Background: Clinical trials have shown cardiovascular benefits and potential risks from sodium glucose cotransporter 2 inhibitors (SGLT2i). Trials may have limited ability to address individual end points or safety concerns.

Methods: We performed a population-based cohort study among patients with type 2 diabetes mellitus with established cardiovascular disease newly initiated on antihyperglycemic agents within the US Department of Defense Military Health System between April 1, 2013, and December 31, 2016. Incidence rates, hazard ratios (HRs), and 95% confidence intervals (CIs) for time to first composite end point of all-cause mortality and hospitalization for heart failure event, major adverse cardiovascular events (defined as all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke), and individual end points were evaluated using conditional Cox models comparing new SGLT2i users with other antihyperglycemic agents. The exploratory safety end point was below-knee lower extremity amputation. Intent-to-treat and on-treatment analyses were performed.

Results: After propensity matching, 25 258 patients were followed for a median of 1.6 years. Compared with non-SGLT2i, initiation of SGLT2i was associated with a lower rate of all-cause mortality and hospitalization for heart failure (1.73 versus 3.01 events per 100 person-years; HR, 0.57; 95% CI, 0.50–0.65) and major adverse cardiovascular events (2.31 versus 3.45 events per 100 person-years; HR, 0.67; 95% CI, 0.60–0.75). SGLT2i initiation was also associated with an ≈2-fold higher risk of below-knee lower extremity amputation (0.17 versus 0.09 events per 100 person-years; HR, 1.99; 95% CI, 1.12–3.51). Because of the disproportionate canagliflozin exposure in the database, the majority of amputations were observed on canagliflozin. Results were consistent in the on-treatment analysis.

Conclusions: In this high-risk cohort, initiation of SGLT2i was associated with lower risk of all-cause mortality, hospitalization for heart failure, and major adverse cardiovascular events and higher risk of below-knee lower extremity amputation. Findings underscore the potential benefit and risks to be aware of when initiating SGLT2i. It remains unclear whether the below-knee lower extremity amputation risk extends across the class of medication, because the study was not powered to make comparisons among individual treatments.

背景：临床试验表明，钠葡萄糖共转运蛋白2抑制剂（SGLT2i）有心血管益处和潜在风险。尝试解决个别终点或安全问题的能力可能有限。

方法：我们在2013年4月1日至2016年12月31日期间，对美国国防部军事卫生系统中使用降糖药新发起的患有心血管疾病的2型糖尿病患者进行了基于人群的队列研究。发生率，危险比（HRs）和心力衰竭事件，重大心血管不良事件（定义为全因死亡率，非致命性心肌梗塞和非致命性中风）的全因死亡率首次住院和到达复合终点的时间的95％置信区间（CIs） ），并使用条件Cox模型评估各个终点，将新的SGLT2i用户与其他降糖药进行比较。探索性安全终点为膝下肢截肢。进行意向治疗和治疗中分析。

结果：倾向匹配后，随访25 258例患者，中位时间为1.6年。与非SGLT2i相比，SGLT2i的启动与心衰全因死亡率和住院率较低相关（每100人年1.73比3.01事件； HR，0.57； 95％CI，0.50-0.65）和主要不良心血管事件（每100人年2.31事件与3.45事件； HR，0.67； 95％CI，0.60-0.75）。SGLT2i的启动还与膝下肢截肢的风险增加约2倍相关（每100人年0.17比0.09事件； HR，1.99； 95％CI，1.12-3.51）。由于canagliflozin在数据库中的暴露比例不成比例，因此在canagliflozin上观察到大部分截肢手术。在治疗分析中结果是一致的。

结论：在这个高危人群中，SGLT2i的启动与全因死亡率，心力衰竭住院，重大心血管不良事件的风险较低以及膝下肢截肢的风险较高有关。研究结果强调了在启动SGLT2i时要意识到的潜在利益和风险。尚不清楚膝下下肢截肢的风险是否在整个药物类别中扩展，因为该研究无权在各个治疗方法之间进行比较。