Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Massachusetts General Hospital Diabetes Center, Harvard Medical School, Boston, Massachusetts.
JAMA Netw Open. 2022 Oct 3;5(10):e2237606. doi: 10.1001/jamanetworkopen.2022.37606.
Limited evidence is available on the comparative effectiveness of empagliflozin vs alternative second-line glucose-lowering agents in patients with type 2 diabetes (T2D) receiving routine care who have a broad spectrum of cardiorenal risk.
To evaluate the association of empagliflozin with cardiovascular outcomes relative to liraglutide and sitagliptin, stratified by age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD).
DESIGN, SETTING, AND PARTICIPANTS: This retrospective comparative effectiveness cohort study used deidentified Medicare claims data from August 1, 2014, to September 30, 2018, with follow-up from drug initiation until treatment changes, death, or gap in Medicare enrollment (>30 days). Data analysis was performed from October 1, 2021, to April 30, 2022. Medicare fee-for-service beneficiaries older than 65 years with T2D were included. A total of 45 788 patients (22 894 propensity score-matched pairs initiating treatment with either empagliflozin or liraglutide) were included in cohort 1, and 45 624 patients (22 812 propensity score-matched pairs initiating treatment with either empagliflozin or sitagliptin) were included in cohort 2.
Empagliflozin vs liraglutide (cohort 1) or empagliflozin vs sitagliptin (cohort 2).
Primary outcomes were (1) modified major adverse cardiovascular events (MACEs), including a composite of myocardial infarction, stroke, and all-cause mortality, and (2) hospitalization for heart failure (HHF). Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years were estimated, adjusting for 143 baseline covariates using 1:1 propensity score matching.
Among 45 788 patients in cohort 1, the mean (SD) age was 71.9 (5.1) years; 23 396 patients (51.1%) were female, 22 392 (48.9%) were male, and 38 049 (83.1%) were White. Among 45 624 patients in cohort 2, the mean (SD) age was 72.1 (5.1) years; 21 418 patients (46.9%) were female, 24 206 (53.1%) were male, and 37 814 (82.9%) were White. Relative to patients initiating liraglutide, those initiating empagliflozin had a similar risk of the modified MACE outcome (HR, 0.90; 95% CI, 0.79-1.03) and a reduced risk of HHF (HR, 0.66; 95% CI, 0.52-0.82). Across subgroups, empagliflozin was associated with a lower risk of the modified MACE outcome in patients with a history of ASCVD (HR, 0.83; 95% CI, 0.71-0.98) and HF (HR, 0.77; 95% CI, 0.60-1.00) compared with liraglutide, and potential heterogeneity in estimates was observed by sex (male: HR, 0.85 [95% CI, 0.71-1.01]; female: HR, 1.16 [95% CI, 0.94-1.42]; P = .02 for homogeneity). However, reductions in the risk of HHF were observed across most subgroups (eg, ASCVD: HR, 0.66 [95% CI, 0.51-0.85]; HF: HR, 0.66 [95% CI, 0.49-0.88]). Compared with sitagliptin, empagliflozin was associated with reduced risks of the modified MACE outcome (HR, 0.68; 95% CI, 0.60-0.77) and HHF (HR, 0.45; 95% CI, 0.36-0.56), which were consistent across all subgroups. Absolute benefits of empagliflozin vs sitagliptin were larger in patients with a history of ASCVD (modified MACE: RD, -17.6 [95% CI, -24.9 to -10.4]; HHF: RD, -16.7 [95% CI, -21.7 to -11.9]), HF (modified MACE: RD, -41.1 [95% CI, -59.9 to -22.6]; HHF: RD, -50.4 [95% CI, -67.5 to -33.9]), or CKD (modified MACE: RD, -26.7 [95% CI, -41.3 to -12.3]; HHF: RD, -31.9 [95% CI, -43.5 to -20.8]).
In this comparative effectiveness study of older adults, empagliflozin was associated with a lower risk of HHF (relative to both liraglutide and sitagliptin) and the modified MACE outcome (relative to sitagliptin), with larger absolute benefits in patients with established cardiorenal diseases. These findings suggest that older adults with T2D might benefit more from empagliflozin vs liraglutide or sitagliptin with respect to the risk of HHF; with respect to the risk of MACEs, empagliflozin might be preferable to liraglutide only in patients with cardiovascular disease history and to sitagliptin across all patient subgroups.
重要性：在接受常规护理且具有广泛心肾风险的 2 型糖尿病（T2D）患者中，与替代二线降糖药物利拉鲁肽和西格列汀相比，恩格列净在心血管结局方面的比较效果，证据有限。
目的：评估恩格列净与利拉鲁肽和西格列汀相比，在年龄、性别、基线动脉粥样硬化性心血管疾病（ASCVD）、心力衰竭（HF）和慢性肾脏病（CKD）分层下，与心血管结局的关联。
设计、设置和参与者：这项回顾性比较有效性队列研究使用了 2014 年 8 月 1 日至 2018 年 9 月 30 日的医疗保险索赔数据，从药物开始到治疗变化、死亡或医疗保险登记中断（>30 天）进行随访。数据分析于 2021 年 10 月 1 日至 2022 年 4 月 30 日进行。纳入年龄大于 65 岁、患有 T2D 的医疗保险收费服务受益人的数据。共有 45788 名患者（22894 对经倾向评分匹配的接受恩格列净或利拉鲁肽治疗的患者）被纳入队列 1，45624 名患者（22812 对经倾向评分匹配的接受恩格列净或西格列汀治疗的患者）被纳入队列 2。
暴露：恩格列净与利拉鲁肽（队列 1）或恩格列净与西格列汀（队列 2）。
主要结局和措施：主要结局是（1）改良的主要不良心血管事件（MACEs），包括心肌梗死、中风和全因死亡率的综合指标，以及（2）因心力衰竭（HF）住院。使用 1:1 倾向评分匹配，通过调整 143 个基线协变量，使用 143 个基线协变量，估计每 1000 人年的风险比（HR）和率差（RD）。
结果：在队列 1 中的 45788 名患者中，平均（SD）年龄为 71.9（5.1）岁；23396 名患者（51.1%）为女性，22392 名患者（48.9%）为男性，38049 名患者（83.1%）为白人。在队列 2 中的 45624 名患者中，平均（SD）年龄为 72.1（5.1）岁；21418 名患者（46.9%）为女性，24206 名患者（53.1%）为男性，37814 名患者（82.9%）为白人。与起始使用利拉鲁肽的患者相比，起始使用恩格列净的患者发生改良 MACE 结局的风险相似（HR，0.90；95%CI，0.79-1.03），心力衰竭住院的风险降低（HR，0.66；95%CI，0.52-0.82）。在亚组中，与利拉鲁肽相比，有 ASCVD 病史（HR，0.83；95%CI，0.71-0.98）和 HF（HR，0.77；95%CI，0.60-1.00）的患者，恩格列净与改良 MACE 结局的风险降低，并且观察到性别存在估计值的异质性（男性：HR，0.85[95%CI，0.71-1.01]；女性：HR，1.16[95%CI，0.94-1.42]；P=0.02 用于同质性）。然而，在大多数亚组中观察到心力衰竭住院风险降低（例如，ASCVD：HR，0.66[95%CI，0.51-0.85]；HF：HR，0.66[95%CI，0.49-0.88]）。与西格列汀相比，恩格列净与改良 MACE 结局（HR，0.68；95%CI，0.60-0.77）和心力衰竭住院（HR，0.45；95%CI，0.36-0.56）的风险降低，在所有亚组中均一致。与西格列汀相比，恩格列净在有 ASCVD（改良 MACE：RD，-17.6[95%CI，-24.9 至-10.4]；HF：RD，-16.7[95%CI，-21.7 至-11.9]）、HF（改良 MACE：RD，-41.1[95%CI，-59.9 至-22.6]；HF：RD，-50.4[95%CI，-67.5 至-33.9]）或 CKD（改良 MACE：RD，-26.7[95%CI，-41.3 至-12.3]；HF：RD，-31.9[95%CI，-43.5 至-20.8]）病史的患者中，风险降低的绝对获益更大。
结论和相关性：在这项针对老年人的比较有效性研究中，与利拉鲁肽和西格列汀相比，恩格列净与心力衰竭住院（与两者相比）和改良 MACE 结局（与西格列汀相比）的风险降低，在患有已确立的心肾疾病的患者中，绝对获益更大。这些发现表明，与利拉鲁肽相比，患有 2 型糖尿病的老年人可能从恩格列净治疗中获益更多，以降低心力衰竭风险；就 MACE 风险而言，恩格列净可能仅在有心血管疾病史的患者中优于利拉鲁肽，并且在所有患者亚组中优于西格列汀。
