Many studies in this field have evaluated the efficacy and effectiveness of etelcalcetide, through RCTs and observational Studies (particularly in real-world setting).11,19,20,23–27

Two RCTs, involving 1023 patients, comparing etelcalcetide versus placebo, showed statistically significant results (p<0.001) in favor of etelcalcetide (RCT A – 74% versus 8.3%; RCT B – 75.3% versus 9.6%) in reducing >30% of baseline serum PTH levels.19 Another RCT, with 683 patients, comparing etelcalcetide versus cinacalcet, demonstrated not only non-inferiority (p<0.001) but also superiority (p<0.004) in favor of etelcalcetide for the aforementioned outcome (68.2% versus 57.7%).20 These three RCTs were crucial for its approval by FDA.19,20

After etelcalcetide approval, additional studies were conducted to further explore this topic. In a systematic review comparing three calcimimetics, including cinacalcet and etelcalcetide, 24 RCTs (6521 patients) were used to evaluated their efficacy in achieving target levels of serum PTH, with the result being statistically significant, considering etelcalcetide the most effective (etelcalcetide versus cinacalcet – odds ratio 2.78; 95% confidence interval (CI), 1.19–6.67).23

A prospective cohort study evaluated the effectiveness of etelcalcetide in 2596 hemodialysis patients with a 12-month follow-up, with and without prior use of cinacalcet.11 After one year of etelcalcetide therapy, the mean serum PTH level reached target values (according to KDIGO8), decreasing from 948 to 566pg/mL, with the proportion of patients within target values increasing from 33 to 64%.11 Also, serum calcium levels were substantially reduced at the end of the study (from 38 to 15–20% of patients with corrected calcium levels≥9.5mg/dl). Etelcalcetide appears to have good effectiveness regardless of prior use of calcimimetics.11 These findings are supported by another study where in an etelcalcetide-treated group versus control group (without calcimimetic), there was a reduction in PTH, calcium and phosphate levels in favor of the etelcalcetide group, effectively achieving target PTH levels in 73.2% versus 10.6% (p<0.0001) of patients in each group, respectively, after 12 months of follow-up.24

Superior efficacy/effectiveness of etelcalcetide versus cinacalcet was evident in three more studies.25–27 In a prospective cohort study by Pereira et al., in patients poorly controlled with cinacalcet, with a 6-month follow-up, statistically significant reductions in serum phosphate and PTH levels were observed, decreasing from 5.4 to 4.9mg/dl (p=0.01) and from 1005 to 702pg/mL (p<0.001), respectively.25 In a “real life” retrospective observational study by Morosetti et al., after a 12–18 month follow-up, 87% of patients in the vitamin D-only group (serum PTH level – 846±306pg/mL) and 58% of patients in the vitamin D and cinacalcet group (serum PTH level – 1429±729pg/mL) had PTH levels within recommended targets after the introduction of etelcalcetide, reinforcing its impact, even in patients poorly controlled with cinacalcet.26 Lastly, in a large registry study (prospective cohort study) involving 112 hemodialysis facilities in the United States, the cinacalcet-first hemodialysis facilities that switched to etelcalcetide-first showed that the mean serum PTH level decreased from 671 to 484pg/mL and the prevalence of patients with PTH levels>600pg/mL decreased from 39 to 21%. On the other hand, in hemodialysis facilities that stayed as cinacalcet-first, the mean serum PTH level increased from 632 to 698pg/mL and the prevalence of patients with PTH levels>600pg/mL increased from 37% to 43%.27 Also, when both types of facilities (cinacalcet-first versus etelcalcetide-first) were compared, there was an adjusted mean difference in PTH values of −115pg/mL (95% CI, −196 to −34), as well as a decrease of 11.4% (95% CI, −19.3% to −3.5%) in the prevalence of PTH level>600pg/mL, with both results statistically significant in favor of etelcalcetide.27

Therapeutic response of etelcalcetide is rapid and sustained.26,27 In Morosetti et al.’s study, the impact of etelcalcetide on reducing serum PTH level was primarily observed in the first months of treatment (first 4 months), demonstrating a rapid response.26 The studies by Morosetti et al. and Karaboyas et al. concluded that etelcalcetide had a sustained effect over time, which is particularly important in chronically hemodialyzed patients.26,27 Several referenced studies have a follow-up≥1 year, reinforcing this long-lasting effect of the drug.11,24,26

Thus, etelcalcetide appears to be effective in different biochemical parameters (PTH, calcium and phosphate), showing superiority to cinacalcet in this regard. Fig. 2 demonstrates the main actions of calcimimetics. Table 2 summarizes the main characteristics and conclusions of articles focusing on this topic.

Fig. 2.

Action of calcimimetics on the main target organs of the body. Description: Demonstration of how calcimimetics act on different organs that express CaSR, such as parathyroid, kidney and bone. Abbreviations: CaSR, calcium-sensing receptor; PTH, parathormone; Ca2+, calcium; FGF23, fibroblast growth factor 23; ↓, decrease.

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Regarding the adverse effects of etelcalcetide, this issue has been a subject of controversy. While it is true that studies with higher quality/evidence (systematic reviews/RCTs) did not find statistically significant differences in terms of adverse effects when comparing etelcalcetide versus cinacalcet,20,23 some recent studies in a real-world setting suggest that etelcalcetide appears to be better tolerated than cinacalcet.11,18,30

Hypocalcemia is an important concern. Etelcalcetide is more effective than cinacalcet in reducing PTH,11,19,20,23–27 so it tends to have a greater impact on reducing serum calcium levels.11,24 In fact, in the systematic review by Palmer et al., etelcalcetide had higher odds of hypocalcemia compared to cinacalcet (odds ratio 1.47; 95% CI, 1.08–2.00), which was statistically significant.23 In a prospective cohort study by Karaboyas et al., hypocalcemia was the most commonly adverse effect associated with etelcalcetide due to its potency, however, the frequency of severe hypocalcemia (<7.5mg/dl) after 1 year of treatment was low (<1–2%).11 The occurrence of symptomatic hypocalcemia or the discontinuation of etelcalcetide due to hypocalcemia were rarely reported.11 In another study, hypocalcemia was common, with 52.1%, 14.7% and 6.4% of patients having serum calcium levels of 7.5–8.3mg/dl, 7.0–7.5mg/dl and <7.0mg/dl, respectively.28 However, only 3.7% of patients experienced symptomatic hypocalcemia. Thus, although common, the clinical impact of hypocalcemia associated with etelcalcetide is minimal.28 To avoid severe and symptomatic hypocalcemia, an integrated review advised a pause of at least 7 days between discontinuing cinacalcet and starting etelcalcetide, with serum calcium levels within the normal range before its introduction.22

In relation to hypocalcemia in dialysis patients, it should be noted that the measurement of corrected calcium (cCa) levels may overestimate ionized calcium (iCa) (biologically active) levels and may erroneously consider that a patient has normocalcemia when, in fact, he has hidden hypocalcemia (normal cCa with low iCa).31 This is relevant because there are some studies, in particular the one by Yamaguchi et al., showed that when assessing the risk of cardiovascular disease and death from all causes, this risk was higher in patients with hidden hypocalcemia versus normocalcemia (normal iCa), with a statistically significant result (hazard ratio, 2.56; 95% CI, 1.11–5.94).31 However, when comparing patients with evident hypocalcemia (low cCa and iCa) versus normocalcemia, no statistically significant differences were found, probably because in this group (evident hypocalcemia) interventions (e.g., analogs of vitamin D and calcium carbonate) to correct hypocalcemia were more timely than in the group with hidden hypocalcemia.31 Thus, as highlighted by Yamaguchi et al., it is crucial to measure iCa (which is more expensive) in order to correctly and timely identify hidden hypocalcemia, with the aim of preventing/reducing the risk of associated serious adverse events.

Regarding the gastrointestinal effects, controversy prevails. In disagreement with several RCTs on this topic, a phase 3 RCT demonstrated that despite gastrointestinal effects being evident with both drugs, these effects were milder with etelcalcetide, leading to a lower discontinuation rate and higher tolerability.29 This lower severity may justify its preference in certain patients.

According to the systematic review by Palmer et al., concerning gastrointestinal effects (nausea and vomiting), etelcalcetide did not show statistically significant differences versus cinacalcet (odds ratio cinacalcet versus etelcalcetide 1.07; 95% CI, 0.63–1.80). However, the authors suggested that for healthcare professionals etelcalcetide was the preferred drug for minimizing gastrointestinal adverse effects.23

The integrated analysis by Block et al. highlighted adverse effects related to mineral-bone metabolism (particularly hypocalcemia) and gastrointestinal tract (diarrhea, nausea and vomiting) as the main adverse effects associated with etelcalcetide, with a low discontinuation rate versus cinacalcet.22 The study by Bushinsky et al. corroborated these findings, emphasizing asymptomatic hypocalcemia (43.3% of patients) and gastrointestinal symptoms (diarrhea (10.8%), vomiting (10.4%) and nausea (9.6%)) as the main adverse effects associated with etelcalcetide. Despite 89.8% of patients experienced at least one adverse effect related to this drug, only 4.6% had to discontinue it, indicating their reduced severity.28

Regarding the discontinuation of calcimimetics, in a prospective cohort study, individuals on etelcalcetide had discontinuation rates of 9%, 17% and 27% at 3, 6 and 12 months on this therapy, respectively, with a higher discontinuation rate observed in individuals who were not previously on cinacalcet.11 Patients who took cinacalcet in the previous 3 months tolerated etelcalcetide better, suggesting that these adverse effects may not be as pronounced as those of cinacalcet, justifying lower discontinuation rates associated with etelcalcetide.11 Patients with lower PTH values (<600pg/mL), younger age (<65 years), recently on dialysis (<3 years) and with lower starting doses of etelcalcetide (7.5mg/week) had higher discontinuation rates since, presumably, for younger patients and those with milder/early disease, the benefit gained from the medication is not worth it given these adverse effects.11 Previous studies reinforce higher discontinuation rates (lower tolerability) with the use of cinacalcet (40% and 73%).15,16 Finally, in a 52-week follow-up study, 23.2% of patients discontinued etelcalcetide, but only 4.6% discontinued it due to associated adverse effects. Cardiac arrest, nausea, vomiting, cellulitis, hypocalcemia and seizures were the main reasons for discontinuation.28

The “real-life” study by Russo et al. deserves particular relevance as the authors used self-reporting (instead of questionnaires) to identify the most bothersome adverse effects for patients.18 Patients’ submission to cinacalcet and then to etelcalcetide allowed understanding how the same patient evaluated the inconvenience of two different drugs, reducing interindividual subjectivity. In fact, the recording of gastrointestinal adverse events was clearly higher with cinacalcet (53%) versus etelcalcetide (3–4%), demonstrating that, at least for the studied population, the tolerability of etelcalcetide was much higher than cinacalcet, especially in terms of gastrointestinal effects. Thus, although both drugs reported similar adverse effects, tolerability was clearly superior with etelcalcetide.18

The results of Khan et al.’s study are even more surprising. In 148 hemodialyzed patients with SHPT treated with etelcalcetide, no gastrointestinal adverse effects were documented, greatly increasing the compliance of these patients with this treatment.30 However, it is important to realize that there were significant follow-up losses, which could explain the absence of some adverse effects and make some interpretations more difficult.30 Although previous studies have reported gastrointestinal adverse effects, making it difficult to believe that this drug does not cause any gastrointestinal adverse effects at all, this study at least demonstrated that the frequency of these adverse effects is probably much lower than that demonstrated with the use of cinacalcet.

Regarding the pathophysiology behind gastrointestinal complaints associated with etelcalcetide, this is still unclear and not universally accepted within the scientific community. Pereira et al. group point to nausea and vomiting as a likely systemic effect, independent of the administration route.12 Additionally, the study by Friedl et al. assumes that this effect is also related to the action on non-parathyroid organs that have the CaSR.32

Table 3 summarizes the main conclusions of the most relevant articles on this topic (adverse effects associated with etelcalcetide).

LVH and left atrial volume (LAV) increase the risk of cardiac events and associated mortality, particularly in patients with CKD.33,34 The association between CKD and CV disease, especially with LVH, is depicted in Fig. 3.

Fig. 3.

Pathophysiological mechanisms and corresponding association between chronic kidney disease and cardiovascular disease. Description: Demonstration of the correlation between chronic kidney disease and cardiovascular disease, highlighting the complications associated with these diseases, as well as the different mechanisms that contribute to both pathologies. Abbreviations: P04(3-), phosphate; FGF23, fibroblast growth factor 23; ↑, increase.

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According to Park et al., an increase >10% in left ventricular mass index (LVMI – good correlation with LVH) is an independent predictor for adverse CV events.35 Conversely, a 10% reduction in hemodialysis patients was associated with reductions in CV and all-cause mortality.36 According to Dörr et al.’s post hoc analysis, left atrial volume index (LAVI – good correlation with LAV) correlates with CV events and all-cause mortality. Delaying the progression of LAVI may imply better outcomes at this level.34

Dörr et al.’s RCT evaluated the progression of LVH (measured through LVMI, assessed by magnetic resonance imaging) in patients undergoing etelcalcetide versus alfacalcidol therapy for 12 months. Both intent-to-treat (ITT) and per-protocol (PP) analyses showed statistically significant differences favoring etelcalcetide in stabilizing the progression of LVMI and corresponding LVH. The adjusted mean difference in LVMI estimate was −6.9g/m2 (p=0.022) and −8.2g/m2 (p=0.008), respectively.33 This study also assessed the impact of therapies on FGF23 levels, with significant reductions in the etelcalcetide-treated group (factor 0.13; 95% CI, 0.06–0.26; etelcalcetide versus alfacalcidol, ITT analysis).33 There was a positive association between FGF23 levels and LVMI (LVMI increased by 2.0g/m2 by doubling the ratio of FGF23 values; 95% CI, 1.0–3.1g/m2),33 consistent with another study indicating that FGF23 was independently correlated with LVMI (p=0.01) and with the risk of LVH (odds ratio 2.1; 95% CI, 1.03–4.2), with both results statistically signifcant.37 Therefore, Dörr et al.’s study concluded that FGF23 suppression by etelcalcetide helped to stabilize the progression of LVH compared to alfacalcidol (which increased that progression), particularly in hemodialysis patients.33 The post hoc analysis by Dörr et al. evaluated the relationship between etelcalcetide and alfacalcidol in LAVI progression. Both ITT and PP analyses showed a reduction in LAVI of 5.0mL/m2 (95% CI: −0.04, 10; p=0.052) and 5.8mL/m2 (95% CI: 0.36, 11; p=0.037), respectively, in favor of etelcalcetide.34 In a sub-analysis, a close relationship between LAVI and LVMI was demonstrated, with the effect of etelcalcetide on inhibiting LAVI progression partly mediated by its effect on LVMI.34 Thus, both studies suggest that since LAV and LVH are CV risk factors, etelcalcetide, by stabilizing their progression, may lead to a reduction of CV mortality, particularly in hemodialysis patients.33,34 Studies directly addressing the impact of etelcalcetide on CV and all-cause mortality are needed for more informed conclusions.

FGF23 is a hormone synthesized in the bone and its levels are increased in CKD.38 FGF23 levels are independently associated with CV outcomes and mortality in individuals who have not started dialysis, those who recently initiated it, and even in chronically dialyzed patients.38–40 According to the post hoc analysis of the EVOLVE trial, reductions in FGF23 levels were associated with lower rates of major CV events and CV mortality.41 In line with this evidence, sub-analysis results from this trial showed that patients treated with cinacalcet had higher survival rates in the group with low FGF23 levels compared to those with high levels.41 Etelcalcetide, as mentioned earlier, significantly reduces FGF23 levels, suggesting a potential beneficial impact on CV outcomes.33

Concerning CV outcomes, vascular calcification is another important aspect as it correlates with CV mortality.42 Vascular calcification is a common complication in CKD patients, resulting from mineral homeostasis dysregulation.43 High levels of calcium and phosphate as well as extreme levels of PTH are essential for the initiation and progression of this issue.43

Studies assessing the impact of etelcalcetide on vascular calcification are scarce, with no human studies to date. A preclinical study in rats with CKD and SHPT compared etelcalcetide and paricalcitol, with vascular calcification being measured by aortic calcium content (ACC).44 63% of the 24 rats treated with paricalcitol had ACC>400μg/g, while none of the 24 rats treated with etelcalcetide had it. This result suggests a positive impact of etelcalcetide on the attenuation of vascular calcification, consistent with previous findings on cinacalcet.44

The pathophysiology explaining the attenuation of vascular calcification by etelcalcetide remains unclear. Other calcimimetics had shown a direct effect on vascular cells due to CaSR activation in endothelial and vascular smooth muscle cells, increasing matrix Gla protein (calcification inhibitor) in the arterial wall. Thus, since etelcalcetide acts on CaSR in a similar way as other calcimimetics, the mechanism that explain the attenuation of vascular calcification process is probably identical.12,17,44

In a more recent prospective cohort study, sclerostin, a protein apparently relevant in the vascular calcification process, was evaluated.25 Sclerostin is expressed in osteocytes and it is elevated in the early stages of CKD.45 Elevated levels of sclerostin were associated with better outcomes in terms of vascular calcification.46 Physiologically, it is believed to have beneficial protective paracrine effects, suppressing the transformation of vascular smooth muscle cells into osteoblast-like cells, slowing down the vascular calcification process.25 Also, in this Pereira et al's study, a negative correlation between sclerostin and PTH levels was found, both at the beginning and at the end of the study,25 a predictable correlation since PTH negatively regulates sclerostin in osteocytes.47 In individuals already taking cinacalcet, sclerostin concentration significantly increased after etelcalcetide use.25 Thus, this seems to be another mechanism that can explain the possible role of etelcalcetide in attenuating the vascular calcification process beyond its effect on vascular CaSR, as mentioned earlier. In severe cases of SHPT, PTH levels are higher and, consequently, sclerostin levels are lower.25 In these cases, drugs aiming to increase sclerostin levels may be advantageous, particularly in attenuating the progression of vascular calcification.

Table 4 summarizes the main results of the aforementioned studies regarding this topic (CV outcomes).

Some studies have addressed the impact of etelcalcetide on certain complications of the bone metabolism in SHPT, especially renal osteodystrophy.24,29,48,49

In Dudar et al.’s prospective cohort study, with a 12-month follow-up, 203 hemodialyzed patients with SHPT were evaluated, divided into two groups: one under etelcalcetide treatment and another without calcimimetic treatment (this control group was evaluated retrospectively).24 Regarding primary endpoints, the assessment of bone fracture frequency stood out. At the end of the 12-month follow-up, the bone fracture frequency was about three times higher in the control group compared to the etelcalcetide group, although these results were not statistically significant (p>0.1). The small sample size (203 patients) may explain the lack of power to find statistically significant differences.24

In a very recent study with a 36-week follow-up, the impact of etelcalcetide on bone quality and strength was assessed, in hemodialyzed patients, with the advantage of being the first bone biopsy trial using nanoscale measures of bone quality to assess the impact of calcimimetics on bone.48 In addition, this was the first trial specifically designed to evaluate the effect of etelcalcetide on bone tissue. At the end of the study, PTH levels decreased significantly (67±9%; p<0.001), areal bone mineral density of the spine, femoral neck and hip increased (3±1%, 7±2% and 3±1%, respectively; p<0.05), there was an improvement in trabecular microarchitecture of the spine (with an increase in spine trabecular bone score of 10±2%; p<0.001) and etelcalcetide was associated with a decrease in bone formation rate (p<0.01) without negatively affecting intrinsic bone properties.48 Despite these positive results, the number of participants ultimately limited the power of the study, with only 13 of the initial 22 participants completing the follow-up and only 5 of them undergoing bone biopsy. Despite this limitation, in this studied population, treatment with etelcalcetide was associated with suppression of bone turnover markers, improvement in bone mineral density (with an increase in Z scores adjusted for age and sex at the spine and femoral neck) and improvement in trabecular properties of the central skeleton.48

A preclinical study on rats with SHPT showed that etelcalcetide treatment significantly reduced PTH, FGF23 and osteocalcin (marker of bone turnover).49 The study also found reduction in bone turnover, attenuation of mineralization defects and bone marrow fibrosis, and preservation of cortical bone structure and strength.49 Additionally, etelcalcetide reduced levels of a bone resorption marker, tartrate-resistant acid phosphatase 5b (TRACP-5b).29,49 These findings suggest that etelcalcetide has a possible beneficial impact on renal osteodystrophy.24,29,48,49

In summary, these data suggest that etelcalcetide appears to have a positive impact on bone structure with a possible reduction in the risk of fractures.24,29,48,49 However, to date, there is a lack of studies specifically designed to evaluate the impact of etelcalcetide on reducing the risk of fractures in patients with CKD and SHPT.

Table 5 summarizes the main results of the aforementioned studies regarding this topic (bone metabolism).

To date, there is a lack of studies that have directly addressed the primary outcome of the impact of calcimimetics on reducing CV and all-cause mortality. However, some studies have assessed their impact on surrogate markers of mortality in patients with CKD and SHPT.24,33,34,50,51

Before the introduction of etelcalcetide, some authors studied the relationship between cinacalcet and CV mortality.50 In the EVOLVE trial (RCT), 3883 patients with moderate to severe SHPT undergoing hemodialysis were evaluated over 64 months.50 The primary composite endpoint included time until death, myocardial infarction, hospitalization for unstable angina, heart failure and peripheral vascular events. 48.2% of patients on cinacalcet versus 49.2% of patients on placebo reached the primary composite endpoint, with results not statistically significant in favor of cinacalcet (hazard ratio 0.93, CI 0.85–1.02, p=0.11). Thus, in this studied population, cinacalcet did not appear to significantly reduce the risk of death and major CV events.50

Regarding the study by Dudar et al., previously mentioned, one of the evaluated primary endpoints was mortality due to CV events. At the end of the 12-month follow-up, all-cause mortality was not statistically lower in the etelcalcetide group versus in the non-calcimimetic group (p>0.2).24 The small sample size (203 patients) may explain the lack of power to find statistically significant differences. However, considering overall mortality in each group, the proportion of cases due to CV mortality was much lower in the etelcalcetide group (40% versus 69.2%) (both groups presented identical characteristics), with authors noting a greater than 2.5-fold reduction in CV mortality rate in this group compared to the control group.24

A RCT performed by Shoji et al. assessed the impact of etelcalcetide versus maxacalcitol on the reducing of a surrogate marker of mortality (serum calcification propensity – measured through T50 value) in patients with SHPT.51 A total of 425 patients from 23 dialysis centers were evaluated, with 321 included in the ITT analysis. At the end of the study, the authors observed an increase in T50 value for both drugs, but its increase (which means a decrease in the calcification propensity) was greater in the etelcalcetide group versus maxacalcitol group, with a statistically significant result (p=0.004).51 Low T50 levels correlate with a higher risk of all-cause mortality in patients with CKD (dialyzed or not),51 suggesting that etelcalcetide may have a positive impact on this outcome. It is important to notice that there was no difference in cognition and handgrip strength between both drugs.51

In conclusion, as previously described, etelcalcetide has demonstrated an impact on reducing LVH and LAV, suggesting it may have a beneficial effect on reducing CV mortality.33,34 Since the EVOLVE trial and the study by Dudar et al. did not confirm the possible effect of calcimimetics on mortality,24,50 more studies specifically designed, such as RCTs, are needed to evaluate this association.

Table 6 summarizes the main results of the aforementioned studies regarding this topic (CV and all-cause mortality).

About etelcalcetide, there are some areas that need further exploration.

Regarding tolerability, it is necessary to address the discrepancy between the results of RCTs and observational studies (in a real-world setting).

The relationship between etelcalcetide and CV and all-cause mortality still needs to be more thoroughly studied, with studies specifically designed to assess this association.

The topic of bone fractures is scarcely mentioned in some articles about etelcalcetide, and it is also necessary to have studies specifically designed to evaluate this association.

Finally, bone biopsy is an excellent method for assessing bone quality and structure. More studies that preferentially use this method are needed.