1. 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

2. Background: Diabetes Mellitus
Epidemiology
7th leading cause of death in the U.S.
Leading cause of kidney failure, responsible for 44% of new cases

3. Diabetic Nephropathy Microvascular complications
Hyperglycemia causes changes in the cells of the glomeruli of the kidney:
Basement membrane thickening, microaneurysm formation, and other changes

4. Diabetic Nephropathy
As the glomerulus cells weaken, albumin from the blood leaks into the urine
Microalbuminuria: mg/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%

5. Background As eGFR decreases, calcitriol concentrations decrease
Has been associated with higher urinary albumin to creatinine ratios
Paricalcitol reduced albuminuria in preclinical models

6. 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 mg/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

7. 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

8. 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

9. 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

10. 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)

11. Results
2mg lowered eGFR and blood pressure significantly within 4 weeks
These, along with UACR, returned to baseline after discontinuation of the drug

12. 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

14. 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, 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:
3. Fowler, Michael J. Microvascular and Macrovascular Complications of Diabetes. Clinical Diabetes April 2008 vol. 26 no
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.