Paricalcitol (Vit. D) Significantly Reduces Albuminuria

The addition of a vitamin-D receptor activator, paricalcitol (Zemplar, Abbott Laboratories), to therapy in patients with diabetic nephropathy reduces albuminuria and risk of kidney failure….

Lead author Dr. Dick de Zeeuw (University Medical Center, Groningen, The Netherlands) stated that, the results suggest that paricalcitol could be an important adjunctive treatment and a novel way to lower residual renal risk in diabetes.  He stressed, however, that, “Hard end-point studies are needed to prove what we are suggesting in this article.“

Drs. Merlin C. Thomas (Baker IDI Heart and Diabetes Institute, Melbourne, Australia) and Mark E. Cooper (Monash University, Melbourne, Australia), in an accompanying editorial agree that this approach appears promising. “Patients with diabetes have increased rates of vitamin-D deficiency, especially in those with chronic kidney disease. For these patients, it seems rational to replace vitamin D. Selective analogs that restore vitamin-D receptor-signaling without risking hypercalcemia or hyperphosphatemia might have particular advantages, because of the aberrant calcification of diabetic vessels,” they note.

Yet they also emphasize that “long-term and larger clinical trials in patients with diabetes should now test whether such analogs can ultimately improve mortality and cardiovascular outcomes.”

De Zeeuw explained that plasma levels of vitamin D drop in patients with chronic renal failure, often leading to secondary hyperparathyroidism, so paricalcitol and other similar agents are licensed for the prevention and treatment of this condition and are used as standard therapy in this patient population.

However, by chance, when paricalcitol was being developed, one investigator also discovered that it reduced albuminuria; some small studies have looked at this outcome, but the current trial is the first large randomized controlled trial to look at using this agent “for the totally different purpose” of reducing albuminuria in patients with diabetic nephropathy, he says.

In the study, called VITAL, de Zeeuw and colleagues randomized 281 patients with Type 2 diabetes and albuminuria who were already receiving conventional renin-angiotensin-system (RAS) blockade with either an ACE inhibitor or an angiotensin-receptor blocker (ARB) to one of three arms: placebo (n=93) or one of two oral doses of paricalcitol, 1 µg (n=93) or 2 µg (n=95) per day for 24 weeks.The primary end point was the percentage change in geometric mean urinary albumin/creatinine ratio (UACR) from baseline to last measurement during treatment for the combined paricalcitol groups vs. the placebo group.

The change in UACR was -3% (from 61 to 60 mg/mmol) in the placebo group and -16% (from 62 to 51 mg/mmol) in the combined paricalcitol groups, with a between-group difference vs. placebo of -15% (p=0.071).

The primary end point was not significantly reduced vs. placebo because the reduction in UACR in the 1-µg paricalcitol group was not significant, the researchers explain. But in the higher, 2-µg-paricalcitol group, the change in UACR was -20%, with a between-group difference vs. placebo of -18% (p=0.053). This reduction in albuminuria was reversible when paricalcitol was stopped.

De Zeeuw says, “This is a very interesting finding, because finally we have a drug that lowers albuminuria without doing anything to blood pressure or other parameters,” so future trials with this agent might help to resolve debate about whether lowering albuminuria, considered a surrogate end point, is causally associated with better outcomes or is just a coincident effect.

“Could we prescribe this drug for this condition? The answer is no, we need long-term follow-up and large, long-term safety studies on hard outcomes. But for me, this is a very strong indicator that we should do a big trial, because I have not seen any studies where this effect occurs, and the drug didn’t, in the end, protect the organs. But nevertheless you have to do the studies,” he added.

Another “intriguing” thought is that reduction in albuminuria is not only associated with protection of the kidney but is linked to cardiovascular protection, he explains, adding that paricalcitol has been demonstrated to lower cardiovascular risk in some small studies.

“Could this drug also help in CV risk containment in a much larger population of both diabetics and nondiabetics at increased risk of cardiovascular morbidity and mortality?” he wonders.

Another interesting aside to the research, says de Zeeuw, is that he and his colleagues discovered in post hoc analyses that paricalcitol appeared most effective at reducing albuminuria in people with the highest sodium intake. This is in contrast to ACE inhibitors and ARBs, which work best when given alongside sodium-depleted diets.

“Since people have trouble staying on low-sodium diets and since you don’t have the optimum effect of an ACE or ARB [in a high-sodium environment], paricalcitol could also be useful for kidney protection in the large number of people with Type 2 diabetes that is resistant to ACE/ARB intervention and who have high-sodium diets,” he observed.

• Point out that although paricalcitol appeared to reduce proteinuria in patients with Type 2 diabetes, it is not known if this will reflect a decrease in the rate of progression to renal insufficiency.

de Zeeuw D, et al “Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with Type 2 diabetes (VITAL study): A randomized controlled trial” The Lancet 2010; DOI: 10.1016/S0140-6736(10)61032-X.