SO022VITAMIN D RECEPTOR ACTIVATION DOES NOT IMPROVE INSULIN SENSITIVITY IN PATIENTS WITH STAGE 3 TO 4 CHRONIC KIDNEY DISEASE

Abstract

INTRODUCTION AND AIMS: Insulin resistance (IR) has been implicated in the high risk for cardiovascular disease and progressive glomerular filtration rate (GFR) loss over time in chronic kidney disease (CKD) patients but no specific intervention targeting the CKD milieu has been identified so far. Low levels of 1,25‐OH vitamin D have been associated with IR in several observational studies in this condition. However, the nature of this link (causal vs non‐causal) in CKD patients remains elusive. METHODS: In the frame of a randomized, double‐blind, placebo controlled trial, the Paracalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY, Hypertension 2014;64:1005‐11), we investigated whether vitamin D receptor activation by paricalcitol (2 μg/day x 12 weeks) increases insulin sensitivity in 88 patients with stage 3 to 4 CKD patients. Insulin sensitivity was measured by five biomarkers (HOMA‐IR, QUICKI, McAuley index, HOMA‐AD, Leptin/Adiponectin ratio) which showed a fair to good agreement with the golden standard measurement of insulin sensitivity (i.e. glucose disposal rate by the hyperinsulinemic euglycemic clamp technique) in a previous validation study in CKD patients (Clin J Am Soc Nephrol 2011; 6: 767‐ 774). RESULTS: : At baseline, the proportion of patients with IR (i.e. presenting levels above the upper limit of corresponding normal range) was substantial with all biomarkers, being highest with the Leptin/adiponectin ratio (87%), the HOMA‐IR (83%) and QUICKI (83%), intermediate (64%) with the McAuley index and lowest (31%) with the HOMA‐AD. At baseline, indexes of IR were identical in patients randomized to paricalcitol and in those randomized to placebo. After 12 weeks of treatment, the changes in the biomarkers of IR brought about by paricalcitol did not differ from those registered in the placebo arm (P ranging from 0.25 to 0.62) and this was also true in multivariate analyses (P ranging from 0.30 to 0.76) adjusting for the potential confounding effect of GFR. On the other hand, as expected, serum parathormone markedly reduced (‐73%) in the active arm and remained unchanged in the placebo arm (between‐groups comparison, P<0.001) and the PTH change by paricalcitol was accompanied by a small but significant rise (P<0.01) in serum calcium (3%) and phosphate (11%). CONCLUSIONS: Insulin resistance assessed by 5 functional biomarkers of this alteration, is pervasive in CKD patients. Paricalcitol does not improve any of these biomarkers in CKD patients. These findings indicate that reduced vitamin D receptor activation is not a major player in the markedly reduced insulin sensitivity in the CKD population.