Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical TrialJAMAEarly Recent, Sept 19, 10.1001/jama..13772本文由“天纳”临床学术信息人工智能系统自动翻译Key PointsQuestionWhat is the effect of linagliptin compared with glimepiride on major cardiovascular events in patients with relatively early type 2 diabetes and elevated cardiovascular risk?与格列美脲相比，利格列汀对相对早期2型糖尿病和心血管风险升高患者的主要心血管事件有什么影响？FindingsIn this randomized noninferiority clinical trial that included 6033 participants followed up for a median of 6.3 years, the use of linagliptin compared with glimepiride added to usual care resulted in rates of the composite outcome (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) of 11.8% vs 12.0%. The upper limit of the 95.47% CI of the hazard ratio was 1.14, which met the noninferiority criterion of a hazard ratio of less than 1.3.在这项随机非劣效性临床试验中，6033名受试者平均随访6.3年，与格列美脲相比，在常规治疗中使用利格列汀可导致复合结果的发生率（心血管死亡、非致命性心肌梗死或非致命性卒中）分别为11.8%和12.0%。危险比95.47%CI的上限为1.14，符合危险比小于1.3的非劣效性标准。MeaningCompared with glimepiride, the use of linagliptin demonstrated noninferiority with regard to the risk of major cardiovascular events over a median of 6.3 years in patients with relatively early type 2 diabetes and elevated cardiovascular risk.与格列美脲相比，在中位6.3年以上的2型糖尿病相对早期和心血管风险升高的患者中，使用利格列汀对主要心血管事件的风险无不良影响。ImportanceType 2 diabetes is associated with increased cardiovascular risk. In placebo-controlled cardiovascular safety trials, the dipeptidyl peptidase-4 inhibitor linagliptin demonstrated noninferiority, but it has not been tested against an active comparator.2型糖尿病与心血管风险增加有关。在安慰剂对照的心血管安全性试验中，二肽基肽酶-4抑制剂利格列汀显示出非劣效性，但还没有用活性药物对照进行试验。ObjectiveThis trial assessed cardiovascular outcomes of linagliptin vs glimepiride (sulfonylurea) in patients with relatively early type 2 diabetes and risk factors for or established atherosclerotic cardiovascular disease.本试验评估了利格列汀与格列美脲（磺脲类）治疗相对早期2型糖尿病患者的心血管预后，以及动脉粥样硬化性心血管疾病的危险因素。Design, Setting, and ParticipantsRandomized, double-blind, active-controlled, noninferiority trial, with participant screening from November to December , conducted at 607 hospital and primary care sites in 43 countries involving 6042 participants. Adults with type 2 diabetes, glycated hemoglobin of 6.5% to 8.5%, and elevated cardiovascular risk were eligible for inclusion. Elevated cardiovascular risk was defined as documented atherosclerotic cardiovascular disease, multiple cardiovascular risk factors, aged at least 70 years, and evidence of microvascular complications. Follow-up ended in August .11月至12月，在43个国家的607家医院和初级保健点进行了随机、双盲、活性药物对照、非劣效性试验，共有6042名参与者。患有2型糖尿病、糖化血红蛋白为6.5%至8.5%以及心血管风险升高的成年人有资格被纳入研究。心血管风险升高被定义为动脉粥样硬化性心血管疾病、多个心血管风险因素、年龄至少70岁以及微血管并发症。于8月随访结束。InterventionsPatients were randomized to receive 5 mg of linagliptin once daily (n = 3023) or 1 to 4 mg of glimepiride once daily (n = 3010) in addition to usual care. Investigators were encouraged to intensify glycemic treatment, primarily by adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to clinical need.除常规治疗外，患者随机接受5 mg利格列汀每日一次（n=3023）或1-4 mg格列美脲每日一次（n=3010）。鼓励研究人员加强血糖治疗，主要是根据临床需要添加或调整二甲双胍、α-葡萄糖苷酶抑制剂、噻唑烷二酮类或胰岛素。Main Outcomes and MeasuresThe primary outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride, defined by the upper limit of the 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3.主要结果是首次发生心血管死亡、非致命性心肌梗死或非致命性卒中的时间，目的是确定利格列汀对格列美脲的非劣效性，由利格列汀相对于格列美脲的风险比（HR）小于1.3的双侧95.47％CI的上限定义。ResultsOf 6042 participants randomized, 6033 (mean age, 64.0 years; 2414 [39.9%] women; mean glycated hemoglobin, 7.2%; median duration of diabetes, 6.3 years; 42% with macrovascular disease; 59% had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years. The primary outcome occurred in 356 of 3023 participants (11.8%) in the linagliptin group and 362 of 3010 (12.0%) in the glimepiride group (HR, 0.98 [95.47% CI, 0.84-1.14]; P < .001 for noninferiority), meeting the noninferiority criterion but not superiority (P = .76). Adverse events occurred in 2822 participants (93.4%) in the linagliptin group and 2856 (94.9%) in the glimepiride group, with 15 participants (0.5%) in the linagliptin group vs 16 (0.5%) in the glimepiride group with adjudicated-confirmed acute pancreatitis. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6%) participants in the linagliptin group and 1132 (37.7%) in the glimepiride group (HR, 0.23 [95% CI, 0.21-0.26]).在6042名随机参与者中，6033名（平均年龄64.0岁；2414名（39.9%）女性；平均糖化血红蛋白7.2%；糖尿病中位病程6.3年；42%患有大血管疾病；59%接受过二甲双胍单药治疗）接受了治疗和分析。中位随访时间为6.3年。利格列汀组的3023名受试者中有356名（11.8％）发生主要结果，格列美脲组的3010名受试者中有362名（12.0％）发生主要结果（HR，0.98[95.47%CI，0.84-1.14]；P＜0.001，非劣效性），符合非劣效性标准，但不优于优效性标准（P=0.76）。利格列汀组2822名受试者（93.4%）和格列美脲组2856名受试者（94.9%）出现不良事件，其中利格列汀组15名受试者（0.5%）和格列美脲组16名受试者（0.5%）判定为急性胰腺炎。利格列汀组320名参与者（10.6%）和格列美脲组1132名参与者（37.7%）发生至少1次低血糖不良事件（HR，0.23[95%CI，0.21-0.26]）。Conclusions and RelevanceAmong adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median 6.3 years resulted in a noninferior risk of a composite cardiovascular outcome.在患有相对早期2型糖尿病和心血管风险升高的成年人中，与格列美脲相比，平均使用6.3年的利格列汀，导致复合心血管结局的非劣效风险。Trial RegistrationClinicalTrials.gov Identifier: NCT01243424clinicaltrials.gov标识符：nct01243424IntroductionWhen choosing medications to manage type 2 diabetes, cardiovascular safety, glucose-lowering potency, hypoglycemia risk, effect on body weight, and cost are important considerations.1-3 Most guidelines state that metformin should be first-line therapy followed by various options for second-line treatment if sufficient glycemic control is not achieved after metformin monotherapy.1-3 Sulfonylureas and dipeptidyl peptidase-4 (DPP-4) inhibitors are the most commonly used second-line glucose-lowering treatments in many countries.4 Sulfonylureas are used mainly based on their low cost, well-established glucose-lowering action, and a long-standing experience in clinical practice. However, sulfonylureas are associated with increased risk of hypoglycemia1,3,5-7 and modest weight gain.1,5 In addition, there is an ongoing controversy regarding their long-term cardiovascular safety, based on early >8 and multiple observational and smaller studies indicating conflicting results.9,10当选择药物治疗2型糖尿病时，心血管安全性，降糖效力，低血糖风险，对体重的影响，成本是重要的考虑因素。1-3大多数指南规定，二甲双胍应为一线治疗，如果二甲双胍单药治疗后不能达到足够的血糖控制，则应选择各种二线治疗。1-3磺酰脲和二肽基肽酶-4（DPP-4）抑制剂是许多国家最常用的二线降糖治疗方法。4磺脲类药物主要是基于其低成本、良好的降糖作用和长期的临床实践经验。然而，磺脲类药物与低血糖风险增加1,3,5-7和适度体重增加有关。1,5此外，关于它们的长期心血管安全性仍存在争议，根据1960s8年大学糖尿病组项目的早期数据，以及多个观察和小规模的研究，结果相互矛盾。9,10Linagliptin is a selective, once-daily, DPP-4 inhibitor approved for glycemic management of type 2 diabetes, with low risk of hypoglycemia and weight neutrality.11 To date, no head-to-head trial has compared the long-term effect of these agents on cardiovascular morbidity and mortality or glucose-lowering efficacy in patients with type 2 diabetes.利格列汀是一种选择性的DPP-4抑制剂，每日一次，被批准用于2型糖尿病的血糖控制，低血糖风险低，体重中性。在2型糖尿病患者的心血管疾病发病率、死亡率或降糖疗效方面，没有一项直接对照试验比较了这些药物的长期效果。The Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes (CAROLINA) examined the effect of treatment with the DPP-4 inhibitor linagliptin vs the commonly used sulfonylurea glimepiride on cardiovascular safety in patients with relatively early type 2 diabetes and cardiovascular risk factors or established atherosclerotic cardiovascular disease using a noninferiority design.利格列汀与格列美脲治疗2型糖尿病的心血管结局研究（卡罗莱纳州）考察了DPP-4抑制剂利格列汀与常用磺脲类药物格列美脲治疗对相对早期2型糖尿病患者心血管安全性的影响。使用非劣效性设计确定心血管危险因素或动脉粥样硬化性心血管疾病。MethodsThe study protocol was approved by the institutional review board or independent ethics committee from each site, and all patients provided written informed consent; the trial protocol is available is Supplement 1 and the statistical analysis plan in Supplement 2.研究方案经机构审查委员会或独立伦理委员会批准，所有患者均提供书面知情同意书；试验方案见附录1，统计分析计划见附录2。The trial was conducted in accordance with the principles of the Declaration of Helsinki and the Harmonized Tripartite Guideline for Good Clinical Practice from the International Conference on Harmonisation and was approved by local authorities.这项试验是根据《赫尔辛基宣言》的原则和国际协调会议关于良好临床实践的协调三方准则进行的，并得到了地方当局的批准。An independent, unmasked data monitoring committee regularly reviewed trial data. Investigator-reported cardiovascular outcome events, deaths, pancreatitis, and pancreatic cancer were prospectively captured and centrally adjudicated by clinical events committees masked to treatment assignment.一个独立的、无遮掩的数据监测委员会定期审查试验数据。研究者报告心血管结局事件、死亡、胰腺炎和胰腺癌被前瞻性地捕获，并由临床事件委员会在治疗任务中进行集中裁决。The trial design has been previously published.12 In brief, this was a multicenter, randomized, double-blind, active-controlled clinical trial conducted at 607 centers across 43 countries, aimed to continue until at least 631 participants had an adjudication-confirmed primary outcome event.该试验设计已在之前发表。12简言之，这是一项多中心、随机、双盲、主动对照临床试验，在43个国家的607个中心进行，旨在继续进行，直到至少631名参与者获得裁决确认的主要结果事件。Adults with type 2 diabetes, glycated hemoglobin (HbA1c) level of 6.5% to 8.5%, and high cardiovascular risk were eligible for inclusion. Participants naive to sulfonylurea or glinide therapy had to have a HbA1c level of 6.5% to 8.5%, while participants who were currently treated with a sulfonylurea or glinide as monotherapy or in a dual combination with metformin or α-glucosidase inhibitor (who also were eligible for the trial) had to have an HbA1c level of 6.5% to 7.5%. The sulfonylurea or glinide were discontinued at randomization. High cardiovascular risk was defined as (1) established atherosclerotic cardiovascular disease (documented ischemic heart disease, cerebrovascular disease, or peripheral artery disease), (2) multiple risk factors (at least 2 of the following: type 2 diabetes duration >10 years, systolic blood pressure >140 mm Hg [or receiving at least 1 blood pressure–lowering treatment], current smoker, low-density lipoprotein cholesterol ≥135 mg/dL [3.5 mmol/L], or receiving lipid-lowering treatment), (3) age at least 70 years, and (4) evidence of microvascular complications (impaired kidney function [estimated glomerular filtration rate of 30-59 mL/min/1.73 m2], urine albumin/creatinine ratio ≥30 μg/mg, or proliferative retinopathy). Insulin therapy or previous exposure to DPP-4 inhibitors, glucagonlike peptide-1 receptor agonists, or thiazolidinediones were exclusion criteria, as was New York Heart Association class III to IV heart failure (eAppendix 3 and 4 in Supplement 3).患有2型糖尿病、糖化血红蛋白（HbA1c）水平为6.5%至8.5%和心血管风险高的成年人有资格入选。未接受磺酰脲或格列奈治疗的受试者的HbA1c水平必须在6.5%到8.5%之间，而目前接受磺酰脲或格列奈作为单一治疗或与二甲双胍或α-葡萄糖苷酶抑制剂（也有资格参加试验）双重联合治疗的受试者糖化血红蛋白水平为6.5%至7.5%。磺酰脲或格列奈在随机分组时停用。高心血管风险被定义为（1）已建立的动脉粥样硬化性心血管疾病（记录的缺血性心脏病、脑血管病或外周动脉疾病），（2）多种危险因素（至少2种：2型糖尿病持续时间>，收缩压>140毫米汞柱[或接受至少一次降压治疗]，吸烟者，低密度脂蛋白胆固醇≥135毫克/分升[3.5毫摩尔/升]，或接受降脂治疗，（3）年龄至少70岁，微血管并发症的证据（肾功能受损[肾小球滤过率估计为30-59ml/min/1.73m2]、尿白蛋白/肌酐比值≥30μg/mg或增殖性视网膜病变）。胰岛素治疗或之前接触过DPP-4抑制剂、胰高血糖素样肽-1受体激动剂或噻唑烷二酮类药物是排除标准，纽约心脏协会III至IV级心力衰竭也是排除标准（补充3中的EAppendix 3和4）。Information on race and ethnicity was captured by investigators based on self-classification by trial participants as reported in the electronic case record form (fixed categories) following written informed consent. This information was collected to allow for subgroup analysis, given some previous reports about potential heterogeneity of effects of sulfonylureas and incretin-based therapies on different genetic background,13,14 and as required by regulatory bodies.15在获得书面知情同意后，调查人员根据试验参与者在电子病历表（固定类别）中报告的自我分类收集了有关种族和族裔的信息。鉴于之前关于磺脲类药物和肠促胰岛素类药物在不同遗传背景下作用的潜在异质性的一些报告，收集这些信息是为了进行亚组分析，13、14和监管机构的要求。Participants were randomized 1:1 using an interactive telephone- and web-based system in a block size of 4 to receive 5 mg of once-daily oral linagliptin or 1 to 4 mg of once-daily glimepiride (Figure 1). Treatment assignment was determined by a computer-generated random sequence with stratification by center. Glimepiride was started at 1 mg/d and uptitrated to a potential maximum dose of 4 mg/d every 4 weeks during the first 16 weeks. After the first 16 weeks, participants returned for follow-up study visits every 16 weeks until the end of the study. A final follow-up visit was scheduled 30 days after treatment cessation. Investigators were encouraged to monitor and use additional medication for glycemic control per local guidelines, particularly if HbA1c was greater than 7.5% after the end of the titration phase. Recommended strategies were adjustments of background therapy or addition of pioglitazone, metformin, α-glucosidase inhibitor, or basal insulin. Investigators were also encouraged to manage all other cardiovascular risk factors in accordance with applicable guidelines and current standards of care. Participants who prematurely discontinued the study medication were followed up for ascertainment of cardiovascular events, mortality, adverse events, and other end points. Attempts were made to collect vital status and outcome event information on every randomized individual at study completion, in compliance with local law and regulations.参与者被随机分为1:1，使用交互式电话和网络系统，分块大小为4，每天口服5毫克利格列汀或每天服用1-4毫克格列美脲（图1）。治疗分配由计算机生成的随机序列决定，按中心分层。格列美脲从1 mg/d开始，在最初的16周内每4周增加一次潜在的最大剂量4 mg/d。前16周后，参与者每16周返回一次随访研究，直到研究结束。最后一次随访安排在治疗结束后30天。鼓励研究人员根据当地指南监测和使用额外的血糖控制药物，特别是在滴定阶段结束后HbA1c大于7.5%的情况下。推荐的策略是调整背景治疗或添加吡格列酮、二甲双胍、α-葡萄糖苷酶抑制剂或基础胰岛素。还鼓励研究人员根据适用的指导方针和当前的护理标准管理所有其他心血管危险因素。对过早停止研究药物的参与者进行随访，以确定心血管事件、死亡率、不良事件和其他终点。在研究完成时，根据当地法律法规，尝试收集每个随机个体的生命状态和结果事件信息。The primary end point was time to first occurrence of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke (3-point major cardiovascular event [3P-MACE] composite). The original protocol included hospitalization for unstable angina in the primary end point (4-point major cardiovascular event [4P-MACE] composite); however, this was changed by a protocol amendment in April , based on emerging evidence that a primary end point definition of 3P-MACE was preferred by regulators and consistent with other outcome trials of glucose-lowering therapies.16,17 The steering committee and sponsor remained blinded to all trial data prior to database lock. Time to first occurrence of 4P-MACE was hierarchically evaluated as the first of the prespecified key secondary end points, followed by analyses of the proportion of patients receiving treatment and maintaining HbA1c of less than or equal to 7.0% at the final follow-up visit who (1) were without the need for rescue medication, did not have any moderate/severe hypoglycemic episodes, and did not have greater than 2% weight gain or (2) were without the need for rescue medication and did not have greater than 2% weight gain between the end of titration and final visit.主要终点是首次发生心血管死亡、非致命性心肌梗死（mi）或非致命性卒中（3点主要心血管事件[3p-mace]复合）的时间。最初的方案包括在主要终点（4点主要心血管事件[4P-MACE]复合）因不稳定心绞痛住院治疗；然而，4月的方案修正案改变了这一点，基于新出现的证据，即监管机构倾向于3P-MACE的主要终点定义，并且与其他降糖治疗的结果试验一致。16,17在数据库锁定之前，指导委员会和申办方对所有试验数据仍然一无所知。首次出现4P-MACE的时间作为预先指定的关键次要终点的第一个进行分级评估，然后分析在最后一次随访中接受治疗并维持糖化血红蛋白低于或等于7.0%的患者的比例，这些患者（1）不需要抢救药物，没有任何中/重度低血糖发作，体重增加不超过2%或（2）无需抢救药物，滴定结束至最后就诊期间体重增加不超过2%。Other secondary cardiovascular end points included individual components of 3P-MACE and 4P-MACE and time to any confirmed adjudicated cardiovascular events (cardiovascular death, including fatal stroke and fatal MI; nonfatal MI; nonfatal stroke; hospitalization for unstable angina; transient ischemic attack; hospitalization for HF; hospitalization for coronary revascularization procedures). Secondary diabetes-related end points included change in laboratory parameters from baseline to final visit (eg, HbA1c, fasting plasma glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides). In addition, we prespecified several tertiary cardiovascular end points (ie, occurrence of and time to first occurrence of each of the confirmed adjudicated end points), tertiary diabetes-related end points (eg, change of laboratory parameters from baseline to each planned week, hypoglycemia occurrence, change in weight and rescue medication use), and other end points (including noncardiovascular death and adverse events). All predefined outcomes and end point definitions are presented in Supplement 1, Supplement 3 (eAppendix 5), and Supplement 4.其他次要心血管终点包括3p-mace和4p-mace的单个成分和任何已确诊心血管事件（心血管死亡，包括致命中风和致命心肌梗死；非致命心肌梗死；非致命中风；不稳定心绞痛住院治疗）的时间；短暂性脑缺血发作；心衰住院治疗；冠状动脉重建术住院治疗）。继发性糖尿病相关终点包括从基线检查到最后就诊期间实验室参数的变化（如糖化血红蛋白、空腹血糖、总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、甘油三酯）。此外，我们预先指定了几个三级心血管终点（即每个确诊终点的出现和首次出现的时间）、三级糖尿病相关终点（如从基线到每个计划周实验室参数的变化，低血糖发生、体重变化和抢救药物使用）等终点（包括非心血管死亡和不良事件）。所有预定义结果和终点定义见附录1、附录3（EAppendix 5）和附录4。Safety was assessed based on adverse events that occurred during treatment or within 7 days after the last dose of a study drug and coded using the Medical Dictionary for Drug Regulatory Activities version 21.0. Adverse events prespecified as being of special interest included hypersensitivity reactions, skin lesions, pancreatitis, pancreatic cancer, and hypoglycemia. Categories of hypoglycemia were analyzed as “any,” “moderate or severe,” “severe,” or “leading to hospitalization” (for definitions of each categorization, see eAppendix 5 in Supplement 3).安全性根据治疗期间或最后一次服用研究药物后7天内发生的不良事件进行评估，并使用21.0版药物管理活动医学词典进行编码。特别关注的不良事件包括过敏反应、皮肤损伤、胰腺炎、胰腺癌和低血糖。低血糖的分类被分析为“任何”、“中等或严重”、“严重”或“导致住院”（每一分类的定义见附录3中的EAppendix 5）。The primary aim of the study was to evaluate whether linagliptin was noninferior to glimepiride for the time to 3P-MACE, defined by the upper limit of the multiplicity-adjusted 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3.15 This margin (ie, an upper limit of the 2-sided 95% CI <1.3) was deemed able to demonstrate a reassuring point estimate of overall cardiovascular risk between study groups in the context of a noninferiority assessment by the US Food and Drug Administration. A 5-step hierarchical testing strategy was prespecified, in which each subsequent test would be performed in case of significant prior results. If noninferiority was achieved for the primary outcome, the subsequent tests were (1) superiority test of 3P-MACE, (2) superiority test of 4P-MACE, (3) superiority test of the second key secondary end point (ie, proportion of patients receiving treatment and maintaining HbA1c ≤7.0% at the final visit who were without the need for rescue medication following the end of titration, did not have moderate/severe hypoglycemic episodes, and did not have >2% weight gain), and (4) superiority test of the third key secondary end point (ie, proportion of patients receiving treatment and maintaining HbA1c ≤7.0% at the final visit who were, from the end of titration, without the need for rescue medication and did not have >2% weight gain). Not adjusted for interim analyses, a total of 631 individuals with an adjudication-confirmed 3P-MACE would provide 90.9% power to demonstrate noninferiority (noninferiority margin, 1.3) of linagliptin vs glimepiride at the overall 1-sided α level of 2.5% assuming an HR of 1.0, and80% power for superiority assuming an HR of 0.80. The 95.47% bound for the CI reflected an O’Brien-Fleming α-spending adjustment for the 2 interim analyses of the primary outcome,18 in addition to Bonferroni adjustment, to control for type I error for the change from 4P-MACE to 3P-MACE after the first interim analysis. The interim analyses were planned to be performed after 190 and 411 participants experienced a primary outcome event. Outcomes were analyzed in all randomized patients treated with at least 1 dose of the study drug (treated set) using the intention-to-treat principle. Patients were analyzed according to their randomized treatment group. Additional sensitivity analyses are described in eAppendix 6 in Supplement 3. Time-to-event outcomes were analyzed using a Cox proportional hazards model, with treatment assignment as a factor in the model. Proportional hazards assumptions were explored by plotting log(−log [survival function]) against the log of time × treatment group and checked for parallelism. Further, Schoenfeld residuals were plotted against time and log(time). For all Cox proportional hazards analyses, the proportional hazard assumption was met. Subgroup analyses included additional factors for subgroup and treatment by subgroup interaction.本研究的主要目的是评估利格列汀在3P-MACE时间内是否不劣于格列美脲，定义为利格列汀相对于格列美脲的危险比（HR）的多重调整双边95.47%置信区间上限小于1.3.15，即双侧95%ci<1.3）的上限被认为能够证明在美国食品和药物管理局的非劣效性评估的背景下，研究组之间总体心血管风险的可靠点估计。提出了一种5步分层测试策略，在有显着的先验结果的情况下进行后续的测试。如果主要结果为非劣效，则随后的试验为（1）3P-MACE的优越性试验，（2）4P-MACE的优越性试验，（3）第二个关键次要终点的优越性试验（即，在最后一次就诊时接受治疗并维持HbA1c≤7.0%的患者中，滴定结束后无需抢救药物，无中/重度低血糖发作，体重增加不超过2%，（4）第三个关键次要终点的优越性检验（即从滴定结束起，在最后一次就诊时接受治疗并维持HbA1c≤7.0%且无需抢救药物且体重增长不超过2%的患者的比例）。未经中期分析调整，在假设HR为1.0的情况下，共有631名经裁定确认的3P-MACE患者在2.5%的总单侧α水平下，提供90.9%的能力证明利格列汀与格列美脲的非劣效性（非劣效性裕度，1.3）。假设HR为0.80，80%的优势力量。95.47%的置信区间反映了除了Bonferroni调整之外的2项主要结果中期分析的O"Brien-Flemingα-支出调整，以控制第一次中期分析后从4P-MACE变为3P-MACE的I型误差。中期分析计划在190名和411名参与者经历主要结果事件后进行。采用意向性治疗原则，对所有接受至少1剂研究药物（治疗组）治疗的随机患者的结果进行分析。按随机治疗组进行分析。附加灵敏度分析见附录3中的EAppendix 6。采用cox比例危险度模型，以治疗分配为因素，对事件发生时间的结果进行分析。通过绘制对数（－对数[生存函数]）与时间×治疗组的对数，探讨比例危险假设，并检查平行性。此外，根据时间和对数（时间）绘制了Schoenfeld残差图。对于所有cox比例风险分析，均满足比例风险假设。亚组分析包括亚组的附加因素和亚组间相互作用的治疗。In addition, Kaplan-Meier estimates are presented. Censoring was applied the day a participant was last known to be free of the specific outcome event. Because of declining numbers of participants at risk, Kaplan-Meier plots were truncated at 6.5 years after randomization. Logistic regression models with randomized treatment as the factor and χ2 tests were used to analyze noncardiovascular key secondary efficacy end points. For continuous parameters, the change from baseline over time was evaluated with a restricted maximum likelihood–based mixed-model repeated-measures approach (2-sided significance threshold P < .05; eAppendix 6 in Supplement 3). As prespecified, data were included up to the planned week that could theoretically be achieved by all patients. The prespecified approach for handling missing data are described in the statistical analysis plan (Supplement 2). The approach varied according to the statistical analysis employed (eg, censoring in Cox models and Kaplan-Meier plots for time-to-event analysis and mixed models for continuous variables). Specifically, we defined the censoring date for the time-to-event analysis as the last date a patient was known to be free of an end point event, including any start dates of adverse event/outcome events, onset dates of adjudicated-confirmed events, date of percutaneous coronary intervention/coronary artery bypass grafting, or date of trial completion (defined as the latest of date of the last clinic visit, telephone call, or contact if lost to follow-up). Except for the prespecified 5-step hierarchical testing strategy, there was no adjustment for multiple comparisons and, therefore, the results of subgroup analyses and other end points should be interpreted as exploratory. Safety assessments were conducted using descriptive statistics for adverse events, except for analyses of hypoglycemia, which was analyzed using a Cox proportional hazards model (2-sided P value threshold < .05). Analyses were conducted using SAS version 9.4 (SAS Institute).此外，还提出了kaplan-meier估计。审查是在参与者最后一次被认为没有特定结果事件的那一天应用的。由于有风险的参与者数量减少，随机分组后6.5年卡普兰-迈尔图被截断。采用logistic回归模型，以随机治疗为因素，经χ2检验，分析非心血管病的主要次要疗效终点。对于连续参数，使用基于限制最大似然的混合模型重复测量法（补充3中的双侧显着性阈值p<.05；eappendix 6）评估基线随时间的变化。如前所述，数据包含到所有患者理论上可以实现的计划周。统计分析计划（补充2）描述了处理缺失数据的预先指定方法。该方法根据所采用的统计分析而有所不同（例如，对时间到事件分析的cox模型和kaplan-meier图进行审查，对连续变量的混合模型进行审查）。具体地说，我们将事件分析时间的审查日期定义为已知患者没有终点事件的最后日期，包括不良事件/结果事件的任何开始日期、判定的确认事件的开始日期，经皮冠状动脉介入治疗/冠状动脉旁路移植术的日期，或试验完成日期（定义为最后一次临床访问、电话或联系（如果失去随访）的最晚日期）。除了预先指定的5步分层测试策略外，没有对多重比较进行调整，因此，子组分析和其他终点的结果应解释为探索性的。安全性评估使用不良事件的描述性统计进行，低血糖分析除外，低血糖分析使用Cox比例危险模型进行分析（双侧P值阈值<8201;.05）。使用SAS 9.4版（SAS协会）进行分析。ResultsParticipants were screened from November through December , with final follow-up on August 21, . A total of 6042 participants were randomized, of whom 6033 received at least 1 dose of the study medication and were included in the primary outcome analysis (Figure 1).参与者于11月至12月进行筛选，最终随访时间为8月21日。共有6042名受试者被随机分配，其中6033名受试者至少接受了1剂研究药物，并被纳入主要结果分析（图1）。Baseline clinical characteristics were well balanced between groups (Table 1), with 42% of all participants having prevalent atherosclerotic cardiovascular disease at the time of screening. Median (quartile [Q] 1, Q3) follow-up was 6.3 (5.9, 6.6) years in both the linagliptin and glimepiride groups. Median (Q1, Q3) study medication exposure was 5.9years in the linagliptin group and 5.9 (3.4, 6.4) years in the glimepiride group (eAppendix 7 in Supplement 3). Cumulative participant-years of follow-up was 18 336 for the linagliptin group and 18 212 for the glimepiride group. Overall, 96.0% of participants completed the study, with 38.2% prematurely discontinuing the study drug (incidence rate per 100 years at risk of 7.6 in the linagliptin group and 8.0 in the glimepiride group). Vital status was available for 99.3% of participants at the end of the study (Figure 1).两组之间的基线临床特征很好地平衡（表1），在筛查时42%的受试者患有普遍的动脉粥样硬化性心血管疾病。利格列汀组和格列美脲组的中位（四分位[q]1，q3）随访时间均为6.3（5.9，6.6）年。利格列汀组研究药物暴露的中位数（Q1，Q3）为5.9年，格列美脲组为5.9年（3.4，6.4年）（补充3中的eappendix 7）。利格列汀组和格列美脲组的累积随访参与者年数分别为18 336和18 212。总体而言，96.0%的受试者完成了研究，38.2%的受试者过早中止了研究药物（利格列汀组和格列美脲组每100年的风险发生率分别为7.6和8.0）。研究结束时，99.3%的受试者的生命状态可用（图1）。The primary 3P-MACE end point occurred in 356 of 3023 participants (11.8%) treated with linagliptin (2.1 per 100 person-years) and 362 of 3010 (12.0%) treated with glimepiride (2.1 per 100 person-years), meeting the criterion for noninferiority (HR, 0.98 [95.47% CI, 0.84-1.14], P <.001 for noninferiority; Table 2 and Figure 2A). The subsequent testing for superiority according to the prespecified testing procedure was not statistically significant (P = .76). Overall, the HR for 3P-MACE was consistent across prespecified subgroups (eAppendix 8 in Supplement 3).主要3P-MACE终点发生在3023名受试者中的356名（11.8%）接受了利格列汀（2.1/100人-年）治疗，3010名受试者中的362名（12.0%）接受了格列美脲（2.1/100人-年）治疗，符合非劣效性标准（HR，0.98[95.47%CI，0.84-1.14]，非劣效性p<0.001；表2和图2a）。根据预先指定的测试程序进行的随后的优势测试没有统计学意义（p=.76）。总的来说，3P-MACE的HR在预先指定的亚组中是一致的（补充3中的EAppendix 8）。Because the result of the test for superiority was null, findings for the key secondary outcomes are presented descriptively. Post hoc analytic results can be found in eAppendix 9 and eTable 3 in Supplement 3. The secondary 4P-MACE outcome occurred in 398 of 3023 participants (13.2%) in the linagliptin group and 401 of 3010 (13.3%) in the glimepiride group (Table 2). The second key secondary end point of the proportion of patients receiving treatment and maintaining HbA1c less than or equal to7.0% at the final visit who were (following the end of titration) without the need for rescue medication, without any moderate/severe hypoglycemic episodes, and without greater than 2% weight gain occurred in 481 of 3023 participants (16.0%) in the linagliptin group and 305 of 3010 (10.2%) in the glimepiride group (Table 2; eAppendix 9 in Supplement 3). The third key secondary end point of the proportion of patients receiving treatment and maintaining HbA1c less than or equal to 7.0% at the final visit who were (following the end of titration) without the need for rescue medication and did not have greater than 2% weight gain occurred in 524 of 3023 participants (17.4%) in the linagliptin group and in 422 of 3010 (14.1%) in the glimepiride group (Table 2; eAppendix 9 Supplement 3).由于优势检验的结果为空，因此描述了主要次要结果的结果。事后分析结果见附录3中的eappendix 9和etable 3。第二次4P-MACE结果发生在利格列汀组3023名参与者中的398名（13.2%）和格列美脲组3010名参与者中的401名（13.3%）（表2）。接受治疗并在最后就诊时维持糖化血红蛋白低于或等于7.0%（滴定结束后）且无需抢救药物、无任何中/重度低血糖发作的患者比例的第二个关键次要终点，在3023名受试者中，利格列汀组481名（16.0%）和格列美脲组3010名（10.2%）中305名（表2；补充3中的eappendix 9）体重增加不超过2%。接受治疗并在最后就诊时维持糖化血红蛋白低于或等于7.0%（滴定结束后）且无需抢救药物且体重增加不超过2%的患者比例的第三个关键次要终点发生在利格列汀组3023人（17.4%），格列美脲组3010人中422人（14.1%）（表2；eappendix 9增补3）。
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JAMAEarly Recent, Sept 19, 10.1001/jama..13772
JAMA｜利格列汀与格列美脲对2型糖尿病患者主要不良心血管结局的影响：CAROLINA随机临床试验
