Parving Hans-Henrik, de Zeeuw Dick, Cooper Mark E, Remuzzi Giuseppe, Liu Nancy, Lunceford Jared, Shahinfar Shahnaz, Wong Peggy H, Lyle Paulette A, Rossing Peter, Brenner Barry M
Department of Medical Endocrinology, Department 2132, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark.
J Am Soc Nephrol. 2008 Apr;19(4):771-9. doi: 10.1681/ASN.2007050582. Epub 2008 Jan 16.
Losartan treatment reduced renal outcomes in proteinuric patients with type 2 diabetes in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. It is unknown whether an insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene predicts renal outcomes and death and influences the effect of losartan in these patients. Pharmacogenetic analyses were performed comparing losartan with placebo administered with conventional blood pressure-lowering therapy in 1435 (95%) of the 1513 RENAAL study patients. The primary endpoint was the composite of doubling of baseline serum creatinine concentration, end-stage renal disease (ESRD) or death. Cox regression models were stratified on baseline proteinuria and included treatment, geographic region, ACE/ID genotype, and treatment x genotype interaction. Within the placebo group, subjects with the ID or DD genotype were more likely than those with the II genotype to reach the composite endpoint (by 17.5% and 38.1%, respectively, P = 0.029) or its individual components. Within the losartan group, genotype did not correlate with reaching the composite endpoint. Compared with placebo, however, losartan reduced the risk of reaching the composite endpoint by 5.8% (95% confidence interval, -23.3, 28.0), 17.6% (3.8, 29.4), and 27.9% (7.0, 44.1) among those with the II, ID, and DD genotypes, respectively. Similar trends were demonstrated for the individual endpoints. In conclusion, proteinuric type 2 diabetic patients with the D allele of the ACE gene have an unfavorable renal prognosis, which can be mitigated and even improved by losartan.
在“用血管紧张素II拮抗剂氯沙坦降低非胰岛素依赖型糖尿病终点事件（RENAAL）”研究中，氯沙坦治疗可降低2型糖尿病蛋白尿患者的肾脏不良结局风险。血管紧张素转换酶（ACE）基因插入（I）/缺失（D）多态性是否能预测肾脏不良结局和死亡情况，以及是否会影响氯沙坦对这些患者的疗效尚不清楚。我们对RENAAL研究中1513例患者中的1435例（95%）进行了药物遗传学分析，比较氯沙坦与接受传统降压治疗的安慰剂的效果。主要终点为基线血清肌酐浓度翻倍、终末期肾病（ESRD）或死亡的复合终点。Cox回归模型根据基线蛋白尿情况进行分层，纳入治疗、地理区域、ACE/ID基因型以及治疗×基因型交互作用。在安慰剂组中，ID或DD基因型的受试者比II基因型的受试者更有可能达到复合终点（分别高出17.5%和38.1%，P = 0.029）或其单个组分终点。在氯沙坦组中，基因型与达到复合终点无关。然而，与安慰剂相比，氯沙坦使II、ID和DD基因型患者达到复合终点的风险分别降低了5.8%（95%置信区间，-23.3, 28.0）、17.6%（3.8, 29.4）和27.9%（7.0, 44.1）。各个终点也呈现出类似趋势。总之，携带ACE基因D等位基因的2型糖尿病蛋白尿患者肾脏预后不良，而氯沙坦可减轻甚至改善这种情况。
