Shadyab Aladdin H, Espeland Mark A, Odegaard Andrew O, Manson JoAnn E, Haring Bernhard, Johnson Karen C, Chen Zhao, Zhang Bowei, LaCroix Andrea Z
Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, California, USA.
Division of Geriatrics, Gerontology, and Palliative Care, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
J Gerontol A Biol Sci Med Sci. 2025 Jun 10;80(7). doi: 10.1093/gerona/glaf095.
The association of metformin with mortality has been mixed, and no prior study has determined whether metformin initiation is associated with exceptional longevity, defined as survival to ages 90 and older.
We performed a new-user, active comparator cohort study using the target trial emulation framework among the Women's Health Initiative cohort to determine whether metformin versus sulfonylurea initiation was associated with exceptional longevity (survival to age 90). We identified participants ≥60 years with incident type 2 diabetes and no history of hypoglycemic agents or insulin prior to treatment initiation to perform intention-to-treat analyses. We used 1:1 propensity score matching on demographic characteristics, lifestyle behaviors, diabetes duration, comorbidities (hypertension, cardiovascular disease, chronic obstructive pulmonary disease, and cancer), body mass index, and concomitant medications to balance treatment groups on key confounders.
Among 438 propensity score-matched women with type 2 diabetes, the incidence rate of death before age 90 per 100 person-years in women initiating metformin monotherapy was 3.7 (95% CI: 3.1-4.4) compared with 5.0 (95% CI: 4.2-5.8) for sulfonylurea monotherapy. The adjusted risk of death before age 90 was 30% lower for initiation of metformin monotherapy versus sulfonylurea monotherapy (hazard ratio, 0.70; 95% CI: 0.56-0.88).
In this first target trial emulation of metformin and exceptional longevity, we found that metformin initiation increased exceptional longevity compared with sulfonylurea initiation among women with type 2 diabetes. Because this comparison was not made to placebo in a randomized controlled trial and given the observational design with potential for residual confounding, causality cannot be inferred.
二甲双胍与死亡率之间的关联尚无定论，此前也没有研究确定起始使用二甲双胍是否与超长寿命相关，超长寿命定义为活到90岁及以上。
我们在女性健康倡议队列中使用目标试验模拟框架进行了一项新用户、活性对照队列研究，以确定起始使用二甲双胍与磺脲类药物相比是否与超长寿命（活到90岁）相关。我们纳入了年龄≥60岁、新发2型糖尿病且在开始治疗前无降糖药物或胰岛素使用史的参与者进行意向性分析。我们根据人口统计学特征、生活方式行为、糖尿病病程、合并症（高血压、心血管疾病、慢性阻塞性肺疾病和癌症）、体重指数和伴随用药情况进行1:1倾向评分匹配，以平衡治疗组的关键混杂因素。
在438例倾向评分匹配的2型糖尿病女性中，起始使用二甲双胍单药治疗的女性每100人年90岁前的死亡率为3.7（95%CI：3.1-4.4），而磺脲类药物单药治疗的死亡率为5.0（95%CI：4.2-5.8）。起始使用二甲双胍单药治疗与磺脲类药物单药治疗相比，90岁前死亡的校正风险降低了30%（风险比，0.70；95%CI：0.56-0.88）。
在这项首次对二甲双胍与超长寿命进行的目标试验模拟研究中，我们发现，与2型糖尿病女性起始使用磺脲类药物相比，起始使用二甲双胍可提高超长寿命。由于该比较未在随机对照试验中与安慰剂进行，且鉴于观察性设计存在潜在的残余混杂因素，因此无法推断因果关系。
