Extended-Release Calcifediol Effectively Raises Serum Total 25-Hydroxyvitamin D Even in Overweight Nondialysis Chronic Kidney Disease Patients with Secondary Hyperparathyroidism

Abstract

<b><i>Introduction:</i></b> Obesity increases the risk of vitamin D insufficiency, which exacerbates secondary hyperparathyroidism in chronic kidney disease. Recent studies suggest that serum total 25-hydroxyvitamin D (25OHD) levels of ≥50 ng/mL are necessary to produce significant reductions in elevated parathyroid hormone levels in nondialysis patients. Data from real-world and randomized controlled trials (RCTs) involving these patients were examined for (1) relationships between vitamin D treatments and the achieved levels of serum 25OHD and between serum 25OHD and body weight (BW)/body mass index (BMI); and (2) the impact of BW/BMI on achieving serum 25OHD levels ≥50 ng/mL with extended-release calcifediol (ERC) treatment or vitamin D supplementation (cholecalciferol or ergocalciferol). <b><i>Methods:</i></b> Data obtained from nondialysis patients participating in two real-world studies, one conducted in Europe (Study 1) and the other (Study 2) in the USA, and in two US RCTs (Studies 3 and 4) were analyzed for serum 25OHD outcomes after treatment with ERC, vitamin D supplements, or placebo. <b><i>Results:</i></b> More than 50% of subjects treated with vitamin D supplements in both real-world studies (Studies 1 and 2) failed to achieve serum 25OHD levels ≥30 ng/mL, a level widely viewed by nephrologists as the threshold of adequacy; only 7.3–7.5% of subjects achieved levels ≥50 ng/mL. Data from the European study (Study 1) showed that serum 25OHD levels had significant and nearly identical inverse relationships with BW and BMI, indicating that high BW or BMI thwarts the ability of vitamin D supplements to raise serum 25OHD. One RCT (Study 3) showed that 8 weeks of ERC treatment (60 μg/day) raised serum 25OHD levels to ≥30 and 50 ng/mL in all subjects, regardless of BW, while cholecalciferol (300,000 IU/month) raised serum 25OHD to these thresholds in 56% and 0% of subjects, respectively. The other RCT (Study 4) showed that ERC treatment (30 or 60 μg/day) successfully raised mean serum 25OHD levels to at least 50 ng/mL for subjects in all BW categories, whereas no increases were observed with placebo treatment. <b><i>Conclusion:</i></b> Real-world studies conducted in Europe and USA in nondialysis patients (Studies 1 and 2) showed that vitamin D supplements (cholecalciferol or ergocalciferol) were unreliable in raising serum total 25OHD to targets of 30 or 50 ng/mL. In contrast, ERC was demonstrated to be effective in one real-world study (Study 2) and two RCTs (Studies 3 and 4) conducted in US nondialysis patients in raising serum 25OHD to these targeted levels irrespective of BW.

Evaluation of Therapies for Secondary Hyperparathyroidism Associated with Vitamin D Insufficiency in Chronic Kidney Disease

“…An inverse relationship has been consistently observed in the absence of CKD between serum 25OHD and both body weight and BMI [27–31] . Observations of this relationship have been recently extended to include patients with stage 3–5 CKD [32] and indicate that obesity limits the effectiveness of cholecalciferol and ergocalciferol to treat SHPT.…”

Real-world assessment: effectiveness and safety of extended-release calcifediol and other vitamin D therapies for secondary hyperparathyroidism in CKD patients

“…The lack of PTH lowering with AVD was surprising and possibly due to routine prescription of insufficient dosages without up-titration, but was expected with NVD, as numerous meta-analyses [4,[16][17][18][19][20] have concluded that PTH lowering with cholecalciferol or ergocalciferol supplements is unproven and clinically insignificant. NVD has been shown to be less effective in raising serum 25D in overweight patients [25,26] and most CKD patients are overweight, developing kidney disease from hypertension or type 2 diabetes, both common complicaitons of obesity. Disparities in PTH-lowering efficacy in this study were not related to differences in the bioavailabilities of the various treatments, as ERC has a slow-release formulation with only 25% bioavailabilty [23] compared to substantially higher bioavailabities reported for AVD and NVD [27,28].…”

Scientific and technical assistance to the evaluation of the safety of calcidiol monohydrate as a novel food

“…11 Hepatic 25-hydroxylase activity is reduced in both obesity 12 and CKD, 13 slowing the intended elevation of serum total 25D. 14 In contrast, immediate-release calcidiol (IRC) rapidly produces peak serum 25D levels (at approximately 6 h), 15 requires no hepatic activation, is more water soluble, and travels in mesenteric lymph bound to DBP (not in chylomicrons). 7 It is stored, contrary to the Panel's conclusion, in serum bound to DBP, which reduces its accumulation in adipose tissue, muscle and liver and enables its circulation to the kidney and to other tissues containing the 1a-hydroxylase (CYP27B1) for both endocrine and intracrine conversion to calcitriol, respectively.…”