The addition of the vitamin D receptor activator (VDRA) paricalcitol will reduce alubiminuria in type 2 diabetics already receiving angiotensin converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARBs).
Study design and study population:
A multinational double-blind, placebo controlled trial of the use of two separate doses of paricalcitol (1 & 2 μg/dy). The study population was type 2 diabetics receiving ACE-I or ARBs. Patients had nephropathy defined as UACR of 11 – 339 mg/mmol and eGFR of 15 – 90 ml/min. Doses of ACE-I or ARBs had to be stable for at least 3 months. Patients had to be normocalcemic and neither hyper- (> 500 ng/L) or hypo- (< 35 ng/L) parathyroid.
The study was sponsored by Abbott, the manufacturers of paricalcitol (ZemplarTM)
Intervention or observation:
Patients were randomized in a 1:1:1 method to receive placebo, paricalcitol 1μg/dy or paricalcitol 2 μg/dy. The study duration was 24 weeks.
Primary end point, secondary end points:
The primary outcome was percentage change in geometric mean of UACR from baseline to last measurement on treatment.
Secondary outcomes were percentage change in geometric mean of 24 h urinary albumin, and proportion of patients achieving a >15% decrease in geometric mean of UACR.
Safety parameters included observation of patient reported side effects, development of hypercalcemia and suppression of parathyroid hormone levels.
The sample size was based on an 82% power to detect an absolute difference in log transformed UACR of -0.034 mg/mmol.
Two hundred and eight-one patients were enrolled from a screening sample of 904. Clinical and biochemical comparison between the three subsequent randomization groups was satisfactory. The primary end point was not met by statistical significance, but there was a strong trend in that direction which did appear to be dose dependent. (Between group differences placebo to 2 μg paricalcitol -18%: 95%CI – 32 - 0 p = 0.053). Both secondary end points of reduction in geometric mean of 24 h albumin excretion and percentage of patients achieving a > 15% reduction in UACR were significant when comparing the placebo and 2 μg paricalcitol groups. The effect seemed greatest in the group with the highest sodium intake.
eGFR also fell in 2 μg paricalcitol group.
There were highly significant declines in PTH levels in both paricalcitol groups requiring dose reduction to thrice weekly, as might be expected, but interestingly no change in inflammatory markers.
Hypercalcemia was very infrequent.
Parameters returned towards baseline after withdrawal of active therapy.
The hypothesis has biologic plausibility and support from animal and human studies with small numbers. The randomized placebo controlled double blind multicentre design is strong. The selected outcome measures were highly skewed both at baseline and after treatment so the use of geometric mean differences and log transformed values is reasonable. The power calculation is a little odd.
Most patients in the study were 25-OHD deplete. Perhaps repletion of 25-OHD prior to undertaking the study would have strengthened the results. The authors do not report on changes in serum phosphate concentration which may be of significant relevance to the use of higher doses of paricalcitol in patients at lower eGFRs.
The drop out rate ranged from 16 – 27%, with the highest drop out in the 2 μg/dy arm.
The authors acknowledge the concern of using albuminuria as a surrogate marker for need for dialysis, and that the dose of ACE-I and / or ARB was often submaximal.
Impact on practice:
It is certainly very relevant to attempt to find methods in addition to inhibition of the rennin-angiotensin-aldoterone system to delay progression of diabetic nephrosclerosis. The findings of reduced 24 h albuminuria using paricalcitol are provocative. The need for dose reduction because of PTH suppression may prevent the maximal effect of paricalcitol from being realized, and may be of long term safety concern if there are even small elevations in the Ca x P. A long term study would be advisable to confirm delay of progression of renal disease, and with data on vascular calcification.
Reviewed by Reviewed by Dr. Ross Morton
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