Selective vitamin D receptor activation with paricalcitol for

reduction of albuminuria in patients with type 2 diabetes

(VITAL study) Lambers Heerspink, H J, et. al.

American Journal of Nephrology, 2009

October 19, 2012Rachel McLaughlinPharmD candidate

University of Georgia

Background: Diabetes Mellitus

Epidemiology 7th leading cause of death in the U.S. Leading cause of kidney failure, responsible

for 44% of new cases

Diabetic Nephropathy

Microvascular complications Hyperglycemia causes changes in the cells of

the glomeruli of the kidney:

http://www.unckidneycenter.org/kidneyhealthlibrary/glomerulardisease.html

Basement membrane thickening, microaneurysm formation, and other changes

Diabetic Nephropathy

As the glomerulus cells weaken, albumin from the blood leaks into the urine

Microalbuminuria: 30-299mg/24 hours Proteinuria: 300+mg/24 hours Nephropathy: 500+mg/24 hours

Preventative guidelines Glycemic control ACEI/ARBs: decrease intraglomerular

pressure, shown to decrease risk of progressing from micro to macroalbuminuria by 60-70%

Background

As eGFR decreases, calcitriol concentrations decrease

Has been associated with higher urinary albumin to creatinine ratios

Paricalcitol reduced albuminuria in preclinical models

http://www.aacc.org/publications/cln/2007/dec/Pages/cover2_1207.aspx#

Methods February 2007- October 2008 (24 weeks) Enrolled 281 patients from hospital and clinic in Germany,

Greece, the Netherlands, Italy, Poland, Portugal, Spain, Taiwan, USA

Inclusion:

Over 20 years old Type 2 diabetes and nephropathy (defined as

UACR average morning void of 100-3000mg/g and eGFR of 15-90mL/min)

Have received ACEI or ARB for at least 3 months Exclusion:

Acute renal failure (rise in SCr of 0.5mg/dl) Primary glomerulonephritis or secondary nephritis

Methods Randomly assigned to receive paricalcitrol 1mg,

2mg, or placebo once daily ACEI and ARB doses could not be adjusted Every 4 weeks, and 30 days and 60 days after

completion: vitals, blood chemistry, adverse events, urine at first morning void for 3 consecutive days

24 urine samples taken at baseline, completion and 60 days after treatment completion

Paricalcitrol blood levels taken at weeks 4, 8, 12, 16, and 20

Endpoints

Primary: percent change from baseline to completion UACR from first morning void urine sample

Secondary: Percent change from baseline to completion

mean 24hour urinary albumin Proportion of participants achieving 15%

reduction in mean UACR

Statistics

ANCOVA: analysis of covariance Adjusts the dependent variable means to what

they would be if all groups were equal in regards to the covariates

Enables you to compare only one variable Used to compare change in log-transformed

UACR, with baseline UACR as a covariate among the treatment groups

Results

Change in mean UACR between-groups difference

Amount achieving change in UACR by at least -15%

Change in 24hr urinary albumin excretion between-groups difference

1 mg -11% (p=0.23) 52% -2% (p=0.86)

2 mg -18% (p=0.053) 55% -28% (p=0.009)

Placebo 40%

Combined paricalcitol groups

-15% (p=0.071)

Results

2mg lowered eGFR and blood pressure significantly within 4 weeks

These, along with UACR, returned to baseline after discontinuation of the drug

Discussion

2mg daily of paricalcitrol significantly lowers albuminuria, and also lowers eGFR and blood pressure

These effects are reversible It could be an important adjunct therapy for

residual albuminuria, offering low chance hypercalcemia or other side effects

References

1. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011. 2. De Zeeuw, Dick, et. al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. The Lancet November 2010; 376:1543-1551.3. Fowler, Michael J. Microvascular and Macrovascular Complications of Diabetes. Clinical Diabetes April 2008 vol. 26 no. 2 77-82.4. Lambers Heerspink, H J, et. al. The Selective Vitamin D Receptor Activator for Albuminuria Lowering (VITAL) Study: Study Design and Baseline Characteristics. Am J Nephrol 2009;30:280–286.