ArticlesSelective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial
Introduction
Diabetes mellitus represents a worldwide epidemic, and increases macrovascular and microvascular risk. Drugs that intervene in the renin–angiotensin–aldosterone system (RAAS), such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), can retard both cardiovascular and renal morbidity and mortality. This effect is partly due to the lowering of albuminuria associated with RAAS intervention. However, residual cardiovascular and renal risk can be extremely high in patients receiving treatment.1, 2 Moreover, residual renal risk is positively associated with residual albuminuria.3 To address this residual risk, therapies are needed to further reduce risk factors, including high blood pressure and albuminuria.
Strategies to effectively inhibit RAAS and interventions in new pathways have had little success in hard outcome studies. The combination of an ACE inhibitor and ARB, or increased doses of each of these drug types have not reduced cardiovascular or renal risk.4, 5 Despite reduction in albuminuria, endothelin antagonists have an unacceptable side-effect profile, which led to termination of a trial investigating hard renal outcomes (composite of doubling of serum creatinine, end-stage renal disease, or death) with avosentan.6 Trials with sulodexide, a heparinoid drug, were stopped because of absence of effect.7 New approaches to stop progressive renal failure are needed.
The natural activator of the vitamin D receptor, calcitriol, is produced by the kidney, but plasma concentrations decline as estimated glomerular filtration rate (eGFR) reduces.8 In a multivariable analysis of patients with chronic kidney disease, lower calcitriol concentrations strongly correlated with higher risk of diabetes, higher urinary albumin-to-creatinine ratio (UACR), and lower eGFR.8 In preclinical models, a selective activator of the vitamin D receptor, paricalcitol, reduced albuminuria and slowed the progression of kidney injury9, 10, 11 with little effect on mineral metabolites. Knockout of the vitamin D receptor in diabetic mice was associated with severe albuminuria and glomerulosclerosis from increased thickening of the glomerular basement membrane and podocyte effacement.12 Moreover, in models of diabetic nephropathy, combined treatment with paricalcitol and an ARB blocked the development of albuminuria, maintained the structure of the glomerular filtration barrier, and reduced glomerulosclerosis in association with reduced renal expression of renin.13 In a randomised trial investigating the efficacy of paricalcitol for lowering of parathyroid hormone concentrations in patients with stage 3 and 4 chronic kidney disease, findings of a post-hoc analysis showed that the paricalcitol group had a higher proportion of patients with significant reductions in semi-quantitative (dipstick) proteinuria than did the placebo group,14 with and without RAAS blockade.
We undertook a randomised trial to prospectively test the effectiveness of paricalcitol for the reduction of residual albuminuria in patients with type 2 diabetic nephropathy who were receiving stable treatment with an ACE inhibitor or ARB. Additionally, we studied the effects of dose and time on albuminuria, eGFR, and blood pressure.
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Patients
Between February, 2007, and October, 2008, we enrolled patients from 33 hospitals and 27 clinics in Germany, Greece, Italy, the Netherlands, Poland, Portugal, Spain, Taiwan, and the USA (including Puerto Rico). Patients were eligible if they were older than 20 years, had type 2 diabetes and nephropathy, which was defined by a UACR at first morning void of 11–339 mg/mmol and eGFR of 15–90 mL/min per 1·73 m2, and had been receiving stable doses of ACE inhibitors or ARBs for 3 months or more.
Results
904 patients were screened for eligibility, of whom 281 (31%) were enrolled (figure 1). Baseline demographic, clinical, and biochemical characteristics and concomitant treatments were balanced between the placebo and paricalcitol groups (table 1). Overall, 78 patients (28%) had microalbuminuria, 203 (72%) had macroalbuminuria, and 33 (12%) had eGFR of more than 60 mL/min per 1·73m2.
The numbers of patients included in assessments of change in UACR varied dependent on the timepoints between which
Discussion
We have shown that 24 weeks' treatment with 2 μg 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. By contrast, the reduction in UACR in the 1 μg paricalcitol group was not significant, which meant that the primary efficacy outcome of the change in UACR with the combined paricalcitol groups was also not significant versus placebo. The fact that
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