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Unmet needs in treating SHPT in stages 3 and 4 CKD

Unmet needs in treating SHPT in stages 3 and 4 CKD

The goal of SHPT treatment

The treatment goal for secondary hyperparathyroidism (SHPT) is to lower parathyroid hormone (PTH) levels by regaining calcium, vitamin D and phosphorus homeostasis, thus potentially reducing the risks of bone and cardiovascular complications.1–3

 

The optimal SHPT treatment would:4

  • Increase 25(OH)D
  • Reduce PTH
  • Produce minimal changes in serum calcium, phosphorus and fibroblast growth factor-23 (FGF-23)

However, due to difficulties associated with lowering PTH while simultaneously controlling serum levels of calcium and phosphorous, achieving these goals with traditional therapies can be challenging.5

 

Limitations of current treatments

Current treatment options for SHPT in CKD patients with low vitamin D levels include:6

  • Nutritional vitamin D (NVD)
  • Immediate-release (IR) calcifediol
  • Active vitamin D (AVD) and AVD analogues

Many of these treatment options are not indicated for stage 3 or 4 chronic kidney disease (CKD) patients with SHPT and are associated with efficacy or safety limitations (Figure 1).7–14

Figure 1. NVD, IR calcifediol and AVD/AVD analogues vs the optimal treatment4,7–14
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Adapted from Sprague SM 2017,4 Agarwal R et al. 20167 and 2021,8 Bover J et al. 2021,9 Westerberg PA et al. 2018,10 Petkovich M et al. 2015,11 Li X et al.2015,12 Coyne DW 201313 and Coyne DW 2014.14

NVD

Limitations of nutritional vitamin D

  • There is a lack of evidence from randomised controlled trials (RCTs) to support the effectiveness of NVD supplements (ergocalciferol or cholecalciferol) in non-dialysis CKD patients with vitamin D insufficiency2,7–9
  • The available data have shown that NVD only moderately increases 25(OH)D levels and does not consistently and reliably reduce PTH.†7–10 There is also concern that the use of NVD may delay the initiation of therapies that are effective at reducing PTH levels, such as AVD and its analogues7
  • One meta-analysis of 14 studies found that, in 64% (9/14) of the studies, NVD did not achieve average 25(OH)D levels above 50 ng/mL (124.8 nmol/L),9 which might be necessary for clinically meaningful PTH reductions in CKD patients (figures 2A and 2B)15
Figure 2A. Changes in 25(OH)D (ng/mL) from baseline to end of study in the NVD arms9

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Figure 2B. Changes in PTH (pg/mL) from baseline to end of study in the NVD study arms9

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Meta-analysis of 14 RCTs (N=974) investigating the effects of NVD supplements on 25(OH)D and PTH in ND-CKD.

 

Reproduced from Bover J et al. 2021.9

 

Learn about KDIGO's NVD recommendations

IR calcifediol

Limitations of IR calcifediol

  • Although not indicated for SHPT in ND-CKD patients, IR formulations of calcifediol have been used occasionally in some EU countries4
  • Clinical studies have shown that IR calcifediol can increase serum 25(OH)D but fails to produce clinically meaningful reductions in PTH in many patients with stage 3 or 4 CKD at doses considered to be safe4,16,17
  • Rapid increases in 25(OH)D also trigger 24-hydroxylase (CYP24A1) and FGF-23 induction, limiting effective exposure to 1,25(OH)2D and PTH reduction in SHPT11

AVD and AVD analogues

Limitations of AVD and AVD analogues

  • Although AVD (calcitriol) and AVD analogues (e.g. paricalcitol) can effectively suppress PTH levels in ND-CKD,14 they can lead to PTH oversuppression18
  • Through stimulating increased intestinal absorption of calcium and phosphorus, AVD and AVD analogues may significantly increase the risks of hypercalcaemia12,18,19 (figures 3A and 3B) and hyperphosphataemia,13,14,20 which can lead to vascular calcification5
Figure 3A. Risk of hypercalcaemia in a meta-analysis of six RCTs evaluating AVD or its analogues in ND-CKD patients with SHPT19

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Figure 3B. Risk of hypercalcaemia in a secondary sensitivity analysis of four RCTs evaluating AVD or its analogues in ND-CKD patients with SHPT19

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A. Risk of hypercalcaemia in a meta-analysis of six RCTs (n=799) of ND-CKD patients with SHPT, treated with either alfacalcidol or paricalcitol. Odds ratio (OR): 6.63; 95% CI: 2.37, 18.55; p<0.001. B. Risk of hypercalcaemia in a secondary sensitivity analysis of four RCTs (n=512) that excluded the OPERA21 and PRIMO22 studies, which accounted for a large number of the observed hypercalcaemia events. OR: 3.03; 95% CI: 1.06, 8.71; p=0.039.

 

Adapted from Csomor P et al. 2019.19

 
  • AVD and AVD analogues may also produce spikes in 1,25(OH)2D that lead to changes in the levels of enzymes involved in the synthesis and/or breakdown of both 25(OH)D and 1,25(OH)2D.23,24 One such change is upregulation of CYP24A1, the enzyme that catabolises 25(OH)D and 1,25(OH)2D.24 The increase in 25(OH)D and 1,25(OH)2D catabolism and the reduction in their anabolism may exacerbate the underlying vitamin D insufficiency/deficiency6,23,24
 

Learn about KDIGO's AVD recommendations

Footnotes, abbreviations and references

*The increase in FGF-23 has been investigated and observed in rats; it has not been investigated in humans.11

 

Data are based on a moderate number of studies, with substantial amounts of heterogeneity amongst them.7–9

 

1,25(OH)2D: 1,25-dihydroxyvitamin D; 25(OH)D: 25-hydroxyvitamin D; AVD: active vitamin D; CI: confidence interval; CKD: chronic kidney disease; CKD–MBD: chronic kidney disease–mineral and bone disorder; CYP24A1: cytochrome P450 family 24 subfamily A member 1; D+L: DerSimonian and Laird method;  FGF-23: fibroblast growth factor-23; IR: immediate-release; I-V: inverse variance; KDIGO: Kidney Disease–Improving Global Outcomes; ND-CKD: non-dialysis chronic kidney disease; NVD: nutritional vitamin D; OR: odds ratio; PTH: parathyroid hormone; RCT: randomised controlled trial; SHPT: secondary hyperparathyroidism.

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