Chan J C N, Scott R, Arjona Ferreira J C, Sheng D, Gonzalez E, Davies M J, Stein P P, Kaufman K D, Amatruda J M, Williams-Herman D
Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region, China.
Diabetes Obes Metab. 2008 Jul;10(7):545-55. doi: 10.1111/j.1463-1326.2008.00914.x. Epub 2008 Jun 1.
To assess the safety of sitagliptin in patients with type 2 diabetes and moderate [creatinine clearance (CrCl) > or =30 to <50 ml/min] or severe renal insufficiency [CrCl <30 ml/min including patients with end-stage renal disease (ESRD) on dialysis]. The efficacy of sitagliptin in this patient population was also assessed.
In a 54-week, randomized, double-blind, parallel-group study, patients with baseline glycosylated haemoglobin A(1c) (HbA(1c)) values of 6.5-10% were allocated (2:1) to sitagliptin (for 54 weeks) or the sequence of placebo (for 12 weeks) followed by active treatment with glipizide (for 42 weeks). To achieve plasma concentrations similar to those observed in patients with normal renal function treated with 100 mg sitagliptin once daily, patients with moderate renal insufficiency were allocated to receive sitagliptin 50 mg once daily and patients with severe renal insufficiency to receive 25 mg once daily. Glipizide treatment was initiated at 2.5 or 5 mg/day and uptitrated to a maximum of 20 mg/day.
Patients (N = 91) with a mean baseline HbA(1c) value of 7.7% (range: 6.2-10.3%) were randomized to sitagliptin (n = 65) or placebo (n = 26). After 12 weeks, the mean change [95% confidence interval (CI)] from baseline in HbA(1c) was -0.6% (-0.8, -0.4) in the sitagliptin group compared with -0.2% (-0.4, 0.1) in the placebo group [between-group difference (95% CI) = -0.4% (-0.7, -0.1)]. At 54 weeks, patients continuously treated with sitagliptin had a mean change (95% CI) from baseline in HbA(1c) of -0.7% (-0.9, -0.4). The overall incidence of adverse experiences was generally similar between groups. Between-group differences in incidences of specific clinical adverse experiences were generally small; however, the proportion of patients for whom hypoglycaemia was reported was lower in the sitagliptin group (4.6%) compared with the placebo/glipizide group (23.1%). Consistent with the high mortality risk in this patient population, there were six deaths during this 54-week study [5 of 65 patients (7.7%) in the sitagliptin group and 1 of 26 patients (3.8%) in the placebo/glipizide group]; no death was considered by the investigator to be drug related. The overall incidences of drug-related and serious adverse experiences and discontinuations because of adverse experiences were generally similar between groups.
In this study, sitagliptin was generally well tolerated and provided effective glycaemic control in patients with type 2 diabetes and moderate to severe renal insufficiency, including patients with ESRD on dialysis.
评估西格列汀在2型糖尿病合并中度[肌酐清除率（CrCl）≥30至<50 ml/分钟]或重度肾功能不全[CrCl<30 ml/分钟，包括接受透析的终末期肾病（ESRD）患者]患者中的安全性。同时评估西格列汀在该患者群体中的疗效。
在一项为期54周的随机、双盲、平行组研究中，将基线糖化血红蛋白A1c（HbA1c）值为6.5 - 10%的患者按2:1分配至西格列汀组（治疗54周）或先接受安慰剂治疗12周，随后接受格列吡嗪活性治疗42周的序列组。为使血浆浓度与每日服用100 mg西格列汀的肾功能正常患者中观察到的浓度相似，中度肾功能不全患者分配至接受每日一次西格列汀50 mg，重度肾功能不全患者分配至接受每日一次25 mg。格列吡嗪治疗起始剂量为2.5或5 mg/天，最大滴定至20 mg/天。
平均基线HbA1c值为7.7%（范围：6.2 - 10.3%）的91例患者被随机分配至西格列汀组（n = 65）或安慰剂组（n = 26）。12周后，西格列汀组HbA（1c）自基线的平均变化[95%置信区间（CI）]为-0.6%（-0.8，-0.4），而安慰剂组为-0.2%（-0.4，0.1）[组间差异（95%CI）=-0.4%（-0.7，-0.1）]。在54周时，持续接受西格列汀治疗的患者HbA（1c）自基线的平均变化（95%CI）为-0.7%（-0.9，-0.4）。不良事件的总体发生率在两组之间通常相似。特定临床不良事件发生率的组间差异通常较小；然而，西格列汀组报告低血糖的患者比例（4.6%）低于安慰剂/格列吡嗪组（23.1%）。鉴于该患者群体的高死亡风险，在这项54周的研究中有6例死亡[西格列汀组65例患者中有5例（7.7%），安慰剂/格列吡嗪组26例患者中有1例（3.8%）]；研究者认为没有死亡与药物相关。药物相关和严重不良事件以及因不良事件停药的总体发生率在两组之间通常相似。
在本研究中，西格列汀总体耐受性良好，在2型糖尿病合并中度至重度肾功能不全（包括接受透析的ESRD患者）患者中提供了有效的血糖控制。
