [34]\u003c/p\u003e\n\u003cp\u003eThe deterioration of DR caused by rapid control of early blood sugar often occurs within one year of intensive insulin therapy and appears to be reversible. At the 18th month of follow-up, 51% of patients with type 1 diabetes whose DR worsened could recover, and early good HbAlc control in the average 6.5 years of follow-up would significantly delay DR progress (compared with conventional insulin treatment, DR progress in the insulin pump treatment group slowed by 54%)[12]. Timely and appropriate strengthening of blood glucose control is necessary, because long-term (more than one year) glycosylated hemoglobin higher than 6.5% will aggravate diabetes retinopathy[35]. The main purpose of this article is to discuss whether the initial application of GLP-1RA in type 2 diabetes patients with poorly controlled blood glucose has a new DR or a worsening DR due to the improvement of blood glucose in the first 16 weeks.\u003c/p\u003e\n\u003cp\u003eTo explore the appropriate targets for enhanced blood glucose control using GLP-1RA, we conducted a subgroup analysis of the decrease in glycosylated hemoglobin and DR risk in the first 4 weeks, first 8 weeks, and first 12 weeks (no subgroup analysis was conducted in the 16th week, as glycosylated hemoglobin had relatively small changes between the 16th and 12th weeks). The reason for selecting these time nodes was because the included RCT had data for our analysis at this time node.The results showed that in the type 2 diabetes population with poor blood glucose control and lower than 8.5% glycosylated hemoglobin level, a large range of blood glucose control in the first 12 weeks would increase the risk of retinopathy in type 2 diabetes, and appropriate glycosylated hemoglobin control ( 1% -1.5%) could reduce the risk of DR.For people with type 2 diabetes whose baseline glycosylated hemoglobin level is higher than 8.5%, no similar conclusion has been drawn.While the previous 8 weeks and the first 4 weeks did not show any correlation with DR risk or DR benefits, which may be related to the shorter duration of GLP-1RA application. The initial dose of GLP-1RA application in the early stage was relatively small, and gradually increased to the treatment dose over time.Besides HbAlc is usually applied in measuring the average of three months(12 weeks) blood glucose.So there is inaccuracy in measuring blood glucose control levels in the first 8 weeks and the first 4 weeks using glycated hemoglobin.\u003c/p\u003e\n\u003cp\u003eA study investigated GLP-1 receptor (GLP-1R) expression in normal human eyes and eyes of patients with advanced stages of proliferative DR (PDR) by immunohistochemistry with the thoroughly validated monoclonal antibody 3F52 and found GLP-1Rs are rarely expressed in the normal human eye(only detected in single cells in the retinal ganglion cell layer) and appear undetectable in advanced stages of PDR[36].GLP-1Rs were not detected in the retinal and choroid vasculature, the retinal pigment epithelium, or in any other ocular structure which means GLP-1RA may play an insignificant role in diabetes retinopathy.A meta-analysis pointed out that a higher level of glycosylated hemoglobin variation means an increased risk of diabetes retinopathy (HR1.49 (1.19\u0026ndash;1.87))[37]. In our meta-analysis we grouped patients with type 2 diabetes mellitus at different baseline levels to obtain different effects of GLP-1RA on DR caused by different degrees of enhanced glucose control.And we confirm that previous studies believed that the potential DR risk of GLP-1RA was derived from enhanced glucose control.At the same time, the goal of strengthening blood glucose control for reference was proposed in our study. TIR% (percentage in range, the time when the blood glucose level is within the target value in one day) was used to measure the early blood glucose control. Compared with measuring glycosylated hemoglobin, it was more timely, and TIR% was related to the microvascular complications of diabetes. TIR%＞70% can reduce DR risk [38\u0026ndash;40], but it\u0026rsquo;s difficult to obtain. Whether it is self-testing blood glucose 7 times a day or using a continuous blood glucose monitor, it increases the difficulty for patients to monitor and control blood glucose. Patients with self-testing blood sugar have poor compliance, and the cost of continuous blood glucose monitors is higher. Regular monitoring of glycated hemoglobin is easier and less expensive, and using this indicator to measure whether blood sugar fortification meets the standard is easier to achieve.\u003c/p\u003e\n\u003cp\u003eA retrospective study provided us with the corresponding relationship between TIR% and HbAlc[38]. Here we raise a general reference goal to measure whether the enhanced blood sugar control is up to the standard through the change of HbAlc indicators.HbAlc should finally be controlled at the corresponding level of TIR%＞70%, that is, HbAlc＜7.57%. For people with type 2 diabetes whose baseline glycosylated hemoglobin level is less than 8.5%, the decrease should be controlled between 1% and 1.5% in the first 12 weeks, and the decrease should not exceed 1.5%. Limits: In the subgroup analysis, due to the different dosages of GLP-1RA, the rate and magnitude of glycated hemoglobin decrease were not stratified for all 20 RCTs; The number of RCT tests with an early decrease of over 1.5% and over 2% in glycated hemoglobin is not enough, and the sample size included in the group still needs to be further expanded; The data on the decrease rate and magnitude of glycated hemoglobin obtained in this article comes from the graph of glycated hemoglobin and time variation in RCT experiments, which may have some errors.Even though the use of IDegLira reduces the total amount of insulin,different dosage of insulin between experiment and control group may have effect on RR.\u003c/p\u003e\n\u003cp\u003eIn type 2 diabetes population with unsatisfactory blood glucose control ( HbAlc＜8.5%), GLP-1RA should be used to control the decline of glycosylated hemoglobin between 1% and 1.5% in the first 12 weeks to reduce the risk of diabetes retinopathy. The use of degludec and liraglutide mixture will increase the risk of diabetes retinopathy. The appropriate decline of glycosylated hemoglobin in the first 4 weeks and the first 8 weeks still needs further discussion.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study were accessed in 2023 and are available from the pubmed,embase, Cochrane or corresponding author on reasonable request.\u003c/p\u003e\n\u003ch2\u003eEthical Approval\u003c/h2\u003e\n\u003cp\u003enot applicable\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003enot applicable\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eWang wenxuan and Lu jingyi wrote the main manuscript text.Li jing、Ma yuchen、Wang xin and Jiang jiajia collected the data. Hao yongmei、Zhang fang and Li chunhui revised the paper.Hao Yongmei was responsible for drafting writing ideas, guiding the writing of articles, and finalizing the manuscript\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAhmad E, Lim S, Lamptey R, Webb DR, Davies MJ. Type 2 diabetes. Lancet. 2022;400(10365):1803-20.\u003c/li\u003e\n\u003cli\u003eYau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556-64.\u003c/li\u003e\n\u003cli\u003eRuta LM, Magliano DJ, Lemesurier R, Taylor HR, Zimmet PZ, Shaw JE. Prevalence of diabetic retinopathy in Type 2 diabetes in developing and developed countries. Diabet Med. 2013;30(4):387-98.\u003c/li\u003e\n\u003cli\u003eTing DS, Cheung GC, Wong TY. Diabetic retinopathy: global prevalence, major risk factors, screening practices and public health challenges: a review. 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Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2019;7(5):356-67.\u003c/li\u003e\n\u003cli\u003eSeino Y, Kaneko S, Fukuda S, Osonoi T, Shiraiwa T, Nishijima K, et al. Combination therapy with liraglutide and insulin in Japanese patients with type 2 diabetes: A 36-week, randomized, double-blind, parallel-group trial. J Diabetes Investig. 2016;7(4):565-73.\u003c/li\u003e\n\u003cli\u003eDavies M, Faerch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021;397(10278):971-84.\u003c/li\u003e\n\u003cli\u003eLingvay I, Catarig AM, Frias JP, Kumar H, Lausvig NL, le Roux CW, et al. Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial. Lancet Diabetes Endocrinol. 2019;7(11):834-44.\u003c/li\u003e\n\u003cli\u003eAroda VR, Rosenstock J, Terauchi Y, Altuntas Y, Lalic NM, Morales Villegas EC, et al. PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes. Diabetes Care. 2019;42(9):1724-32.\u003c/li\u003e\n\u003cli\u003eKaku K, Araki E, Tanizawa Y, Ross Agner B, Nishida T, Ranthe M, et al. Superior efficacy with a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with insulin degludec and liraglutide in insulin-naive Japanese patients with type 2 diabetes in a phase 3, open-label, randomized trial. Diabetes Obes Metab. 2019;21(12):2674-83.\u003c/li\u003e\n\u003cli\u003eWang W, Agner BFR, Luo B, Liu L, Liu M, Peng Y, et al. DUAL I China: Improved glycemic control with IDegLira versus its individual components in a randomized trial with Chinese participants with type 2 diabetes uncontrolled on oral antidiabetic drugs. J Diabetes. 2022;14(6):401-13.\u003c/li\u003e\n\u003cli\u003eHernandez AF, Green JB, Janmohamed S, D\u0026apos;Agostino RB, Sr., Granger CB, Jones NP, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018;392(10157):1519-29.\u003c/li\u003e\n\u003cli\u003eBethel MA, Mentz RJ, Merrill P, Buse JB, Chan JC, Goodman SG, et al. Microvascular and Cardiovascular Outcomes According to Renal Function in Patients Treated With Once-Weekly Exenatide: Insights From the EXSCEL Trial. Diabetes Care. 2020;43(2):446-52.\u003c/li\u003e\n\u003cli\u003eRodbard HW, Rosenstock J, Canani LH, Deerochanawong C, Gumprecht J, Lindberg SO, et al. Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial. Diabetes Care. 2019;42(12):2272-81.\u003c/li\u003e\n\u003cli\u003ePratley R, Amod A, Hoff ST, Kadowaki T, Lingvay I, Nauck M, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet. 2019;394(10192):39-50.\u003c/li\u003e\n\u003cli\u003eZinman B, Aroda VR, Buse JB, Cariou B, Harris SB, Hoff ST, et al. Efficacy, Safety, and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin With or Without Metformin in Patients With Type 2 Diabetes: The PIONEER 8 Trial. Diabetes Care. 2019;42(12):2262-71.\u003c/li\u003e\n\u003cli\u003ePei Y, Agner BR, Luo B, Dong X, Li D, Liu J, et al. DUAL II China: Superior HbA1c reductions and weight loss with insulin degludec/liraglutide (IDegLira) versus insulin degludec in a randomized trial of Chinese people with type 2 diabetes inadequately controlled on basal insulin. Diabetes Obes Metab. 2021;23(12):2687-96.\u003c/li\u003e\n\u003cli\u003eKaku K, Rasmussen MF, Nishida T, Seino Y. Fifty-two-week, randomized, multicenter trial to compare the safety and efficacy of the novel glucagon-like peptide-1 analog liraglutide vs glibenclamide in patients with type 2 diabetes. J Diabetes Investig. 2011;2(6):441-7.\u003c/li\u003e\n\u003cli\u003eRosenstock J, Fonseca VA, Gross JL, Ratner RE, Ahren B, Chow FC, et al. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care. 2014;37(8):2317-25.\u003c/li\u003e\n\u003cli\u003eKaku K, Kiyosue A, Ono Y, Shiraiwa T, Kaneko S, Nishijima K, et al. Liraglutide is effective and well tolerated in combination with an oral antidiabetic drug in Japanese patients with type 2 diabetes: A randomized, 52-week, open-label, parallel-group trial. J Diabetes Investig. 2016;7(1):76-84.\u003c/li\u003e\n\u003cli\u003eEarly worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol. 1998;116(7):874-86.\u003c/li\u003e\n\u003cli\u003eBethel MA, Diaz R, Castellana N, Bhattacharya I, Gerstein HC, Lakshmanan MC. HbA(1c) Change and Diabetic Retinopathy During GLP-1 Receptor Agonist Cardiovascular Outcome Trials: A Meta-analysis and Meta-regression. Diabetes Care. 2021;44(1):290-6.\u003c/li\u003e\n\u003cli\u003eVilsboll T, Bain SC, Leiter LA, Lingvay I, Matthews D, Simo R, et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. Diabetes Obes Metab. 2018;20(4):889-97.\u003c/li\u003e\n\u003cli\u003eLaiteerapong N, Ham SA, Gao Y, Moffet HH, Liu JY, Huang ES, et al. The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes \u0026amp; Aging Study). Diabetes Care. 2019;42(3):416-26.\u003c/li\u003e\n\u003cli\u003eHebsgaard JB, Pyke C, Yildirim E, Knudsen LB, Heegaard S, Kvist PH. Glucagon-like peptide-1 receptor expression in the human eye. Diabetes Obes Metab. 2018;20(9):2304-8.\u003c/li\u003e\n\u003cli\u003eQu F, Shi Q, Wang Y, Shen Y, Zhou K, Pearson ER, et al. Visit-to-visit glycated hemoglobin A1c variability in adults with type 2 diabetes: a systematic review and meta-analysis. Chin Med J (Engl). 2022;135(19):2294-300.\u003c/li\u003e\n\u003cli\u003eSheng X, Xiong GH, Yu PF, Liu JP. The Correlation between Time in Range and Diabetic Microvascular Complications Utilizing Information Management Platform. Int J Endocrinol. 2020;2020:8879085.\u003c/li\u003e\n\u003cli\u003eYapanis M, James S, Craig ME, O\u0026apos;Neal D, Ekinci EI. Complications of Diabetes and Metrics of Glycemic Management Derived From Continuous Glucose Monitoring. J Clin Endocrinol Metab. 2022;107(6):e2221-e36.\u003c/li\u003e\n\u003cli\u003eLu J, Ma X, Zhou J, Zhang L, Mo Y, Ying L, et al. Association of Time in Range, as Assessed by Continuous Glucose Monitoring, With Diabetic Retinopathy in Type 2 Diabetes. Diabetes Care. 2018;41(11):2370-6.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e "}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3834867/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3834867/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e：Whether glucagon-like peptide-1 receptor agonists(GLP-1RA) has adverse effects on diabetes retinopathy(DR) due to blood glucose control is unclear.The main purpose of this article is to evaluate the effect of GLP-1RA or GLP-1RA combined with insulin on DR by inducing different degrees of glycosylated hemoglob(HbAlc).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e：This is a meta-analysis of 20 randomized controlled trial which including a total of 56204 type 2 diabetes(T2DM) patients.We used risk ration(RR) and 95% cofidence intervals(CIs) to estimate the influence of varying descending HbAlc levels in DR.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e：GLP-1RA does not increase the risk of DR in T2DM,IDegLira was associated with an increased risk of DR (RR 1.69 95% CI 1.11-2.57), while the use of liraglutide did not increase the risk of DR (RR 0.70, 0.48-1.01). In the group with baseline glycation levels＜8.5% in the first 12 weeks, a decrease of over 1.5% in glycated hemoglobin was associated with an increased risk of DR (RR 1.75 95% CI 1.01-3.04), a decrease of 1% -1.5% in glycated hemoglobin reduced the risk of DR (RR 0.59 95% CI 0.37-0.93), and a decrease of＜1% in glycated hemoglobin was not associated with DR (RR 1.25 95% CI 0.93-1.69). In the group with baseline glycation levels ≥ 8.5% \u0026nbsp;in the first 12 weeks, the decrease in glycated hemoglobin by more than 1.5% (RR 0.95 95% CI 0.66-1.38) and less than 1% (RR 0.77 95% CI 0.39-1.51) had no effect on DR. In the group with baseline glycation levels＜8.5% in the first 8 weeks, a decrease of 1% -1.5% in glycated hemoglobin (RR 0.94 95% CI 0.42-2.06), a decrease of less than 1% in glycated hemoglobin (RR 1.26 95% CI 0.62-2.59), and a decrease of more than 1.5% (RR 1.40 95% CI 0.68-2.87) had no effect on DR. In the group with baseline glycation levels ≥ 8.5% in the first 8 weeks, a decrease of less than 1% (RR 0.77 95% CI 0.39-1.51), and a decrease of 1% -1.5% (RR 1.09 95% CI 0.71-1.66) had no effect on DR. In the group with baseline glycation levels＜8.5% in the first 4 weeks, a decrease less than 0.5% (RR1.47 95% CI 0.47-4.58), 0.5% -＜1% (RR0.85 95% CI 0.30-2.46), and 1% -＜1.5% (RR1.40 95% CI 0.68-2.87) in glycated hemoglobin did not affect DR. In the group with baseline glycation levels ≥ 8.5%, a decrease of 0.5% -＜1% (RR0.99 95% CI 0.69-1.41) in glycated hemoglobin did not affect DR.The use of GLP-1RA combined with insulin did not increase the risk of DR (RR 1.24, 95% CI 0.90-1.71),however in the group with baseline glycation levels＜8.5% in the first 12 weeks,a decrease of over 1.5% in glycated hemoglobin was associated with an increased risk of DR (RR 1.75 95% CI 1.01-3.04).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e：When GLP-1RA is applied in T2DM patients with HbAlc level under 8.5%, controlling the decrease of HbAlc by 1% -1.5% in the first 12 weeks can reduce the risk of DR, and the decrease of HbAlc by more than 1.5% will increase the risk of DR.GLP-1RA combined with insulin does not show the risk of DR. The promoting effect by IDegLira in DR may be mediated by the quick variation of blood glucose.\u003c/p\u003e","manuscriptTitle":"Change on glycosylated hemoglob with glucagon-like peptide-1 receptor agonists affecting the progress of diabetes retinopathy in type 2 diabetes– A systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-09 19:20:14","doi":"10.21203/rs.3.rs-3834867/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5b2703bd-f502-411d-9bcd-fddf8d784643","owner":[],"postedDate":"January 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-01-25T12:35:10+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-09 19:20:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3834867","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3834867","identity":"rs-3834867","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}