Lower Risk of Cardiovascular Events in Adult Patients with Chronic Hypoparathyroidism Treated with rhPTH(1-84): A Retrospective Cohort Study

Olulade Ayodele, Fan Mu, Richard Berman, Elyse Swallow, Lars Rejnmark, Elvira O Gosmanova, Sanjiv Kaul, Olulade Ayodele, Fan Mu, Richard Berman, Elyse Swallow, Lars Rejnmark, Elvira O Gosmanova, Sanjiv Kaul

Abstract

Introduction: Patients with chronic hypoparathyroidism are at increased risk of cardiovascular disease. This study evaluated the risk of developing cardiovascular conditions over a period of 5 years in adult patients with chronic hypoparathyroidism treated with recombinant human parathyroid hormone (1-84), rhPTH(1-84), compared with a historical control cohort of patients not treated with rhPTH(1-84).

Methods: This retrospective cohort study comprised patients with chronic hypoparathyroidism treated with rhPTH(1-84) in the REPLACE (NCT00732615), RELAY (NCT01268098), and RACE (NCT01297309) clinical trials, and controls selected from the IBM® Explorys electronic medical record database (January 2007-August 2019) who did not receive parathyroid hormone but who had enrollment criteria similar to those for the clinical trials. Cardiovascular outcomes were the first diagnosis of cerebrovascular, coronary artery, peripheral vascular disease, or heart failure during the study period.

Results: We evaluated 113 adult patients with chronic hypoparathyroidism treated with rhPTH(1-84) and 618 control patients who did not receive rhPTH(1-84). Over the 5-year follow-up period, 3.5% of patients (n = 4) in the rhPTH(1-84) cohort had a cardiovascular event compared with 16.3% (n = 101) in the control cohort. Kaplan-Meier analysis demonstrated that patients in the rhPTH(1-84) cohort had lower risk of experiencing a cardiovascular event compared with patients in the control cohort (P = 0.005). Multivariable analyses adjusted for baseline variables showed that patients in the rhPTH(1-84) cohort had 75% lower risk for a cardiovascular event compared with patients in the control cohort (adjusted hazard ratio, 0.25 [95% CI 0.08-0.81]; P = 0.020).

Conclusion: Long-term treatment with rhPTH(1-84) was associated with a lower risk of incident cardiovascular conditions compared with conventional therapy in patients with chronic hypoparathyroidism. Previous studies demonstrated that mineral homeostasis was maintained with lower use of calcium and active vitamin D when rhPTH(1-84) was added to conventional therapy. Future studies are needed to understand whether improved regulation of mineral homeostasis conferred by rhPTH(1-84) may provide long-term cardiovascular benefits to patients with chronic hypoparathyroidism.

Keywords: Cardiovascular disease; Electronic health records; Hypoparathyroidism; Parathyroid hormone; Retrospective cohort study; rhPTH(1–84).

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Selection of the study analyses cohorts. CV cardiovascular, rhPTH(1–84) recombinant human parathyroid hormone (1–84)
Fig. 2
Fig. 2
Time to first diagnosis of a cardiovascular event during the study period. A cardiovascular event was defined as any diagnosis of cerebrovascular disease, coronary artery disease, heart failure, or peripheral vascular disease. CKD chronic kidney disease, CV cardiovascular, rhPTH(1–84) recombinant human parathyroid hormone (1–84)

References

    1. Shoback D. Hypoparathyroidism. N Engl J Med. 2008;359:391–403. doi: 10.1056/NEJMcp0803050.
    1. Khan MI, Waguespack SG, Hu MI. Medical management of postsurgical hypoparathyroidism. Endocr Pract. 2011;17(Suppl 1):18–25. doi: 10.4158/EP10302.RA.
    1. Powers J, Joy K, Ruscio A, Lagast H. Prevalence and incidence of hypoparathyroidism in the United States using a large claims database. J Bone Miner Res. 2013;28:2570–2576. doi: 10.1002/jbmr.2004.
    1. Karpf D, Catsburg C, Smith A. Prevalence of hypoparathyroidism in the EU: a systematic review and meta-analysis. Endocr Abstr. 2020;70:AEP140.
    1. Vokes T. Quality of life in hypoparathyroidism. Bone. 2019;120:542–547. doi: 10.1016/j.bone.2018.09.017.
    1. Chen K, Krasner A, Li N, et al. Clinical burden and healthcare resource utilization among patients with chronic hypoparathyroidism, overall and by adequately vs not adequately controlled disease: a multi-country chart review. J Med Econ. 2019;22:1141–1152. doi: 10.1080/13696998.2019.1624081.
    1. Brandi ML, Bilezikian JP, Shoback D, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab. 2016;101:2273–2283. doi: 10.1210/jc.2015-3907.
    1. Bollerslev J, Rejnmark L, Marcocci C, et al. European Society of Endocrinology Clinical Guideline: treatment of chronic hypoparathyroidism in adults. Eur J Endocrinol. 2015;173:G1–20. doi: 10.1530/EJE-15-0628.
    1. Bollerslev J, Rejnmark L, Zahn A, et al. European expert consensus on practical management of specific aspects of parathyroid disorders in adults and in pregnancy: recommendations of the ESE Educational Program of Parathyroid Disorders. Eur J Endocrinol. 2022;186(2):R33–R63.
    1. Abate EG, Clarke BL. Review of hypoparathyroidism. Front Endocrinol (Lausanne) 2017;7:172. doi: 10.3389/fendo.2016.00172.
    1. Underbjerg L, Sikjaer T, Rejnmark L. Long-term complications in patients with hypoparathyroidism evaluated by biochemical findings: a case-control study. J Bone Miner Res. 2018;33:822–831. doi: 10.1002/jbmr.3368.
    1. Siggelkow H, Clarke BL, Germak J, et al. Burden of illness in not adequately controlled chronic hypoparathyroidism: findings from a 13-country patient and caregiver survey. Clin Endocrinol (Oxf) 2020;92:159–168. doi: 10.1111/cen.14128.
    1. Mitchell DM, Regan S, Cooley MR, et al. Long-term follow-up of patients with hypoparathyroidism. J Clin Endocrinol Metab. 2012;97:4507–4514. doi: 10.1210/jc.2012-1808.
    1. Bilezikian JP, Brandi ML, Cusano NE, et al. Management of hypoparathyroidism: present and future. J Clin Endocrinol Metab. 2016;101:2313–2324. doi: 10.1210/jc.2015-3910.
    1. Khan AA, Koch C, Van Uum SHM, et al. Standards of care for hypoparathyroidism in adults: a Canadian and international consensus. Eur J Endocrinol. 2019;180:P1–P22. doi: 10.1530/EJE-18-0609.
    1. Kim SH, Rhee Y, Kim YM, et al. Prevalence and complications of nonsurgical hypoparathyroidism in Korea: a nationwide cohort study. PLoS ONE. 2020;15:e0232842. doi: 10.1371/journal.pone.0232842.
    1. Vadiveloo T, Donnan PT, Leese CJ, Abraham KJ, Leese GP. Increased mortality and morbidity in patients with chronic hypoparathyroidism: a population-based study. Clin Endocrinol (Oxf) 2019;90:285–292. doi: 10.1111/cen.13895.
    1. Gosmanova EO, Chen K, Ketteler M, et al. Risk of cardiovascular conditions in patients with chronic hypoparathyroidism: a retrospective cohort study. Adv Ther. 2021;38:4246–4257. doi: 10.1007/s12325-021-01787-7.
    1. Bergenfelz A, Nordenstrom E, Almquist M. Morbidity in patients with permanent hypoparathyroidism after total thyroidectomy. Surgery. 2020;167:124–128. doi: 10.1016/j.surg.2019.06.056.
    1. Bollerslev J, Sjostedt E, Rejnmark L. Cardiovascular consequences of parathyroid disorders in adults. Ann Endocrinol (Paris) 2021;82:151–157. doi: 10.1016/j.ando.2020.02.003.
    1. Tabacco G, Naciu AM, Maggi D, et al. Cardiovascular autonomic neuropathy as a new complication of postsurgical chronic hypoparathyroidism. J Bone Miner Res. 2019;34:475–481. doi: 10.1002/jbmr.3623.
    1. da Silva ST, de Carvalho AC. Hypocalcemic cardiomyopathy—a rare and reversible entity. Am J Emerg Med. 2021 doi: 10.1016/j.ajem.2021.06.060.
    1. Ix JH, De Boer IH, Peralta CA, et al. Serum phosphorus concentrations and arterial stiffness among individuals with normal kidney function to moderate kidney disease in MESA. Clin J Am Soc Nephrol. 2009;4:609–615. doi: 10.2215/CJN.04100808.
    1. Caudarella R, Vescini F, Buffa A, Francucci CM. Hyperphosphatemia: effects on bone metabolism and cardiovascular risk. J Endocrinol Invest. 2007;30:29–34.
    1. Foley RN, Collins AJ, Herzog CA, Ishani A, Kalra PA. Serum phosphorus levels associate with coronary atherosclerosis in young adults. J Am Soc Nephrol. 2009;20:397–404. doi: 10.1681/ASN.2008020141.
    1. Sheridan K, Logomarsino JV. Effects of serum phosphorus on vascular calcification in a healthy, adult population: a systematic review. J Vasc Nurs. 2017;35:157–169. doi: 10.1016/j.jvn.2017.01.003.
    1. Van den Bergh G, Opdebeeck B, D'Haese PC, Verhulst A. The vicious cycle of arterial stiffness and arterial media calcification. Trends Mol Med. 2019;25:1133–1146. doi: 10.1016/j.molmed.2019.08.006.
    1. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;55:1318–1327. doi: 10.1016/j.jacc.2009.10.061.
    1. Weber T, Auer J, O'Rourke MF, et al. Arterial stiffness, wave reflections, and the risk of coronary artery disease. Circulation. 2004;109:184–189. doi: 10.1161/01.CIR.0000105767.94169.E3.
    1. Gosmanova EO, Chen K, Rejnmark L, et al. Risk of chronic kidney disease and estimated glomerular filtration rate decline in patients with chronic hypoparathyroidism: a retrospective cohort study. Adv Ther. 2021;38:1876–1888. doi: 10.1007/s12325-021-01658-1.
    1. Provenzano M, Coppolino G, Faga T, et al. Epidemiology of cardiovascular risk in chronic kidney disease patients: the real silent killer. Rev Cardiovasc Med. 2019;20:209–220. doi: 10.31083/j.rcm.2019.04.548.
    1. Natpara® parathyroid hormone. Lexington: Shire-NPS Pharmaceuticals; 2020.
    1. Natpar® (parathyroid hormone). Dublin: Shire Pharmaceuticals Ireland; 2021.
    1. Mannstadt M, Clarke BL, Bilezikian JP, et al. Safety and efficacy of 5 years of treatment with recombinant human parathyroid hormone in adults with hypoparathyroidism. J Clin Endocrinol Metab. 2019;104:5136–5147. doi: 10.1210/jc.2019-01010.
    1. Tay YD, Tabacco G, Cusano NE, et al. Therapy of hypoparathyroidism with rhPTH(1–84): a prospective, 8-year investigation of efficacy and safety. J Clin Endocrinol Metab. 2019;104:5601–5610. doi: 10.1210/jc.2019-00893.
    1. Chen KS, Gosmanova EO, Curhan GC, et al. Five-year estimated glomerular filtration rate in patients with hypoparathyroidism treated with and without rhPTH(1–84) J Clin Endocrinol Metab. 2020;105:e3557–e3565. doi: 10.1210/clinem/dgaa490.
    1. Mannstadt M, Clarke BL, Vokes T, et al. Efficacy and safety of recombinant human parathyroid hormone (1–84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study. Lancet Diabetes Endocrinol. 2013;1:275–283. doi: 10.1016/S2213-8587(13)70106-2.
    1. Bilezikian JP, Clarke BL, Mannstadt M, et al. Safety and efficacy of recombinant human parathyroid hormone in adults with hypoparathyroidism randomly assigned to receive fixed 25-μg or 50-μg daily doses. Clin Ther. 2017;39:2096–2102. doi: 10.1016/j.clinthera.2017.08.011.
    1. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–612. doi: 10.7326/0003-4819-150-9-200905050-00006.
    1. Wang Y, He K, Wang O, et al. Manifestations of left ventricular dysfunction and arrhythmia in patients with chronic hypoparathyroidism and pseudohypoparathyroidism: a preliminary study. BMC Endocr Disord. 2020;20:61. doi: 10.1186/s12902-020-0541-6.
    1. Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. The epidemiology of nonsurgical hypoparathyroidism in Denmark: a nationwide case finding study. J Bone Miner Res. 2015;30:1738–1744. doi: 10.1002/jbmr.2501.
    1. Meola A, Vignali E, Matrone A, Cetani F, Marcocci C. Efficacy and safety of long-term management of patients with chronic post-surgical hypoparathyroidism. J Endocrinol Invest. 2018;41:1221–1226. doi: 10.1007/s40618-018-0857-5.
    1. Zavatta G, Clarke BL. Basal ganglia calcification in hypoparathyroidism and pseudohypoparathyroidism: local and systemic metabolic mechanisms. J Endocrinol Invest. 2021;44:245–253. doi: 10.1007/s40618-020-01355-w.
    1. Nielsen CV, Underbjerg L, Grove-Laugesen D, Sikjaer T, Rejnmark L. Lower leg arterial calcifications assessed by high-resolution peripheral quantitative computed tomography in hypoparathyroid and pseudohypoparathyroid patients. Calcif Tissue Int. 2021;108:775–784. doi: 10.1007/s00223-021-00814-7.
    1. Pamuk N, Akkan T, Dagdeviren M, et al. Central and peripheral blood pressures and arterial stiffness increase in hypoparathyroidism. Arch Endocrinol Metab. 2020;64:374–382.
    1. Erben RG. Physiological actions of fibroblast growth factor-23. Front Endocrinol (Lausanne) 2018;9:267. doi: 10.3389/fendo.2018.00267.
    1. Jacquillet G, Unwin RJ. Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi) Pflugers Arch. 2019;471:83–98. doi: 10.1007/s00424-018-2231-z.
    1. Wesseling-Perry K, Pereira RC, Sahney S, et al. Calcitriol and doxercalciferol are equivalent in controlling bone turnover, suppressing parathyroid hormone, and increasing fibroblast growth factor-23 in secondary hyperparathyroidism. Kidney Int. 2011;79:112–119. doi: 10.1038/ki.2010.352.
    1. Gutierrez OM, Januzzi JL, Isakova T, et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation. 2009;119:2545–2552. doi: 10.1161/CIRCULATIONAHA.108.844506.
    1. Ix JH, Katz R, Kestenbaum BR, et al. Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study) J Am Coll Cardiol. 2012;60:200–207. doi: 10.1016/j.jacc.2012.03.040.
    1. Scialla JJ, Xie H, Rahman M, et al. Fibroblast growth factor-23 and cardiovascular events in CKD. J Am Soc Nephrol. 2014;25:349–360. doi: 10.1681/ASN.2013050465.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj