1. Estimated glomerular filtration rate (eGFR) declined less over one year of treatment for patients with later-stage autosomal dominant polycystic kidney disease (ADPKD) taking tolvaptan than those taking placebo.
2. Liver enzyme increases above 3 times the upper limit of normal (ULN) and serious liver-related events occurred more in the tolvaptan group than the placebo group.
Evidence Rating: 1 (Excellent)
Study Rundown: ADPKD is a condition which results in vasopressin sensitive sections of the renal tubule proliferating and expressing proinflammatory signals, ultimately leading to renal damage. Various methods for reducing vasopressin action in the renal tubule have showed benefit in protecting kidney function and prolonging survival in both animal and human studies. Tolvaptan is a vasopressin V2-receptor antagonist which has previously shown efficacy in reducing eGFR decline in early-stage ADPKD, and its efficacy for later-stage disease is of interest. This phase 3 trial included patients with stage 2 to early stage 4 ADPKD and randomized them to receive tolvaptan or placebo for 12 months. The primary endpoint was the change in eGFR from baseline. Patients in the tolvaptan group had significantly lower reductions in eGFR from baseline compared to the placebo group. Tolvaptan treated patients also experienced a greater number of liver enzyme elevations and serious hepatic adverse events. This study indicates efficacy of tolvaptan for decreasing eGFR decline in later-stage ADPKD, though long-term effectiveness is not yet understood.
In-Depth [randomized controlled trial]: This phase 3 multinational randomized clinical trial enrolled 1370 patients from 2014 to 2016. Eligible patients had stage 2 to early stage 4 ADPKD as determined by eGFR and were randomized in a 1:1 manner, stratified by eGFR, age, and total kidney volume, to receive either tolvaptan (n = 683) or placebo (n = 687). Monthly laboratory studies were performed during the study assessing creatinine, liver enzymes, and bilirubin. The primary trial endpoint was the change in eGFR from baseline to the trial conclusion, with a secondary endpoint being the slope of eGFR change.
The mean change in eGFR over 1 year was -2.34 mL/min/1.73m2 (95%CI, -2.81 to -1.87) in the tolvaptan group and -3.61 mL/min/1.73m2 (95%CI, -4.08 to -3.17) in the placebo group. Comparison showed a slower decline in the tolvaptan group vs the placebo group (difference of 1.27 mL/min/m2; 95%CI, 0.86 to 1.68, p < 0.001). Subgroup analysis indicated an eGFR benefit in the tolvaptan group regardless of patient sex, baseline eGFR, or stage of ADPKD. The slope of eGFR decline was significantly less in the tolvaptan group compared to the placebo group (difference of 1.01 mL/min/1.73m2; 95%CI, 0.62 to 1.40; p < 0.001). Serious hepatic related adverse events and elevations of liver enzymes greater than 3 times the ULN occurred in more patients in the tolvaptan group. This study does suggest that eGFR is better maintained for later-stage ADPKD patients on tolvaptan than those treated with placebo, though long term effects of both treatment and liver related complications require further investigation.
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