News Release

New drug treatment for diabetes patients to reduce their kidney-related and cardiovascular risk (VITAL study)

Peer-Reviewed Publication

The Lancet_DELETED

Patients with diabetes can have a high residual risk of kidney and cardiovascular problems, even when being treated with standard therapies such as angiotensin-converting enzyme (ACE) inhibitors. These patients can be demonstrated to be at high risk by a protein urine test, with high levels of protein (albuminuria) indicating increased risk. Lowering of this albuminuria may be of extreme importance for further reduction of renal and/or cardiovascular risk. These are the conclusions of an Article published Online First by The Lancet, written by Professor Dick de Zeeuw, Department of Clinical Pharmacology, University Medical Centre Groningen, Netherlands, and colleagues.

Previous work has shown that the natural activator of the vitamin D receptor, calcitriol (which regulates the body's calcium metabolism) is produced by the kidney, and that plasma concentrations decline as the kidney filtration rate declines leading to abnormalities in calcium metabolism. To prevent and treat this vitamin D receptor activators are given to patients with chronic renal failure. Recently it was discovered that the lower calcitriol concentrations are also related with other cardiovascular and renal disease progression. In animal models, use of the selective vitamin D receptor activator analogue paricalcitol reduced albuminuria and slowed the progression of kidney injury. No clinical studies on renal disease progression have yet been performed.

In the current study, the authors examined effectiveness of paricalcitol (a selective vitamin D receptor activator licensed for the prevention and treatment of secondary hyperparathyroidism) for the reduction of residual albuminuria in patients with type 2 diabetic nephropathy (diabetes-related kidney damage) who were receiving stable treatment with an ACE inhibitor or angiotensin receptor blocker (ARB). They also studied the effects of dose and time on albuminuria, kidney filtration rate, and blood pressure.

In this randomised controlled trial, patients were assigned (1:1:1) by computer-generated randomisation sequence to receive 24 weeks' treatment with placebo, 1 μg/day paricalcitol, or 2 μg/day paricalcitol. The primary endpoint was the percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) from baseline to last measurement during treatment for the combined paricalcitol groups versus the placebo group.

A total of 281 patients were enrolled and 88 patients on placebo, 92 on 1 μg paricalcitol, and 92 on 2 μg paricalcitol received at least one dose of study drug, and had UACR data at baseline and at least one timepoint during treatment, and so were included in the primary analysis. Change in UACR was: 𔃁% (from 61 to 60 mg/mmol) in the placebo group; and 󈞀% (from 61 to 49 mg/mmol) when looking at the 2 μg paricalcitol group (a finding on the borderline of statistical significance). UCAR improvements were 󈝺% (in the 1 μg paricalcitol group and 󈝼% in the combined paricalcitol groups, but these results were not statistically significant.

The authors say: "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...Existing drug strategies have substantial limitations and have not been successful so far. However, paricalcitol could be an important adjunctive treatment."

The authors explain the importance of paricalcitol's effects even when dietary sodium intake is high: important because resistance to ACE inhibitor/ARB 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. The authors conclude: "Therefore, paricalcitol could 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 a high sodium diet."

In a linked Comment, Dr Merlin C Thomas and Dr Mark E Cooper, Baker IDI Heart and Diabetes Institute, Melbourne, Australia, say: "Long-term and larger clinical trials in patients with diabetes should now test whether [these] analogues can ultimately improve mortality and cardio¬vascular outcomes, as suggested in studies of patients with end-stage renal disease."

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Professor Dick de Zeeuw, Department of Clinical Pharmacology, University Medical Centre Groningen, Netherlands. T) +31 50 3632810 E) d.de.zeeuw@med.umcg.nl

Dr Mark E Cooper, Baker IDI Heart and Diabetes Institute, Melbourne, Australia E) mark.cooper@bakeridi.edu.au

For full Article and Comment, see: http://press.thelancet.com/vital.pdf

NOTE: THE ABOVE LINK IS FOR JOURNALISTS ONLY; IF YOU WISH TO PROVIDE A LINK TO THE FREE ABSTRACT OF THIS PAPER FOR YOUR READERS, PLEASE USE THE FOLLOWING, WHICH WILL GO LIVE AT THE TIME THE EMBARGO LIFTS: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61032-X/abstract


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