缺血性中风或短暂性脑缺血发作后的吡格列酮
Pioglitazone after Ischemic Stroke or Transient Ischemic Attack.
作者信息
Kernan Walter N, Viscoli Catherine M, Furie Karen L, Young Lawrence H, Inzucchi Silvio E, Gorman Mark, Guarino Peter D, Lovejoy Anne M, Peduzzi Peter N, Conwit Robin, Brass Lawrence M, Schwartz Gregory G, Adams Harold P, Berger Leo, Carolei Antonio, Clark Wayne, Coull Bruce, Ford Gary A, Kleindorfer Dawn, O'Leary John R, Parsons Mark W, Ringleb Peter, Sen Souvik, Spence J David, Tanne David, Wang David, Winder Toni R
机构信息
From the School of Medicine (W.N.K., C.M.V., L.H.Y., S.E.I., A.M.L., L.M.B., J.R.O.) and the School of Public Health (P.D.G., P.N.P., J.R.O.), Yale University, New Haven, and the Cooperative Studies Program Coordinating Center, Veteran Affairs (VA) Connecticut HealthCare System, West Haven (P.D.G., P.N.P.) - all in Connecticut; Alpert Medical School, Brown University, Providence, RI (K.L.F.); Vermont College of Medicine, Burlington (M.G.); the National Institute of Neurological Disorders and Stroke, Bethesda, MD (R.C.); the VA Medical Center and the University of Colorado School of Medicine, Denver (G.G.S.); the University of Iowa, Iowa City (H.P.A.); Hôpital Charles LeMoyne, Greenfield Park, QC (L.B.), the University of Western Ontario, London (J.D.S.), and the Center for Neurological Research, Lethbridge, AB (T.R.W.) - all in Canada; University of L'Aquila, L'Aquila, Italy (A.C.); Oregon Health Sciences University, Portland (W.C.); the University of Arizona, Tucson (B.C.); the University of Oxford and Oxford University Hospitals NHS Foundation Trust, Oxfordshire, United Kingdom (G.A.F.); the University of Cincinnati, Cincinnati (D.K.); John Hunter Hospital, University of Newcastle, New Lambton Heights, NSW, Australia (M.W.P.); the University of Heidelberg, Heidelberg, Germany (P.R.); the University of South Carolina School of Medicine, Columbia (S.S.); Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel (D.T.); and the Illinois Neurological Institute-OSF Saint Francis Medical Center and the Department of Neurology, University of Illinois College of Medicine at Peoria, Peoria (D.W.).
出版信息
N Engl J Med. 2016 Apr 7;374(14):1321-31. doi: 10.1056/NEJMoa1506930. Epub 2016 Feb 17.
BACKGROUND
Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease.
METHODS
In this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction.
RESULTS
By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P=0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003).
CONCLUSIONS
In this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).
背景
尽管有当前的预防性治疗，但缺血性中风或短暂性脑缺血发作（TIA）患者未来发生心血管事件的风险仍会增加。胰岛素抵抗被确定为中风和心肌梗死的一个危险因素，这引发了一种可能性，即改善胰岛素敏感性的吡格列酮可能会使脑血管疾病患者受益。
方法
在这项多中心、双盲试验中，我们将3876例近期有缺血性中风或TIA的患者随机分配，分别接受吡格列酮（目标剂量为每日45毫克）或安慰剂治疗。符合条件的患者没有糖尿病，但根据胰岛素抵抗的稳态模型评估（HOMA-IR）指数得分超过3.0，被发现存在胰岛素抵抗。主要结局是致命或非致命性中风或心肌梗死。
结果
到4.8年时，吡格列酮组1939例患者中有175例（9.0%）发生了主要结局，安慰剂组1937例中有228例（11.8%）发生了主要结局（吡格列酮组的风险比为0.76；95%置信区间[CI]为0.62至0.93；P = 0.007）。分别有73例（3.8%）和149例（7.7%）患者发生了糖尿病（风险比为0.48；95% CI为0.33至0.69；P < 0.001）。全因死亡率在组间无显著差异（风险比为0.93；95% CI为0.73至1.17；P = 0.52）。与安慰剂相比，吡格列酮与体重增加超过4.5千克的频率更高相关（52.2%对33.7%，P < 0.001）、水肿（35.6%对24.9%，P < 0.001）以及需要手术或住院治疗的骨折（5.1%对3.2%，P = 0.003）。
结论
在这项涉及无糖尿病但有胰岛素抵抗且近期有缺血性中风或TIA病史的患者的试验中，接受吡格列酮治疗的患者发生中风或心肌梗死的风险低于接受安慰剂治疗的患者。吡格列酮还与较低的糖尿病风险相关，但与体重增加、水肿和骨折的风险较高相关。（由美国国立神经疾病与中风研究所资助；ClinicalTrials.gov编号，NCT00091949。）
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