Long-term delirium and survival outcomes in patients treated with GLP-1 receptor agonists versus metformin in type 2 diabetes: A population-based cohort study

IF 5.4 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes, Obesity & Metabolism Pub Date : 2025-05-07 DOI:10.1111/dom.16434

Mingyang Sun MD, Xiaoling Wang PhD, Zhongyuan Lu PhD, Yitian Yang MD, Shuang Lv MD, Mengrong Miao MD, Wan-Ming Chen PhD, Szu-Yuan Wu MD, Jiaqiang Zhang MD

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Abstract

Aim

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of delirium and mortality. While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) provide metabolic and neuroprotective benefits, their long-term impact on delirium risk remains uncertain. This study compares GLP-1 RAs and metformin in relation to delirium and mortality in T2DM patients using real-world data.

Methods

A retrospective cohort study was conducted using the TriNetX global federated research network, which primarily comprises U.S.-based healthcare organisations (approximately 85%), with additional sites in Europe, Asia-Pacific and the Middle East. Adults (≥18 years) with T2DM who initiated GLP-1 RAs or metformin were included. Propensity score matching (PSM) balances baseline characteristics. The primary outcome was incident delirium; the secondary outcome was all-cause mortality. Kaplan–Meier survival curves and time-dependent Cox models assessed associations.

Results

After 1:1 PSM (N = 63 096 per group), GLP-1 RAs showed no overall reduction in delirium risk (AHR: 0.98, 95% CI: 0.94–1.02, p = 0.3628). However, they were protective in the first 5 years (AHR: 0.89, 95% CI: 0.86–0.92, p < 0.0001) but increased delirium risk between 5 and 10 years (AHR: 1.15, 95% CI: 1.04–1.26, p = 0.0046). Subgroup analysis revealed lower delirium risk with GLP-1 RAs in middle-aged patients (40–79 years) and those with HbA1c <7.5%. Higher risk was observed in Asian and Native Hawaiian/Pacific Islander populations. However, these findings should be interpreted with caution due to the relatively small subgroup sizes and the limited representativeness of these groups within the predominantly U.S.-based database, in which Asian and Native Hawaiian/Pacific Islander patients together accounted for less than 5% of the overall cohort. Mortality risk was lower in absolute terms for GLP-1 RAs (6.28% vs. 9.95%) but higher in long-term hazard (AHR: 1.16, 95% CI: 1.12–1.21, p < 0.001).

Conclusions

GLP-1 RA use was initially associated with a lower risk of delirium, but this association reversed over time. Subgroup variations suggest individualised treatment considerations. Metformin remains a preferred option given its stable cognitive and survival benefits.

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GLP-1受体激动剂与二甲双胍治疗2型糖尿病患者的长期谵妄和生存结局：一项基于人群的队列研究

目的：2型糖尿病（T2DM）与谵妄和死亡风险增加相关。虽然胰高血糖素样肽-1受体激动剂（GLP-1 RAs）具有代谢和神经保护作用，但其对谵妄风险的长期影响仍不确定。本研究使用真实数据比较GLP-1 RAs和二甲双胍与T2DM患者谵妄和死亡率的关系。方法：采用TriNetX全球联合研究网络进行回顾性队列研究，该网络主要包括美国的医疗机构（约85%），在欧洲、亚太和中东设有其他站点。纳入了接受GLP-1 RAs或二甲双胍治疗的T2DM成人（≥18岁）。倾向评分匹配（PSM）平衡基线特征。主要结局为偶发性谵妄；次要终点是全因死亡率。Kaplan-Meier生存曲线和随时间变化的Cox模型评估了相关性。结果：1:1 PSM后（N = 63 096 /组），GLP-1 RAs未显示谵妄风险总体降低（AHR: 0.98, 95% CI: 0.94-1.02, p = 0.3628）。然而，它们在前5年具有保护作用（AHR: 0.89, 95% CI: 0.86-0.92, p）。结论：GLP-1 RA的使用最初与谵妄的风险降低相关，但随着时间的推移，这种关联被逆转。亚组差异提示个体化治疗考虑。鉴于其稳定的认知和生存益处，二甲双胍仍然是首选的选择。

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来源期刊

Diabetes, Obesity & Metabolism 医学-内分泌学与代谢

CiteScore

10.90

自引率

6.90%

发文量

319

审稿时长

3-8 weeks

期刊介绍： Diabetes, Obesity and Metabolism is primarily a journal of clinical and experimental pharmacology and therapeutics covering the interrelated areas of diabetes, obesity and metabolism. The journal prioritises high-quality original research that reports on the effects of new or existing therapies, including dietary, exercise and lifestyle (non-pharmacological) interventions, in any aspect of metabolic and endocrine disease, either in humans or animal and cellular systems. ‘Metabolism’ may relate to lipids, bone and drug metabolism, or broader aspects of endocrine dysfunction. Preclinical pharmacology, pharmacokinetic studies, meta-analyses and those addressing drug safety and tolerability are also highly suitable for publication in this journal. Original research may be published as a main paper or as a research letter.