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, 2012 Rachel McLaughlin PharmD 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: Basement membrane thickening, microaneurysm formation, and other changes http://www.unckidneycenter.org/kidneyhealthlibrary/glomerulardisease.html

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.