Thrombolysis in Myocardial Infarction (TIMI) Study Group (B.A.B., D.L.B., K.I., E.K., Y.G., E.B., B.M.S.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Cardiovascular Division, Heart and Vascular Center (B.A.B., D.L.B., K.I., E.K., Y.G., E.B., B.M.S.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Circulation. 2019 Sep 17;140(12):1004-1014. doi: 10.1161/CIRCULATIONAHA.119.040144. Epub 2019 Jul 31.
BACKGROUND: Metformin is first-line therapy for type 2 diabetes mellitus, although its effects on the cardiovascular system are unproved. METHODS: In this post hoc analysis, patients in SAVOR-TIMI 53 (Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus) with baseline biomarker samples (n=12 156) were classified as ever versus never taking metformin during the trial period. Associations between metformin exposure and outcomes were estimated with inverse probability of treatment weighting Cox modeling for the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke, as well as cardiovascular death and all-cause mortality, with biomarkers included as covariates. Additional sensitivity analyses included propensity score matching and Cox multivariable models. RESULTS: Of the 12 156 patients with baseline biomarker samples, 8971 (74%) had metformin exposure, 1611 (13%) had prior heart failure, and 1332 (11%) had at least moderate chronic kidney disease (estimated glomerular filtration rate ≤45 mL·min·1.73 m). Metformin use was associated with no difference in risk for the composite end point (hazard ratio for inverse probability of treatment weighting, 0.92 [95% CI, 0.76-1.11]) but lower risk of all-cause mortality (hazard ratio for inverse probability of treatment weighting, 0.75 [95% CI, 0.59-0.95]). There was no significant relationship between metformin use and these end points in patients with prior heart failure or moderate to severe chronic kidney disease. CONCLUSIONS: In a cohort of 12 156 patients with type 2 diabetes mellitus and high cardiovascular risk, metformin use was associated with lower rates of all-cause mortality, including after adjustment for clinical variables and biomarkers, but not lower rates of the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01107886.
背景：二甲双胍是 2 型糖尿病的一线治疗药物，但其对心血管系统的影响尚未得到证实。
方法：在 SAVOR-TIMI 53（沙格列汀与 2 型糖尿病患者心血管结局）的这项事后分析中，根据试验期间是否服用二甲双胍，将基线生物标志物样本（n=12156）的患者分为从未服用和曾服用二甲双胍两组。采用逆概率治疗加权 Cox 模型估计二甲双胍暴露与结局之间的相关性，复合终点为心血管死亡、心肌梗死或缺血性卒中，以及心血管死亡和全因死亡率，将生物标志物作为协变量。另外还进行了倾向评分匹配和 Cox 多变量模型的敏感性分析。
结果：在有基线生物标志物样本的 12156 例患者中，8971 例（74%）有二甲双胍暴露史，1611 例（13%）有既往心力衰竭史，1332 例（11%）至少有中度慢性肾脏病（估算肾小球滤过率≤45 mL·min·1.73 m）。二甲双胍治疗与复合终点的风险无差异（逆概率治疗加权的危险比为 0.92[95%置信区间，0.76-1.11]），但全因死亡率风险较低（逆概率治疗加权的危险比为 0.75[95%置信区间，0.59-0.95]）。在既往有心力衰竭或中重度慢性肾脏病的患者中，二甲双胍的使用与这些终点之间没有显著关系。
结论：在 12156 例 2 型糖尿病合并高心血管风险的患者中，二甲双胍的使用与全因死亡率降低相关，包括在调整临床变量和生物标志物后，而与心血管死亡、心肌梗死或缺血性卒中的复合终点无降低趋势。这种相关性在既往无心力衰竭或中重度慢性肾脏病的患者中最为明显。
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