Tang Bowen, Sjölander Arvid, Wastesson Jonas W, Maura Géric, Blotiere Pierre-Olivier, Szilcz Máté, Mak Jonathan K L, Qin Chenxi, Alvarsson Michael, Religa Dorota, Johnell Kristina, Hägg Sara
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China.
EClinicalMedicine. 2024 Jun 20;73:102689. doi: 10.1016/j.eclinm.2024.102689. eCollection 2024 Jul.
The comparative effectiveness of glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas on the risk of dementia in older individuals with type 2 diabetes mellitus (T2DM) is unknown.
We conducted a sequential trial emulation from 1st January 2010 to 30th June 2020 using data from Swedish national registers. Swedish residents who were aged 65 or older, had type 2 diabetes (T2DM), and initiated GLP-1 agonists, DPP-4 inhibitors, or sulfonylureas were followed for up to 10 years to assess the risk of dementia. Participants who had dementia, used the three drug classes, or had contraindications were excluded from enrollment. The characteristics between arms were balanced through the application of propensity scores estimated from predefined covariates. Intention-to-treat effects were analysed with all enrolled participants, while the per-protocol effects were analysed with participants who adhered to the assigned treatment.
The pooled trial included 88,381 participants who received prescriptions for GLP-1 agonists (n = 12,351), DPP-4 inhibitors (n = 43,850), or sulfonylureas (n = 32,216) at baseline and were followed for an average of 4.3 years. A total of 4607 dementia cases developed during follow-up: 278 for the GLP-1 agonist initiators (incidence rate: 6.7 per 1000 person years), 1849 for DPP-4 inhibitor initiators (IR: 11.8), and 2480 for sulfonylurea initiators (IR: 13.7). In an intention-to-treat analysis, GLP-1 agonist initiation was associated with a reduced risk of dementia compared to sulfonylureas (hazard ratio: 0.69, 95% CI: 0.60-0.79, p < 0.0001) and DPP-4 inhibitors (HR: 0.77, 95% CI: 0.68-0.88, p < 0.0001), after adjusting for age, enrollment year, sex, socioeconomic factors, health conditions, and past medication uses. These findings were consistent in several sensitivity analyses, including a per-protocol analysis (HR for sulfonylureas: 0.41, 95% CI: 0.32-0.53, p < 0.0001; HR for DPP-4 inhibitors: 0.38, 95% CI: 0.30-0.49, p < 0.0001).
Our research suggested that GLP-1 agonists were associated with a lower risk of dementia compared to sulfonylureas and DPP-4 inhibitors in older individuals with T2DM. Further clinical trials are needed to validate these findings.
Swedish Research Council, Karolinska Institutet, the National Institute on Aging, the National Institutes of Health, and Riksbankens Jubileumsfond.
胰高血糖素样肽-1（GLP-1）激动剂、二肽基肽酶-4（DPP-4）抑制剂和磺脲类药物对老年2型糖尿病（T2DM）患者患痴呆症风险的比较有效性尚不清楚。
我们利用瑞典国家登记处的数据，于2010年1月1日至2020年6月30日进行了一项序贯试验模拟。对年龄在65岁及以上、患有2型糖尿病（T2DM）并开始使用GLP-1激动剂、DPP-4抑制剂或磺脲类药物的瑞典居民进行了长达10年的随访，以评估痴呆症风险。患有痴呆症、使用这三类药物或有禁忌症的参与者被排除在入组之外。通过应用从预定义协变量估计的倾向得分，使各组之间的特征达到平衡。对所有入组参与者进行意向性分析，而对坚持分配治疗的参与者进行符合方案分析。
汇总试验包括88381名参与者，他们在基线时接受了GLP-1激动剂（n = 12351）、DPP-4抑制剂（n = 43850）或磺脲类药物（n = 32216）的处方，平均随访4.3年。随访期间共发生4607例痴呆症病例：GLP-1激动剂起始者278例（发病率：每1000人年6.7例），DPP-4抑制剂起始者1849例（发病率：11.8），磺脲类药物起始者2480例（发病率：13.7）。在意向性分析中，与磺脲类药物（风险比：0.69，95%置信区间：0.60 - 0.79，p < 0.0001）和DPP-4抑制剂（风险比：0.77，95%置信区间：0.68 - 0.88，p < 0.0001）相比，起始使用GLP-1激动剂与痴呆症风险降低相关，这是在对年龄、入组年份、性别、社会经济因素、健康状况和既往用药情况进行调整之后。这些发现在多项敏感性分析中是一致的，包括符合方案分析（磺脲类药物的风险比：0.41，95%置信区间：0.32 - 0.53，p < 0.0001；DPP-4抑制剂的风险比：0.38，95%置信区间：0.30 - 0.49，p < 0.0001）。
我们的研究表明，在老年T2DM患者中，与磺脲类药物和DPP-4抑制剂相比，GLP-1激动剂与较低的痴呆症风险相关。需要进一步的临床试验来验证这些发现。
瑞典研究理事会、卡罗林斯卡学院、美国国立衰老研究所、美国国立卫生研究院和瑞典银行三百周年纪念基金会。
