Goldstein Barry J, Rosenstock Julio, Anzalone Deborah, Tou Conrad, Ohman K Peter
Department of Medicine, Jefferson Medical College of Thomas Jefferson University, 349 Jefferson Alumni Hall, 1020 Locust Street, Philadelphia, PA 19107, USA.
Curr Med Res Opin. 2006 Dec;22(12):2575-90. doi: 10.1185/030079906x154169.
The Glucose and Lipid Assessment in Diabetes (GLAD) trial examined the dose-response relationship of the dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist tesaglitazar in type 2 diabetic patients.
GLAD was a 12-week, multicenter, international, randomized, parallel-group trial. Five-hundred men and women aged 30-80 years with type 2 diabetes (fasting plasma glucose [FPG] > or = 126 mg/dL [> or = 7.0 mmol/L]) received once-daily, double-blind placebo or tesaglitazar (0.1 mg, 0.5 mg, 1.0 mg, 2.0 mg, or 3.0 mg) or open-label pioglitazone (45 mg), included as a therapeutic benchmark.
Placebo-corrected changes from baseline in FPG (primary end point), plasma lipids, and insulin-resistance measures.
At baseline, the mean patient age was 56.1 years, 57.5 years, and 58.9 years for placebo, across tesaglitazar groups, and for pioglitazone, respectively. For the corresponding groups, mean body mass index was 30.6 kg/m2, 30.9 kg/m2, and 29.7 kg/m2, and mean HbA1c was 7.0%, 7.2%, and 7.0%, respectively. At 12 weeks, tesaglitazar 0.5 mg, 1.0 mg, 2.0 mg, and 3.0 mg produced statistically significant reductions in FPG (-30.3 mg/dL, -41.1 mg/dL, -55.0 mg/dL, -60.9 mg/dL; p < 0.0001), triglycerides (-17.2%, -32.9%, -41.0%, -40.9%; p < 0.01), and apolipoprotein B (-15.0%, -15.7%, -21.0%, -22.3%, respectively; p < 0.0001). Tesaglitazar at doses > or = 1.0 mg significantly increased high-density lipoprotein-cholesterol (HDL-C) (15.0%, 13.0%, 12.9%; p < 0.001), and reduced non-HDL-C (-13.2%, -22.2%, -25.0%; p < 0.0001), very-low-density lipoprotein-cholesterol (VLDL-C) (-36.9%, -49.8%, -52.5%; p < 0.0001), and total cholesterol (-6.8%, -14.1%, -15.5%, respectively; p < 0.01). Tesaglitazar > or = 0.5 mg improved insulin-resistance measures. Although no formal statistical analyses were performed between active treatments, improvements in efficacy measures with tesaglitazar 1.0 mg were numerically similar to or greater than those with pioglitazone. Similar numbers of adverse events occurred in the tesaglitazar < or = 1.0 mg, placebo, and pioglitazone arms, but there was an increasing frequency of discontinuations due to pre-specified hematologic and clinical-chemistry criteria with tesaglitazar doses > or = 1.0 mg.
In type 2 diabetic patients, tesaglitazar dose-dependently reduced FPG levels at doses > or = 0.5 mg. Other markers of glycemic control, atherogenic dyslipidemia, and measures associated with insulin resistance were improved at doses > or = 0.5 mg or > or = 1.0 mg. Study limitations included that the majority of patients were white, patients had good glycemic control at baseline, and the increased number of early withdrawals in the tesaglitazar 2.0 mg and 3.0 mg doses limits conclusions about the efficacy of these doses. The 0.5 mg and 1.0 mg tesaglitazar doses were identified for further investigation.
糖尿病患者的血糖和血脂评估（GLAD）试验研究了双重过氧化物酶体增殖物激活受体（PPAR）α/γ激动剂替格列扎在2型糖尿病患者中的剂量反应关系。
GLAD是一项为期12周的多中心、国际、随机、平行组试验。500名年龄在30 - 80岁的2型糖尿病患者（空腹血糖[FPG]≥126 mg/dL[≥7.0 mmol/L]）每日接受一次双盲安慰剂或替格列扎（0.1 mg、0.5 mg、1.0 mg、2.0 mg或3.0 mg）或开放标签的吡格列酮（45 mg）治疗，吡格列酮作为治疗对照。
FPG（主要终点）、血脂和胰岛素抵抗指标相对于基线的安慰剂校正变化。
基线时，安慰剂组、替格列扎各剂量组和吡格列酮组的患者平均年龄分别为56.1岁、57.5岁和58.9岁。相应组的平均体重指数分别为30.6 kg/m²、30.9 kg/m²和29.7 kg/m²，平均糖化血红蛋白分别为7.0%、7.2%和7.0%。12周时，0.5 mg、1.0 mg、2.0 mg和3.0 mg的替格列扎使FPG有统计学显著降低（分别为-30.3 mg/dL、-41.1 mg/dL、-55.0 mg/dL、-60.9 mg/dL；p<0.0001），甘油三酯降低（分别为-17.2%、-32.9%、-41.0%、-40.9%；p<0.01），载脂蛋白B降低（分别为-15.0%、-15.7%、-21.0%、-22.3%；p<0.0001）。剂量≥1.0 mg的替格列扎显著升高高密度脂蛋白胆固醇（HDL-C）（分别为15.0%、13.0%、12.9%；p<0.001），降低非HDL-C（分别为-13.2%、-22.2%、-25.0%；p<0.0001）、极低密度脂蛋白胆固醇（VLDL-C）（分别为-36.9%、-49.8%、-52.5%；p<0.0001）和总胆固醇（分别为-6.8%、-14.1%、-15.5%；p<0.01）。剂量≥0.5 mg的替格列扎改善了胰岛素抵抗指标。虽然未在活性治疗组之间进行正式的统计分析，但1.0 mg替格列扎的疗效指标改善在数值上与吡格列酮相似或更优。替格列扎≤1.0 mg组、安慰剂组和吡格列酮组发生的不良事件数量相似，但替格列扎剂量≥1.0 mg时，因预先指定的血液学和临床化学标准导致的停药频率增加。
在2型糖尿病患者中，剂量≥0.5 mg的替格列扎剂量依赖性地降低FPG水平。剂量≥0.5 mg或≥1.0 mg时，血糖控制、致动脉粥样硬化性血脂异常的其他指标以及与胰岛素抵抗相关的指标均得到改善。研究局限性包括大多数患者为白人，患者基线血糖控制良好，以及替格列扎2.0 mg和3.0 mg剂量组早期停药数量增加限制了对这些剂量疗效的结论。确定了0.5 mg和1.0 mg替格列扎剂量用于进一步研究。
