Cardiometabolic and psychological effects of dual-release hydrocortisone: a cross-over study

in European Journal of Endocrinology
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  • 1 Academic Department of Endocrinology, Beaumont Hospital/
  • 2 Robert Graves Institute of Endocrinology, Tallaght University Hospital
  • 3 Department of Endocrinology, Connolly Hospital
  • 4 Department of Endocrinology, St James Hospital, Dublin, Ireland

Correspondence should be addressed to M Sherlock; Email: marksherlock@beaumont.ie
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Background

Adrenal insufficiency (AI) is associated with increased cardiovascular morbidity and mortality and reduced quality of life (QoL). Optimum glucocorticoid (GC) dosing and timing are crucial in the treatment of AI, yet the natural circadian secretion of cortisol is difficult to mimic. The once-daily dual-release hydrocortisone (DR-HC) preparation (Plenadren®), offers a more physiological cortisol profile and may address unmet needs.

Methods

An investigator-initiated, prospective, cross-over study in patients with AI. Following baseline assessment of cardiometabolic risk factors and QoL, patients switched from their usual hydrocortisone regimen to a once-daily dose equivalent of DR-HC and were reassessed after 12 weeks of treatment.

Results

Fifty-one patients (21 PAI/30 SAI) completed the study. Mean age was 41.6 years (s.d. 13), and 58% (n = 30) were male. The median daily HC dose before study entry was 20 mg (IQR 15–20 mg). After 3 months on DR-HC, the mean SBP decreased by 5.7 mmHg, P = 0.0019 and DBP decreased by 4.5 mmHg, P = 0.0011. There was also a significant reduction in mean body weight (−1.23 kg, P = 0.006) and BMI (−0.3 kg/m2, P = 0.003). In a sub-analysis, there was a greater reduction in SBP observed in patients with SAI when compared to PAI post-DR-HC. Patients reported significant improvements in QoL using three validated QoL questionnaires, with a greater improvement in PAI.

Conclusion

Dual-release hydrocortisone decreases BP, weight and BMI compared with conventional HC treatment, even at physiological GC replacement doses. Additionally, DR-HC confers significant improvements in QoL compared to immediate-release HC, particularly in patients with PAI, which is also reflected in the patient preference for DR-HC.

 

     European Society of Endocrinology

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  • 1

    Arlt W & Allolio B Adrenal insufficiency. Lancet 2003 361 188118 93. (https://doi.org/10.1016/S0140-6736(0313492-7)

  • 2

    Bensing S, Brandt L, Tabaroj F, Sjoberg O, Nilsson B, Ekbom A, Blomqvist P & Kampe O Increased death risk and altered cancer incidence pattern in patients with isolated or combined autoimmune primary adrenocortical insufficiency. Clinical Endocrinology 2008 69 697704. (https://doi.org/10.1111/j.1365-2265.2008.03340.x)

    • Search Google Scholar
    • Export Citation
  • 3

    Erichsen MM, Lovas K, Fougner KJ, Svartberg J, Hauge ER, Bollerslev J, Berg JP, Mella B & Husebye ES Normal overall mortality rate in Addison’s disease, but young patients are at risk of premature death. European Journal of Endocrinology 2009 160 23323 7. (https://doi.org/10.1530/EJE-08-0550)

    • Search Google Scholar
    • Export Citation
  • 4

    Bergthorsdottir R, Leonsson-Zachrisson M, Oden A & Johannsson G Premature mortality in patients with Addison’s disease: a population-based study. Journal of Clinical Endocrinology and Metabolism 2006 91 484948 53. (https://doi.org/10.1210/jc.2006-0076)

    • Search Google Scholar
    • Export Citation
  • 5

    Skov J, Sundstrom A, Ludvigsson JF, Kampe O & Bensing S Sex-specific risk of cardiovascular disease in autoimmune Addison disease-a population-based cohort study. Journal of Clinical Endocrinology and Metabolism 2019 104 203120 40. (https://doi.org/10.1210/jc.2018-02298)

    • Search Google Scholar
    • Export Citation
  • 6

    Aulinas A & Webb SM Health-related quality of life in primary and secondary adrenal insufficiency. Expert Review of Pharmacoeconomics and Outcomes Research 2014 14 87388 8. (https://doi.org/10.1586/14737167.2014.963559)

    • Search Google Scholar
    • Export Citation
  • 7

    Filipsson H, Monson JP, Koltowska-Haggstrom M, Mattsson A & Johannsson G The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. Journal of Clinical Endocrinology and Metabolism 2006 91 395439 61. (https://doi.org/10.1210/jc.2006-0524)

    • Search Google Scholar
    • Export Citation
  • 8

    Johannsson G, Nilsson AG, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, Engstrom BE, Olsson T, Ragnarsson O & Ryberg M Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation. Journal of Clinical Endocrinology and Metabolism 2012 97 4734 81. (https://doi.org/10.1210/jc.2011-1926)

    • Search Google Scholar
    • Export Citation
  • 9

    Johannsson G, Skrtic S, Lennernas H, Quinkler M & Stewart PM Improving outcomes in patients with adrenal insufficiency: a review of current and future treatments. Current Medical Research and Opinion 2014 30 183318 47. (https://doi.org/10.1185/03007995.2014.925865

    • Search Google Scholar
    • Export Citation
  • 10

    Isidori AM, Venneri MA, Graziadio C, Simeoli C, Fiore D, Hasenmajer V, Sbardella E, Gianfrilli D, Pozza C & Pasqualetti P Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomised controlled trial. Lancet: Diabetes and Endocrinology 2018 6 1731 85. (https://doi.org/10.1016/S2213-8587(1730398-4)

    • Search Google Scholar
    • Export Citation
  • 11

    Isidori AM, Hasenmajer V & Venneri MA Once-daily, modified-release hydrocortisone in patients with adrenal insufficiency – authors’ reply. Lancet: Diabetes and Endocrinology 2018 6 27027 1. (https://doi.org/10.1016/S2213-8587(1830040-8)

    • Search Google Scholar
    • Export Citation
  • 12

    Khoo B Once-daily, modified-release hydrocortisone in patients with adrenal insufficiency. Lancet: Diabetes and Endocrinology 2018 6 269. (https://doi.org/10.1016/S2213-8587(1830044-5)

    • Search Google Scholar
    • Export Citation
  • 13

    Behan LA, Rogers B, Hannon MJ, O’Kelly P, Tormey W, Smith D, Thompson CJ & Agha A Optimizing glucocorticoid replacement therapy in severely adrenocorticotropin-deficient hypopituitary male patients. Clinical Endocrinology 2011 75 5055 13. (https://doi.org/10.1111/j.1365-2265.2011.04074.x)

    • Search Google Scholar
    • Export Citation
  • 14

    Quinkler M, Miodini Nilsen R, Zopf K, Ventz M & Oksnes M Modified-release hydrocortisone decreases BMI and HbA1c in patients with primary and secondary adrenal insufficiency. European Journal of Endocrinology 2015 172 6196 26. (https://doi.org/10.1530/EJE-14-1114)

    • Search Google Scholar
    • Export Citation
  • 15

    Mongioi LM, Condorelli RA, La Vignera S & Calogero AE Dual-release hydrocortisone treatment: glycometabolic profile and health-related quality of life. Endocrine Connections 2018 7 21121 9. (https://doi.org/10.1530/EC-17-0368)

    • Search Google Scholar
    • Export Citation
  • 16

    Guarnotta V, Di Stefano C, Santoro A, Ciresi A, Coppola A & Giordano C Dual-release hydrocortisone vs conventional glucocorticoids in adrenal insufficiency. Endocrine Connections 2019 8 8538 62. (https://doi.org/10.1530/EC-19-0176)

    • Search Google Scholar
    • Export Citation
  • 17

    Guarnotta V, Mineo MI, Radellini S, Pizzolanti G & Giordano C Dual-release hydrocortisone improves hepatic steatosis in patients with secondary adrenal insufficiency: a real-life study. Therapeutic Advances in Endocrinology and Metabolism 2019 10 2042018819871169. (https://doi.org/10.1177/2042018819871169)

    • Search Google Scholar
    • Export Citation
  • 18

    Ceccato F, Selmin E, Sabbadin C, Dalla Costa M, Antonelli G, Plebani M, Barbot M, Betterle C, Boscaro M & Scaroni C Improved salivary cortisol rhythm with dual-release hydrocortisone. Endocrine Connections 2018 7 965974. (https://doi.org/10.1530/EC-18-0257)

    • Search Google Scholar
    • Export Citation
  • 19

    Frara S, Chiloiro S, Porcelli T, Giampietro A, Mazziotti G, De Marinis L & Giustina A Bone safety of dual-release hydrocortisone in patients with hypopituitarism. Endocrine 2018 60 5285 31. (https://doi.org/10.1007/s12020-017-1512-1)

    • Search Google Scholar
    • Export Citation
  • 20

    Boffa RJ, Constanti M, Floyd CN, Wierzbicki ASGuideline Committee. Hypertension in adults: summary of updated NICE guidance. BMJ 2019 367 l5310. (https://doi.org/10.1136/bmj.l5310)

    • Search Google Scholar
    • Export Citation
  • 21

    Brazier JE, Harper R, Jones NM, O’Cathain A, Thomas KJ, Usherwood T & Westlake L Validating the SF-36 health survey questionnaire: new outcome measure for primary care. BMJ 1992 305 16016 4. (https://doi.org/10.1136/bmj.305.6846.160)

    • Search Google Scholar
    • Export Citation
  • 22

    Oksnes M, Bensing S, Hulting AL, Kampe O, Hackemann A, Meyer G, Badenhoop K, Betterle C, Parolo A & Giordano R Quality of life in European patients with Addison’s disease: validity of the disease-specific questionnaire AddiQoL. Journal of Clinical Endocrinology and Metabolism 2012 97 5685 76. (https://doi.org/10.1210/jc.2011-1901)

    • Search Google Scholar
    • Export Citation
  • 23

    Hunt SM, McKenna SP, McEwen J, Backett EM, Williams J & Papp E A quantitative approach to perceived health status: a validation study. Journal of Epidemiology and Community Health 1980 34 28128 6. (https://doi.org/10.1136/jech.34.4.281)

    • Search Google Scholar
    • Export Citation
  • 24

    Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad MH & Stratakis CA Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2016 101 3643 89. (https://doi.org/10.1210/jc.2015-1710)

    • Search Google Scholar
    • Export Citation
  • 25

    Schofl C, Mayr B, Maison N, Beuschlein F, Meyer G, Badenhoop K, Kienitz T & Quinkler M Daily adjustment of glucocorticoids by patients with adrenal insufficiency. Clinical Endocrinology 2019 91 2562 62. (https://doi.org/10.1111/cen.14004)

    • Search Google Scholar
    • Export Citation
  • 26

    Johannsson G, Lennernas H, Marelli C, Rockich K & Skrtic S Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study. European Journal of Endocrinology 2016 175 8593. (https://doi.org/10.1530/EJE-15-1212)

    • Search Google Scholar
    • Export Citation
  • 27

    Johannsson G, Bergthorsdottir R, Nilsson AG, Lennernas H, Hedner T & Skrtic S Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study. European Journal of Endocrinology 2009 161 1191 30. (https://doi.org/10.1530/EJE-09-0170)

    • Search Google Scholar
    • Export Citation
  • 28

    Dunne FP, Elliot P, Gammage MD, Stallard T, Ryan T, Sheppard MC & Stewart PM Cardiovascular function and glucocorticoid replacement in patients with hypopituitarism. Clinical Endocrinology 1995 43 62362 9. (https://doi.org/10.1111/j.1365-2265.1995.tb02928.x)

    • Search Google Scholar
    • Export Citation
  • 29

    Danilowicz K, Bruno OD, Manavela M, Gomez RM & Barkan A Correction of cortisol overreplacement ameliorates morbidities in patients with hypopituitarism: a pilot study. Pituitary 2008 11 2792 85. (https://doi.org/10.1007/s11102-008-0126-2)

    • Search Google Scholar
    • Export Citation
  • 30

    Peacey SR, Guo CY, Robinson AM, Price A, Giles MA, Eastell R & Weetman AP Glucocorticoid replacement therapy: are patients over treated and does it matter? Clinical Endocrinology 1997 46 2552 61. (https://doi.org/10.1046/j.1365-2265.1997.780907.x)

    • Search Google Scholar
    • Export Citation
  • 31

    Sherlock M, Ayuk J, Tomlinson JW, Toogood AA, Aragon-Alonso A, Sheppard MC, Bates AS & Stewart PM Mortality in patients with pituitary disease. Endocrine Reviews 2010 31 301342. (https://doi.org/10.1210/er.2009-0033)

    • Search Google Scholar
    • Export Citation
  • 32

    Bates AS, Van’t Hoff W, Jones PJ & Clayton RN The effect of hypopituitarism on life expectancy. Journal of Clinical Endocrinology and Metabolism 1996 81 116911 72. (https://doi.org/10.1210/jcem.81.3.8772595)

    • Search Google Scholar
    • Export Citation
  • 33

    Bulow B, Hagmar L, Mikoczy Z, Nordstrom CH & Erfurth EM Increased cerebrovascular mortality in patients with hypopituitarism. Clinical Endocrinology 1997 46 7581. (https://doi.org/10.1046/j.1365-2265.1997.d01-1749.x)

    • Search Google Scholar
    • Export Citation
  • 34

    Rosen T & Bengtsson BA Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990 336 28528 8. (https://doi.org/10.1016/0140-6736(9091812-o)

    • Search Google Scholar
    • Export Citation
  • 35

    Deepak D, Furlong NJ, Wilding JP & MacFarlane IA Cardiovascular disease, hypertension, dyslipidaemia and obesity in patients with hypothalamic-pituitary disease. Postgraduate Medical Journal 2007 83 2772 80. (https://doi.org/10.1136/pgmj.2006.052241)

    • Search Google Scholar
    • Export Citation
  • 36

    Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, Chalmers J, Rodgers A & Rahimi K Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 2016 387 9579 67. (https://doi.org/10.1016/S0140-6736(1501225-8)

    • Search Google Scholar
    • Export Citation
  • 37

    Stewart PM & Edwards CR The cortisol-cortisone shuttle and hypertension. Journal of Steroid Biochemistry and Molecular Biology 1991 40 50150 9. (https://doi.org/10.1016/0960-0760(9190269-b)

    • Search Google Scholar
    • Export Citation
  • 38

    Margolis KL, Manson JE, Greenland P, Rodabough RJ, Bray PF, Safford M, Grimm RH Jr, Howard BV, Assaf AR & Prentice R Leukocyte count as a predictor of cardiovascular events and mortality in postmenopausal women: the Women’s Health Initiative Observational Study. Archives of Internal Medicine 2005 165 50050 8. (https://doi.org/10.1001/archinte.165.5.500)

    • Search Google Scholar
    • Export Citation
  • 39

    Zalokar JB, Richard JL & Claude JR Leukocyte count, smoking, and myocardial infarction. New England Journal of Medicine 1981 304 46546 8. (https://doi.org/10.1056/NEJM198102193040806)

    • Search Google Scholar
    • Export Citation
  • 40

    Danesh J, Collins R, Appleby P & Peto R Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 1998 279 147714 82. (https://doi.org/10.1001/jama.279.18.1477)

    • Search Google Scholar
    • Export Citation
  • 41

    Sabatine MS, Morrow DA, Cannon CP, Murphy SA, Demopoulos LA, DiBattiste PM, McCabe CH, Braunwald E & Gibson CM Relationship between baseline white blood cell count and degree of coronary artery disease and mortality in patients with acute coronary syndromes: a TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18 trial) substudy. Journal of the American College of Cardiology 2002 40 1761176 8. (https://doi.org/10.1016/s0735-1097(0202484-1)

    • Search Google Scholar
    • Export Citation
  • 42

    Rana JS, Boekholdt SM, Ridker PM, Jukema JW, Luben R, Bingham SA, Day NE, Wareham NJ, Kastelein JJ & Khaw KT Differential leucocyte count and the risk of future coronary artery disease in healthy men and women: the EPIC-Norfolk Prospective Population Study. Journal of Internal Medicine 2007 262 6786 89. (https://doi.org/10.1111/j.1365-2796.2007.01864.x)

    • Search Google Scholar
    • Export Citation
  • 43

    Wheeler JG, Mussolino ME, Gillum RF & Danesh J Associations between differential leucocyte count and incident coronary heart disease: 1764 incident cases from seven prospective studies of 30,374 individuals. European Heart Journal 2004 25 128712 92. (https://doi.org/10.1016/j.ehj.2004.05.002)

    • Search Google Scholar
    • Export Citation
  • 44

    Westerbacka J, Corner A, Tiikkainen M, Tamminen M, Vehkavaara S, Hakkinen AM, Fredriksson J & Yki-Jarvinen H Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women: implications for sex differences in markers of cardiovascular risk. Diabetologia 2004 47 1360136 9. (https://doi.org/10.1007/s00125-004-1460-1)

    • Search Google Scholar
    • Export Citation
  • 45

    Kim WR, Flamm SL, Di Bisceglie AM, Bodenheimer HCPublic Policy Committee of the American Association for the Study of Liver Disease. Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease. Hepatology 2008 47 136313 70. (https://doi.org/10.1002/hep.22109)

    • Search Google Scholar
    • Export Citation
  • 46

    Giordano R, Guaraldi F, Marinazzo E, Fumarola F, Rampino A, Berardelli R, Karamouzis I, Lucchiari M, Manetta T & Mengozzi G Improvement of anthropometric and metabolic parameters, and quality of life following treatment with dual-release hydrocortisone in patients with Addison’s disease. Endocrine 2016 51 36036 8. (https://doi.org/10.1007/s12020-015-0681-z)

    • Search Google Scholar
    • Export Citation
  • 47

    Hahner S, Loeffler M, Bleicken B, Drechsler C, Milovanovic D, Fassnacht M, Ventz M, Quinkler M & Allolio B Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. European Journal of Endocrinology 2010 162 597602. (https://doi.org/10.1530/EJE-09-0884)

    • Search Google Scholar
    • Export Citation
  • 48

    Grossman A, Johannsson G, Quinkler M & Zelissen P Therapy of endocrine disease: perspectives on the management of adrenal insufficiency: clinical insights from across Europe. European Journal of Endocrinology 2013 169 R165R1 75. (https://doi.org/10.1530/EJE-13-0450)

    • Search Google Scholar
    • Export Citation
  • 49

    Hahner S, Loeffler M, Fassnacht M, Weismann D, Koschker AC, Quinkler M, Decker O, Arlt W & Allolio B Impaired subjective health status in 256 patients with adrenal insufficiency on standard therapy based on cross-sectional analysis. Journal of Clinical Endocrinology and Metabolism 2007 92 391239 22. (https://doi.org/10.1210/jc.2007-0685)

    • Search Google Scholar
    • Export Citation
  • 50

    Stewart PM Modified-release hydrocortisone: is it time to change clinical practice? Journal of the Endocrine Society 2019 3 11501153. (https://doi.org/10.1210/js.2019-00046)

    • Search Google Scholar
    • Export Citation