Calcimimetics: Survey Results

by Dr. Pablo Urena

At the KDIGO era, it is surprising the answer we see to question 5. Fifty-seven percent of people consider a serum PTH value > 300 pg/ml as clinical relevant and not a value 9 times higher than the normal upper limit (around 500 pg/ml) as recommended by the KDIGO. The results also suggest that most physicians are still applying the K-DOQI ranges of 150-300 pg/ml for serum PTH levels.
One can also ask why 16% of participants waited until the PTH values is > 600 pg/ml to take this biological abnormality as relevant. It must remind that several studies have clearly shown that the higher the basal PTH value the lower chances of an optimal response to vitamin D and calcimimetics therapies. There is also a risk of parathyroid cells autonomization and monoclonal transformation.
Regarding the 10% of participants considering important PTH values greater than 60 and 120 pg/ml, this is probably excessive. 

In spite of the bad reputation recently made to calcium-based phosphate binders, it is interesting seeing that this is the first-line therapeutical option for 50% of the participants. This answer is in line with the parathyroid gland physiology and with the calcium-set point regulating PTH secretion through the modulation of the parathyroid calcium-sensing receptor. Normalizing or increasing serum calcium concentration is the most powerful mean to suppress PTH. Calcium-free phosphate binders was the second choice, probably led by the finding that high phosphate can directly stimulate PTH synthesis and secretion. Personally, I would have placed it in the third choice, after native and active vitamin D. Indeed, it have been largely demonstrated the inhibitory genomic effect of vitamin D on the PTH gene expression. Moreover, recent data have demonstrated that native vitamin D can be locally transformed in its more active form calcitriol into the parathyroid cells.

These answers are reassuring and in accordance with most of the recent surveys, only one third of dialysis patients have actually a serum PTH > 300 pg/ml.

This is a very informative slide. Fifty-five of participants answered that the mean daily dose of calcimimetic was between 30-60 mg. Less than 1% goes up to the maximal dose of 180 mg/day, which raises the question why the calcimimetic is not titrated up to the maximal dose? Is it because of side effects or intolerance?
Another point to be stressed is the one third were using between 0 and 30 mg/d, which suggests that probably a substantial number of patients were splitting or spacing the daily dose of 30 mg to 15 mg/d or 30 mg every other day. A pill with a lower calcimimetic concentration (10-20 mg) is probably needed.

This 54% of participants responding that only 0-10% of patients do not respond well to the calcimimetic therapy confirms the results obtained in several randomized trials such as OPTIMA, CONTROL, ACHIEVE, and others phase II and phase III studies.

Poor adherence to the treatment and GI side effect are well known reasons for the lack of efficacy of calcimimetics. However, it is surprising that one third of participants believe that the lack of response is due to parathyroid gland autonomization. This is an important issue that has not been yet demonstrated and that calls for additional studies in non-responders patients.

The answer was 2.10 mM and fortunately most of the participants are correct. However, 27% of them considered that it was possible starting the calcimimetic with a calcemia lower than 2.05 even 2.00 mM, which is not approved.

The message to take home here was that native vitamin D should be maintained or corrected up to a value > 20 ng/ml.

Still very interesting slide, 50% considered the use of a dialysate fluid with a calcium concentration of 1.50 mM and not 1.25 as recommended by the KDIGO.
With 1.50 mM calcium concentration in the dialysate and a high serum PTH the calcium balance can be neutral even negative as shown by Karolh et al. NDT 2010. Moreover, the response to the calcimimetic can be improved when increasing the calcium concentration in the dialysate to 1.75 mM as shown by Drueke et al NDT 2009.

The slide shows a quite well distributed answers. One third considered that the best way to correct the calcimimetic-associated hypocalcemia was introducing or increasing the dose of an active vitamin D compound. This option may also potentiate the effect of the calcimimetic on the parathyroid cells since it stimulates the expression of the calcium-sensing receptor. All the other options are also valuable.

Eighty percent of the participants believed that the calcimimetics will reduced the incidence of surgical parathyroïdectomie. That right, as demonstrated in the post-hoc analysis published by Cunningham et al KI 2005, were during the 6 months of treatment the incidence of parathyroïdectomie was reduced by more than 90%.

As many of us, this is an unanswered question for the moment. There is no conclusive study demonstrating the potential beneficial effect of calcimimetic on bone metabolism. The results of the ongoing trial BONAFIDE will surely answer that question.

The incidence of skeletal fracture was reduced by 50% in the post-hoc analysis published by Cunningham et al KI 2005, which is in accord with the answer recorded here.

Seventy percent considered that the calcimimetics might reduce the risk of cardiovascular calcifications. This answer is surely motivates by the results of the ADVANCE study, even if they did not meet the primary end-point. However, they demonstrated a clear tendency to a slower progression of the score of calcification in the coronary arteries, aorta, and cardiac valves.

One third considered that the calcimimetics might improve patient survival in dialysis. The definitive answer to that question will be soon available with the end of the EVOLVE study the next year.