Department of Internal Medicine, University Hospital and School of Medicine, University of Ioannina, Ioannina, Greece.
Clin Ther. 2010 Mar;32(3):492-505. doi: 10.1016/j.clinthera.2010.03.018.
Statin therapy has been reported to be associated with new-onset diabetes. Angiotensin II-receptor blockers (ARBs) are effective antihypertensive drugs that have been reported to activate peroxisome proliferator-activated receptor gamma (PPARgamma) to differing extents, with favorable effects on glucose metabolism and the incidence of new-onset diabetes. Among the ARBs, telmisartan is a partial activator of PPARgamma, irbesartan is a weak partial activator, and olmesartan has no effect on PPARgamma activation.
The goal of this study was to evaluate the effects on glucose homeostasis of combining rosuvastatin with ARBs of varying PPARgamma-activating potency in Greek adults with impaired fasting glucose, mixed dyslipidemia, and stage 1 hypertension.
This was a 24-week, randomized, open-label study. Inclusion criteria were impaired fasting plasma glucose (FPG) (100-125 mg/dL [5.6-6.9 mmol/L]), mixed dyslipidemia (LDL-C >160 mg/dL [4.14 mmol/L] and triglycerides >150 mg/dL [1.69 mmol/L]), and stage 1 hypertension (systolic blood pressure 140-159 mm Hg and/or diastolic blood pressure 90-99 mm Hg). After 12 weeks of dietary intervention, patients were randomly allocated to receive rosuvastatin 10 mg/d plus telmisartan 80 mg/d (RT group), irbesartan 300 mg/d (RI group), or olmesartan 20 mg/d (RO group) for 24 weeks. The primary end point was change in the following indices of glucose metabolism after 6 months of treatment: FPG, homeostasis model assessment of insulin resistance (HOMA-IR), HOMA of beta-cell function (HOMA-B), and glycosylated hemoglobin (HbA(1c)). Secondary end points included changes in anthropometric variables, blood pressure, serum lipids, and high-sensitivity C-reactive protein (hs-CRP). Tolerability was monitored throughout the study.
After the 12-week dietary intervention, 151 white patients (78 female, 73 male) met the inclusion criteria and were randomized to receive RT (n = 52), RI (n = 48), or RO (n = 51). The mean (SD) age of the 3 groups was 60 (10), 60 (10), and 58 (12) years, respectively; their mean weight was 79 (11), 81 (12), and 78 (11) kg. At 6 months, the RT group had a 29% decrease in HOMA-IR (from a median [range] of 2.6 [0.6-6.6] to 1.8 [0.5-5.1]), the RI group had a 16% increase (from 2.5 [0.5-6.2] to 2.9 [0.5-8.1]), and the RO group had a 14% increase (from 2.4 [0.5-7.9] to 2.7 [0.5-5.2]) (all, P < 0.05 vs baseline). The improvement in the RT group was statistically significant compared with the RI group (P < 0.01) and the RO group (P < 0.05). The changes from baseline in FPG and HbA(1c) were not significant in any group. Fasting serum insulin decreased by 21% in the RT group (from 10.4 [2.4-28.1] to 8.2 [2.4-18.8] microU/mL), whereas it increased by 12% in the RI group (from 9.1 [2.0-26.5] to 10.2 [2.0-25.2] microU/mL) and by 8% in the RO group (from 10.1 [2.0-29.6] to 10.9 [2.0-19.1] microU/mL) (all, P < 0.05 vs baseline). Again, there was a significant difference between the RT group and the RI group (P < 0.01) and RO group (P < 0.05). Levels of hs-CRP decreased by 44% in the RT group (from 2.2 [0.3-7.9] to 1.2 [0.4-7.0] mg/L), by 12% in the RI group (from 2.2 [0.3-12.3] to 1.9 [0.2-11.4] mg/L), and by 22% in the RO group (from 2.1 [0.7-4.0] to 1.7 [0.7-6.2] mg/L). The difference was statistically significant for the RT group compared with baseline and with the RI and RO groups (all comparisons, P < 0.05). Blood pressure was significantly reduced from baseline in all 3 groups, with no significant differences between groups. No serious adverse events were reported during the study, nor were there any clinically significant elevations in aminotransferases or creatine kinase.
In this small, randomized, open-label study, the RT combination had favorable effects on HOMA-IR, fasting serum insulin, and hs-CRP compared with the RI and RO combinations in Greek adults with impaired fasting glucose, mixed hyperlipidemia, and stage 1 hypertension.
已有研究报告称，他汀类药物治疗与新发糖尿病有关。血管紧张素 II 受体阻滞剂（ARBs）是有效的降压药物，据报道，它们在不同程度上激活过氧化物酶体增殖物激活受体 γ（PPARγ），对葡萄糖代谢和新发糖尿病的发生率有有利影响。在 ARBs 中，替米沙坦是 PPARγ 的部分激活剂，厄贝沙坦是弱部分激活剂，奥美沙坦对 PPARγ 激活没有作用。
本研究旨在评估在希腊空腹血糖受损、混合性血脂异常和 1 期高血压的成年人中，不同 PPARγ 激活强度的 ARB 与瑞舒伐他汀联合应用对葡萄糖稳态的影响。
这是一项 24 周、随机、开放标签的研究。纳入标准为空腹血糖受损（FPG）（100-125mg/dL [5.6-6.9mmol/L]）、混合性血脂异常（LDL-C >160mg/dL [4.14mmol/L]和甘油三酯 >150mg/dL [1.69mmol/L]）和 1 期高血压（收缩压 140-159mmHg 和/或舒张压 90-99mmHg）。在 12 周的饮食干预后，患者被随机分配接受瑞舒伐他汀 10mg/d 加替米沙坦 80mg/d（RT 组）、厄贝沙坦 300mg/d（RI 组）或奥美沙坦 20mg/d（RO 组）治疗 24 周。主要终点是治疗 6 个月后以下葡萄糖代谢指标的变化：FPG、稳态模型评估的胰岛素抵抗（HOMA-IR）、β细胞功能的 HOMA（HOMA-B）和糖化血红蛋白（HbA1c）。次要终点包括体重指数、血压、血清脂质和高敏 C 反应蛋白（hs-CRP）的变化。在整个研究过程中监测耐受性。
在 12 周的饮食干预后，151 名白人患者（女性 78 名，男性 73 名）符合纳入标准，并被随机分配接受 RT（n=52）、RI（n=48）或 RO（n=51）治疗。三组的平均（SD）年龄分别为 60（10）、60（10）和 58（12）岁，平均体重分别为 79（11）、81（12）和 78（11）kg。在 6 个月时，RT 组的 HOMA-IR 降低了 29%（中位数[范围]从 2.6[0.6-6.6]降至 1.8[0.5-5.1]），RI 组增加了 16%（从 2.5[0.5-6.2]至 2.9[0.5-8.1]），RO 组增加了 14%（从 2.4[0.5-7.9]至 2.7[0.5-5.2]）（均，P<0.05 与基线相比）。与 RI 组和 RO 组相比，RT 组的改善具有统计学意义（均，P<0.01）。各组的 FPG 和 HbA1c 变化均不显著。RT 组的空腹血清胰岛素降低了 21%（从 10.4[2.4-28.1]降至 8.2[2.4-18.8]μU/ml），而 RI 组增加了 12%（从 9.1[2.0-26.5]增至 10.2[2.0-25.2]μU/ml），RO 组增加了 8%（从 10.1[2.0-29.6]增至 10.9[2.0-19.1]μU/ml）（均，P<0.05 与基线相比）。同样，RT 组与 RI 组（均，P<0.01）和 RO 组（均，P<0.05）之间存在显著差异。RT 组的 hs-CRP 水平降低了 44%（从 2.2[0.3-7.9]降至 1.2[0.4-7.0]mg/L），RI 组降低了 12%（从 2.2[0.3-12.3]降至 1.9[0.2-11.4]mg/L），RO 组降低了 22%（从 2.1[0.7-4.0]降至 1.7[0.7-6.2]mg/L）。与基线相比，与 RI 和 RO 组相比，RT 组的差异均具有统计学意义（均，P<0.05）。三组的血压均较基线显著降低，组间无显著差异。研究过程中未报告严重不良事件，也未出现氨基转移酶或肌酸激酶的临床显著升高。
在这项小型、随机、开放标签研究中，与 RI 和 RO 联合治疗相比，RT 联合治疗对希腊空腹血糖受损、混合性血脂异常和 1 期高血压患者的 HOMA-IR、空腹血清胰岛素和 hs-CRP 有有利影响。
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