Inoue Kosuke, Saliba Debra, Gotanda Hiroshi, Moin Tannaz, Mangione Carol M, Klomhaus Alexandra M, Tsugawa Yusuke
Department of Social Epidemiology, Graduate School of Medicine, Kyoto University, and Hakubi Center, Kyoto University, Kyoto, Japan (K.I.).
U.S. Department of Veterans Affairs Greater Los Angeles Healthcare System (VAGLAS) Geriatrics Research, Education and Clinical Centers, Los Angeles, California; Borun Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; and RAND Corporation, Santa Monica, California (D.S.).
Ann Intern Med. 2025 Jul 22. doi: 10.7326/ANNALS-24-02648.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to decrease blood glucose levels, promote weight loss, and prevent cardiovascular events. However, evidence is limited regarding their effect on dementia, although emerging observational studies, some with serious methodological limitations, have suggested large reductions in dementia associated with GLP-1RAs that may not be entirely causally related.
To compare the effect of GLP-1RAs versus dipeptidyl peptidase-4 inhibitors (DPP4is) as second-line therapy for type 2 diabetes on risk for dementia among older adults.
Target trial emulation.
United States from January 2016 to December 2020.
Medicare fee-for-service beneficiaries aged 66 years or older with diabetes who used metformin and did not have dementia at baseline and initiated GLP-1RAs or DPP4is between January 2017 and December 2018.
Onset of dementia was defined as 1 year before the date of a new dementia diagnosis. Risks were calculated at 30 months in GLP-1RA and DPP4i groups matched in a 1:2 ratio on an estimated propensity score and compared via ratios and differences.
Among 2418 patients initiating GLP-1RAs and 4836 matched patients initiating DPP4is, the mean age was 71 years, and 55% were female. Over a median follow-up of 1.9 years, the outcome occurred in 96 patients in the GLP-1RA group and 217 in the DPP4i group. The estimated risk difference at 30 months was -0.93 (95% CI, -2.33 to 0.23) percentage points, and the estimated risk ratio was 0.83 (95% CI, 0.61 to 1.05). The estimated risk ratios were 0.64 (95% CI, 0.46 to 0.93) and 1.22 (95% CI, 0.74 to 1.66) among those younger than 75 years and aged 75 years or older, respectively.
Potential residual confounding (no data on body mass index, glycemic control, or duration of diabetes), outcome misclassification, and short follow-up.
Among older adults with diabetes, no clear evidence was found that the incidence of dementia differed overall between patients using GLP-1RAs versus DPP4is. Under conventional statistical criteria, an effect of GLP-1RAs between a 39% decrease and a 5% increase in risk for dementia was highly compatible with the data, although estimates differed by age. Randomized trials are needed to quantify the effect of GLP-1RAs on dementia.
Gregory Annenberg Weingarten, GRoW @ Annenberg.
胰高血糖素样肽-1受体激动剂（GLP-1RAs）已被证明可降低血糖水平、促进体重减轻并预防心血管事件。然而，关于其对痴呆症的影响的证据有限，尽管一些新兴的观察性研究（其中一些存在严重的方法学局限性）表明，与GLP-1RAs相关的痴呆症大幅减少，但这可能并非完全存在因果关系。
比较GLP-1RAs与二肽基肽酶-4抑制剂（DPP4is）作为2型糖尿病二线治疗药物对老年人痴呆症风险的影响。
目标试验模拟。
2016年1月至2020年12月的美国。
年龄在66岁及以上、患有糖尿病且使用二甲双胍、基线时无痴呆症，并在2017年1月至2018年12月期间开始使用GLP-1RAs或DPP4is的医疗保险按服务收费受益人。
痴呆症的发病定义为新痴呆症诊断日期前1年。在根据估计的倾向评分以1:2比例匹配的GLP-1RA组和DPP4i组中，计算30个月时的风险，并通过比率和差异进行比较。
在2418名开始使用GLP-1RAs的患者和4836名匹配的开始使用DPP4is的患者中，平均年龄为71岁，55%为女性。在中位随访1.9年期间，GLP-1RA组有96名患者出现该结局，DPP4i组有217名患者出现该结局。30个月时的估计风险差异为-0.93（95%CI，-2.33至0.23）个百分点，估计风险比为0.83（95%CI，0.61至1.05）。在75岁以下和75岁及以上的人群中，估计风险比分别为0.64（95%CI，0.46至0.93）和1.22（95%CI，0.74至1.66）。
潜在的残余混杂因素（无体重指数、血糖控制或糖尿病病程数据）、结局错误分类和随访时间短。
在患有糖尿病的老年人中，没有明确证据表明使用GLP-1RAs的患者与使用DPP4is的患者之间痴呆症的总体发病率存在差异。根据传统统计标准，GLP-1RAs使痴呆症风险降低39%至增加5%的效应与数据高度相符，尽管估计值因年龄而异。需要进行随机试验来量化GLP-1RAs对痴呆症的影响。
格雷戈里·安嫩伯格·温加滕，安嫩伯格成长基金。
