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Salt intake influences add-on paricalcitol efficacy in type 2 diabetes
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Patients with type 2 diabetes and macroalbuminuria prescribed the antihypertensive drug losartan saw an enhanced antialbuminuric effect when combining the therapy with a salt-restricted diet, whereas those who combined paricalcitol and losartan therapy saw a benefit only in the setting of a high-salt diet, according to findings from a placebo-controlled, randomized crossover trial.
In experimental diabetes, the vitamin D receptor activator paricalcitol, in combination with losartan, normalized albuminuria and slowed the progression of renal damage more effectively than losartan monotherapy, Aneliya Parvanova, PhD, DSc, of the Mario Negri Institute for Pharmacological Research in Milan, Italy, and colleagues wrote in the study background. In the VITAL trial, researchers found that participants with type 1 diabetes and residual macroalbuminuria despite ACE inhibitor therapy saw reduced albuminuria when adding on paricalcitol; however, post-hoc analyses found that this effect was almost fully driven by 29 patients with natriuresis exceeding 178 mEq per day, according to researchers.
“Thus, we designed a prospective, randomized controlled trial to assess the albuminuria-lowering effect of salt-intake restriction in patients with type 2 diabetes with residual albuminuria despite stable, full-dose losartan therapy, and to assess whether and to what extent salt intake modulates the effect of paricalcitol on urinary albumin as compared with placebo,” the researchers wrote.
Parvanova and colleagues analyzed data from 57 patients with type 2 diabetes and 24-hour urinary albumin level at least 300 mg despite 100 mg per day losartan therapy, recruited between December 2011 and February 2015 from six outpatient clinics in northern Italy. Within the cohort, 57 patients were randomly assigned to a low-sodium diet (100 mEq or less per day), with 28 of those patients assigned to 1 month of paricalcitol therapy, followed by a 1-month washout and then 1-month placebo, and 29 assigned to 1-month placebo followed a 1-month washout and 1-month paricalcitol. Additionally, 58 patients were assigned to a high-sodium diet (at least 200 mEq per day), with 29 of those patients assigned to 1-month paricalcitol followed by 1-month placebo and 29 patients assigned to 1-month placebo followed by 1-month paricalcitol. Primary outcome was 24-hour albuminuria (median of three consecutive measurements) with a modified intention-to-treat analysis (including all patients who took at least one dose of study drug and had an efficacy measurement after the first treatment period).
In the low-sodium group, 24-hour albuminuria was reduced by 36.6% (95% CI, 28.5-44.9), from a mean 724 mg at baseline to a mean 481 mg at month 3 (P < .0001). No change occurred in the high-sodium group; changes between diet groups differed by 32.4% and correlated with changes in natriuresis, according to researchers (r = 0.43; P < .0001).
In the high-sodium diet group, paricalcitol reduced the salt-induced albuminuria increase by 17.8% (95% CI, 3.9-32.3) during 1 month of treatment compared with placebo (P = .02). Researchers did not observe this effect in the low-sodium diet group, they noted.
During placebo treatment, albuminuria decreased with the low-sodium diet (P = .0002) and did not change with the high-sodium diet (P = .1), but changes were significantly different between diet groups (P = .0004).
During paricalcitol therapy, researchers observed 14 cases of hypercalciuria, six cases of hypercalcemia and five cases of hyperphosphatemia in one patient each, all of which were possibly treatment related. One stroke and one coronary event occurred during paricalcitol therapy.
In commentary accompanying the study, Beatriz Fernandez-Fernandez, MD, of the nephrology and hypertension department at Autonomous University School of Medicine in Madrid, and Alberto Ortiz, MD, of the Queen Sophia Institute of Nephrology Research in Madrid, wrote that the study findings send a clear message in favor of moderate salt restriction for the reduction of albuminuria, but a “mixed message” for paricalcitol therapy.
“Given the absence of evidence of long-term preservation of renal function by paricalcitol and the potential safety signal of the 2 µg per day dose, this dose should not be used to reduce albuminuria outside of a clinical trial context,” the researchers wrote. “Prospective registries should be used to assess the cardiovascular and renal safety of this dose of paricalcitol when used for other indications.” – by Regina Schaffer
Disclosures: AbbVie funded this study. Fernandez-Fernandez reports she has received consulting fees from Genzyme, speaker fees from Novartis and travel or accommodation payments from Abbvie, Menarini and Otsuka. Ortiz reports he has received consulting fees from Otsuka and Sanofi, speaker fees from Amgen, Amicus, Fresenius Medical Care, Menarini, Otsuka and Sanofi and travel or accommodation payments from Fresenius Medical Care, Sanofi and Shire.
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