Aims/hypothesis

A protective role of sodium–glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-ra) in the development of diabetic retinopathy and diabetic macular oedema has been described in some recent studies, which may extend beyond glycaemic control. We aimed to review the clinical impact of SGLT2i and GLP1-ra therapy on the risk of diabetic retinopathy and diabetic macular oedema in individuals with type 2 diabetes taking insulin.

Methods

This is a retrospective cohort analysis of approximately two million people with type 2 diabetes receiving insulin across 97 healthcare organisations using a global federated health research network (TriNetX, Cambridge, USA). Two intervention cohorts (SGLT2i + insulin, n=176,409; GLP1-ra + insulin, n=207,034) were compared against a control cohort (insulin with no SGLT2i/GLP1-ra, n=1,922,312). Kaplan–Meier survival analysis was performed and estimated HRs were reported for each outcome. Propensity score was used to 1:1 match for age, sex, ischaemic heart disease, hypertension, microvascular complications, chronic kidney disease, HbA_1c, BMI and use of pioglitazone, lipid modifying agents, antilipemic agents, ACE inhibitors, angiotensin II inhibitors and metformin. A sub-analysis comparing the two intervention cohorts was also performed.

Results

SGLT2i with insulin was associated with a reduced HR (95% CI) for diabetic macular oedema compared with the control cohort (0.835; 0.780, 0.893), while GLP1-ra with insulin demonstrated a lack of signal with no statistical significance to the HR (1.013; 0.960, 1.069). SGLT2i with insulin was not associated with a clinically significant increase in the risk of developing diabetic retinopathy (1.076; 1.027, 1.127), while GLP1-ra with insulin increased diabetic retinopathy risk (1.308; 1.261, 1.357). Compared with SGLT2i with insulin, GLP1-ra with insulin was associated with higher risk of diabetic retinopathy (1.205; 1.153, 1.259) and diabetic macular oedema (1.130; 1.056, 1.208).

Conclusions/interpretation

Our study suggests that the combination of SGLT2i and insulin is associated with lower risk of developing diabetic macular oedema. However, the use of GLP1-ra was associated with an increased risk of diabetic retinopathy in individuals with type 2 diabetes also taking insulin. A comparative analysis showed favourable outcomes with SGLT2i and insulin in the development of diabetic macular oedema and diabetic retinopathy. RCTs using dedicated retinal imaging are required to determine the causal relationship with these therapies.

Graphical Abstract

中文翻译：

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2 型糖尿病中钠-葡萄糖协同转运蛋白 2 抑制剂和胰高血糖素样肽 1 受体激动剂引起糖尿病视网膜病变和糖尿病黄斑水肿的风险：来自全球联合数据库的真实世界数据研究

目标/假设

最近的一些研究描述了钠-葡萄糖协同转运蛋白 2 抑制剂 (SGLT2is) 和胰高血糖素样肽 1 受体激动剂 (GLP1-ra) 在糖尿病视网膜病变和糖尿病黄斑水肿发展中的保护作用，其作用可能超出血糖控制范围。我们的目的是回顾 SGLT2i 和 GLP1-ra 治疗对服用胰岛素的 2 型糖尿病患者患糖尿病视网膜病变和糖尿病黄斑水肿风险的临床影响。

方法

这是一项回顾性队列分析，使用全球联合健康研究网络（美国剑桥 TriNetX）对 97 个医疗机构中约 200 万名接受胰岛素治疗的 2 型糖尿病患者进行了回顾性队列分析。将两个干预队列（SGLT2i + 胰岛素，n = 176,409；GLP1-ra + 胰岛素，n = 207,034）与对照组（不含 SGLT2i/GLP1-ra 的胰岛素，n = 1,922,312）进行比较。进行了 Kaplan-Meier 生存分析并报告了每个结果的估计 HR。倾向评分用于1:1匹配年龄、性别、缺血性心脏病、高血压、微血管并发症、慢性肾病、HbA _1c、BMI以及吡格列酮、调脂剂、降血脂剂、ACE抑制剂、血管紧张素II抑制剂和药物的使用情况。二甲双胍。还进行了比较两个干预队列的子分析。

结果

与对照组相比，SGLT2i 联合胰岛素与糖尿病性黄斑水肿的 HR 降低 (95% CI) 相关 (0.835; 0.780, 0.893)，而 GLP1-ra 联合胰岛素显示缺乏信号，对 HR 没有统计学意义。 1.013；0.960，1.069）。 SGLT2i 联合胰岛素与临床上显着增加糖尿病视网膜病变风险无关 (1.076; 1.027, 1.127)，而 GLP1-ra 联合胰岛素则增加糖尿病视网膜病变风险 (1.308; 1.261, 1.357)。与SGLT2i联合胰岛素治疗相比，GLP1-ra联合胰岛素治疗与糖尿病视网膜病变（1.205；1.153，1.259）和糖尿病黄斑水肿（1.130；1.056，1.208）的风险较高相关。

结论/解释

我们的研究表明，SGLT2i 和胰岛素的组合可降低患糖尿病性黄斑水肿的风险。然而，对于同时服用胰岛素的 2 型糖尿病患者来说，使用 GLP1-ra 会增加患糖尿病视网膜病变的风险。比较分析显示，SGLT2i 和胰岛素在糖尿病黄斑水肿和糖尿病视网膜病变的发展中具有良好的效果。需要使用专用视网膜成像的随机对照试验来确定与这些疗法的因果关系。

图形概要