From the Research Medical Center, Kansas City, MO (S.P.M.); School of Medicine, Swansea University, Swansea, United Kingdom (S.C.B.); Department of Medicine and Aging Science and Center of Excellence on Aging and Translational Medicine, G. d'Annunzio University, Chieti-Pescara, Italy (A.C.); CPClin Research Center/Hospital Israelita Albert Einstein, São Paulo (F.G.E.); Hospital Universitario Quirón Salud Madrid, Facultad de Ciencias de la Salud, Universidad Europea de Madrid, Madrid (E.J.); Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Toronto (L.A.L.), and the University of Manitoba, Winnipeg (V.W.) - both in Canada; University of Texas Southwestern Medical Center (I.L.) and Dallas Diabetes Research Center at Medical City (J.R.) - both in Dallas; University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany (J.S.); Physicians East, Greenville, NC (M.L.W.); and Novo Nordisk, Søborg (O.H., A.G.H., J.P.), and the Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup (T.V.) - both in Denmark.
N Engl J Med. 2016 Nov 10;375(19):1834-1844. doi: 10.1056/NEJMoa1607141. Epub 2016 Sep 15.
Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown.
We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio.
At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.
In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).
监管指导方针规定，需要在 2 型糖尿病患者中确立新的糖尿病治疗方法的心血管安全性，以排除过度的心血管风险。半衰期约为 1 周的胰高血糖素样肽-1 类似物司美格鲁肽在 2 型糖尿病中的心血管作用尚不清楚。
我们随机分配了 3297 名正在接受标准治疗方案的 2 型糖尿病患者，每周接受一次司美格鲁肽（0.5 毫克或 1.0 毫克）或安慰剂治疗 104 周。主要复合结局是心血管死亡、非致死性心肌梗死或非致死性卒中的首次发生。我们假设司美格鲁肽在主要结局方面不劣于安慰剂。非劣效性边界为 95%置信区间上限的 1.8。
在基线时，2735 名患者（83.0%）患有已确立的心血管疾病、慢性肾脏病或两者兼有。在司美格鲁肽组中，1648 名患者中有 108 名（6.6%）和安慰剂组中 1649 名患者中有 146 名（8.9%）发生了主要结局（风险比，0.74；95%置信区间 [CI]，0.58 至 0.95；P<0.001 用于非劣效性）。接受司美格鲁肽治疗的患者中有 2.9%发生非致死性心肌梗死，而接受安慰剂治疗的患者中有 3.9%发生（风险比，0.74；95%CI，0.51 至 1.08；P=0.12）；非致死性卒中分别为 1.6%和 2.7%（风险比，0.61；95%CI，0.38 至 0.99；P=0.04）。两组心血管原因导致的死亡率相似。司美格鲁肽组新发或恶化的肾病发生率较低，但视网膜病变并发症（玻璃体积血、失明或需要玻璃体腔内药物或光凝治疗的情况）发生率明显较高（风险比，1.76；95%CI，1.11 至 2.78；P=0.02）。司美格鲁肽组发生的严重不良事件较少，但更多的患者因不良事件停止治疗，主要是胃肠道不良事件。
在心血管风险较高的 2 型糖尿病患者中，与安慰剂组相比，接受司美格鲁肽治疗的患者心血管死亡、非致死性心肌梗死或非致死性卒中的发生率显著降低，证实了司美格鲁肽的非劣效性。（由 Novo Nordisk 资助；SUSTAIN-6 临床试验.gov 编号，NCT01720446）。
