Selective vitamin D receptor activation with paricalcitol lowers residual albuminuria and could provide renal protection in patients with diabetic nephropathy when added to standard therapies, according the findings of the randomized, controlled VITAL study.
Patients with a high-sodium diet were among those who benefited from the combination of paricalcitol and renin-angiotensin-aldosterone system (RAAS) inhibition therapy, researchers reported online Nov. 4 in the Lancet.
Participants in the multinational, double-blind VITAL study were type 2 diabetes patients who had residual albuminuria – and who thus were at risk of progressive renal failure – despite receiving stable doses of ACE inhibitors or angiotensin receptor blockers (ARBs). They were enrolled between February 2008 and October 2008.
Of 281 patients enrolled in the study and randomized to receive either placebo, 1 mcg, or 2 mcg of paricalcitol for 24 weeks, along with their usual care for diabetes and cardiovascular protection, those in the 2-mcg group had the greatest – and the only statistically significant – percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) at final measurement during treatment, compared with the 1-mcg and placebo groups (–20%, compared with –16% and –3%, respectively). The between-group difference vs. placebo was –18% and –11% for the 2-mcg and 1-mcg groups, respectively, Dr. Dick de Zeeuw of the University of Groningen, the Netherlands, and his colleagues reported.
UACR was reduced significantly by treatment week 4 in the 2-mcg group, and the reduction was sustained during the entire treatment phase, peaking at –28% at week 12. The estimated glomerular filtration rate (eGFR) also decreased substantially by week 4 in the 2-mcg group vs. placebo and remained stable during treatment. An early reduction in systolic blood pressure fluctuated throughout treatment, the investigators found (Lancet 2010[doi:10.1016/S0140-6736(10)61032-X]).
In a post hoc analysis, it was shown that the greatest reduction in UACR was in 29 patients on 2 mcg paricalcitol who had urinary sodium excretion of more than 178 mmol in 24 h.
No serious adverse events deemed to be related to study drug occurred during the course of the study.
"We have shown that 24 weeks’ treatment with 2 mcg paricalcitol daily reduced residual albuminuria in patients with type 2 diabetic nephropathy who were on stable doses of ACE inhibitors or ARBs, particularly in those with high dietary sodium intake," the investigators wrote, adding that the effect on albuminuria, systolic blood pressure, and eGFR all occurred within 4 weeks, and that the reductions in UACR and eGFR were "fairly stable during the treatment phase."
These measurements returned toward baseline after drug withdrawal, indicating that the effects were real and reversible, they said.
The mechanisms of action for paricalcitol for lowering albuminuria appear to be multiple; activation of the vitamin D receptor, which is currently licensed for the prevention and treatment of secondary hyperparathyroidism, intervenes in pathways with well-known associations with renal and vascular progressive disease, they explained.
Additional study to assess the composite end point of doubling of serum creatinine, end stage renal disease, and death is needed for final verification of paricalcitol’s renoprotective effects," they added.
Despite some study limitations, including the use of albuminuria as a surrogate marker of renal disease progression, the lack of measurement of true GFR and ambulatory blood pressure in the study, and fairly small sample size, the findings suggest paricalcitol could be "an important adjunctive treatment providing optimum management to renal osteodystrophy with little hypercalcemia and lowering residual albuminuria.
"Additionally, findings of our study suggest that paricalcitol lowers albuminuria, even when dietary sodium intake is high, which is important because resistance to RAAS intervention occurs in people with high dietary sodium intake and adherence to low sodium diets is desirable but difficult, especially in those with diabetic nephropathy who already have restricted diets," they said.
In an accompanying editorial, Dr. Merlin C. Thomas and Dr. Mark E. Cooper wrote that the findings from the VITAL study add to existing data demonstrating the potential antiproteinuric actions of paricalcitol when added to standard therapies.
They also underscore the fact that patients with diabetes, and particularly those with chronic kidney disease, "in whom the urinary loss of protein-associated vitamin D magnifies reduced activation of vitamin D by the proximal tubule and reduced expression of the vitamin D receptor," have increased rates of vitamin D deficiency. For these patients it "seems rational to replace vitamin D," they wrote (Lancet 2010[doi:10.1016/S0140-6736(10)61301-3]).
Selective analogues that restore vitamin D receptor-signaling without risking hypercalcemia or hyperphosphatemia – as paricalcitol appears to do in the VITAL study – might be of particular benefit, they said, adding that trials in patients with diabetes "should now test whether such analogues can ultimately improve mortality and cardiovascular outcomes, as suggested in studied of patients with end-stage renal disease."