Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
AstraZeneca, Gothenburg, Sweden.
Nephrol Dial Transplant. 2020 Sep 1;35(9):1570-1576. doi: 10.1093/ndt/gfz064.
Besides improving glucose control, sodium-glucose co-transporter 2 inhibition with dapagliflozin reduces blood pressure, body weight and urinary albumin:creatinine ratio (UACR) in patients with type 2 diabetes (T2DM). The parameter response efficacy (PRE) score was developed to predict how short-term drug effects on cardiovascular risk markers translate into long-term changes in clinical outcomes. We applied the PRE score to clinical trials of dapagliflozin to model the effect of the drug on kidney and heart failure (HF) outcomes in patients with T2DM and impaired kidney function.
The relationships between multiple risk markers and long-term outcome were determined in a background population of patients with T2DM with a multivariable Cox model. These relationships were then applied to short-term changes in risk markers observed in a pooled database of dapagliflozin trials (n = 7) that recruited patients with albuminuria to predict the drug-induced changes to kidney and HF outcomes.
A total of 132 and 350 patients had UACR >200 mg/g and >30 mg/g at baseline, respectively, and were selected for analysis. The PRE score predicted a risk change for kidney events of -40.8% [95% confidence interval (CI) -51.7 to -29.4) and -40.4% (95% CI -48.4 to -31.1) with dapagliflozin 10 mg compared with placebo for the UACR >200 mg/g and >30 mg/g subgroups. The predicted change in risk for HF events was -27.3% (95% CI -47.7 to -5.1) and -21.2% (95% CI -35.0 to -7.8), respectively. Simulation analyses showed that even with a smaller albuminuria-lowering effect of dapagliflozin (10% instead of the observed 35% in both groups), the estimated kidney risk reduction was still 26.5 and 26.8%, respectively.
The PRE score predicted clinically meaningful reductions in kidney and HF events associated with dapagliflozin therapy in patients with diabetic kidney disease. These results support a large long-term outcome trial in this population to confirm the benefits of the drug on these endpoints.
除了改善血糖控制外，钠-葡萄糖协同转运蛋白 2 抑制剂达格列净还可降低 2 型糖尿病（T2DM）患者的血压、体重和尿白蛋白与肌酐比值（UACR）。参数反应疗效（PRE）评分是为了预测短期药物对心血管风险标志物的影响如何转化为临床结局的长期变化而开发的。我们将 PRE 评分应用于达格列净的临床试验，以建立该药在伴有肾功能受损的 T2DM 患者中的肾脏和心力衰竭（HF）结局模型。
采用多变量 Cox 模型确定 T2DM 背景人群中多种风险标志物与长期结局之间的关系。然后，将这些关系应用于达格列净试验（n=7）的汇总数据库中观察到的短期风险标志物变化，以预测药物对肾脏和 HF 结局的影响。
分别有 132 例和 350 例患者在基线时 UACR>200mg/g 和>30mg/g，入选分析。PRE 评分预测了肾脏事件的风险变化，与安慰剂相比，达格列净 10mg 可使 UACR>200mg/g 和>30mg/g 亚组的肾脏事件风险分别降低 40.8%（95%CI-51.7 至-29.4）和 40.4%（95%CI-48.4 至-31.1）。HF 事件的预测风险变化分别为-27.3%（95%CI-47.7 至-5.1）和-21.2%（95%CI-35.0 至-7.8）。模拟分析显示，即使达格列净降低蛋白尿的效果较小（两组均为 10%，而不是观察到的 35%），估计的肾脏风险降低仍分别为 26.5%和 26.8%。
PRE 评分预测了达格列净治疗糖尿病肾病患者与肾脏和 HF 事件相关的有临床意义的降低。这些结果支持在该人群中进行大型长期结局试验，以确认该药物对这些终点的益处。
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