*3.2. Calcimimetics*

Calcimimetics act on the calcium-sensing receptor and increase its sensitivity to calcium, thereby lowering the PTH level as a result of the feedback mechanism. Two generations of calcimimetics have been developed, the first of which—calcimimetic cinacalcet—is taken orally once daily. The second generation—calcimimetic etecalcetide—is applied intravenously three times per week after hemodialysis (HD) sessions [39].

In an experimental CKD model of adenine-fed rats, cinacalcet ameliorated aortic calcification (Table 1) [38]. The prospective RCTs EVOLVE and ADVANCE treated HD patients with sHPT daily with 30 to 180 mg cinacalcet [40,41]. In the ADVANCE trial, patients additionally received a low-dose vitamin D therapy. Cinacalcet reduced the progression of aortic valve calcification compared to the vitamin D control group, while it had no effect on aortic calcification [41]. Similar results were found in the EVOLVE trial. In both trials, cinacalcet bore no effect on all-cause mortality and CV event rate [40,41]. A meta-analysis of RCTs considering (pre)-dialysis patients and kidney transplant recipients (KTR) revealed that cinacalcet had no effect on all-cause mortality [42]. An observational study confirmed that cinacalcet is not associated with all-cause mortality but is related to reduced CV events [43]. A variety of adverse effects like diarrhea, hypocalcemia, and nausea have been reported [44]. While calcimimetics are quite effective in lowering serum PTH, the effect on all-cause mortality, CV risk, and calcification is uncertain [37]. Especially in pre-dialysis patients, further studies focusing on clinical rather than biochemical outcomes are needed.

### **4. Novel Therapeutic Strategies—from Experimental Models to the Clinic**
