CAROLINA^{®<\/sup><\/b>（使用利格列汀对比格列美脲治疗2型糖尿病患者的心血管结局研究）是一项多国、随机、双盲、活性药物对照临床试验，入组来自43个国家和地区600多个试验中心的6033名成人2型糖尿病患者，研究随访的中位持续时间超过6年。^{[1],[2]<\/span><\/sup>试验入组早期成人2型糖尿病患者，患者病程的中位时间为6.2年，其中一些从未接受过任何治疗，另一些服用过1-2种降糖药（例如二甲双胍）。^{[2]<\/span><\/sup>试验旨在评估利格列汀（每日一次5毫克）对比磺脲类格列美脲（均添加于稳定的基础降糖药物与心血管标准治疗方法之上）对心血管风险增加或已出现心血管疾病的成人2型糖尿病患者的心血管安全性影响。^{[1],[2]<\/span><\/sup>这些患者反应了医生日常临床实践中常见的患者群。^{^{[6]<\/span><\/sup><\/sup> <\/p> \n}}}}}}

CAROLINA^{®<\/sup><\/b>试验由学术试验指导委员会以及由勃林格殷格翰和礼来组成的糖尿病联盟共同发起。CAROLINA^{®<\/sup><\/b>试验是首个活性药物对照的DPP-4抑制剂心血管结局试验。 <\/p> \n}}

利格列汀是一种无需单剂量调整、每日服用一次的DPP-4抑制剂，能显著降低2型糖尿病患者的血糖水平。成人2型糖尿病患者均可使用，无论年龄、病程、种族、体重指数（BMI）和肝肾功能如何。3在目前上市的DPP-4抑制剂中，利格列汀的肾脏排泄率最低。 ^{[7],[8],[9],[10]<\/span><\/sup><\/p> \n}

由于心血管疾病是2型糖尿病的主要并发症和首要死亡原因，因此心血管结局试验是非常重要的。在全球范围内，大多数2型糖尿病患者死于心血管事件。^{[4]<\/span><\/sup>2015年，勃林格殷格翰和礼来共同宣布了标志性里程碑的EMPA-REGOUTCOME®心血管结局试验结果，试验的研究对象为钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂恩格列净。在标准治疗方法上添加恩格列净，能够将合并心血管疾病的成人2型糖尿病患者的心血管死亡相对风险降低38%。^{^{[a]<\/sup><\/sup>^{^{[b]<\/sup><\/sup>^{^{[11],<\/sup><\/sup>^{^{[12],<\/sup><\/sup>^{^{[13]<\/sup><\/sup><\/span>因此，恩格列净在许多国家成为了首个拥有心血管适应症或在说明书中标明降低心血管死亡风险数据的口服2型糖尿病治疗药物。 ^{[11],[12]<\/span><\/sup><\/p> \n}}}}}}}}}}}}

CAROLINA^{®<\/sup><\/b>是DPP-4抑制剂利格列汀的两项心血管结局试验之一。^{[1],[2]<\/span><\/sup>CAROLINA^{®<\/sup><\/b>和CARMELINA^{®<\/sup>（<\/b>使用利格列汀治疗高血管风险2型糖尿病患者的心血管安全性与肾脏微血管安全性结局试验）^{[5,][14] <\/span><\/sup>提供了DPP-4抑制剂中齐全面的长期安全性数据之一。<\/p> \n}}}}}

CARMELINA^{®<\/sup><\/b>试验是一项多国、随机、双盲、安慰剂对照的临床试验，入组来自27个国家600多个试验中心的6979名成人2型糖尿病患者，研究观察的中位时间为2.2年。^{[5,][14]<\/span><\/sup>该研究旨在评估利格列汀对于心血管高风险和\/或并发肾脏疾病的成人2型糖尿病患者的心血管和肾脏安全性影响。^{[5,][14]<\/span><\/sup>该试验达到主要终点，^{[c]<\/sup><\/span>即在标准治疗方法基础上，联用利格列汀展示出与安慰剂相似的心血管安全性。^{[5]<\/sup><\/span>CARMELINA^{®<\/sup><\/b>试验同时包括了一项关键次要复合终点，^{[d]<\/sup><\/span>展示出与安慰剂相似的肾脏安全性。^{[5]<\/sup><\/span>在CARMELINA^{®<\/sup><\/b>试验中，利格列汀的总体安全性与既往数据保持一致，没有发现新的安全性信号。^{[3],[5]<\/span><\/sup>CARMELINA^{®<\/sup><\/b>试验结果同样显示，利格列汀组与安慰剂组在心衰住院率方面并无差异。^{[5]<\/sup><\/span><\/p> \n}}}}}}}}}}}}

\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n
[a] Adult patients with type 2 diabetes and coronary artery disease, peripheral artery disease, or a history of MI or stroke<\/span><\/span><\/p> <\/td> \n <\/tr> \n
[b] Standard of care included cardiovascular medications and blood sugar lowering agents given at the discretion of physicians<\/span><\/span><\/p> <\/td> \n <\/tr> \n
[c] Primary endpoint defined as time to first occurrence of the 3P-MACE (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke)<\/span><\/span><\/p> <\/td> \n <\/tr> \n
[d] Key secondary endpoint defined as time to first occurrence of sustained end stage kidney disease (ESKD), death due to kidney disease, or a sustained decrease in eGFR from baseline of ≥40 percent compared to placebo<\/span><\/span><\/p> <\/td> \n <\/tr> \n
[1] ClinicalTrials.Gov. CARdiovascular Outcome study of LINAgliptin versus Glimepiride in patients with Type 2 diabetes. Available at: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01243424<\/a>. Accessed: February 2019.<\/span><\/p> <\/td> \n <\/tr> \n
[2] Marx N, et al<\/i>. Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA®). Diabetes & Vascular Disease Research<\/i> 2015;12(3)<\/b>:164-74. <\/span><\/p> <\/td> \n <\/tr> \n
[3] European Medicines Agency. Trajenta® (linagliptin) tablets. EMA Summary of Product Characteristics. Last updated July 2018. Available at: https:\/\/www.ema.europa.eu\/documents\/product-information\/trajenta-epar-product-information_en.pdf<\/a> Accessed: February 2019.<\/span><\/p> <\/td> \n <\/tr> \n
[4]^{<\/sup>World Heart Federation. Cardiovascular Disease Risk Factors. Available at: https:\/\/www.world-heart-federation.org\/resources\/risk-factors\/<\/a>. Accessed: February 2019.<\/span><\/p> <\/td> \n <\/tr> \n}
[5] Rosenstock J, et al<\/i>. Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA^{®<\/sup> Randomized Clinical Trial. JAMA<\/i>. 2018 Nov 9. doi: 10.1001\/jama.2018.18269.<\/span><\/p> <\/td> \n <\/tr> \n}
[6] Boehringer Ingelheim and Eli Lilly and Company. Data on file.<\/span><\/p> <\/td> \n <\/tr> \n
[7] European Medicines Agency. Onglyza^{®<\/sup> (saxagliptin) tablets. EMA Summary of Product Characteristics. Available from: https:\/\/www.ema.europa.eu\/documents\/product-information\/onglyza-epar-product-information_en.pdf<\/a> Last updated: July 2016. Accessed: February 2019.<\/span><\/p> <\/td> \n <\/tr> \n}
[8] European Medicines Agency. Vipidia^{®<\/sup> (alogliptin) tablets. EMA Summary of Product Characteristics. Available from: http:\/\/ec.europa.eu\/health\/documents\/community-register\/2015\/20150115130399\/anx_130399_en.pdf<\/a> Last updated: January 2015. Accessed: February 2019.<\/span><\/p> <\/td> \n <\/tr> \n}
[9] European Medicines Agency. Januvia^{®<\/sup> (sitagliptin) tablets. EMA Summary of Product Characteristics. Available from: https:\/\/ec.europa.eu\/health\/documents\/community-register\/2018\/20180516140764\/anx_140764_en.pdf<\/a> Last updated: August 2017. Accessed: February 2019.<\/span><\/p> <\/td> \n <\/tr> \n}
[10]^{<\/sup>European Medicines Agency. Galvus^{®<\/sup> (vildagliptin) tablets. EMA Summary of Product Characteristics. Available from: https:\/\/www.ema.europa.eu\/documents\/product-information\/galvus-epar-product-information_en.pdf<\/a> Last updated: June 2017. Accessed: February 2019.<\/span><\/p> <\/td> \n <\/tr> \n}}
[11] Jardiance^{®<\/sup> (empagliflozin) tablets U.S. Prescribing Information. FDA. Available at: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2016\/204629s008lbl.pdf<\/a>. Accessed February 2019.<\/span><\/p> <\/td> \n <\/tr> \n}
[12] Jardiance^{®<\/sup> (empagliflozin) Summary of Product Characteristics. EMA. Available at: http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Product_Information\/human\/002677\/WC500168592.pdf<\/a>. Accessed: February 2019.<\/span><\/p> <\/td> \n <\/tr> \n}
[13] Zinman B, et al<\/i>. EMPA-REG OUTCOME^{®<\/sup> Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med.<\/i> 2015;373<\/b>(22)<\/b>:2117-2128.<\/span><\/p> <\/td> \n <\/tr> \n}
[14] ClinicalTrials.Gov. Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus at high vascular risk. Available at: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01897532?term=NCT01897532&rank=1<\/a>. Accessed: February 2019.<\/span><\/p> <\/td> \n <\/tr> \n <\/tbody> \n <\/table> \n<\/div> \n
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